Table of contents :

inherited monogenic immune disorders aminoacidopathies collagen diseases / collagenopathies cancer syndromes clastogenias genodermatoses hamartomatoses phakomatoses

inherited thesaurismoses / storage diseases lipid storage diseases (LSD) triglyceride storage disease (TSD) sphingolipidoses glycoproteinoses mucolipidoses mucopolysaccharidoses glycogen storage diseases (GSD) congenital disorders of glycosylation (CDG) primary hyperlipidemias / familial hyperlipoproteinemias Web resources Bibliography

• various aspects of RNA biology, including splicing, are common targets of phenotypic modifiers
• sodium channel modifier 1 (Scnm1) is a splicing factor whose mutations affect the abundance of correctly spliced Scn8a transcripts. It is widely expressed in mouse embryonic and adult tissues, suggesting that the molecule could also effect genome-wide changes in pre-mRNA processing.

The first published study linking gene to disease is often far from the last word on the subject. Marc-Antoine Crocq, a psychiatrist with the Centre Hospitalier de Rouffach in France, learned this firsthand after leading a 1992 study on a mutation in the dopamine D₃ receptor in the brain^ref. The study found that people with 2 copies of the mutation have a schizophrenia risk roughly 2-4 times higher than others. Partly because these ratios were so high, and because the finding came from 2 independent teams, it looked strong. It was also, as it turns out, quite likely wrong. A flood of 50-odd follow up studies, which piled so thickly that they included meta-analyses of meta-analyses, gave inconsistent results. Eventually Crocq and colleagues reviewed all the data and concluded that no statistically significant link existed where they had initially found one^ref. Experiences like Crocq's, in which follow-up studies overturn an initial finding of a gene-disease association, are strikingly common. 2 recent studies found that typically, when a finding is first published linking a given gene with a complex disease, there is only roughly a 33% chance that studies will reliably confirm the finding. When they do, they usually find the link is weaker than initially estimated^{ref1, ref2}. The first finding is usually either spurious, or it is true, but it happens to be really exaggerated : there may be no way to predict which new gene-association studies will be verified with multiple replication^ref.  The problem is pressing because current trends could exacerbate it : new high-throughput analysis techniques let researchers study many gene-disease associations quickly and cheaply, but also lead to more studies on associations that don't look especially likely at a study's outset. This tends to increase the likelihood of finding spurious links through chance occurrences. By contrast in the old days, it was a big investment to study a hypothesis, and only the best candidates had a shot. Wacholder suggests researchers revise their statistical methods to account for "prior probability," which is a subjective but reasonable measure of how plausible the gene-disease association in question looked before the study^ref. Others suggests bigger sample sizes and more family-based studies. These avoid a confounder called population stratification, the tendency of populations to carry high frequencies of both certain genes and certain diseases owing to mere accidents of ancestry : studies with family-based controls and larger sample sizes are more likely to be replicated^ref. Researchers should treat any finding cautiously until it's replicated, preferably more than once. No effort to address the problem is completewithout a renewed call to publish more negative findings showing no gene-disease association. Such findings often go unpublished, bolstering false impressions of spurious gene-disease associations. Every study provides a piece of evidence and it needs to be made available somehow to people who are interested.

The choice of a gene name can have unforeseen consequences in addition to infringement of trademark (e.g. Pokémon^ref). The quirky sense of humour that researchers display in choosing a gene name often loses much in translation when people facing serious illness or disability are told that they or their child have a mutation in a gene such as Sonic hedgehog, Slug or Pokémon. As with the acronym CATCH22 (from 'cardiac anomaly, T-cell deficit, clefting and hypocalcaemia') for chromosome 22q11.2 microdeletions, which was abandoned because of its no-win connotations^ref, researchers need to be mindful when naming genes and syndromes^ref.

• General resources
• On-line Mendelian Inheritance in Men (OMIM) database by Victor A.McKusick at Johns Hopkins University
• Genes and disease at NCBI, NIH
• Genetic diseases list at Weizmann Institute
• "Hot molecules" that may play crucial roles in common diseases (HotMolecBase) at Weizmann Institute
• Database of disease-causing mutations in tyrosine kinase domains (KinMutBase) at University of Tampere
• Genes and disease at NCBI
• Positionally cloned human disease genes
• Human Genome Landmarks : selected traits and disorders mapped to chromosomes
• Homophila : linkage between OMIM and Drosophila melanogaster genome
• Center for Inherited Disorders of Energy Metabolism (CIDEM)
• Specific resources
• genetic disease : a general term for any disorder caused by a genetic mechanism, comprising
• chromosome aberrations or anomalies
• mendelian or monogenic or single-gene disorders
• multigenic disorders
• multifactorial disorders.
• inherited disease : one transmitted genetically, from parents to offspring
• sex-linked disease : one transmitted via sex chromosomes
• X-linked disease : out of 3,199 identified inherited diseases, 307 can be attributed to mutations, or flaws, on one of the 1,098 genes on the X chromosome that disrupt vital protein-making machinery. Affected males never have affected sons
• autosomal disease : one transmitted via autosomes
• for autosomal dominant diseases each affected member has at least 1 affected parent and the diseases affects men and women equally
• for autosomal recessive diseases affected members may have healthy parents
• contiguous gene syndrome : any syndrome known to be caused by the involvement of contiguous genes on a chromosome, e.g., aniridia–Wilms' tumor association, which may also have genitourinary tract abnormalities, gonadoblastoma, and mental retardation; it is usually caused by chromosome deletions.
• molecular disease : any disease in which the pathogenesis can be traced to a single molecule, usually a protein, which is either abnormal in structure or present in reduced amounts; the classical example is abnormal hemoglobin in sickle cell anemia.
• sex-affected disease :
• disease more common in males (male-to-female ratio 10:1) :
• claudicatio intermittens
• ankylosing spondylitis
• aortic isthmus stenosis
• hemochromatosis
• anticipation : the apparent occurrence of a hereditary disease at a progressively earlier age in successive generations; now considered by most authorities to be an artifact arising from the ease of identification of succeeding cases or because cases of later onset are more likely to be fertile
• genetic counseling and testing (GCT)
• mosaic : in genetics, an individual or cell cultures having two or more cell lines that are karyotypically or genotypically distinct but are derived from a single zygote
• chimera [Gr. chimaira a mythological fire-spouting monster with a lion's head, goat's body, and serpent's tail] : an individual organism whose body contains cell populations derived from different zygotes, of the same or of different species; it may occur spontaneously, as in twins (blood group chimeras), or be produced artificially, as an organism that develops from combined portions of different embryos, or one in which tissues or cells of another organism have been introduced
• heterologous chimera : a chimera in which the foreign cells or tissues are derived from an organism of a different species.
• homologous chimera : a chimera in which the foreign cells or tissues are derived from an organism of the same species but of a different genotype.
• isologous chimera : a chimera in which the foreign cells or tissues are derived from a different organism of the same genotype, such as an identical twin.
• radiation chimera : an organism that survives with immunologic characteristics of host and donor after a bone marrow graft from an antigenically different donor, the host having first been subjected to sublethal whole-body irradiation so that there is reduced or no immune response to foreign cells by the donor.
• chimerism : the quality of being a chimera; in genetics, the presence in an individual of cells of different origin, as of blood cells derived from a dizygotic co-twin
• mosaicism : in genetics, the presence in an individual of two or more cell lines that are karyotypically or genotypically distinct and are derived from a single zygote
• erythrocyte mosaicism : the mixture of 2 blood types in each of nonidentical twins as a result of anastomosis of placental blood vessels.
• confined placental mosaicism : mosaicism in which a chromosomal abnormality (usually trisomy) is restricted to the placenta; it occurs in about 2% of viable pregnancies and is a possible cause of intrauterine growth restriction.
• gonadal mosaicism : mosaicism that results from mosaicism within the gonad so that some of the germ cells are mutants. More than one offspring of a gonadal mosaic for a dominant trait may show the trait although it is not manifested in the parent.
Blaschko's lines : a developmental pattern of skin growth seen in functional X-chromosome mosaicism
Diseases :
• deletion on imprinted gene domain of 15q11-q13
• inherited from the mother : Angelman's syndrome / happy puppet syndrome

Symptoms & signs : jerky puppetlike movements, frequent laughter, mental and motor retardation, peculiar open-mouthed facies, and seizures
• inherited from the father : Prader-Willi syndrome (PWS) / Prader-Labhart-Willi syndrome (PLWS), a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene, the necdin gene, and possibly other genes. It can be considered to be an autosomal dominant disorder and is caused by deletion or disruption of a gene or several genes on paternal 15q11-13 or maternal uniparental disomy 15, because the gene(s) on the maternal chromosome(s) 15 are virtually inactive through imprinting.

Symptoms & signs : diminished fetal activity, congenital obesity, short stature, muscular hypotonia, hypogonadotropic hypogonadism, and central nervous system dysfunction (mental retardation); there is often a characteristic rounded face with almond-shaped eyes and a low forehead, and small hands and feet
• Laurence-Moon-Bardet-Biedl (LMBB) syndrome
• Laurence-Moon syndrome

Aetiology : autosomal recessive
Symptoms & signs : mental retardation, retinitis pigmentosa, hypogonadism, and spastic paraplegia
• Bardet-Biedl syndrome (BBS)

Aetiology : 8 autosomal recessive mutations causing ciliary dysfunction^ref
• BBS1
• BBS2
• BBS3/ARL6
• BBS4
• BBS5
• BBS6 / McKusick-Kaufman syndrome (MKKS)
• BBS7
• BBS8 / tetratricopeptide repeat domain 8 (TTC8)
MGC1203 locus contributes epistatic alleles to Bardet–Biedl syndrome (BBS), a pleiotropic, oligogenic disorder. MGC1203 encodes a pericentriolar protein that interacts and colocalizes with the BBS proteins. Sequencing of 2 independent BBS cohorts revealed a significant enrichment of a heterozygous C430T mutation in patients, and a transmission disequilibrium test (TDT) showed strong over-transmission of this variant. The 430T allele enhances the use of a cryptic splice acceptor site, causing the introduction of a premature termination codon (PTC) and the reduction of steady-state MGC1203 messenger RNA levels. Finally, recapitulation of the human genotypes in zebrafish shows that modest suppression of mgc1203 exerts an epistatic effect on the developmental phenotype of BBS morphants^ref
Symptoms & signs : mental retardation, retinitis pigmentosa, obesity, polydactyly, and hypogonadism
• Miller-Dieker syndrome / lissencephaly syndrome (autosomal recessive)

Symptoms & signs : lissencephaly, microcephaly, mental retardation, dysmorphic facial appearance, and sometimes polydactyly, cryptorchidism, heart lesions, kidney defects, and defects of the gastrointestinal system
• Goldenhar syndrome :
• Shprintzen-Goldberg syndrome^ref is one of a group of disorders
• Symptoms & signs : craniosynostosis and marfanoid habitus, an abnormality of the C1 snd C2 vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain
• Johanson-Blizzard syndrome : a rare genetic disorder
• Liddle syndrome (autosomal dominant)

Aetiology : mutations in b or g subunits of ENaC
Symptoms & signs : secondary systemic arterial hypertension with excessive renal reabsorption of sodium (hyponatriuria => hypernatremia), depletion of potassium (hyperkaliuria => hypokaliemia), and reactive hyporeninemic hypoaldosteronism
Therapy : salt restriction and ENaC inhibitors (triamterene)
• cystic fibrosis (CF) of the pancreas / mucoviscidosis / fibrocystic disease of the pancreas : an autosomal recessive disorder of infants, children, and young adults in which there is widespread dysfunction of the exocrine glands

Epidemiology : prevalence = 1 case every 2,000 newborns
Aetiology : lack of ABCC7 / CFTR (70% has DF508). Hydrophobic side chain interactions of Phe⁵⁰⁸ are required for vectorial folding of nucleotide-binding domain 2 (NBD2) and the domain-domain assembly of CFTR, representing a combined co- and post-translational folding mechanism that may be used by other multidomain membrane proteins^ref. Significant allelic and genotypic associations with phenotype were seen only for TGF-b₁, particularly the –509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGF-b₁ genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGF-b₁ codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV₁ for severity status (P=0.0002) and FEV₁ values directly (P=0.02)^ref. TGF-b₁ is encoded on chromosome 19q13, 4.5 Mbp from the CFM1 locus that confers a risk of meconium ileus^ref
Pathogenesis : CFTR conducts HCO₃^- secretion (although it has been doubted whether this is physiologically significant) => acidic fluids are secreted by mutant CFTR-expressing tissues, indicating the importance of this activity =>
• increased mucin viscosity
• increased bacterial binding.
• impaired HCO₃^- secretion in the uterus => uneffectiveness of sperm to fertilize eggs (sperm capacitation)
There is a pathophysiologically important defect in lipoxin-mediated anti-inflammatory activity in the lung and lipoxins have therapeutic potential^ref
Symptoms & signs : chronic pulmonary disease (due to excess mucus production in the respiratory tract), chronic pancreatitis => pancreatic deficiency, alveolar pneumonia, abnormally high levels of electrolytes in the sweat, and occasionally biliary cirrhosis. Pathologically, the pancreas shows obstruction of its ducts by amorphous eosinophilic concretions, with consequent deficiency of pancreatic enzymes, resulting in steatorrhea and azotorrhea. The degree of involvement of organs and glandular systems may vary greatly, with consequent variations in the clinical picture.
Chronic microbial colonization of the respiratory tract, leading to exacerbations of pulmonary infection, is the major cause of disease and death in patients with CF. Typical pathogens in respiratory secretions of patients with CF include Pseudomonas aeruginosa^ref, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex^{ref1, ref2, ref3}. Other gram-negative glucose nonfermenters, such as Achromobacter xylosoxidans, Burkholderia gladioli, Ralstonia pickettii, and Stenotrophomonas maltophilia are also occasionally recovered from respiratory samples from CF patients, but their pathogenic importance remains to be clarified^{ref1, ref2, ref3}. Determining the clinical relevance of nonfermentative microbes is hampered by the difficulty in identifying these pathogens by conventional laboratory techniques. Recent studies that applied molecular approaches to identify unusual pathogens in patients with CF showed various infrequently encountered and novel species including Ralstonia mannitolytica^ref, Pandoraea ssp.^ref, Cupriavidus respiraculi^ref, Bordetella bronchiseptica^refand Inquilinus limosus^ref. Elastase and neutrophil counts were able to explain the majority of variation in FEV₁. Elastase was further shown to have a significant longitudinal association with FEV₁, specifically a -2.9% decline in FEV₁ (95% CI: -5.0,-0.9) per 1 log increase in elastase. Although correlated with FEV₁, bacterial densities were unable to explain clinically meaningful differences in FEV1 within and across patients^ref. Rapid IL-1 release and signaling through the IL-1R represent key steps in the innate immune response to P. aeruginosa infection, and this process is deficient in cells lacking functional CFTR^ref.
Laboratory examinations :
• Shwachman-Kulczyki morbidity scores^ref
• Brasfield score^ref
• metabolic alkalosis
Therapy :
• inhalation of hypertonic saline (5 ml of 7% sodium chloride) 4 times daily produced a sustained acceleration of mucus clearance and improved lung function. This treatment may protect the lung from insults that reduce mucus clearance and produce lung disease^{ref1, ref2}
• DF508 CFTR correctors :
• MPB-07^ref produces an anti-inflammatory effect in CF bronchial cells exposed to P.aeruginosa in vitro^ref
• VX-770 (Vertex Pharmaceuticals)
• VX-809
• ataluren / PTC124 (PTC Therapeutics) is an oral drug that permits ribosomes to read through premature stop codons in mRNA to produce functional protein in children with nonsense mutations (10%)
• activators of alternate (non-CF transmembrane regulator [CFTR]) chloride channels
• lancovutide (Moli1901, duramycin)
• denufosol
• sodium channel antagonists : GS 9411
• gene therapy
• rDNAse / dornase a
• curcumin, an antioxidant found in turmeric, alters the calcium influx to the endoplasmic reticulum (ER), thereby preventing calcium-dependent chaperone binding of the misfolded but still functional cystic fibrosis transmembrane conductance regulator. Recent work shows that curcumin allows misfolded proteins to be transported correctly to their destination in the case of CF^{ref1, ref2}
• lung transplantation
Prevention :
• newborn screening was associated with improved growth, reduced morbidity, and reduced therapy, yet generated equivalent pulmonary outcome compared with late clinical diagnosis, suggesting that newborn screening may slow cystic fibrosis lung disease progression^ref
• maintenance azithromycin therapy in patients with CF leads to macrolide resistance in nearly all S. aureus carriers. Pulmonary function improvement after initiation of azithromycin therapy seems to be temporary and appears not to be related to macrolide resistance of S. aureus^ref. Photodynamic antimicrobial chemotherapy (PACT) could be one potential alternative antimicrobial method. As photosensitisers could be delivered to the lungs of CF patients via inhalation, the current in vitro study investigated the potential use of PACT in the treatment of P. aeruginosa CF pulmonary infection. Delivery of red light (635 nm) and 2 photosensitisers (toluidine blue O (TBO) and m-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP)) across artificial CF mucus was successfully achieved^ref. Biofilm formation in the CF lung likely occurs under anaerobic conditions, is controlled by bacterial quorum-sensing mechanisms, and is enhanced by environmental components in the CF airway. P. aeruginosa possesses regulatory pathways that recognize environmental cues to favor either acute infection or chronic colonization. P. aeruginosa that inhabit the respiratory tract accumulate mutations favoring chronic colonization. Azithromycin, a macrolide with clinical benefit in CF, alters P. aeruginosa biofilm formation. Promising new therapies that target biofilm formation include molecules that disrupt quorum sensing^ref.
Prognosis : the median survival is only about 35 years^ref
Web resources :
• Cystic Fibrosis Foundation (CFF)
• Vaincre la Mucoviscidose
Bibliography : Cystic Fibrosis in the 21st Century, (Progress in Respiratory Research. Vol. 34.) Edited by Andrew Bush, Eric W.F.W. Alton, Jane C. Davies, Uta Griesenbach, and Adam Jaffe. 329 pp., illustrated. Basel, Switzerland, Karger, 2006. $180. ISBN 3-8055-7960-8^ref
• galactosemia

Aetiology : mutation in the galactose-1-phosphate uridylyltransferase (GALT)
Symptoms & signs : galactosemic cataract, reactive hypoglycemia, metabolic cirrhosis
Laboratory examinations : [galactose]_plasma
• prune belly syndrome / Eagle-Barrett syndrome

Symptoms & signs : the lower part of the rectus abdominis muscle and the lower and medial parts of the oblique muscles are absent, with hydroureteronephrosis, megaloureter, megabladder, renoureteral dysplasias, oligohydramnios, hyperammonaemia, and bilateral cryptorchidism. The abdomen is protruding and thin-walled, with wrinkled skin, giving the syndrome its name
• hypophosphatasia : a genetic metabolic disorder resulting from serum and bone alkaline phosphatase deficiency leading to hypercalcemia, ethanolamine phosphatemia, and ethanolamine phosphaturia. Clinical manifestations include severe skeletal defects resembling vitamin D–resistant rickets, failure of the calvarium to calcify, early loss of primary teeth, dyspnea, cyanosis, vomiting, constipation, renal calcinosis, failure to thrive, disorders of movement, beading of the costochondral junction, and rachitic bone changes (bowing). There are 3 clinical types based upon age of onset and the severity of the symptoms. 2 are autosomal recessive: infantile, the severest, lethal in > 50% of the cases; childhood, whose first symptom is usually the spontaneous loss of the deciduous teeth; and adult, the mildest form, is autosomal dominant
• infantile neuroaxonal dystrophy (INAD) / Seitelberger disease : symptoms start by age 2 and worsen over time, and include loss of head control and the ability to sit, crawl or walk, as well as deteriorating vision and speech. PLA2G6's discovery means a clinical test can be developed to help families determine their chances of passing the disorders to their children. PLA2G6 is among 18 lipid-metabolizing genes in a protein family known as phospholipase A2 (PLA2), and INAD is the first inherited disorder associated with mutations in one of these genes. Its discovery "unequivocally" links PLA2 defects to neurodegeneration, which is significant because similar lipid metabolism changes are seen in neurodegeneration associated with ischemia from stroke, spinal cord trauma, head injury and Alzheimer's disease, making this metabolic pathway a potential drug target.
• leukodystrophy : disturbance of the white substance of the brain due to defect in the formation and maintenance of myelin in infants and children.
• neurodegeneration with brain iron accumulation (NBIA) / Hallervorden-Spatz syndrome / status dysmyelinatus / status dysmyelinisatus

Epidemiology : incidence is 1 in 500,000 to 1 million.
Aetiology : recessive
Pathogenesis : marked reduction in the number of myelin sheaths of the globus pallidus and substantia nigra, with accumulations of iron pigment
Symptoms & signs : usually begins in the first or second decade, with death usually occurring before the thirtieth year; involuntary muscle contractions, rigidity and spasms beginning in the legs, face and torso, as well as confusion, disorientation, seizures, stupor and dementia, choreoathetoid movements, dysarthria. Rapid deterioration, punctuated by stable periods, lasts 1-2 months, with the rate of progression correlating with the patient's age – the later the onset, the better the patient fares
Therapy : there is no cure
• Alexander's disease : an infantile form of leukodystrophy, characterized histologically by the presence of eosinophilic material at the surface of the brain and around its blood vessels, resulting in brain enlargement.

Laboratory examinations : Rosenthal fibers
• sudanophilic leukodystrophy : a heterogeneous group of diseases characterized by myelin destruction, with resulting breakdown products that stain bright red with fat stains.
• adrenoleukodystrophy (ALD) : an X-linked recessive disease of childhood, closely related to Schilder's disease, marked by diffuse abnormality of the cerebral white matter and adrenal atrophy and characterized by mental deterioration progressing to dementia, and by aphasia, apraxia, dysarthria, and loss of vision in about 33% of the patients. Almost all show abnormal adrenal functioning when tested.

Therapy :
• Lorenzo's oil : after years of hope and provisional evidence, experts are publishing scans from children who started this therapy more than a decade ago. They say the positive results will quiet sceptics and prove the oil's worth. In 1984, Augusto and Michaela Odone learned that their son, Lorenzo, suffered from a genetic disorder known as adrenoleukodystrophy (ALD). The prognosis was frightening: children diagnosed with ALD experience neurological deterioration and typically die from the illness within a few years. Faced with a lack of treatment options for their son, the Odones began pouring over books in the library for more information. They learned that ALD is related to an abnormal accumulation of very-long-chain fatty acids, particularly in the nervous system of the body. Although they tried to cut these fatty acids from their son's diet, his body continued producing them. The literature convinced them that giving their son a different fatty acid, an oily liquid known as oleic acid, would inhibit the synthesis of long chains of saturated fats. It works simply by keeping enzymes busy making chains of unsaturated fats instead. The Odones later improved their formula by using a modified form of rapeseed oil, which seems to keep the enzymes even busier. Their medicine, which improved the health of their ailing son and inspired a Hollywood movie in 1992 , became known as 'Lorenzo's oil'. It quickly became apparent that consuming these oils dramatically reduces levels of very long chain fatty acids in ALD sufferers. And preliminary results in 2002 showed that children on the oil were less likely to become ill. Boys who took this oil had lower levels of very-long-chain fatty acids and a lower risk of developing neurological abnormalities. The trial began in 1989, when researchers started giving Lorenzo's oil to patients that were known to have the genetic disorder but had not yet developed symptoms. The prescribed a daily dosage that provided approximately 20% of caloric intake. For ethical reasons, none of the 89 boys (age 7 or younger) enrolled in the study was given a placebo. Of the boys that were tracked, by 2002 only 24% developed irregularities that MRI of the brain could pick up. Only 10% developed neurological abnormalities^ref. Although it is hard to interpret these results without a control group, you would normally expect about 50% of those diagnosed to produce symptoms. Boys who did not consume the oil as regularly were at greater risk. This evidence justifies the administration of Lorenzo's oil as a preventative treatment for people with this genetic disorder. The results give tremendous hope to families dealing with ALD. Side effects : thrombocytopenia. X-ALD affects 16,000 patients in the USA. The most dangerous form is the childhood cerebral form, in which brain cells are destroyed, and this accounts for up to 40 percent of cases, which usually appear between 4 and 8 years of age. Symptoms are quite devastating and include a loss of the ability to speak, reduced strength and coordination and, eventually, complete breakdown of bodily function and death. At present there is no cure, but potential treatments include the cholesterol drug lovastatin and bone marrow transplants. The Odones say the treatment halted the progression of Lorenzo's disease and their son, now 27, is alive though severely disabled
• childhood cerebral form of X-ALD is a rapidly progressive demyelinating condition affecting the cerebral white matter, which rapidly leads to total disability and death. The only known curative treatment for this condition is allogeneic hematopoietic stem cell transplantation (HSCT). Procedure-related toxicity is assumed to be the cause of death of patients with X-ALD. Three cases of ALD successfully transplanted with the use of non-myeloablative fludarabine based conditioning are described. Patients showed smooth peri-bone marrow transplantation course with fast and stable engraftment. In the 3- to 5 yr follow-up period, patients showed no deterioration in their clinical and neurological condition. Levels of very long chain fatty acids were very variable and had a tendency to decrease in at least one of the three patients. In another patient, an improvement of magnetic resonance imaging changes was found. Non-myeloablative HSCT should be considered as an early treatment for X-ALD^ref
• hereditary cerebral leukodystrophy / Pelizaeus-Merzbacher disease or sclerosis / familial centrolobar sclerosis : an X-linked leukoencephalopathy, occurring in early life and running a slowly progressive course into adolescence or adulthood. It is marked by nystagmus, ataxia, tremor, choreoathetoid movements, parkinsonian facies, dysarthria, and mental deterioration. Pathologically, there is diffuse demyelination in the white substance of the brain, which may involve the brain stem, cerebellum, and spinal cord. The cause is mutation of the gene on the long arm of the X chromosome that codes for proteolipid protein
• globoid cell leukodystrophy (GLD) / Krabbe's disease
• spongy degeneration of central nervous system / spongy degeneration of white matter / Canavan-van Bogaert-Bertrand disease

Aetiology : autosomal recessive
Symptoms & signs : early onset, widespread demyelination and vacuolation of the cerebral white matter that gives rise to a spongy appearance, severe mental retardation, megalocephaly, atony of the neck muscles, spasticity of the arms and legs, and blindness, with death usually occurring at about 18 months of age
• adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis.

Aetiology : autosomal dominant extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis^ref
Pathogenesis : degeneration of the white matter, beginning at the frontal lobes and extending to the centrum semiovale and cerebellum
Symptoms & signs : first appear in the fourth, fifth, or sixth decade and include motor disturbances, bowel and urinary incontinence, and orthostatic systemic arterial hypotension; mental acuity is often retained. Death occurs about 20 years after the appearance of symptoms.
• metachromatic leukodystrophy (MLD) or leukoencephalopathy / sulfatide lipidosis
• leukoencephalopathy with vanishing white matter (VWM) / childhood ataxia with central nervous system hypomyelinization (CACH) / vanishing white matter leukodystrophy / Cree leukoencephalopathy (CLE) / ovarioleukodystrophy
Therapy : cell therapy
Web resources : United Leukodystrophy Foundation (ULF)
• cranio-lenticulo-sutural dysplasia (CLSD)

Aetiology : autosomal recessive F382L amino acid substitution in SEC23A on chromosome 14q13–q21. SEC23A is an essential component of the COPII-coated vesicles that transport secretory proteins from the endoplasmic reticulum to the Golgi complex. Electron microscopy and immunofluorescence show that there is gross dilatation of the endoplasmic reticulum in fibroblasts from individuals affected with CLSD. These cells also exhibit cytoplasmic mislocalization of SEC31. Cell-free vesicle budding assays show that the F382L substitution results in loss of SEC23A function. A phenotype reminiscent of CLSD is observed in zebrafish embryos injected with sec23a-blocking morpholinos^ref
Symptoms & signs : late-closing fontanels, sutural cataracts, facial dysmorphisms and skeletal defects
• pseudohypophosphatasia : a condition resembling hypophosphatasia, characterized by osteopathy of the skull and long bones, muscular hypotonia, hypercalcemia, and increased urinary excretion of phosphoethanolamine. It is distinguished by normal alkaline phosphatase activity
• acatalasia

Epidemiology : rare, observed mainly in Japan and Switzerland
Aetiology : autosomal recessive disorder due to virtual absence of catalase activity
Symptoms & signs :
• hypocatalasia : an asymptomatic variant of acatalasia in which some catalase activity is present; it occurs in some heterozygotes (usually)
• Takahara's disease : oral ulcerations and gangrene (approximately 50% of the Japanese cases)
• multiple carboxylase deficiency
• early onset

Aetiology : autosomal recessive deficiency of holocarboxylase synthetase gene (HLCS)
Laboratory examinations : higher urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxypropionic acid than the late form and was associated with normal plasma biotin concentrations
• late-onset

Aetiology : autosomal recessive deficiency of biotinidase, an enzyme of the hydrolase class essential for the recycling of biotin; it catalyzes the cleavage of biocytin or of biotin in amide linkage with peptide fragments, freeing biotin for reuse
Symptoms & signs : cutaneous and neurologic abnormalities
• aminoacidopathies : any of a group of disorders due to a defect in an enzymatic step in the metabolic pathway of one or more amino acids or in a protein mediator necessary for transport of certain amino acids into or out of cells
• alkaptonuria (AKU)

Aetiology : autosomal recessive deficiency of homogentisate 1,2-dioxygenase (HGD)
Pathogenesis : accumulation of homogentisic acid (HGA)
Symptoms & signs : elevated concentrations of HGA in urine, which darkens on standing or with alkalinization, ochronosis (blue-black discoloration of connective tissues (bone, cartilage, and skin) caused by deposits of ochre-colored pigment), and arthritis
• cystinuria
• type I
• type II
• type III
Symptoms & signs : cystine stone
Laboratory examinations
Web resources : Cystinuria Support Network
• homocystinuria

Aetiology : cystathionine b-synthase deficiency
Symptoms & signs : ectopia lentis, secondary cataract
• hyperphenylalaninemia : any of several autosomal recessive defects in the hydroxylation of phenylalanine resulting in accumulation and excretion of dietary phenylalanine.
• defect is in the enzyme phenylalanine hydroxylase (PAH) / phenylalanine 4-monooxygenase
• (classic) phenylketonuria (PKU) :  the most severe manifestation of hyperphenylalaninemia due to PAH deficiency, with accumulation and excretion of phenylalanine, phenylpyruvic acid, and related compounds and inherited as an autosomal recessive trait

Symptoms & signs : severe mental retardation, tumors, seizures, hypopigmentation of hair and skin, eczema, and mousy odor
Prevention : early restriction of dietary phenylalanine
• persistent hyperphenylalaninemia : minimally elevated plasma and urinary phenylalanine due to partial deficiency of PAH activity.
• transient phenylketonuria or hyperphenylalaninemia / neonatal tyrosinemia : a transitory neonatal disorder characterized by minimal elevation of plasma and urinary phenylalanine and usually due to delayed maturation of PAH
• atypical or malignant hyperphenylalaninemia : any of several disorders in the synthesis or regeneration of the cofactor tetrahydrobiopterin

Symptoms & signs : it is initially clinically similar to phenylketonuria but is unresponsive to dietary phenylalanine restriction, with cerebral dysfunction, muscular hypotonia, and rapid progression to death. Defects in dihydropteridine reductase, GTP cyclohydrolase I, or 6-pyruvoyltetrahydropterin synthase (PTS) activity are known
• maternal hyperphenylalaninemia : elevated serum phenylalanine in a conceiving or gravid woman; when levels are high enough => maternal phenylketonuria : abnormal fetal development in pregnant women with PKU, probably due to intrauterine exposure of the fetus to high levels of phenylalanine. Miscarriages are frequent and most surviving offspring are severely mentally retarded, often with microcephaly, low birth weight, and congenital anomalies.
Symptoms & signs : mental retardation
Laboratory examinations : Guthrie test and ferric chloride test
• hypertyrosinemia : an elevated concentration of tyrosine in the blood, as occurs in a variety of disorders of tyrosine catabolism
• type I : fumarylacetoacetate hydrolase (FAH) deficiency
• type II : tyrosine transaminase deficiency
• type III : 4-hydroxyphenylpyruvate dioxygenase (HPD) deficiency / hawkinsinuria (a rare autosomal dominant form manifested by the excretion of hawkinsin (a cyclic amino acid metabolite of tyrosine formed from an intermediate of the 4-hydroxyphenylpyruvate dioxygenase reaction combined with glutathione) in the urine)
Laboratory examinations
• methionine malabsorption syndrome / oasthouse urine disease / Smith-Strang disease : an autosomal recessive disorder of methionine absorption

Symptoms & signs : the urine has a characteristic odor resembling that of the interior of an oasthouse, due to a-hydroxybutyric acid formed by bacterial action on the unabsorbed methionine; it is characterized by white hair, mental retardation, convulsions, and attacks of hyperpnea
Laboratory examinations (ferric chloride test)
• maple syrup urine disease (MSUD) / branched-chain ketoaciduria

Aetiology : an autosomal recessive aminoacidopathy due to a defect in the second step in branched-chain amino acid (BCAA) catabolism; the decarboxylation of the corresponding a-keto acids by the branched-chain a-keto acid dehydrogenase complex. BCAAs and their keto acid analogues accumulate in blood and urine. In at least some cases, MSUD is due to deficiency of one of the enzymes of the branched-chain a-keto acid dehydrogenase complex
Symptoms & signs : severe ketoacidosis, seizures, coma, physical and mental retardation, and a characteristic smell of maple syrup in the urine and on the body. The disease can be divided into 4 clinical phenotypes:
• classic, the most severe, with neonatal onset and usually rapid death;
• intermediate, of lessened severity and usually later onset;
• intermittent, with normal periods punctuated by periods of ataxia and ketoacidosis;
• thiamine-responsive, caused by decreased affinity of the dehydrogenase complex for the cofactor thiamine pyrophosphate
Laboratory examinations (ferric chloride test)
Therapy : orthotopic liver transplantation has been performed in at least 10 patients who have MSUD. In the first patients, transplantation was for nonmetabolic reasons (hepatic failure with hepatitis A and hypervitaminosis A). In all patients, there was marked improvement in dietary protein tolerance and no evidence of any decompensation episodes during follow-up extending 10 years. Because the long-term outcome and effect on neurologic development remain to be identified, orthotopic liver transplantation remains a controversial therapy. Domino hepatic transplantation has been recently performed^ref.
• blue diaper syndrome : a defect of tryptophan absorption in which, because of intestinal bacterial action on the tryptophan, the urine contains abnormal indoles, giving it a blue color. It is similar to Hartnup's disease.
• congenital lysine intolerance : an autosomal recessive disorder due to a defect in the degradation of lysine, characterized by high levels of ammonia, lysine, and arginine in the blood, with vomiting, rigidity, and coma.
• lysinuric protein intolerance (LPI)

Aetiology : autosomal recessive mutations in dibasic amino acid transport (SLC7A7)
Pathogenesis : lack of sufficient ornithine to support activity of ornithine transcarbamylase, an intramitochondrial urea cycle enzyme, in the liver
Symptoms & signs : growth retardation, episodic hyperammonemia, seizures, mental retardation, hepatomegaly, muscle weakness, hemophagocytic syndrome and osteopenia
Therapy : citrulline supplementation.
• carbohydrate intolerance : inability to properly metabolize one or more carbohydrate(s), as in
• glucose intolerance : inability to properly metabolize glucose, a type of carbohydrate intolerance; see also impaired glucose tolerance, under tolerance, and diabetes mellitus
• hereditary fructose intolerance : an autosomal recessive type of carbohydrate intolerance due to deficiency of fructose bisphosphate aldolase, isozyme B, with onset in infancy; it is characterized by hypoglycemia, with variable manifestations of fructosuria, fructosemia, anorexia, vomiting, failure to thrive, jaundice, splenomegaly, and an aversion to fructose-containing foods. If untreated, it may be fatal
• disaccharide intolerance : inability to properly metabolize one or more disaccharide(s), usually due to deficiency of the corresponding disaccharidase(s), although it may have other causes such as impaired absorption. The results are a complex of symptoms seen after ingestion of the disaccharide, particularly abdominal symptoms such as diarrhea, flatulence, borborygmus, distention, and pain
• disaccharidase deficiency : less than normal activity of disaccharidases of the intestinal mucosa; it usually denotes a generalized deficiency of all such enzymes secondary to a disorder of the small intestine, which clinically may be manifest only as a deficiency of lactase activity, but is sometimes used to denote deficiency of a single enzyme or enzyme complex, e.g., lactase, sucrase-isomaltase, or trehalase
• congenital or intestinal sucrase-isomaltase (sucrase-a-dextrinase) deficiency / disaccharide intolerance I :
• congenital sucrose intolerance : a disaccharide intolerance specific for sucrose, usually due to a congenital defect in the sucrase-isomaltase enzyme complex
• sucrase-isomaltase deficiency : a disaccharidase deficiency in which deficient activity of the sucrase-isomaltase complex of the intestinal mucosa results in malabsorption of sucrose and starch dextrins; it is characterized by watery, osmotic-fermentative diarrhea, sometimes leading to dehydration and malnutrition, manifest in infancy (congenital sucrose intolerance). While sucrase activity is always absent, a-dextrinase (isomaltase) activity may be either greatly reduced or relatively normal
• lactose intolerance : a disaccharide intolerance specific for lactose, usually due to an inherited deficiency of lactase activity in the intestinal mucosa; see also lactase deficiency.
• congenital lactose intolerance : 1. lactose intolerance present at birth, due to deficiency of lactase activity; see lactase deficiency.  2. a severe autosomal dominant disorder with vomiting, dehydration, failure to thrive, disacchariduria (including lactosuria and aminoaciduria), and cataracts; it is probably due to abnormal permeability of the gastric mucosa.
• glutaricaciduria : an autosomal recessive aminoacidopathy characterized by accumulation and excretion of glutaric acid and occurring in 2 types:
• type I is due to deficiency of glutaryl-CoA dehydrogenase and is characterized by excretion also of 3-hydroxyglutaric acid, progressive dystonia and dyskinesia, hypoglycemia, mild ketosis and acidosis, opisthotonus, choreoathetosis, motor delay, mental retardation, hypotonia, and death within the first decade
• type II / multiple acyl CoA dehydrogenation deficiency (MADD) is due to deficiency of either electron transfer flavoprotein (a-subunit) or electron transfer flavoprotein:ubiquinone oxidoreductase and is characterized by accumulation and excretion of glutaric and 2-hydroxyglutaric acids as well as multiple organic acids normally oxidized by mitochondrial flavin-containing acyl-CoA dehydrogenases, which require both proteins for activity. Additional manifestations include hypoglycemia without ketosis, metabolic acidosis, and a spectrum of phenotypic manifestations varying with the particular defect. Increasing age of onset is correlated with decreasing severity; when of neonatal onset it may be accompanied by congenital anomalies and is rapidly fatal
• molybdenum cofactor deficiency : an autosomal recessive disorder in which deficiency of the molybdenum cofactor causes deficiency of the molybdoenzymes sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase, resulting in severe neurologic abnormalities, dislocated ocular lenses, mental retardation, xanthinuria, and early death
• poikiloderma vasculare atrophicans / Rothmund-Thomson syndrome (RTS) / poikiloderma congenitale : an autosomal recessive syndrome occurring principally in females

Symptoms & signs : reticulated, atrophic, hyperpigmented, telangiectatic cutaneous plaques, often accompanied by juvenile cataracts, saddle nose, congenital bone defects, disturbances in the growth of hair, nails, and teeth, and hypogonadism
• Thomson's disease : an autosomal recessive skin disorder similar to Rothmund-Thomson syndrome except that saddle nose and cataract are not manifestations.
• 3-M syndrome

Aetiology : autosomal recessive mutations of cullin 7 (CUL7) on chromosome 6p21.1. CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.
Symptoms & signs : severe pre- and postnatal growth retardation
• Aarskog-Scott syndrome (AAS) / faciogenital dysplasia / faciodigitogenital syndrome : a genetically heterogeneous developmental disorder. However, although AAS may be considered as a relatively frequent clinical diagnosis, mutations have been established in few patients. Genetic heterogeneity and the clinical overlap with a number of other syndromes might explain this discrepancy.
• an X-linked syndrome ascribed to mutations in the FGD1 gene^ref is characterized by ocular hypertelorism, anteverted nostrils, broad upper lip, peculiar scrotal “shawl” above the penis, and small hands.
• Aase-Smith syndrome : a familial syndrome

Symptoms & signs : mild growth retardation, hypoplastic anemia, variable leukocytopenia, triphalangeal thumbs, narrow shoulders, and late closure of fontanels, and occasionally by cleft lip, cleft palate, retinopathy, and web neck. A recessive mode of inheritance has been suggested.
• Achard's syndrome

Symptoms & signs : arachnodactyly associated with receding mandible and joint laxity limited to the hands and feet.
• Aicardi syndrome (AGS) : a syndrome affecting female infants

Symptoms & signs : agenesis of the corpus callosum, large discrete areas of chorioretinopathy, spasms and tonic seizures, and mental retardation.
• Aicardi-Goutieres syndrome (AGS)

Epidemiology : in 1984, Jean Aicardi and Françoise Goutiéres described 8 children
Aetiology : autosomal recessive loss-of-function mutations in AGS1 / TREX1, encoding the major mammalian 3' => 5' DNA exonuclease on chromosome 3p21^{ref1, ref2}. AGS can result from mutations in the genes encoding any one of the 3 subunits of the human ribonuclease H2 enzyme complex, explaining why clinical and immunological features of AGS parallel those of transplacentally acquired congenital viral infection^ref
Symptoms & signs : progressive encephalopathy with onset in the first year of life characterised by calcification of the basal ganglia, white matter abnormalities, a chronic CSF lymphocytosis, and negative serological investigations for common prenatal infections^ref. Acquired microcephaly, severe psychomotor delay, spasticity and extrapyramidal signs. Cutaneous necrotic lesions and the neuropathological aspect of microangiopathy and microinfarctions suggest a vascular process in relation to elevated IFN-a
Laboratory examinations : basal ganglia calcifications, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis and raised IFN-a in the CSF. A genetic defect in the regulation of its synthesis may be the causal factor of the disorder. CT is very important in the diagnosis of AGS, demonstrating clearly the presence of calcifications at basal ganglia level: these are often bilateral and symmetrical. CT scan and MRI reveal leukodystrophy and progressive cerebral atrophy. A raised level of INF-a in the CSF constitutes a marker of the syndrome: this level, which falls with age, is higher in the CSF than in the serum, suggesting intrathecal synthesis. Differential diagnosis in AGS is carried out to exclude the presence of other neurological and endocrinological pathologies characterised by the presence of intracranial calcification; considering the white matter abnormalities, it is necessary to exclude forms of leukodystrophy associated with metabolic defects, known or otherwise. One fundamental aspect that remains to be clarified is the aetiopathogenetic mechanism underlying AGS. There does not exist, to date, any causal therapy for AGS, although genetic studies, particularly those focusing on interferon-regulating genes, may well provide some therapeutic indications. Interestingly, it was the resemblance of the AGS clinical phenotype to the sequelae of congenital infection which led to the measurement of IFN-a in children with the disease^ref. A report of raised levels of CSF IFN-a in 14 of 15 patients with AGS suggests a close association between this parameter and the other clinical and laboratory features, such that an increase of CSF IFN-a in the absence of infection is currently considered a marker for the condition^ref
• Alagille syndrome : an autosomal dominant syndrome

Symptoms & signs : neonatal jaundice, cholestasis with peripheral pulmonic stenosis, and occasionally septal defects or patent ductus arteriosus (PDA), due to paucity or absence of intrahepatic bile ducts; it is characterized by unusual facies and ocular, vertebral, and nervous system abnormalities.
• Allemann's syndrome

Symptoms & signs : double kidney and clubbed fingers, sometimes associated with facial asymmetry and degeneration of various motor nerves.
• Allgrove's syndrome / achalasia-addisonian syndrome / addisonian-achalasia syndrome / triple-A syndrome

Symptoms & signs : glucocorticoid deficiency with achalasia and alacrima; inherited as an autosomal recessive trait
• Andersen's syndrome

Symptoms & signs : bronchiectasis, cystic fibrosis of the pancreas, and vitamin A deficiency.
• arthropathy-camptodactyly syndrome : a rare autosomal recessive disorder

Symptoms & signs : arthropathy associated with congenital flexion contractures of the fingers and synovial and tendon abnormalities, and by constrictive pericarditis.
• Beckwith-Wiedemann syndrome (BWS) / exomphalos-macroglossia-gigantism (EMG) syndrome^ref (Becwith JP. Extreme cytomegaly of the adrenal fetal cortex, omphalocoele, hyperplasia of the kidneys and pancreas, Leydig cell hyperplasia. Another syndrome ? West.Soc.Ped.Res. 1963) : a congenital autosomal dominant syndrome with variable expressivity

Epidemiology : prevalence = 1 in 13,000 (higher in children born via FIVET^ref)
Aetiology : mutations in imprinted gene domain of 11p15.5
Symptoms & signs : exomphalos, macroglossia, and gigantism, often associated with visceromegaly, adrenocortical cytomegaly, and dysplasia of the renal medulla
Prenatal diagnosis : 2 major criteria (abdominal wall defect, macroglossia, macrosomia) or 1 major + 2 minor criteria (nephromegaly/dysgenesis, adrenal cytomegaly, aneuploidy/abnormal loci, polyhydramnios)^ref
• Biemond syndrome II : an autosomal recessive disorder

Symptoms & signs : iris coloboma, obesity, mental retardation, hypogonadism, and postaxial polydactyly
• Birt-Hogg-Dubé syndrome : an autosomal dominant disorder

Symptoms & signs : proliferation of ectodermal and mesodermal components of the pilar system, occurring as multiple trichodiscomas, acrochordons, and fibrofolliculomas on the head, chest, back, and arms
• Björnstad's syndrome : an autosomal recessive disorder

Symptoms & signs : congenital sensorineural deafness and pili torti.
• Börjeson-Forssman-Lehmann syndrome : an X-linked syndrome

Symptoms & signs : severe mental retardation, epilepsy, hypogonadism, hypometabolism, marked obesity, swelling of the subcutaneous tissues of the face, and large ears.
• branchio-oto-renal (BOR) syndrome : inherited as an autosomal dominant trait with high penetrance and variable expression

Symptoms & signs : branchial arch anomalies (preauricular pits, branchial fistulas or pits) associated with Mondini's deafness and renal dysplasi
• brittle cornea syndrome : an X-linked, recessively inherited syndrome

Symptoms & signs : brittle cornea, blue sclerae, and red hair.
• cat-eye syndrome / cat's eye syndrome

Aetiology : partial trisomy 22, i.e., the presence of a partial additional copy of chromosome 22.
Symptoms & signs : coloboma of the iris and anal atresia; there may also be many other anomalies, including preauricular skin tags or fistulas, hypertelorism, congenital heart disease, skeletal abnormalities, and renal malformations
• cerebrocostomandibular syndrome : an autosomal recessive syndrome

Symptoms & signs : severe micrognathia and costovertebral abnormalities, including small bell-shaped thorax, incompletely ossified aberrant rib structure, and abnormal rib attachment to vertebrae. Also present are palatal defects, glossoptosis, prenatal and postnatal growth deficiencies, and mental retardation, the last perhaps due to the neonatal respiratory distress which is frequently the presenting sign of the disorder
• cerebrohepatorenal syndrome / Zellweger syndrome : an autosomal recessive disorder

Symptoms & signs : craniofacial abnormalities, hypotonia, hepatomegaly, polycystic kidneys, jaundice, and death in early infancy, and associated with absence of peroxisomes in the liver and kidneys
• congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome : a disorder of skin cornification

Symptoms & signs : unilateral erythema and scaling and ipsilateral limb defects, sometimes accompanied by ipsilateral skeletal hypoplasia and brain and visceral defects; it is believed to be an X-linked dominant trait
• Chédiak-Higashi anomaly or syndrome (CHS) / Béguez César disease : a lethal autosomal recessive syndrome

Symptoms & signs : oculocutaneous albinism, massive leukocyte inclusions (giant lysosomes), histiocytic infiltration of multiple body organs, development of pancytopenia, hepatosplenomegaly, recurrent or persistent bacterial infections, and a possible predisposition to development of malignant lymphoma
• acrocephalosyndactyly / acrocephalosyndactylism / acrocephalosyndactylia

Symptoms & signs : craniostenosis characterized by acrocephaly and syndactyly, probably occurring as an autosomal dominant trait and usually as a new mutation
• acrocephalosyndactyly type I / Apert-Crouzon disease / Vogt's cephalodactyly : an autosomal dominant disorder

Symptoms & signs : the hand and foot malformations associated with Apert's syndrome together with the facial characteristics of Crouzon's disease
• acrocephalosyndactyly type III / Saethre-Chotzen's syndrome : an autosomal dominant disorder
• Symptoms & signs : acrocephalosyndactyly in which the syndactyly is mild and by hypertelorism, ptosis, and sometimes mental retardation
• acrocephalosyndactyly type V / Pfeiffer's syndrome : an autosomal dominant disorder

Symptoms & signs :  acrocephalosyndactyly associated with broad short thumbs and big toes
• acrocephalopolysyndactyly : acrocephalosyndactyly with polydactyly as an additional feature. 4 types are known:
• type I (ACPS I; Noack's syndrome), autosomal dominant, is the same as acrocephalosyndactyly type V (Pfeiffer type)
• type II (ACPS II; Carpenter syndrome), with mental retardation and brachydactyly is autosomal recessive
• type III (ACPS with leg hypoplasia; Sakati-Nyhan syndrome), with hypoplastic tibias and deformed, displaced fibulas, is autosomal dominant
• type IV (ACPS IV; Goodman syndrome), with congenital heart defects, clinodactyly, camptodactyly, and ulnar deviation, but with unimpaired intelligence, is autosomal recessive.
• Coffin-Lowry syndrome : a condition with onset in the postnatal period

Symptoms & signs : incapability of speech, severe mental deficiency, and muscle, ligament, and skeletal abnormalities; it is transmitted with X-linked intermediate inheritance
• Coffin-Siris syndrome

Symptoms & signs : hypoplasia or absence of the fifth fingers and toenails associated with growth and mental deficiencies, coarse facies, mild microcephaly, hypotonia, lax joints, mild hirsutism, and occasionally cardiac, vertebral, or gastrointestinal anomalies.
• Conradi-Hünermann syndrome : an autosomal dominant form of chondrodysplasia punctata

Symptoms & signs : asymmetric shortening of the extremities and scoliosis; intelligence and life expectancy are normal. The syndrome is also associated with maternal use of warfarin sodium during pregnancy.
• Costello syndrome

Aetiology : germline mutations of HRAS^ref
Symptoms & signs : mental retardation syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition to tumors
• Cree encephalitis : in 1988, Black et al^ref described an early onset, progressive encephalopathy in an inbred Canadian aboriginal community. The disease was termed to distinguish it from another neurological condition, Cree leucoencephalopathy, occurring at high frequency in the same population^{ref1, ref2}

Symptoms & signs : severe psychomotor retardation, progressive microcephaly, cerebral atrophy, white matter attenuation, intracerebral calcification, a CSF lymphocytosis, and systemic immune abnormalities. In 10 of 11 affected children described, premature death resulted at a median age of 20.6 months. Although, these features were noted as reminiscent of AGS, the conditions were considered distinct in view of the observation of immunological abnormalities and an apparent susceptibility to infection in Cree encephalitis
Laboratory examinations : levels of IFN-a, a marker of AGS, are raised in Cree encephalitis. Moreover, linkage analysis indicates that the disorders are allelic and refines the AGS1 locus to a 3.47 cM critical interval. A CSF lymphocytosis is not necessary for the diagnosis of AGS and strongly suggest that AGS and pseudo-TORCH syndrome are the same disorder^ref.
• Cronkhite-Canada syndrome : a rare syndrome

Symptoms & signs : sporadic, widespread intestinal polyps and malabsorption (=> copious diarrhea, weight loss) accompanied by ectodermal defects such as alopecia and onychodystrophy, pigmentary alterations, edema, and neurologic symptoms. Colon carcinoma in 14% intestinal tumors^ref
• Cross-McKusick-Breen syndrome / oculocerebral-hypopigmentation syndrome : an autosomal recessive syndrome

Symptoms & signs : oculocutaneous albinism, microphthalmus, small opaque corneas, oligophrenia with spasticity, high-arched palate, gingival hypertrophy, and scoliosis
• cryptophthalmos syndrome / Fraser's syndrome : an autosomal recessive abnormality

Symptoms & signs : absence of the palpebral apertures, disorganization of one or both ocular globes, malformed ears, cleft palate, laryngeal stenosis, syndactyly, meningoencephalocele, imperforate anus, cardiac defects, and maldeveloped kidneys
• Brachmann-Cornelia de Lange's syndrome / typus degenerativus amstelodamensis : a congenital syndrome

Symptoms & signs : severe mental retardation is associated with many abnormalities, including short stature (Amsterdam dwarf), brachycephaly, low-set ears, webbed neck, carp mouth, depressed bridge of the nose with the end tilted up and forward-directed nostrils, bushy eyebrows meeting at the midline, unruly coarse hair growing low on the forehead and neck, and flat spadelike hands with short tapering fingers
• Denys-Drash syndrome^ref (Denys P., Malvaux P., Vande Berghe H & al. Association d'un syndrome anatomopathologique de pseudohermaphroditisme masculin, d'une tumeur de Wilms et d'un mosaicisme XX/XY. Arch.Franç Pédiatr.24:729-736 (1967))

Aetiology : genetic abnormality in the p13 region of chromosome 11
Symptoms & signs : male pseudohermaphroditism, nephropathy (mesangial sclerosis) leading to renal failure, and, in most cases, Wilms' tumor
• De Sanctis-Cacchione syndrome : a hereditary syndrome, transmitted as an autosomal recessive trait,

Symptoms & signs : xeroderma pigmentosum associated with mental retardation, retarded growth, gonadal hypoplasia, and sometimes neurologic complications and photosensitivity
• de Toni-Debre-Fanconi syndrome

Aetiology : 4,977 base pair "common" deletion flanked by direct repeat sequences or 3.3-kb single deletion flanked by palindrome sequences^ref in the mitochondrial genome => defect in the respiratory chain at the level of complex III
Laboratory examinations : sideroblastic anemia and renal tubulopathy together with a large urinary excretion of lactate (sometimes hyperlactataemia), 3-hydroxybutyrate and citric acid cycle intermediates
• Diamond-Blackfan-Josephs anemia (DBA) / congenital chronic erythroblastopenia / Kaznelson type anemia

Epidemiology : incidence = 2–7 per million live births. The median age at presentation of anemia is 2 months and the median age at diagnosis of DBA is 3 months. > 90% of cases are diagnosed within the first year of life, but the disease is sometimes detected later in childhood and occasionally in adulthood
Aetiology : mutations in
• DBA2 (8p23.3-p22) (autosomal dominant : 40%)^ref
• DBA1 / ribosomal protein S19 (RPS19) (19q1.32)^{ref1, ref2} : ribosomal proteins are expressed in amounts that differ relative to one another in a tissue-specific manner, and that haploinsufficiency for a particular protein may make that protein limiting for ribosome assembly in some tissues, while other tissues remain unaffected. Further, polymorphisms in factors controlling the expression of a particular ribosomal protein gene may alter its expression and expand or contract the number of tissues affected from individual to individual. Support for the hypothesis comes from the observation that promoters in ribosomal protein genes exhibit little conservation and transcription profiling indicates that the absolute amounts of mRNAs for individual ribosomal proteins can vary dramatically relative to one another. Balanced expression of ribosomal proteins is achieved post-translationally, where excess proteins not assembled into ribosomal subunits are often rapidly degraded. The number of ribosomes per cell is therefore determined by the factors that limit assembly. In principle, any essential ribosomal protein could become limiting for assembly if its level of expression falls below a critical threshold. Whether an inactivating mutation in ribosomal protein gene would affect protein synthetic capacity of a tissue would depend on the ratio of the ribosomal protein relative to other ribosomal proteins in that tissue. If the ratio were high, the tissue may not be affected as the level of functional protein may not fall to a point where it becomes limiting for subunit assembly. In contrast, if the ratio were low, an inactivating mutation could make the protein limiting for subunit assembly resulting in a clinical phenotype. Polymorphisms in the myriad of cis- and trans-acting factors, which govern the expression of ribosomal proteins in response to developmental and physiological signals, could act to increase or decrease ribosomal protein expression and thereby impact the profile and severity of clinical phenotypes^ref.
• another not yet identified (autosomal recessive)^ref.
Dominant and recessive forms of DBA have been reported, but 50–60% of cases with RPS19 mutations are de novo and sporadic^ref.
Pathogenesis : the precise function of the 16 kDa nucleolar protein RPS19 is unknown but its nucleolar localization is disrupted by disease-causing mutations, and retroviral expression of RPS19 in progenitor cells from DBA patients with RPS19 mutations enhances erythropoiesis^ref. There is recent direct evidence in studies on knockout mice that complete deficiency of RPS19 is lethal^ref. Subnormal burst-forming unit–erythroid and colony-forming unit–erythroid in vitro activity, and progenitor cells from patients with this disease have reduced sensitivity to exogenous erythropoietin
Symptoms & signs : the Diamond-Blackfan Anemia Registry (DBAR) of North America, established in 1993, has provided demographic, laboratory and clinical data on DBA patients in the USA and Canada^ref. Phenotypic heterogeneity is common in DBA : even within families, the degree of anemia, response to treatment, and presence of congenital anomalies can vary^ref :
• physical anomalies, excluding short stature, were found in 47% of the patients in the DBAR. Of these, 50% were of the face and head, 38% upper limb and hand, 39% genitourinary and 30% cardiac. Patients with multiple anomalies within each of the above 4 categories were considered as having a single anomaly within that category. Using these criteria, more than one anomaly was found in 21% of the patients
• cancer predisposition syndrome, although not to the same extent as is the case with FA and DC, further complicates management decisions. In a recent report there were 6 of 354 evaluable patients in the DBAR with malignancy. 3 patients had osteogenic sarcoma; 1, MDS; 1, colon carcinoma; and 1, a soft tissue sarcoma^ref. A review of the literature revealed 23 additional cases of cancer. Among these were 10 cases of MDS/AML, 4 lymphoid malignancies, 2 cases of osteosarcoma, 2 breast cancers and 5 other cancers^ref. Furthermore instances of significant cytopenias, including aplastic anemia, are emerging^ref.
Laboratory examinations : screening for the RPS19 mutations involves sequencing each of the 5 coding RPS19 exons. However, diagnosis in the majority of DBA patients is made on clinical grounds because only the minority (25%) will have mutations in RPS19. Thus the disease is considered likely in children with :
• normochromic, macrocytic pure red cell aplasia, although neutropenia or thrombocytopenia may occur,  associated with reticulocytopenia and bone marrow erythroblastopenia
• elevated fetal hemoglobin
• no evidence of FA by chromosomal breakage testing
• elevated erythrocyte adenosine deaminase (eADA) activity found in approximately 85% of patients^ref
These parameters have been helpful in distinguishing DBA from transient erythroblastopenia of childhood (TEC), a self-resolving hypoplastic anemia, thus avoiding unnecessary treatment.
Therapy :In about two thirds of patients, the anemia responds to treatment with exogenous glucocorticoids. For patients with corticosteroid-refractory disease or for those who cannot tolerate corticosteroids, stem-cell transplantation from HLA-matched related donors has been performed.16
• GR agonists are effective in 66% of patients : in large series from the European registry representing France and Germany and the DBAR^ref, 63% and 80% initially responded to steroid therapy, respectively. The natural course of the disease in steroid-treated patients is unpredictable. In fact, responses can range from rapid increases in reticulocyte counts within 1–2 weeks followed by a long period of steroid independence, to complete unresponsiveness to corticosteroids. Due to significant side effects (poor growth, pathological fractures and cataracts), only approximately 40% of steroid-responsive patients will remain on corticosteroids at an acceptable every other day dose. Indeed, the current recommendation is to withhold steroids until after the first year of life in order to protect growth during this critical period as well as permit live viral vaccinations. 20% of patients enter a remission and discontinue either corticosteroids or transfusion therapy and their long-term prognosis is excellent. Once a patient enters puberty, the anemia may resolve, as it did in this patient's sister, and it is postulated that the increase in production of endogenous steroids may obviate the need for supplementation. Patients who can be maintained with low doses of steroids also do quite well^ref (Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders Co.; 2003:280–365). Targeted reduction of the RPS19 transcript in human CD34⁺ cells with the use of short hairpin RNA resulted in impaired proliferation and differentiation of erythroid progenitor cells that could be reversed with dexamethasone. Dexamethasone did not appear to alter transcription of RPS19 or other ribosomal genes, but rather it decreased the expression of genes specific to nonerythroid hematopoietic differentiation while increasing the expression of genes found in immature erythroid cells^ref.
• because allogeneic HSCT has been successful in the management of steroid-resistant transfusion-dependent or pancytopenic patients, it is recommended that all probands and siblings be HLA-typed early and that sibling cord blood samples be preserved. Recipients of matched sibling donors have an actuarial survival of about 80%^{ref1, ref2} (Vlachos A, Lipton JM. Hematopoietic stem cell transplant for inherited bone marrow failure syndromes. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett; 2004:281–311).
Prevention : preimplantation genetic diagnosis (PGD)
Web resources : Diamond-Blackfan Anemia Foundation, Inc.
• DOOR syndrome : a rare syndrome existing in autosomal dominant and recessive forms.

Symptoms & signs : congenital deafness, onycho-osteodystrophy, and mental retardation
• dyskeratosis congenita (DC) (Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders Co.; 2003:280–365)

Epidemiology : a rare bone marrow failure syndrome first described in 1906
• X-linked recessive dyskeratosis congenita (80%) caused by mutations in the DKC1 gene (Xq28) encoding the conserved 58 kDa nucleolar protein dyskerin^ref. That this protein is known to associate with TERC RNA is intriguing and suggests that the molecules interact to determine telomerase function. However, confirmatory biochemical studies need to be done to prove this point because nucleolar proteins also participate in ribosomal biogenesis and responses to cellular stress, so dyskerin may have an entirely separate function unrelated to telomerase.
• autosomal dominant dyskeratosis congenita (10%) is due to the RNA component of telomerase hTR / DKC2^ref on chromosome 3q. Disease anticipation is observed in families with this disease and this is associated with progressive telomere shortening^ref. This form of the disease is likely the result of haploinsufficiency and is less severe than the X-linked form. It is, however, characterized by "disease anticipation" in which the onset of disease occurs at increasingly earlier ages in successive generations^ref. Individuals heterozygous for TERC mutations may be asymptomatic well into the sixth decade of life, but this asymptomatic phase is likely to be shorter in each successive generation of heterozygotes^ref.
• autosomal recessive dyskeratosis congenita due to mutations in DKC3
Symptoms & signs : the classic triad of abnormal skin pigmentation, nail dystrophy, and oral leukoplakia. In addition to these defining lesions other common somatic abnormalities include epiphora (tearing secondary to obstructed tear ducts), developmental delay, pulmonary disease, short stature, esophageal webs, dental caries, tooth loss, premature grey hair and hair loss. The skin findings can range from tan macular or reticular hyperpigmentation to hypopigmented macular lesions. The typical location of such lesions is on the sun-exposed areas of the upper trunk, face and arms. Mucosal leukoplakia is almost always in the oropharynx but other aerodigestive and urogenital sites can be involved. Commonly these mucosal abnormalities occur in the second, third or fourth decade of life. Nail dystrophy usually involves the fingernails before the toenails are involved. Dystrophy is characterized by longitudinal fissures, atrophy and, later, by nail distortion and, in some cases, nail loss. The Dyskeratosis Congenita Registry (DCR), established in 1995, has provided valuable data regarding epidemiology, pathophysiology, genetics and treatment of DC. In a recently published report^ref there were 148 patients from 92 families emanating from 20 countries enrolled in the DCR. The median age for the onset of mucocutaneous abnormalities in patients enrolled in the DCR is 6–8 years. Nail changes occur first.
Laboratory examinations : pancytopenia is the hematologic hallmark of DC. The median age for the onset of pancytopenia is 10 years. Approximately 50% of patients reported in the literature develop severe aplastic anemia and > 90% of individuals reported in the DCR have developed at least a single cytopenia by 40 years of age^ref. In a number of cases aplastic anemia preceded the onset of abnormal skin, dystrophic nails or leukoplakia. As with FA it is the nonhematologic manifestations of DC that are of particular concern when hematopoietic stem cell transplantation for bone marrow failure is contemplated. The clinical course is highly variable, even within families. In the less severe forms, clinical manifestations may not be present at the time of birth but evolve during early childhood and adolescence. In the X-linked form one third develop bone marrow failure as teenagers as do 60% of those with the autosomal recessive form (Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders Co.; 2003:280–365). Yet, while most patients have hypoplastic bone marrows at the time of diagnosis, ascertainment of cases does occur in adulthood and such cases, as is the case with FA, can present with MDS (generally hypoplastic), AML, or epithelial malignancies^ref. A very severe variant of the X-linked syndrome, known as the Hoyeraal-Hreidarsson syndrome, involves early onset bone marrow failure, intrauterine growth retardation, microcephaly, cerebellar hypoplasia, mental retardation, and immune deficiency^ref. Epithelial malignancies develop at or beyond the third decade of life. About 1 in 5 patients will develop progressive fibrotic pulmonary disease resulting in diminished diffusion capacity and/or restrictive lung disease. It is likely that more pulmonary disease would be evident if patients did not succumb earlier to the complications of severe aplastic anemia and cancer. The Registry has, somewhat surprisingly, revealed the presence of significant progressive immunodeficiency in DC. The vast majority (80%) of patients who died, with or without significant neutropenia, did so from infection, some opportunistic, usually before 30 years of age. Over half of the patients studied had a predominantly cellular immune defect, and it is therefore reasonable to assume that immunodeficiency as well as neutropenia plays a significant role in infectious morbidity and mortality in DC^ref. screening for the X-linked and autosomal dominant forms of DC should be considered in children and adults who have (1) bone marrow failure, AML or MDS; (2) negative mitomycin C and DEB tests (to rule out FA); and either (3) hypopigmented macules, reticulated hyperpigmentation, dystrophic nails, or oral leukoplakia or (4) evidence in the family history of either X-linked or autosomal dominant bone marrow failure, MDS, or AML, particularly if there is evidence of "disease anticipation." Patients with the X-linked and autosomal dominant forms of DC can be diagnosed by sequencing of genomic DNA. For TERC, the entire coding region is in exon 1 and mutations include large and small deletions, single base changes, and missense mutations. DKC1 screening involves sequencing of 15 exons, and mutations include missense (the majority), splice site mutations, a large deletion, and a promoter mutation. Large deletions of DKC1 may be missed by using sequence analysis in carrier females and may also be missed in the TERC gene.
• GeneDx
• leukocyte subset flow FISH telomere length measurement : diagnostic sensitivity and specificity of very short telomeres for DC were >90% for total lymphocytes, CD45RA⁺/CD20^- naive T-cells, and CD20⁺ B-cells. Granulocyte and total leukocyte assays were not specific; CD45RA^- memory T-cells and CD57⁺ NK/NKT were not sensitive^ref
Therapy : 67% of the deaths reported in the DC appear to be a consequence of bone marrow failure; therefore, therapeutic focus is on transfusion support and measures targeting hematopoietic activity. Androgen therapy, G-CSF and GM-CSF have been used with some temporary successes. But the role of such agents in management of DC has not been as clearly demonstrated as it has in patients with FA. Nonetheless, the use of G-CSF or GM-CSF cannot be avoided in patients whose neutropenia has proven to be severe and life-threatening. Allogeneic HSCT is an acceptable approach, but there are unexplained post-transplant morbidities (Vlachos A, Lipton JM. Hematopoietic stem cell transplant for inherited bone marrow failure syndromes. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett; 2004:281–311) that warrant use of this approach only in the context of a clinical trial. For example, 9% of patients with DC died of lung disease with or without HSCT. It is prudent to assume that all DC patients are at a high risk of interstitial pulmonary disease when undergoing HSCT, and it is now recommended that conditioning regimens take this into account by avoiding lung radiation (by shielding) and avoiding chemotherapeutic agents known to have pulmonary toxicities. As is the case in FA patients, nonmyeloablative conditioning regimens may reduce the incremental risk of pulmonary toxicity as well as the hypothesized incremental nonhematologic cancer risk^ref. Unfortunately, there have been too few transplant survivors to determine whether an increase in the prevalence of cancer will follow as a consequence of HSCT. Stem cell gene therapy or stem cell telomere engineering are rational future considerations. As in patients with FA, surveillance bone marrow studies are generally performed annually unless there is myelodysplasia or a complex clonal cytogenetic abnormality, in which case more frequent follow-up may be warranted.
Prognosis : almost 9% (13/148) of patients developed cancer. Of these, 4 patients had MDS, 1 had Hodgkin disease and 8 had carcinoma. The relative risk of leukemia has not yet been defined.
Web resources :
• www.icomm.ca/geneinfo/dysker.htm
• http://www.cafamily.org.uk/Direct/d42
• Ellis-Van Creveld syndrome

Symptoms & signs : short stature. The extremities are often plump and markedly shortened, progressively from the trunk to the fingers and the toes. A bilateral postaxial sixth finger is frequent. The most striking and consistent finding in the mouth is fusion of the middle part of the upper lip to the labial sulcus, resulting in a so-called 'whistling deformity'. Congenitally missing teeth, particularly in the frontal region, are a constant finding too. Teeth are usually small and have conical crowns. Supernummer teeth have also been noted. The oral and maxillofacial surgeon will treat the hypertrophic upper frenulum; the dentist will treat the oligodontia of the frontal region and the conical crowns by means of laminated veneers and etch composite bridgework^ref
• Fèvre-Languepin syndrome / popliteal pterygium syndrome

Symptoms & signs : popliteal webbing associated with cleft lip and palate, fistula of the lower lip, syndactyly, onychodysplasia, and pes equinovarus
• FG syndrome : an X-linked recessive syndrome

Symptoms & signs : mental retardation, megalencephaly, imperforate anus and other gastrointestinal defects, delayed motor development, congenital hypotonia, characteristic facies and personality, short stature, skeletal anomalies, and congenital cardiac defects.
• first arch syndrome :

Symptoms & signs : macrostomia, hemignathia, and deformities of the external ear, resulting from an inhibitory process occurring toward the seventh week of embryonic life and affecting the facial bones derived from the first pharyngeal (branchial) arch.
• Flynn-Aird syndrome : a rare autosomal dominant syndrome

Symptoms & signs : abnormalities of the nervous system and ectodermal structures, including cataracts, retinitis pigmentosa, myopia, dental caries, skin atrophy and ulceration, peripheral neuropathy, ataxia, deafness, and cystic bone changes.
• PHC syndrome / Böök's syndrome : an autosomal dominant syndrome consisting of premolar aplasia, hyperhidrosis, and premature canities
• Gillespie's syndrome : a rare autosomal recessive syndrome

Symptoms & signs : aniridia, cerebellar ataxia, and mental retardation
• Grönblad-Strandberg syndrome

Symptoms & signs : angioid streaks in the retina together with pseudoxanthoma elasticum of the skin.
• Hadju-Cheney syndrome (HCS) is a rare autosomal-dominant disorder with variable expressivity. It is characterized by facial dysmorphism, premature tooth loss, osteolysis of distal phalanges, and skull abnormalities. In some cases, progressive platybasia can occur and can lead to Chiari malformation with an obstruction of cerebrospinal fluid flow^ref
• hand-foot-uterus syndrome : a congenital syndrome

Symptoms & signs : small feet with unusually short great toes, abnormal thumbs, and, in females, duplication of the genital tract.
• Hanhart's syndrome : any of several syndromes of variable inheritance

Symptoms & signs : severe micrognathia, high nose root, small eyelid fissures, low-set ears, and variable absence of digits or limbs, usually below the elbow or knee
• Hay-Wells syndrome / ankyloblepharon–ectodermal dysplasia–clefting (AEC) syndrome : an autosomal dominant syndrome

Symptoms & signs : ectodermal dysplasia, cleft lip and palate, and ankyloblepharon filiforme adnatum; it is also characterized by hypodontia, palmar and plantar keratoderma, partial anhidrosis, sparse wiry hair, and sometimes otologic defects
• Helweg-Larsen's syndrome : an autosomal dominant syndrome

Symptoms & signs : anhidrosis present from birth and labyrinthitis later in life
• hereditary benign intraepithelial dyskeratosis syndrome

Symptoms & signs : plaques of the bulbar conjunctiva and by oral mucosal thickenings clinically similar to white-folded hypertrophy (white sponge nevus of Cannon); it is inherited as an autosomal dominant trait with a high degree of penetrance.
• hereditary neuralgic amyotrophy (HNA) is an autosomal dominant recurrent neuropathy affecting the brachial plexus. HNA is triggered by environmental factors such as infection or parturition

Aetiology : mutations in the gene septin 9 (SEPT9). Septins are implicated in formation of the cytoskeleton, cell division and tumorigenesis^ref
• Herrmann's syndrome : an autosomal dominant syndrome

Symptoms & signs : initially by photomyogenic seizures and progressive deafness, with later development of diabetes mellitus, nephropathy, and mental deterioration progressing to dementia.
• autosomal dominant aplasia of lacrimal and salivary glands (ALSG) is a rare condition characterized by irritable eyes and dryness of the mouth. ALSG was mapped to 5p13.2-5q13.1, which coincides with the gene FGF10. In 2 extended pedigrees, heterozygous mutations in FGF10 were identified in all individuals with ALSG. Fgf10^+/- mice have a phenotype similar to ALSG, providing a model for this disorder. Haploinsufficiency for FGF10 during a crucial stage of development results in ALSG^ref.
• hypertrichosis cubiti (HC) / hairy elbow syndrome consists of a localised form of long vellus hair on the extensor surfaces of the distal third of the upper arm and the proximal third of the forearm bilaterally, or occasionally on other parts of the body. In the 28 cases reported in the literature so far the elbow hair abnormality was either isolated or associated with short stature or other physical abnormalities. Most of these cases were sporadic, but autosomal dominant as well as autosomal recessive inheritance patterns have been postulated^ref
• ornithine aminotransferase (OAT) deficiency

Symptoms & signs : gyrate atrophy of choroid and retina
Therapy : arginine-free diet and vitamin B₆
• ornithine transcarbamylase (OTC) deficiency / hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome : an autosomal recessive syndrome

Aetiology : defect in the transport of ornithine into mitochondria, which disturbs the cycle of ureagenesis
Symptoms & signs : aversion to protein ingestion
Laboratory examinations : elevated plasma levels of ornithine, postprandial hyperammonemia and homocitrullinuria
Therapy : gene therapy
• hypoglossia-hypodactyly syndrome / aglossia-adactylia syndrome : a rare syndrome

Symptoms & signs : partial to complete absence of the tongue and of the digits or one or more limbs
• immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome

Aetiology : mutations in the DNMT3B gene
Symptoms & signs : progressive multifocal leukoencephalopathy (PML)^ref
• IVIC syndrome / oculo-oto-radial syndrome : a rare autosomal dominant syndrome

Symptoms & signs : internal ophthalmoplegia, hearing impairment, and radial ray defects varying from a long slender thumb to deformity of an entire upper limb, first observed in Venezuela and later in Italy
• Jarcho-Levin syndrome / spondylothoracic dysplasia : an autosomal recessive disorder

Symptoms & signs : multiple vertebral defects, short thorax, rib abnormalities, camptodactyly, and syndactyly; urogenital abnormalities are sometimes present. Death, from respiratory insufficiency, usually occurs in infancy
• Joubert's syndrome / Joubert syndrome–related disorders (JSRD)

Aetiology : mutations in the CEP290 / NPHP6 gene, which interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle–dependent manner and in connecting cilia of photoreceptors. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies^ref
Symptoms & signs : partial or complete agenesis of the cerebellar vermis, with hypotonia, episodic hyperpnea, mental retardation, nephronophthisis^ref, and abnormal eye movements
Laboratory examinations : neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'.
Prognosis : most patients die in infancy.
• Juberg-Hayward or orocraniodigital syndrome

Symptoms & signs : severe mental retardation (MR), microcephaly, Dandy-Walker malformation, bilateral lip/palate clefts, hypertrophied sublingual frenulum, lobular tongue, absent thumbs, and other skeletal abnormalities, including bilateral Y-shaped metacarpals and urogenital abnormalities, unilateral distal displacement of elbow position, second-site radioulnar synostosis. Possible overlap with other syndromes, such as orofaciodigital and Malpuech syndromes^ref
• Kabuki make-up syndrome : a congenital, possibly inherited,

Symptoms & signs : mental retardation, dwarfism, scoliosis, peculiar facies resembling the makeup of Japanese actors of Kabuki, and frequently cardiovascular abnormalities.
• Kallmann's syndrome
• KAL1 (X-linked recessive, mutations in anosmin, that plays a key role in the migration of GnRH neurons and olfactory nerves to the hypothalamus)
• KAL2 (autosomal recessive, loss-of-function mutations in FGFR1)
• KAL3 (?)
• with spastic paraplegia
• with brachytelephalangy and characteristic facies
Symptoms & signs : hypogonadotropic hypogonadism and anosmia/hyposmia, short fourth metacarpal, achromatopsia, normoprolactinemia.
• Kaufman-McKusick syndrome : a rare autosomal recessive disorder

Symptoms & signs : hydrometrocolpos accompanied by postaxial polydactyly, congenital cardiac defects, and sometimes subsequent bilateral hydronephrosis. Manifestations in males include hypospadias and prominent scrotal raphe
• Clarke-Hadfield syndrome : an autosomal recessive generalised disorder of infants, children and young adults

Symptoms & signs : widespread dysfunction of the exocrine glands, characterised by signs of chronic pulmonary disease (due to excess mucus production in the respiratory tract), pancreatic deficiency, abnormally high levels of electrolytes in the sweat and occasionally by biliary cirrhosis. There is an ineffective immunologic defense against bacteria in the lungs. Pathologically, the pancreas shows obstruction of the pancreatic ducts by amorphous eosinophilic concretions, with consequent deficiency of pancreatic enzymes, resulting in steatorrhoea and azotorrhoea and intestinal malabsorption. The degree of involvement of organs and glandular systems may vary greatly, with consequent variations in the clinical picture.
• Kearns-Sayre syndrome / ophthalmoplegia plus

Symptoms & signs : progressive ophthalmoplegia, pigmentary degeneration of the retina, myopathy, ataxia, and cardiac conduction defect; onset is before age 20. Almost all patients have large mitochondrial DNA deletions, and ragged red fibers are seen on muscle biopsy
• Langer-Giedion syndrome

Symptoms & signs : mental retardation, microcephaly, multiple exostosis, characteristic facies with bulbous nose, sparse hair, cone shaped epiphyses, loose redundant skin, joint laxity, and other anomalies
• Larsen's syndrome

Epidemiology : although the first case of Larsen Syndrome was found to be in the year of 1929, it was in 1950 that Dr. Loren Larsen described a syndrome that was found to be present at birth, which he named after himself.
Aetiology : a generalized embryonic connective tissue disorder during gestation inherited as an autosomal dominant (mutations in FLNB) or recessive trait
Symptoms & signs : cleft palate, multiple congenital dislocations of the major joints, deformities of the feet and hands, abnormal segmentation of the spine, an unusual facial appearance (which include a flat nasal bridge, wide-spaced eyes, and a prominent forehead), airway problems, caused by lack of rigidity of the upper airway.
Treatments may vary according to which symptoms the child may have. Joint abnormalities require prolonged orthopedic treatment. To correct joint defects, treatments could include special exercises, casting, braces, or surgery. Abnormal spinal segmentations may possibly be treated either by use of a brace or surgical procedure. If the child is born with cleft palate or cleft lip, speech therapy or surgical procedure may be necessary. If affected by respiratory problems, it can be treated with chest physiotherapy, tracheotomy, and the assistance of a ventilator. With the aid of medical equipment that is present at this time, the death rate has decreased drastically.
• boomerang dysplasia (BD) is a perinatal lethal osteochondrodysplasia, characterised by absence or underossification of the limb bones and vertebrae. The BD phenotype is similar to a group of disorders including atelosteogenesis I, atelosteogenesis III, and dominantly inherited Larsen syndrome

Aetiology : mutations in FLNB, the gene encoding the actin binding cytoskeletal protein, filamin B. The resultant substitutions, L171R and S235P, lie within the calponin homology 2 region of the actin binding domain of filamin B and occur at sites that are evolutionarily well conserved. These findings expand the phenotypic spectrum resulting from mutations in FLNB and underline the central role this protein plays during skeletogenesis in humans^ref.
• Leigh syndrome / infantile subacute necrotizing encephalopathy (SEN)

Aetiology : mutations have been identified in many nuclear- and mitochondrial-encoded genes involved in energy metabolism, specifically oxidative phosphorylation and the generation of ATP. Mitochondrial genes include those encoding the ATP6 subunit of ATP synthase, complex V (MTATP6), complex I subunits (MTND3), MTND5, and MTND6, subunit 3 of complex IV (MTCO3; 516050), the tRNA for valine (MTTV; 590105), the tRNA for lysine (MTTK), and the tRNA for tryptophan (MTTW). Nuclear genes include those encoding complex I subunits NDUFV1), NDUFS3, NDUFS4, NDUFS7, and NDUFS8, complex II flavoprotein subunit (SDHA), and complex III subunit (BCS1L). Leigh syndrome may also be caused by mutation in the DLD gene. Many cases of Leigh syndrome have been attributed to deficiency of cytochrome c oxidase (complex IV). In these patients, mutations have been found in the surfeit-1 gene (SURF1), which plays a role in the assembly or maintenance of complex IV, in the COX10 gene, and in the COX15 gene. The French-Canadian (or Saguenay-Lac Saint Jean) type of Leigh syndrome with COX deficiency (LSFC) has been found to be due to mutation in the LRPPRC gene. An X-linked form of Leigh syndrome is caused by mutation in the E1-a subunit of the pyruvate dehydrogenase complex (PDHA1).
• Lenz's syndrome : a hereditary syndrome, transmitted as an X-linked trait

Symptoms & signs : microphthalmia or anophthalmos, unilateral or bilateral, and digital anomalies; narrow shoulders, double thumbs, and other skeletal abnormalities; dental, urogenital, and cardiovascular defects may also occur
• Lesch-Nyhan syndrome : a rare X-linked disorder of purine metabolism

Aetiology : deficient hypoxanthine phosphoribosyltransferase (HPRT1)
Symptoms & signs : physical and mental retardation, compulsive self-mutilation of the fingers and lips by biting, choreoathetosis, spastic cerebral palsy, impaired renal function; and by excessive purine synthesis and consequent hyperuricemia and uricaciduria
• multiple pterygium syndrome / Escobar syndrome : an autosomal recessive syndrome

Symptoms & signs : pterygia of the neck, axillae, and popliteal, antecubital, and intercrural areas, accompanied by hypertelorism, cleft palate, micrognathia, ptosis of eyelids, and short stature. Skeletal abnormalities include camptodactyly, syndactyly, equinovarus, and rocker-bottom feet, as well as vertebral fusion and rib anomalies. Cryptorchidism is present in males and labia majora are absent in females
• lethal multiple pterygium syndrome : a lethal autosomal recessive disorder

Symptoms & signs : multiple pterygia, lung hypoplasia, flexion contractures of the limbs, characteristic facies, and other abnormalities.
• Marinesco-Sjögren syndrome : a hereditary syndrome transmitted as an autosomal recessive trait

Symptoms & signs : cerebellar ataxia, mental and somatic growth retardation, congenital cataracts, inability to chew, thin brittle fingernails, and sparse, incompletely keratinized hair.
• Mauriac syndrome

Symptoms & signs : dwarfism, hepatomegaly, obesity, and retarded sexual maturation, in association with diabetes mellitus
• May-White syndrome : a rare autosomal dominant syndrome

Symptoms & signs : myoclonus, cerebellar ataxia, and deafness
• PHPIA / McCune-Albright hereditary osteodystrophy : heterozygous inactivating mutations in the Ga_S gene that lead to a reduction by approximately 50% in activity/protein and thus explain, at least partially, the resistance toward TSH and other hormones (PTH) that mediate their actions through GPCR

Epidemiology : female-to-male ratio 6:1
Symptoms & signs : cafe-au-lait spots, osseous fibrocystic dysplasia, infantile primary hypothryoidism, pituitary adenomas, secondary hyperthyroidism, pseudohypoparathyroidism (PHP), secondary diabetes mellitus with hypoinsulinism
• Meckel-Gruber syndrome / dysencephalia splanchnocystica

Aetiology : autosomal recessive. MKS is genetically heterogeneous, with 3 loci mapped: MKS1, 17q21-24; MKS2, 11q13 and MKS3 (a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which pathogenic mutations for 5 MKS3-linked consanguineous families were identified. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995–amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin^ref)
Symptoms & signs : most frequently characterized by sloping forehead, posterior meningoencephalocele, bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and postaxial polydactyly, with death occurring in the perinatal period
• median cleft facial syndrome / frontonasal dysplasia : a hereditary form

Symptoms & signs : defective midline development of the head and face, including ocular hypertelorism, occult cleft nose and maxilla, and sometimes mental retardation or other defects
• megacystis-microcolon–intestinal hypoperistalsis syndrome (MMIHS)

Symptoms & signs : dilated bladder, microcolon with dilated small intestine, and hypoperistalsis, inherited as an autosomal dominant trait
• Melkersson-Rosenthal syndrome : an autosomal dominant condition usually beginning in childhood or adolescence

Symptoms & signs : chronic noninflammatory facial swelling, usually confined to the lips in the form of granulomatous cheilitis, with recurrent facial palsy and sometimes fissured tongue. Associated ophthalmic symptoms may include lagophthalmos, blepharochalasis, swollen eyelids, burning sensation of the eyes, corneal opacities, retrobulbar neuritis, and exophthalmos.
• inherited defect in cholesterol and nonsterol isoprene biosynthesis
• mevalonic aciduria was the first defect to be recognized^{ref1, ref2, ref3, ref4, ref5}.

Aetiology : autosomal recessive disease is caused by a severe deficiency of mevalonate kinase (residual activity, <1%) that results from a mutation in the mevalonate kinase gene^ref. Mevalonate kinase is ubiquitously expressed and plays a crucial role in the early stages of the isoprenoid biosynthesis pathway. The enzyme catalyzes the phosphorylation of mevalonic acid to 5-phosphomevalonate. The main end products include prenylated proteins, heme A, dolichol, ubiquinone (coenzyme Q-10), and cholesterol. As a result of mevalonate kinase deficiency, mevalonic acid accumulates and is excreted in the urine. Mutations in the same gene are also responsible for the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS)^{ref1, ref2}, an autosomal recessive disorder characterized by recurrent febrile attacks^ref. Classically, HIDS is not associated with dysmorphic features or neurologic impairment. In addition, mevalonic acid is excreted in the urine only during febrile attacks, and mevalonate kinase activity is less severely impaired in HIDS than in mevalonic aciduria (residual activity, >1%)^{ref1, ref2}. In a subgroup of patients with HIDS, neurologic abnormalities (e.g., mental retardation, ataxia, and epilepsy) may develop with increasing age^{ref1, ref2}. These findings suggest a continuum between mevalonic aciduria and HIDS. The two syndromes belong to the group of autoinflammatory syndromes, all of which are characterized by recurrent episodes of inflammation without major involvement of the adaptive immune system.
Symptoms & signs : the clinical manifestations of mevalonic aciduria are diverse^ref. Severely affected patients present from birth with failure to thrive, microcephaly, dysmorphic features, and neurologic involvement, including psychomotor retardation, cerebellar atrophy, ataxia, and progressive myopathy. A periodic fever syndrome with hepatosplenomegaly, lymphadenopathy, arthralgia, and rashes dominates the clinical picture from infancy. Severe polyarthritis and ocular involvement with retinal dystrophy and cataracts develop in some patients^ref.
Laboratory examinations : during the febrile episodes, the erythrocyte sedimentation rate, blood leukocyte counts, serum C-reactive protein levels, IgD and IgA₁ levels, and urinary leukotriene excretion are greatly increased. Despite a lack of residual mevalonate kinase activity in cultured cells from affected patients, plasma levels of cholesterol lipoprotein, apolipoproteins, steroid hormones, and primary bile acids are normal in most patients. This paradox is related to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and the LDL cholesterol receptor, which are key regulatory sites in the cholesterol pathway. In cultured skin fibroblasts from patients with mevalonic aciduria, the activities of HMG-CoA reductase and LDL cholesterol receptors are up-regulated, apparently as compensatory responses that ensure sufficient production of mevalonic acid and thus almost normal function of the pathway. The biosynthesis of coenzyme Q10, by contrast, is decreased in patients' fibroblasts, and there are decreased levels of coenzyme Q10 in plasma. These findings suggest that farnesyl pyrophosphate, an important intermediate at the branch point between sterol and isoprenoid biosynthesis, is shuttled toward cholesterol synthesis at the expense of isoprene biosynthesis. The cause of the inflammatory attacks is unclear. Mevalonic aciduria and HIDS trigger a dominance of T_h2, resulting in elevated levels of IL-4, IL-5, and IL-6, TNF-a, and immunoglobulins (hyper-IgD or hyper-IgE). Potential mechanisms by which mevalonate kinase deficiency might induce a T_h2 bias may reside within cell-signaling proteins and lipid rafts — assemblages of cholesterol and sphingolipids in the lipid bilayer. Recently, a link was shown between apoptosis and aberrant isoprenylation of proteins involved in cell-cycle regulation: the apoptosis that statin-induced mevalonate depletion induces in cultured cells could be inhibited with the addition of farnesyl diphosphate or geranylgeranyl diphosphate, both of which are cell-permeable isoprenoid analogues^ref. Urinary excretion of LTE₄ is elevated in most patients with mevalonic aciduria, and there is a positive linear correlation between this elevation and increased excretion of mevalonic acid. Increased urinary LTE₄ excretion suggests that there is increased total systemic cysteinyl leukotriene synthesis^ref. The cysteinyl leukotrienes — LTC₄, LTD₄, and LTE₄ — are lipid mediators that are generated in the 5-lipoxygenase pathway from arachidonic acid. The cysteinyl leukotrienes are believed to increase vascular permeability through the contraction of endothelial cells, which results in edema and hemoconcentration.
Prognosis is poor; > 50% of patients die during an inflammatory crisis in infancy or early childhood, and very few survive to adolescence^ref.
Treatment is mainly supportive. in patients with mevalonic aciduria, the attacks can be influenced only marginally, and the overall prognosis remains poor. Direct replacement of the end product (coenzyme Q10 or cholesterol) has failed to control the syndrome. Corticosteroid treatment is effective in diminishing the severity of attacks but cannot prevent crises. Treatment with simvastatin (an inhibitor of hydroxymethylglutaryl coenzyme A reductase, the enzyme that catalyzes the formation of mevalonic acid) worsened the clinical status of two patients with mevalonic aciduria^ref. The drug has also been tested recently in 6 patients with HIDS, 5 of whom had a reduction in the number of febrile days^ref. Anakinra, an interleukin-1–receptor antagonist, and TNF-a antagonists (e.g., etanercept) have also been used with a degree of success in patients with HIDS^ref. The mechanism by which mevalonate kinase deficiency causes recurrent episodes of fever and inflammation is unclear. Serum levels of proinflammatory cytokines increase during attacks, and mononuclear cells from patients with HIDS produce high levels of interleukin-1 after in vitro stimulation^ref. A 3-year-old boy with mevalonic aciduria whose condition had failed to improve with antiinflammatory treatment underwent allogeneic HSCT from an HLA-identical sister who was a heterozygous carrier of the mutant gene. Successful donor lymphohematopoietic engraftment resulted in correction of the immune function and in a clear decrease in inflammatory cytokines, a reduction in mevalonate excretion, and most important, a cessation of febrile attacks during a 15-month follow-up period^ref. The marked enlargement of the liver and the spleen resolved after the procedure, indicating that the hepatosplenomegaly was an effect of extramedullary hematopoiesis rather than a primary process in those organs. Although the results reported by Neven et al. are encouraging, and bone marrow transplantation may become an important therapeutic option for patients with mevalonic aciduria who have primarily inflammatory disease, important questions remain. Since the excretion of mevalonate derived from extramedullary sources remained high after the transplantation, it will be most important to know whether further neurologic disease, such as cerebellar atrophy or myopathy, develops. Concentrations of coenzyme Q10 and other isoprenoid derivatives may not increase sufficiently in other body tissues.
• Moynahan syndrome / progressive cardiomyopathic lentiginosis

Symptoms & signs : multiple symmetric lentigines, congenital mitral valve stenosis, dwarfism, genital hypoplasia, and mental retardation. Also a familial congenital syndrome consisting of delayed hair growth on the scalp, epilepsy, mental retardation, and unusual EEG.
• nail-patella syndrome / hereditary osteo-onychodysplasia : a hereditary syndrome

Symptoms & signs : dystrophy of the nails, absence or hypoplasia of the patella, hypoplasia of the lateral side of the elbow joint, and bilateral iliac horns
• Netherton's syndrome : a congenital autosomal recessive syndrome

Symptoms & signs : lamellar ichthyosis or ichthyosis linearis circumflexa, hair shaft defects, atopic diathesis, and sometimes mental retardation and aminoaciduria
• Neu-Laxova syndrome (NLS)

Symptoms & signs : diagnosis is made by ultrasonography at 32 wks of gestation. Ultrasonographic examination shows intrauterine growth retardation (IUGR), Dandy-Walker anomaly, choroid plexus cysts, receding forehead and microcephaly, bilateral cataract without prominent eyes, scalp edema with no generalized edema, retrognathia, curved penis, and flexion deformities of limbs. The findings can not fit any of Curry's 1982 groups.
• Noonan's syndrome 1 (NS1), autosomal dominant / Ullrich-Turner syndrome : the phenotype of Turner's syndrome (webbed neck, ptosis, hypogonadism, congenital heart disease, and short stature) without gonadal dysgenesis; formerly called male Turner's syndrome until the female counterpart was identified

Aetiology : mutations in PTPN11
• Noonan's syndrome 2 (NS2), autosomal recessive
• Norrie's disease / atrophia bulborum hereditaria : a congenital, X-linked disorder

Symptoms & signs : bilateral blindness from retinal detachment, hypoplasia, or dysplasia; and sometimes mental retardation and deafness developing later
• oculocerebrorenal syndrome / Lowe-Terrey-MacLachlan syndrome : an X-linked disorder

Symptoms & signs : vitamin D–refractory rickets, hydrophthalmia, congenital glaucoma and cataracts, mental retardation, and tubule reabsorption dysfunction as evidenced by hypophosphatemia, acidosis, and aminoaciduria
• oculomandibulofacial syndrome / Hallermann-Streiff-François syndrome / mandibulo-oculofacial dyscephaly

Symptoms & signs : dyscephaly (usually brachycephaly), parrot nose, mandibular hypoplasia, proportionate nanism, hypotrichosis, bilateral congenital cataracts, and microphthalmia
• Opitz-Frias syndrome / G syndrome / hypertelorism-hypospadias syndrome : an autosomal dominant syndrome

Symptoms & signs : hypertelorism and hernias, and in males hypospadias, cryptorchidism, and bifid scrotum. Cardiac anomalies, laryngotracheal malformations, imperforate anus, renal defects, lung hypoplasia, and downslanted palpebral fissures may also be present
• orofaciodigital syndrome I

Aetiology : X-linked dominant mode of transmission trait limited to females and lethal in males
Symptoms & signs : affects the maxillofacial region. Abnormally developed vestibular frenulum, cleft tongue, asymmetric cleft palate, pseudocleft of the upper lip and hypoplasia of the nasal cartilages are some of the other features. There are some malformations in foot and hand fingers and also mild mental deficiency is present^ref
• Ostrum-Furst syndrome

Symptoms & signs : congenital synostosis of the neck, platybasia, and Sprengel's deformity.
• Pallister-Killian syndrome (PKS) is a rare, sporadic, genetic disorder characterized by dysmorphic features, learning disability, and epilepsy. It is caused by a mosaic supernumerary isochromosome 12p (i[12p]). The i(12p) is rarely found in peripheral blood but it is present in skin fibroblasts. This chromosomal abnormality has been reported also in human germ cell tumors and a patient with Pallister-Killian syndrome and pineal tumor has been reported^ref
• pancreatic and cerebellar agenesis

Aetiology : 705insG and C886T mutations in PTF1A cause truncation of the expressed PTF1A protein C-terminal to the bHLH domain^ref
• Paas's disease : a familial disorder

Symptoms & signs : skeletal deformities such as coxa valga, shortening of phalanges, scoliosis, spondylitis, etc.
• Pai syndrome

Symptoms & signs : median cleft palate, cutaneous nasal polyp, and midline lipoma of the corpus callosum
• Papillon-Lefèvre syndrome : an autosomal recessive disorder occurring between the first and fifth years of life

Symptoms & signs : psoriasiform palmoplantar keratoderma, which may also involve the elbows, knees, tibias, external malleoli, and other areas; ectopic calcifications of the skull; and periodontitis and premature shedding of both the deciduous and permanent teeth.
• Pearson's syndrome : a rare congenital syndrome

Symptoms & signs : refractory sideroblastic anemia with vacuolization of bone marrow precursors and exocrine pancreatic insufficiency
Prognosis : most affected children die in infancy unless given transfusions.
• Pendred's syndrome : a hereditary syndrome

Symptoms & signs : congenital bilateral nerve deafness with development in middle childhood of goiter without hypothyroidism; the main biochemical feature is defective thyroxine biosynthesis.
• Perlman syndrome : a rare, lethal autosomal recessive syndrome^ref

Symptoms & signs : renal dysplasia, nephroblastoma, fetal gigantism, and hypertrophy of the islets of Langerhans with hyperinsulinism, multiple congenital anomalies and mental retardation
• Pierre Robin syndrome or anomalad : an autosomal recessive disorder

Symptoms & signs : brachygnathia and cleft palate, often associated with glossoptosis, backward and upward displacement of the larynx, and angulation of the manubrium sterni; cleft palate makes sucking and swallowing difficult, permitting easy access of fluids into the larynx. It may appear in several syndromes or as an isolated hypoplasia
• Poland's syndrome or anomaly

Symptoms & signs : unilateral absence of the sternocostal head of the pectoralis major muscle and ipsilateral syndactyly. It has been reported in association with lymphoreticular malignancies and some solid tumors (e.g. breast cancer).
• Polhemus-Schafer-Ivemark syndrome / asplenia syndrome

Symptoms & signs : congenital splenic agenesis, cardiac defects, and partial situs inversus viscerum
• polysplenia syndrome : a congenital syndrome

Symptoms & signs : multiple splenic masses, bilateral left-sidedness, abnormal position and development of visceral organs, complex cardiovascular defects, and abnormal, usually bilobate, lungs. It may be related to Ivemark's syndrome.
• popliteal pterygium or web syndrome : a congenital syndrome

Symptoms & signs : popliteal webs, cleft palate, lower lip pits, and dysplasia of the toenails; a wide variety of other abnormalities may be associated
• Proteus syndrome : a rare congenital disorder

Symptoms & signs : highly variable manifestations, including partial gigantism of the hands and feet with hypertrophy of the palms and soles, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly and other skull abnormalities, and abdominal or pelvic lipomatosis. The etiology is unknown, although a genetic origin, possibly of autosomal dominant transmission, has been conjectured.
• Richards-Rundle syndrome : a congenital syndrome

Symptoms & signs : ketoaciduria, mental retardation, underdevelopment of secondary sex characteristics, deafness, ataxia, and peripheral muscular wasting which progresses during childhood but eventually becomes static
• Rieger's syndrome

Symptoms & signs : Rieger's anomaly accompanied by hypodontia, anal stenosis, hypertelorism, mental deficiency, and agenesis of the facial bones
• Riley-Smith syndrome

Symptoms & signs : macrocephaly without hydrocephalus, multiple hemangiomas, and pseudopapilledema; presumed to be transmitted as an autosomal dominant trait.
• Roberts' syndrome : a hereditary syndrome, transmitted as an autosomal recessive trait

Symptoms & signs : imperfect development of the long bones of the limbs associated with cleft palate and lip and other anomalies
• Robinow's dwarfism or syndrome / fetal face syndrome

Symptoms & signs : dwarfism associated with increased interorbital distance, malaligned teeth, bulging forehead, depressed nasal bridge, and short limbs
• progressive facial hemiatrophy / hemifacial atrophy / Romberg's disease or trophoneurosis / facial trophoneurosis / Parry-Romberg syndrome

Aetiology : unknown, some hypothesize that involves borreliosis
Symptoms & signs : unilateral atrophy of the skin, subcutaneous tissue and the underlying bony structures of the face, frequently accompanied by pigmentation disorders and alopecia, jacksonian epilepsy, and trigeminal neuralgia; both sides of the face are occasionally affected and the ipsilateral trunk, viscera, and extremities are sometimes involved. This syndrome has many features of linear scleroderma 'en coup de sabre' but is distinguished by more extensive involvement of the lower face with only slight cutaneous sclerosis. The onset typically occurs in childhood or young adult years.
• pyridoxine-dependent seizures (PDS)

Aetiology : mutations in the ALDH7A1 gene, which encodes antiquitin
Pathogenesis : these mutations abolish the activity of antiquitin as a D¹-piperideine-6-carboxylate (P6C)–a-aminoadipic semialdehyde (a-AASA) dehydrogenase. The accumulating P6C inactivates pyridoxal 5'-phosphate (PLP) by forming a Knoevenagel condensation product
Laboratory examinations : measurement of urinary a-AASA provides a simple way of confirming the diagnosis of PDS and ALDH7A1 gene analysis provides a means for prenatal diagnosis^ref.
• Rosenberg-Bergstrom syndrome : an autosomal recessive syndrome

Symptoms & signs : hyperuricemia, renal insufficiency, ataxia, and deafness, probably due to deficiency of ribose-phosphate pyrophosphokinase.
• Rosenberg-Chutorian syndrome : a rare X-linked hereditary syndrome

Symptoms & signs : optic atrophy, progressive neural deafness, and polyneuropathy.
• Rosenthal-Kloepfer syndrome

Symptoms & signs : corneal leukomata, acromegaloid appearance, and cutis verticis gyrata.
• Rothmund-Thomson syndrome / poikiloderma congenitale : an autosomal recessive syndrome occurring principally in females

Symptoms & signs : reticulated, atrophic, hyperpigmented, telangiectatic cutaneous plaques, often accompanied by juvenile cataracts, saddle nose, congenital bone defects, disturbances in the growth of hair, nails, and teeth, and hypogonadism
• Rubinstein-Taybi syndrome : a congenital condition

Symptoms & signs : mental and motor retardation, broad thumbs and great toes, short stature, characteristic facies, including high-arched palate and straight or beaked nose, various eye abnormalities, pulmonary stenosis, keloid formation in surgical scars, large foramen magnum, and abnormalities of the vertebra and sternum.
• Rud's syndrome : congenital syndrome

Symptoms & signs : ichthyosis simplex, mental deficiency, epilepsy, and infantilism.
• Ruvalcaba's syndrome : brachymetapody, hypogenitalism, and retardation of unknown etiology but present from birth in males; it is characterized by microcephaly, skeletal abnormalities, hypoplastic genitalia, and mental and physical retardation.
• Schimmelpenning-Feuerstein-Mims syndrome (SFM syndrome) is a rare and variable multisystem defect consisting of congenital, extensive linear nevus sebaceus and associated abnormalities in different neuroectodermal organ systems
• chondrodystrophic myotonia / Schwartz-Jampel-Aberfeld syndrome : an autosomal recessive disorder characterized by myotonic myopathy, dwarfism, blepharophimosis, joint contractures, and flat facies
• Smith-Magenis syndrome

Aetiology : a microdeletion syndrome involving chromosome 17p11.2
Symptoms & signs : mental retardation, dysmorphic facial features, minor skeletal anomalies including brachydactyly or polydactyly and behavioural abnormalities, such as disturbed sleep pattern, restlessness and self-destructive behaviour.
• Virchow-Seckel dwarfism or syndrome / bird-headed dwarfism / microcephalic primordial dwarfism
• SCKL1

Aetiology : mutation in the gene encoding ataxia-telangiectasia and RAD3-related protein (ATR)
• SCKL2

Aetiology : ?
• SCKL3

Aetiology : ?
Symptoms & signs : intrauterine growth retardation and postnatal dwarfism with a small head, narrow birdlike face with a beaklike nose, large eyes with an antimongoloid slant, receding mandible, and mild mental retardation. It could affect many organ systems but renal involvement due to polyarteritis nodosa is uncommon
• renal-retinal Senior-Loken syndrome (SLSN) : nephronophthisis (NPHP) is the most frequent genetic cause of chronic renal failure in children. Identification of 4 genes mutated in NPHP subtypes 1-4 has linked the pathogenesis of NPHP to ciliary functions. 10% of affected individuals have retinitis pigmentosa, constituting the SLSN.

Aetiology : mutations in an evolutionarily conserved gene, IQCB1 (also called NPHP5), as the most frequent cause of SLSN. IQCB1 encodes an IQ-domain protein, nephrocystin-5. All individuals with IQCB1 mutations have retinitis pigmentosa. Nephrocystin-5 interacts with RPGR (retinitis pigmentosa GTPase regulator), which is expressed in photoreceptor cilia and associated with 10-20% of retinitis pigmentosa. Nephrocystin-5, RPGR and calmodulin can be coimmunoprecipitated from retinal extracts, and that these proteins localize to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Ciliary dysfunction has a central role in the pathogenesis of SLSN^ref
• Senter syndrome / keratitis-ichthyosis-deafness (KID) syndrome : a rare disorder

Symptoms & signs : lamellar ichthyosis, hyperkeratosis, and sensorineural deafness, sometimes with postnatal growth deficiency, variable alopecia, nail dystrophy, tooth malformations, decreased sweating, and inflammatory corneal vascularization
• Shwachman-Bodian-Diamond syndrome (SDS / SBDS) / congenital lipomatosis of pancreas

Epidemiology : described simultaneously in the USA and in Great Britain in 1964; rare; presenting in childhood
Aetiology : autosomal recessive inactivating mutations of the SBDS gene located on chromosome 7q11^ref. This highly conserved gene is widely expressed in most human cell types and encodes a 250 amino acid protein the function of which is unclear, although indirect genetic evidence suggests that SBDS may be involved in RNA processing^{ref1, ref2}. Mutant forms of other rRNA processing proteins are associated with other marrow failure syndromes, including DC and cartilage-hair hypoplasia. Whether the RNA-processing defect is directly linked with the hematopoietic or pancreatic phenotype is not yet known, and it is important that scientists working in the field evaluate potential non-RNA functions of the protein.
Symptoms & signs : bone marrow failure (classically neutropenia and less commonly anemia), exocrine pancreatic insufficiency with normal sweat chloride values, and metaphyseal dysostosis of the hips. There is also an increased relative risk of MDS and AML^ref. One of the 2 most common causes of pancreatic insufficiency in children, this disorder ordinarily presents in early childhood as failure-to-thrive. It can be associated with other congenital anomalies, prominently skeletal (rib and thoracic cage abnormalities), short stature, delayed puberty, developmental delays and learning disabilities, ichthyosis, liver dysfunction, dental caries and dysplastic teeth. Interestingly, while pancreatic insufficiency can improve later in life^ref, bone marrow failure persists and can be later accompanied by clonal evolution to MDS and AML.
Pathogenesis : PMNs are incapable of orienting in and chemotaxing up a spatial gradient of fMLP^ref
Laboratory examinations : hypoplastic granulopoiesis is the most reliable hematologic abnormality. In a series of 88 patients, 86 had neutropenia, only 36 (of 86) had anemia, 28 of 82 had thrombocytopenia, and pancytopenia was present in only 16 of 85^ref. Bone marrow biopsies are typically hypocellular. MDS was present in 10% and clonal abnormalities in 14%, but the lifetime risk of MDS/AML is unknown. There are reports of clonal cytogenetic abnormalities occurring in marrow cells resembling those seen in FA, commonly involving chromosome 7 but including chromosomes 1, 9, and 20^ref. As has been described anecdotally in patients with FA, some clonal chromosome abnormalities disappear over time. Naturally, the ascertainment of this type of cytogenetic information is on a macroscopic scale, so whether the mutant stem cell is entirely gone for good or merely quiescent (in which case its progeny would not be ascertained in the bone marrow sample but might reappear again later) is not yet known. It is fair to say that, in this disease, to date there is no clear prognostic value in the discovery of only one or two cytogenetic defects in a hematopoietic clone^ref. For selectively neutropenic children, evidence of pancreatic insufficiency (low serum trypsinogen and isoamylase, abnormal 72-hour fecal fat content) should clearly suggest the diagnosis. Patients may have fatty infiltration of the pancreas on sonogram, MRI or CT scans. For patients presenting with bone marrow failure, FA, DC and even DBA should be excluded. Genetic testing for SBDS mutations can be performed on DNA from buccal swabs or blood (blood as a source of DNA cannot be used if patients have had a stem cell transplant). Such testing involves bidirectional sequencing of the exons and intron/exon boundaries of exons 1 through 5 of the SDBS gene on chromosome 7q11. 75% of the alleles associated with SBDS represent gene conversion mutations involving an SBDS pseudogene. 90% of patients carry at least 1 converted allele and 60% carry 2. The majority of conversion events involve exons 2 and 3. Prenatal diagnosis is available.
• GeneDx
Therapy : supportive care, pancreatic enzyme replacement, G-CSF for severe neutropenia, and matched sibling stem cell transplantation are current standards of care for SDS. Because the disease is rare, the rationale for each of these approaches is empirical. As with FA and DC, somatic cell intolerance has resulted in poor transplant outcomes. Thus, transplant should be carefully considered on a case-by-case basis using carefully designed attenuated conditioning regimens. Regular hematologic, gastrointestinal, and orthopedic follow-up is required to monitor evolving clones, resolution of pancreatic insufficiency, and development of hip and knee dysfunction, respectively.
Web resources : Shwachman-Diamond Syndrome Foundation
• Silver-Russell dwarfism or syndrome

Symptoms & signs : low birth weight despite normal length of gestation, short stature, lateral asymmetry, and slight to moderate increase in excretion of gonadotropins, which may be associated with incurved fifth fingers, café-au-lait spots, syndactyly, triangular face, downturned corners of the mouth, and precocious puberty
• Simpson-Golabi-Behmel syndrome type 1 (SGBS1) / dysplasia gigantism syndrome, X-linked (DGSX) / bulldog syndrome

Aetiology : mutation in the gene for glypican-3 (GPC3)
Symptoms & signs : gigantism, mental retardation, Wilms' tumor, and craniofacial anomalies
• Simpson-Golabi-Behmel syndrome type 2 (SGBS2)
• Sjögren-Larsson syndrome (SLS)

Aetiology : autosomal recessive mutations in the ALDH3A2 gene (also known as FALDH and ALDH10) on chromosome 17p11.2 that encodes fatty aldehyde dehydrogenase (FALDH), an enzyme that catalyzes the oxidation of long-chain aldehydes derived from lipid metabolism. In SLS patients, 72 mutations have been identified, with a distribution that is scattered throughout the ALDH3A2 gene. Most mutations are private but several common mutations have been detected, which probably reflect founder effects or recurrent mutational events. Missense mutations comprise the most abundant class (38%) and expression studies indicate that most of these result in a profound reduction in enzyme activity. Deletions account for about 25% of the mutations and range from single nucleotides to entire exons. 12 splice-site mutations have been demonstrated to cause aberrant splicing in cultured fibroblasts. To date, > 12 intragenic ALDH3A2 polymorphisms consisting of SNPs and 1 microsatellite marker have been characterized, although none of them alter the FALDH protein sequence. The striking mutational diversity in SLS offers a challenge for DNA-based diagnosis, but promises to provide a wealth of information about enzyme structure-function correlations^ref
Symptoms & signs : mental retardation (congenital oligophrenia), ichthyosis, and spastic pyramidal symptoms (diplegia or tetraplegia)
• Smith-Lemli-Opitz syndrome : a hereditary syndrome, transmitted as an autosomal recessive trait,

Symptoms & signs : multiple congenital anomalies, including microcephaly, mental retardation, hypotonia, incomplete development of male genitalia, short nose with anteverted nostrils, and syndactyly of second and third toes
• Sneddon's syndrome : a rare condition

Symptoms & signs : cerebral arteriopathy and ischemia are accompanied by diffuse non-inflammatory livedo reticularis
• Sohval-Soffer syndrome : a congenital syndrome

Symptoms & signs : male hypogonadism associated with multiple skeletal abnormalities of the cervical spine and ribs and mental retardation
• Sorsby's syndrome : a congenital condition

Symptoms & signs : bilateral macular coloboma associated with apical dystrophy of the hands and feet, usually brachydactyly confined to the distal 2 phalanges.
• succinic semialdehyde dehydrogenase (SSADH) deficiency is one of the disorders of GABA metabolism

Aetiology : many mutations in the gene on chromosome 6p
Symptoms & signs : seizures occur as one of the symptoms in affected patients. Other features that are described include delayed development, hypotonia, myopathy with ragged red fibres, abnormal behaviour, and ocular abnormalities. Neonatal problems include prematurity, respiratory difficulties, and hypoglycaemia
Laboratory examinations : MRI examination can help if it shows abnormalities in the globus pallidus. It will be confirmed by finding an excess of 4-hydroxybutyric acid in the body fluids; and the methods of estimation are discussed. Prenatal diagnosis is possible using a combination of methods.
Treatment possibilities are limited. Vigabatrin should be of value as it is an inhibitor of GABA transaminase, but results have been disappointing. Symptomatic treatment may well be needed for control of seizures, abnormal behaviour and other disorders; and special educational needs must be served.
• thrombocytopenia–absent radius (TAR) syndrome : an autosomal recessive syndrome

Symptoms & signs : thrombocytopenia associated with absence or hypoplasia of the radius and sometimes congenital heart disease and renal anomalies
• Tonoki syndrome

Symptoms & signs : microcephaly, short stature, type B brachydactyly, nail dysplasia, skeletal anomalies, and mental retardation.^ref
• Townes' syndrome : an autosomal dominant syndrome

Symptoms & signs : auricular anomalies, anal defects, limb and digit—particularly thumb—anomalies, and renal deficiencies; it occasionally includes cardiac disease, deafness, or cystic ovary.
• trichorhinophalangeal syndrome : an autosomal recessive syndrome

Symptoms & signs : sparse, slowly growing hair, pear-shaped nose with high philtrum, and brachyphalangia with deformity of the fingers and wedge-shaped epiphyses. Up to 50% of individuals may have Perthes-like hip changes
• trismus-pseudocamptodactyly syndrome : a rare autosomal dominant disorder

Symptoms & signs : inability to open the mouth fully, facultative camptodactyly resulting from shortened finger-flexor tendons, and short stature.
• Ullrich-Feichtiger syndrome

Symptoms & signs : a condition of micrognathia, hexadactyly, and genital abnormalities, with depressed nose, small eyes, hypertelorism, and protuberant ears, along with other defects.
• Van der Woude's syndrome : an autosomal dominant syndrome

Symptoms & signs : cleft lip with or without cleft palate, with cysts of the lower lip.
• DiGeorge syndrome (DGS) / thymic aplasia or hypoplasia and pharyngeal pouch syndrome (DiGeorge AM. Congenital absence of the thymus and its immunological consequences concurrence with congenital hypoparathyroidism. Birth Def.Orig.Abstr.Ser 4:116-121 (1968)^{ref1, ref2})

Aetiology : a hemizygous deletion in chromosome 22q11.2 is found in 60-70% of patients^{ref1, ref2}. This deletion removes 24 genes, of which TBX1 seems the most important, causing a decrease in VEGF₁₆₄ levels. Other deleted genes are :
• DGCR1
• DGCR2
• DGCR5 (non coding)
• DGCR6
• DGCR7
• DGCR8
• DGCR9
• DGCR10
• DGCR11
• DGCR12
• DGCR13
• DGCR14
• guanine nucleotide binding protein (G protein), beta polypeptide 1-like
• goosecoid-like
• HIR histone cell cycle regulation defective homolog A
• leucine-zipper-like transcriptional regulator, 1
• mitochondrial ribosomal protein L40
• proline dehydrogenase (oxidase) 1
• peanut-like 1
In rare instances, patients are hemizygous for 10p13, which encodes DGS2^ref. Deletion in the UFD1L gene at 22q11 has been described^ref. The term complete DiGeorge syndrome is used to describe patients with the syndrome who have profound T-cell deficiency^{ref1, ref2, ref3, ref4, ref5}. VEGF -1154A SNP is a modifier in determining the susceptibility of DiGeorge patients to cardiovascular defects.
Pathogenesis : defective development of the third and fourth pharyngeal pouches
Symptoms & signs : congenital hypoplasia or aplasia of the thymus and parathyroid glands, often associated with congenital heart defects, anomalies of the great vessels, esophageal atresia, and abnormalities of facial structures. Depending on the degree of parathyroid and thymic hypoplasia, there is hypocalcemic tetany or seizures due to lack of PTH and deficiency of T lymphocytes resulting in increased susceptibility to low-grade or opportunistic pathogens, e.g., fungi, viruses, and Pneumocystis carinii
Laboratory examinations : the spectrum of T-cell abnormalities is quite broad, ranging from profound and life threatening to non-existent defects. 7.7% have a complete IgA deficiency, 30.7% have minor immunoglobulin abnormalities, and 38% have an impaired production of specific antibodies. 38% has recurrent infections. Interestingly, peripheral CD27⁺ B cells are reduced compared with age-matched healthy controls, and this decrement was statistically significant for IgM⁺ IgD⁺ CD27⁺ B cells. Immunoglobulin abnormalities are associated with the occurrence of recurrent infections^ref.
Therapy :
• HSCT :
• in 2 patients, HLA-identical bone marrow transplantation successfully restored T-cell function by adoptive transfer of mature T cells^{ref1, ref2}
• immune reconstitution was reported after transplantation of peripheral-blood mononuclear cells (PBMCs) in one patient^ref
• thymic transplantation :
• in a few cases, transplantation of fetal thymus was followed by immune reconstitution^{ref1, ref2, ref3, ref4}. However, some of those patients had partial DiGeorge syndrome with detectable T-cell function before transplantation and might have improved without therapy^{ref1, ref2}. Most published trials of postnatal thymus transplantation have been unsuccessful^{ref1, ref2, ref3}. Transplantation of bone marrow stem cells has not been successful^ref
• allogeneic, cultured, postnatal thymus tissue in 5 patients  can restore normal immune function. Early thymus transplantation — before the development of infectious complications — may promote successful immune reconstitution^ref
• velocardiofacial syndrome (VCFS) / Shprintzen's syndrome : an autosomal dominant syndrome

Aetiology : abnormalities of chromosome 22
Symptoms & signs : cardiac defects and characteristic craniofacial abnormalities including cleft palate, jaw abnormalities, and prominent nose. Learning disabilities occur often; short stature, slender hyperextensible hands and digits, scoliosis, mental retardation, inguinal hernia, auricular abnormalities, and microcephaly occur less frequently
• Klein-Waardenburg's syndrome / acrocephalosyndactyly type IV : an autosomal dominant disorder

Symptoms & signs : wide bridge of the nose due to lateral displacement of the inner canthi and puncta, pigmentary disturbances, including white forelock, heterochromia iridis, white eyelashes, leukoderma, and sometimes cochlear deafness.  Also an autosomal dominant disorder characterized by acrocephaly, orbital and facial deformities, and brachydactyly with mild soft tissue syndactyly; cleft palate, hydrophthalmos, cardiac malformation, and contractures of the elbows and knees may also be present
• Duane retraction syndrome
• type 1
• type 2
• Waardenburg's syndrome : A defect in neural crest cell migration and melanin synthesis may be responsible for the heterochromia iridis
• type 1 (WS1) is an autosomal dominant disorder characterized by deafness, dystopia canthorum, heterochromia iridis, white forelock, and premature greying. A similar phenotype is caused in the mouse by mutations in the Pax-3 gene. This observation, together with comparisons of conserved syntenies in the murine and human genetic maps, suggested that at least some WS1 mutations should occur in HuP2, the probable human homolog of Pax-3. Two mutations in the HuP2 sequence of individuals with WS1 have been reported recently. Both of them occur in the highly conserved paired box region of the gene, which encodes a DNA binding domain. The functional consequences of these mutations are at present speculative. We report here a 14 bp deletion in the paired domain encoded by exon 2 of HuP2 in an Indonesian family segregating for WS1. This frameshift mutation results in a premature termination codon in exon 3. The HuP2 product is a truncated protein lacking most of the paired domain and all of the predicted homeo domain. The WS1 phenotype in this family is due to loss of function of HuP2 and discuss two mechanisms for the dominant effect of this mutation^ref.
• type 2A (WS2A)
• type 2B (WS2B)
• type 2C (WS2C)
• type 2D (WS2C)
• type 3 (WS3)
• Wilms' tumor, aniridia, genitourinary abnormalities or gonadoblastoma, and mental retardation (WAGR) syndrome / Miller syndrome

Aetiology : small interstitial deletion of the p13 region of chromosome 11 (familial inheritance in 1% of cases)
• Walker-Warburg syndrome / Walker's lissencephaly / HARD syndrome / Warburg's Micro syndrome : a congenital syndrome, usually fatal before the age of 1 year

Aetiology : homozygous inactivating mutations in RAB3GAP, encoding RAB3 GTPase activating protein, a key regulator of the Rab3 pathway implicated in exocytic release of neurotransmitters and hormones
Pathogenesis : failure of exocytic release of ocular and neurodevelopmental trophic factors.
Symptoms & signs : hydrocephalus, agyria, various ocular anomalies such as retinal dysplasia, corneal opacity, or microphthalmia, and sometimes an encephalocele, microgenitalia
• Weill-Marchesani syndrome / dystrophia mesodermalis congenita hyperplastica / Marchesani's syndrome / spherophakia-brachymorphia syndrome : a congenital disorder of connective tissue transmitted as an autosomal dominant or recessive trait

Symptoms & signs : brachycephaly, brachydactyly, short stature with a broad chest and heavy musculature, reduced joint mobility, spherophakia, ectopia lentis, myopia, and glaucoma
• Weyers' oligodactyly syndrome : a congenital syndrome

Symptoms & signs : deficiency of the ulna and ulnar rays, antecubital pterygia, reduced sternal segments, malformations of the kidney and spleen, and cleft lip and palate
• leukoencephalopathy with vanishing white matter (VWM) / childhood ataxia with central nervous system hypomyelinization (CACH) / vanishing white matter leukodystrophy / Cree leukoencephalopathy (CLE) / ovarioleukodystrophy

Aetiology : mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. VWM leukodystrophy with ovarian failure, or ovarioleukodystrophy, is caused by mutations in the EIF2B2, EIF2B4, and EIF2B5 genes
• mutations in translation initiation factor 2B (eIF2B). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generatedin vitro. In contrast, few GFAP⁺ astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy^ref.
• Williams-Beuren syndrome (WS) / elfin facies syndrome

Epidemiology : prevalence = 1 every 20,000
Aetiology : the Williams syndrome transcription factor (WSTF) is targeted to replication foci through direct interaction with the DNA clamp PCNA, an important coordinator of DNA and chromatin replication. WSTF, in turn, recruits imitation switch (ISWI)-type nucleosome-remodelling factor SNF2H to replication sites. These findings reveal a novel recruitment mechanism for ATP-dependent chromatin-remodelling factors that is fundamentally different from the previously documented targeting by sequence-specific transcriptional regulators. RNAi-mediated depletion of WSTF or SNF2H causes a compaction of newly replicated chromatin and increases the amount of heterochromatin markers, including HP1. This increase in the amount of HP1 protein is mediated by progression through S phase and is not the result of an increase in HP1 mRNA levels. The WSTF–ISWI complex has a role in the maintenance of chromatin structures during DNA replication^ref.
Symptoms & signs : supravalvular aortic stenosis, mild to moderate mental retardation, elfin facies, transient hypercalcemia in infancy, high proficiency in language skills, social drive and musical ability
Laboratory examinations : isolated, thickened cortical region in language areas at MRI^ref
• Williams-Campbell syndrome

Symptoms & signs : congenital bronchomalacia and bronchiectasis, resulting from absence of annular cartilage distal to the first division of the peripheral bronchi
• Winter's syndrome : a congenital syndrome

Symptoms & signs : renal hypoplasia or aplasia, anomalies of the internal genitalia, especially vaginal atresia, and anomaly of the ossicles of the middle ear
• Witkop's syndrome / tooth-and-nail syndrome is a rare autosomal dominant

Symptoms & signs : ectodermal dysplasia manifest by defects of the nail plates of the fingers and toes and hypodontia with normal hair and sweat gland function^ref
• Wolfram syndrome / DIDMOAD syndrome : an autosomal recessive syndrome, first evident in childhood,

Symptoms & signs : diabetes mellitus, diabetes insipidus, optic atrophy, and neural deafness
• Wright's syndrome

Symptoms & signs : multifocal areas of osteitis fibrosa, patchy cutaneous pigmentation, and precocious puberty
• Wyburn-Mason's syndrome

Symptoms & signs : arteriovenous aneurysms on one or both sides of the brain, with ocular anomalies, especially in the retina, facial nevi, and sometimes mental retardation
• collagen diseases / collagenopathies
• Ehlers-Danlos syndrome (EDS) / cutis hyperelastica / dermatosparaxis / cutaneous asthenia : a group of inherited disorders of the connective tissue, occurring in at least 10 types, I to X, based on clinical, genetic, and biochemical evidence, varying in severity from mild to lethal, and transmitted genetically as autosomal recessive, autosomal dominant, or X-linked recessive traits. The biochemical defects are known for several types
• type 1 : lack of collagen a₁(V) gene (COL5A1), the collagen a₂(V) gene (COL5A2), or the collagen a₁(I) gene (COL1A1)
• type 2, mild classic type : lack of COL5A1 or COL5A2
• type 3, benign hypermobility syndrome : lack of COL3A1 or tenascin-XB (TNXB)
• type 4, autosomal dominant / arterial, vascular or ecchymotic Sack-Barabas type : lack of type III collagen (COL3A1)
• type 5 : lack of ?
• type 6 : prominent ocular manifestations, is caused by a deficiency of lysyl hydroxylase (PLOD)
• type 6A or 7, autosomal dominant / arthrochalasis multiplex congenita / kyphoscoliotic or arthroscoliotic type : lack of lysyl hydroxylase (PLOD); multiple joint dislocations, is caused by mutations involving the normal cleavage sites of some procollagen chains
• arthrochalasia type (EDS VIIA and VIIB)
• dermatosparaxis type (EDS VIIC).
• type 8, periodontosis type : lack of ?
• type 9 / X-linked cutis laxa / occipital horn syndrome (OHS) : lack of ATP7A as in Menkes disease
• type 10, with platelet dysfunction from fibronectin abnormality : functionally abnormal fibronectin
• type 11 (formerly) / familial joint instability syndrome / articular hypermobility syndrome : lack of ?
• autosomal dominant, Friedman-Harrod type unspecified : lack of
• due to tenascin-X deficiency :  due to a defect in fibronectin that interferes with normal platelet aggregation
Symptoms & signs : hyperextensible skin and joints (Gorlin's sign : the ability to touch the tip of the nose with the tongue), easy bruisability, friability of tissues with bleeding and poor wound healing, calcified subcutaneous spheroids, and pseudotumors; variably present in some types are cardiovascular, gastrointestinal, orthopedic, and ocular defects.
Web resources :
• Ehlers-Danlos disease at Medicine Net
• Ehlers-Danlos disease at Arthritis Foundation
• Ehlers-Danlos National Foundation (EDNF)
• osteogenesis imperfecta (OI) congenita (OIC) / osteopsathyrosis congenita / brittle bone disease

Aetiology : a collagen disorder due to defective biosynthesis of type I collagen. There are 4 major types (I–IV) plus variants of OI. Sillence classification :
• type I / osteogenesis imperfecta with blue sclerae / osteogenesis imperfecta tarda / Adair Dighton's, Eddowes', Ekman's, Lobstein's, Spurway's, and van der Hoeve's syndrome : the classic, most common, mildest type, autosomal dominant
• type II / Porak-Durante syndrome : the perinatal lethal type, has at least 3 clinical and genetic subtypes :
• autosomal dominant / osteogenesis imperfecta congenita, neonatal lethal form, and lethal perinatal OI
• autosomal recessive / osteogenesis imperfecta congenita / Vrolik type of osteogenesis imperfecta / Vrolik's disease / lethal perinatal OI
• autosomal dominant new mutation
• type 2/3, with abnormality of type I collagen : lack of
• type III / osteogenesis imperfecta, progressively deforming, with normal sclerae : the progressive deforming type, may be autosomal recessive or a new mutation
• type IV / osteogenesis imperfecta with normal sclerae : an autosomal dominant form
• progressively deforming, with normal sclerae : lack of
• with opalescent teeth : lack of
• with opalescent teeth, blue sclerae, and wormian bones, but without fractures : lack of
• with unusual skeletal lesions : lack of
• with microcephaly and cataracts : lack of
Symptoms & signs : brittle, osteoporotic, bones => fractures every 2-3 cm, growth retardation, no walking, hypoacusia. Other defects that may appear include blue sclerae, wormian bones, lax joints, and dentinogenesis imperfecta. OI is variable in manifestation and severity and has great molecular, genetic, and clinical heterogeneity.
Therapy : HLA-mismatched fetal mesenchymal stem cells (MSCs) transplantationin utero.
• Marfan syndrome (MFS)

Aetiology : autosomal dominant mutations in fibrillin 1 => dysregulation of either the gene for TGF-b receptor 1or that for TGF-b receptor 2
Symptoms & signs : dolichostenomelia and arachnodactyly, as well as the pectus excavatum and pectus carinatum (due to represent excessive longitudinal growth of tubular bones in the limbs, fingers, and ribs), subluxation of the lens, cardiovascular abnormalities (commonly aneurysm of the ascending aorta), vertebral column deformity (scoliosis and thoracic lordosis), wide-set eyes, a cleft palate or split uvula. In these patients, the aorta breaks at a much smaller size than it does in people with Marfan syndrome or other causes of aneurysm, making identifying these patients critical. The syndrome-defining traits can have a wide range of severity, and some other abnormalities, including congenital heart and brain defects and skeletal abnormalities such as early fusion of the bones of the skull or curvature of the spine
Web resources : The William S. Smilow Center for Marfan Syndrome Research at the Johns Hopkins University School of Medicine
• Marfan-like connective tissue disorder : lack of
• pseudoxanthoma elasticum : lack of
• Menkes disease / kinky- or steely-hair syndrome : a X-linked recessive abnormality in copper absorption due to mutations in ATP7A

Symptoms & signs : sparse brittle twisted scalp hair, severe cerebral degeneration, and arterial changes with death in infancy
• Wilson disease / hepatolenticular degeneration or disease / familial hepatitis / Westphal-Strümpell disease or pseudosclerosis / amyostatic syndrome : mutations in ATP7B

Epidemiology : late-onset homozygous cases have been reported^ref
Pathogenesis : impaired copper excretion by liver causes copper accumulation in liver (up to 1 mg/g of dry tissue, 40-folds the normal value), encephalus (lenticular nucleus > pons, medulla oblungata, thalamus, cerebellum, and cerebral cortex), and other organs
Symptoms & signs (onset near adolescence) :
• hepatopathy
• acute hepatitis
• parenchymal liver disease (subacute or after acute hepatitis, with histology and clinic similar to chronic active hepatitis or liver cirrhosis)
• liver cirrhosis
• fulminating hepatitis
• Kayser-Fleischer ring in Descemet's membrane of cornea
• intentional and resting tremors, spasticity, stiffness, chorea, sialorrhea, dysphagia, dysarthria, Babinski reflex, headache, schizophrenia, maniac-depressive psychoses, classical nevroses
• primary amenorrhea or secondary amenorrhea, relapsing spontaneous abortion (copper excess in uterine secretions)
Laboratory examinations :
• Opalski cells
• type II Alzheimer's cells (giant astrocytes with large, prominent nuclei found in the brain)
• glycosuria
• hemolytic anemia and thrombocytopenia as the initial manifestation^ref
Therapy :
• copper chelators
• zinc acetate or gluconate (150 mg/die)
• liver transplantation for fulminating hepatitis + Coombs^- hemolytic anemia or progressive liver failure
• 50% of patients present with hepatic disturbance^ref. Acute hepatic failure tends to be fulminant when it is associated with Coombs^- hemolytic anemia^ref; patients can survive for only days or weeks unless liver transplantation is performed^ref. Plasma exchange has proven effective^ref
• primary (hereditary or idiopathic) hemochromatosis : an autosomal recessive disorder of iron metabolism
• milder type 1 (HFE1) / classical hemochromatosis

Aetiology : mutations in
• HFE / HLA-H C282Y (a gene tightly linked to the A locus of the HLA complex on chromosome 6) => deficient hepcidin response
• hepcidin (more severe form)
Epidemiology : penetrance of the homozygous HFE mutation : the C282Y mutation of the HFE gene is a very common one. . This gene mutation can be traced back several centuries in Celtic history, and the disease has now spread to become the most common inherited disease in the Western world. About 15% of the northern European population is heterozygous; accordingly, one would expect over 1 per 250 in the population to be homozygous, and this is, indeed, the case.
• biochemical penetrance : relatively few studies have been conducted in which an unbiased population was screened for the C282Y mutation and the transferrin saturation and ferritin levels of the homozygotes were determined. Deugnier et al^ref screened over 9000 individuals (3367 men and 6029 women) in France and found 10 homozygous men and 44 homozygous women. Although the population was relatively young, 80% of the men had transferrin saturations over 55%, and 44% of the women had transferrin saturations > 50%. In a study of patients in the health appraisal clinic of Kaiser Permanente in San Diego, that among 152 homozygotes, 75% of men and 40% of women had a transferrin saturation > 50%^{ref1, ref2, ref3}. Serum ferritin levels were increased in 76% of the men and 54% of the women. In another small study all 5 homozygotes detected have transferrin saturations > 55%^ref. Thus, there is agreement that homozygotes for the HFE C282Y mutation usually have increased serum transferrin saturation levels and increased serum ferritin levels. Clearly, there is a subset of homozygotes who do not show these biochemical stigmata. A few of these prove to be frequent blood donors, but most of them are not. It is simply that even on a biochemical level the homozygous state is not always expressed.
• clinical penetrance : clinicians do not encounter many cases of full-blown hemochromatosis. Most of the many patients that have been diagnosed as having hemochromatosis have been diagnosed on the basis of biochemical changes and non-specific symptoms, such as fatigue and arthropathy. Neither common clinical experience^{ref1, ref2} nor autopsy series^{ref1, ref2, ref3} (MacSween RNM, Scott AR. Hepatic cirrhosis: A clinicopathological review of 520 cases. J Clin Pathol. 1972;26: 936) suggest that hemochromatosis is a common cause of death. However, it has been a common belief that milder symptoms are, in contrast, very common in patients homozygous for the C282Y mutation, and it has been suggested that most of the homozygous males will develop symptoms by the time they are 40 years of age^ref. This impression that a mild phenotype exists (and the accompanying assumption that this leads to the more severe phenotype if not treated) has been based largely on uncontrolled observations in which the patients being assessed and the physician performing the assessment knew the diagnosis and could well have been influenced by it. Between 1998 and 2001 there was the opportunity for the first time to study a large population, genotyping 26,000 participants for the HFE mutations and comparing symptoms, laboratory findings, and survival in homozygotes for the HFE C282Y mutation, C282Y/H63D compound heterozygotes, and homozygous wildtype individuals (Beutler E, Ho N, Gelbart T. Low clinical penetrance of homozygotes for hemochromatosis detected in a health screening clinic. Blood. 2000;96:484a),. Although many homozygotes manifested the non-specific symptoms that are associated with hemochromatosis—fatigue, arrhythmias, impotence, and arthralgias—the prevalence of such symptoms proved to be no higher than those in homozygous wildtype controls. There was no demonstrable effect on lifespan. The only significant difference found between homozygotes for the C282Y mutation and controls was a higher prevalence of abnormal liver function tests. Upon completion of the study^{ref1, ref2, ref3}, the preliminary findings were confirmed. Only one of 152 homozygotes had the typical clinical syndrome of hemochromatosis and we estimated the clinical penetrance of the homozygous state to be of the order of 1%. Symptoms and laboratory findings in white homozygotes for the C282Y mutation (light bars) and in wildtype controls (heavy bars). Adapted from the data of the Kaiser/Scripps study^ref


No one had expected the penetrance to be so low, and predictably, the results were greeted with considerable skepticism. In attempting to reconcile these data with the concept that the homozygous state had a much higher penetrance, it was suggested that the data were "flawed" in a number of respects. It was proposed that researchers were dealing with an unusually healthy population^ref or a population with an extraordinarily healthy life style. Alternatively, it was proposed that the population was unusually "sickly" and that the manifestations of hemochromatosis had been obscured by the poor health of the controls^ref. Obviously it is impossible to reconcile these two objections: the population cannot be too well and too sickly at the same time. But, in fact, neither criticism applies. The most cogent objection was that the study was biased by selecting a healthy population. If, indeed, patients with symptoms had been excluded because they did not attend a health appraisal clinic, having died or being taken care of in a more intense medical setting, researchers might have erroneously concluded that the penetrance of the homozygous state is very low. But there is a straightforward way to address this problem. If homozygotes were systematically excluded then the number found in the population should fall short of the number predicted by the Hardy-Weinberg equilibrium based on the gene frequency in the population. But in fact, the number of homozygotes actually exceeds the predicted number^{ref1, ref2, ref3, ref4, ref5, ref6}. Another way to examine the possible lethal effect of the hemochromatosis mutation is to examine the age distribution of homozygotes. Since hemochromatosis is a late-onset disease, one would expect underrepresentation of the homozygous genotype in the elderly if the disease caused an appreciable number of early deaths. No significant shift in age distribution has been observed. In fact, extensive meta-analysis of 161 publications giving gene frequency data and the number of homozygotes in each population confirms these results (J Waalen et al, unpublished). Numerous studies from different parts of the world have all confirmed these findings: the homozygous state is only rarely associated with illness^{ref1, ref2, ref3, ref4, ref5, ref6}. The percentage of homozygotes for the C282Y mutation (genotypic homozygotes) and of subjects with persistently elevated transferrin saturation and ferritin (phenotypic homozygotes) who consider themselves to be in less than good or excellent health. Based on the data from Åsberg et al^ref) :

Why, then, is there a controversy about the penetrance of hemochromatosis? One issue that seems to have muddied the waters is the interpretation of non-specific symptoms such as fatigue, joint pains or impotence. Suggestions that symptoms are common come from uncontrolled studies in which the subjects knew their diagnosis^{ref1, ref2}. But to be meaningful the history must be elicited before the patient has been informed of the diagnosis and must be compared with age, sex and ethnically matched wildtype controls. Studies that have been carried out in this manner show that no symptoms are statistically significantly more common in homozygotes than controls in any study^{ref1, ref2}. The only possible exception is a small French study in which 7 of 10 male homozygotes complained a fatigue, a number that was statistically significant, but had not been corrected for multiple comparisons^ref. The other issue is the significance of the abnormality in liver function tests and biopsy interpretations in homozygotes. The reading of liver biopsies is subject to observer bias and, unfortunately, there are never control biopsies with which to compare the patient cohort. Nonetheless, there is considerable consistency in the data. Olynyk^ref reported that of 16 homozygotes (of whom two refused biopsy) 3 had fibrosis, and one alcoholic subject had cirrhosis (25%). Bulaj^ref found 16 patients with cirrhosis and 17 with fibrosis out of 210 homozyotes (15%), and Åsberg et al^ref found 12 of an estimated 400 homozygotes had fibrosis or cirrhosis (3%). 8.2% had elevated SGOT levels compared to 3.2% of controls. Serum collagen IV levels, considered a surrogate for hepatic fibrosis, were elevated in 25.8% of the homozygotes in our study compared with only 11.1% of matched controls. Notably, the elevated liver function tests were not age-related. Thus, all of the data, including our own (except for a small French study that found 3/54 [5.5%] homozygotes had elevated ALT levels, compared to 5% in controls^ref), indicate that there is a subset of patients, considerably > 1% who have abnormal liver function tests. Those who hold that the penetrance of hemochromatosis is > 1% estimate can point to the presence of hepatic fibrosis as an indication that iron overload is clinically important. Since the fibrosis did not produce any clinical symptoms in the vast majority of subjects, and that it does not appear progressive, it is not important for the person to whom it should matter the most, the patient. Thus, to some degree the disagreement about penetrance comes down to the single issue of whether hepatic fibrosis seen on liver biopsy by pathologists or abnormal liver function is important if it is not associated with measurable morbidity or mortality.
• penetrance of the compound heterozygous C282Y/H63D HFE mutation : on the average, compound heterozygotes manifest significantly higher transferrin saturations and serum ferritin levels than do individuals with the wildtype genotype. Because the H63D mutation is very prevalent in the population, this compound heterozygous genotype is very common in the population. Among patients who had been classified as having "hemochromatosis" on the basis of increased biochemical parameters there is an increased number of compound heterozygotes, and it has been calculated that the biochemical penetrance of this genotype is only about 1% of that of the homozygous genotype^ref. Accordingly, patients with this genotype who develop severe cirrhosis and other clinical manifestations of hemochromatosis are very rare.
• penetrance of the simple heterozygous genotype : it is clear from large studies that simple heterozygotes for the C282Y or H63D mutations have, on the average, very slightly higher transferrin saturations and ferritin levels than do homozygotes for the wildtype. Numerous claims have been made that these minor changes translate into increased prevalence of a variety disorders including diabetes^{ref1, ref2}, heart disease^{ref1, ref2}, and cancer^{ref1, ref2}. None of these claims has been widely substantiated^{ref1, ref2, ref3, ref4}, and it seems unlikely that the heterozygote for these common mutations suffers ill health because of them with one notable, rather uncommon exception. Carrying either the C282Y or H63D does appear to be a risk factor for porphyria cutanea tarda^{ref1, ref2}. In general, however, it is much more likely that mutations that have gained a high prevalence in the genome have a beneficial effect, i.e., that they constitute a balanced polymorphism. Their beneficial effect is probably that of preventing iron deficiency in women^{ref1, ref2}.
Pathogenesis : HFE C282Y is an example of a mutant protein that does not fold correctly, is retained in the endoplasmic reticulum, and was found previously to diminish surface expression of MHC class I (MHC-I). We now show that its expression in 293T cells triggers an unfolded protein response (UPR), as revealed by the increased levels of H chain binding protein, GRP94, and C/EBP homologous protein. Elevated levels of these proteins were also found in HFE C282Y homozygous PBMCs. Following the UPR induction, a decrease in MHC-I cell surface expression was observed. This defect in MHC-I could be mimicked, however, by overexpression of transcriptionally active isoforms of activating transcription factor-6 and X box-binding protein-1, which induced the UPR, and reversed in HFE C282Y-expressing cells by using dominant-negative constructs that block UPR signaling. The present results provide evidence to the finding that stimulation of an UPR affects MHC-I expression^ref
• type 2 (HFE2) / juvenile hemochromatosis (JH) : early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s.
• chromosome 1q-linked
• abnormality of hepcidin
Aetiology : mutations in HFE2 / hemojuvelin (whose expression is restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism; G320V in 66%) that down-regulate hepcidin expression
• type 3 (HFE3) : an autosomal recessive disorder caused by mutation in the gene encoding transferrin receptor-2 (TFR2)
• type 4 (HFE4) : an autosomal dominant disorder caused by mutation in the SLC11A3 / ferroportin (includes some cases of African iron overload^{ref1, ref2}). Most patients develop iron loading of Kupffer cells with relatively low saturation of plasma transferrin, but others present with high transferrin saturation and iron-loaded hepatocytes. Known human mutations introduced into mouse Fpn-GFP generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. Studies using coimmunoprecipitation of epitope-tagged Fpn and size-exclusion chromatography demonstrated that Fpn is multimeric. Both WT and mutant Fpn participate in the multimer, and mutant Fpn can affect the localization of WT Fpn, its stability, and its response to hepcidin. The behavior of mutant Fpn in cell culture and the ability of mutant Fpn to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes^ref.
• African iron overload
• neonatal or perinatal hemochromatosis : a rare fulminant disease of the liver, of unknown cause, characterized by massive deposition of iron in the liver, pancreas, heart, and endocrine glands; symptoms are those of neonatal hepatitis and appear in utero or within the first week of life, with death usually occurring by 4 months of age.
Symptoms & signs and Laboratory examinations : appearing usually in the fifth or sixth decades of life; see hemochromatosis
Web resources : HFE gene and hereditary hemochromatosis at CDC
• congenital atransferrinemia : lack of transferrin
• trimethylaminuria
  

• cancersyndromes : early onset, multifocal, bilateral. TGFBR1*6A gene is prevalent in around 15-16% of the cancer patients and is found in around 10% of the general population. People with 2 copies of the mutated gene have double this risk. By contrast BRCA1 and BRCA2, which are thought to account for between 5% and 10% of breast cancer cases, are found in 1 in 500 people. In normal cells it inhibits their growth : however, once a cell becomes cancerous it accelerates their growth. TGFRB1-6A gene may be to blame for 7% of all breast cancers, nearly 11% of all ovarian cancers and 5.5% of all colon cancers. It is less commonly involved in a range of other cancers.
• inherited autosomal recessive inactivating mutations in oncosuppressor genes
• clastogenias : inherited diseases giving rise to or inducing disruption or breakages of chromosomes
• ataxia telangiectasia (AT) / Louis-Bar's syndrome (Louis Bar D. Sur un syndrome progressif comprenant des téléangiectasies capillaires cutanées et conjunctivales symmétriques à disposition naevoide e des troubles cérébelleux. Confin. Neurol. 4:3242 (1941))

Aetiology : autosomal recessive mutations in MRE11
Symptoms & signs : cerebellar ataxia, choreoathetosis and nystagmus may beecome apparent during infancy, whereas oculocutaneous telangiectasia may not appear until the fifht or sixth year; variable degrees of humoral and cellular immunodeficiency, recurrent bacterial infections of the respiratory tract from sinuses to lungs, and an increased incidence of lymphoreticular malignancies (NHL, ALL) and stomach cancer. The heterozygous carriers are prone to cancer expecially of the breast. There is an increased sensitivity to ionizing radiation caused by a defect in DNA repair. Gonadal hypoplasia, insulin resistance and hyperglycemia, liver function abnormalities, and elevated levels of a-fetoprotein (AFP) and CEA are also seen in some patients
• Bloom syndrome (BS)^ref

Aetiology : autosomal recessive mutations in BLM
Epidemiology : about 50% of the patients are of Jewish ancestry.
Symptoms & signs : developing during infancy, consisting of erythema and telangiectasia in a butterfly distribution on the face, photosensitivity, and dwarfism of prenatal onset. Sister chromatid exchange and abnormalities in immunoglobulins are present, and there is a high incidence of malignancy, especially leukemia
• Cockayne syndrome (CS)

Aetiology : autosomal recessive
• type I : mutations in CKN1
• type II : mutations in ERCC6
• type III
Symptoms & signs : dwarfismwith retinal atrophy and deafness, associated with progeria, prognathism, mental retardation, and photosensitivity.
• Fanconi anemia (FA) or syndrome^ref (Fanconi G. Familiare, infantile perniziosartige Anémie (perniziozes Blutbild und Konsttution). Jahrbuch Kinderhk. 117:257-280 (1927)

Aetiology : autosomal recessive mutation in one of the following caretaker oncosuppressor genes^ref :
• FANCA (65-70%) on chromosome 16q24.3 => FANCA/163
• FANCB (< 1%) is an essential component of the nuclear protein 'core complex' responsible for monoubiquitination of FANCD2, a key event in the DNA-damage response pathway associated with Fanconi anemia and BRCA. FANCB, is localized at Xp22.31 and subject to X-chromosome inactivation. X-linked inheritance has important consequences for genetic counseling of families with Fanconi anemia belonging to complementation group B^ref
• FANCC (8-10%) on chromosome 9q22.3 => FANCC/63
• FANCD1 (3%) on chromosome 3q12.3 => BRCA2/380
• FANCD2 (3%) on chromosome 13p25.3 => FANCD2/155,162 : biallelic germline mutations in BRCA2 are associated with the very rare complementation group of Fanconi anaemia. The clinical features of FA-D1 patients - who develop Wilms' tumour, breast cancer and medulloblastoma, differ from typical FA cases. BRCA and FA proteins work in a network of connected biological processes, and not in a linear sequence of evens that constitutes a single "pathway". One key purpose of the network is to deal with lesions that block DNA replication - such as intra- or inter-strand DNA crosslinks - so preserving chromosome stability during the S and G2 phases of the cell cycle. When sensed, replication-blocking lesions trigger cell-cycle arrest, which requires DNA-damage-activated checkpoint kinases such as ATM or ATR, as well as BRCA1 and the FA protein FANCD2. Replication-blocking lesions cn be repaired - and replication resumed - through error-free processes that involve homologous recombination or error-prone, mutagenic processes that involve translesion synthesis. BRCA2 and RAD51 work directly to mediate recombination, as might FNACD2 (which acts downstream of the FA nuclear complex and is phosphorylated by ATM in response to ionizing radiation => monoubiquitylation by FANCL / PHF9 => formation of nuclear foci and co-localization with the DNA repair proteins BRCA1 and RAD51 => DNA damage-induced arrest of DNA synthesis), whereas the precise function of other FA proteins in recombination or translesion synthesis are unclear at present. Each of the BRCA and FA proteins is likely to have very distinct functions within this network of biological processes. So, the clinical syndromes - including cancers - that are associated with their inactivation could be more mechanistically distinct than is supposed at present
• FANCE (3%) on chromosome 6p21.3 => FANCE/60
• FANCF (2%) on chromosome 11p15 => FANCF/40
• FANCG (8-10%) on chromosome 9p13 => FANCG/68
• FANCI/FANCJ (1%)
• FANCL (< 1%) on chromosome 2p16.1 => FANCL/43
Pathogenesis : hypersensitivity to DNA crosslinking agents => chromosomal instability. All racial and ethnic groups are at risk, and 11 or more complementation groups are known to date. One in 300 persons in Europe and the United States are heterozygotes (Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders Co.; 2003:280–365). Genes for 8 groups have been characterized (FANCA, C, D2, E, F, G, L, and BRCA2)^{ref1, ref2}. FANCA is the most common complementation group in the general population. One clear function of the FA proteins is to maintain chromosomal stability but it is not yet clear how this is accomplished. What is known is that 5 or 6 of the 8 known FA proteins (FANCA, -C, -F, -G, -L and possibly FANCE) bind together in a nuclear complex. This complex may have many functions but so far it is only clear that it can influence the capacity of a seventh, FANCD2, to co-localize with BRCA1 and BRCA2 in "nuclear foci" following genotoxic stress^{ref1, ref2}. This colocalization response requires that FANCD2 be monoubiquitinylated, and monoubiquitinylation is permitted only if the FA core complex is intact. Inactivating mutations of any one of the FA proteins in the complex disrupts the complex and prevents FANCD2 monoubiqutinylation. The ubiquitin ligase that performs this function is unknown but may be FANCL, a newly described FA protein that exhibits general ubiquitin ligase capacity. Carboxy-terminal truncating mutations of the seventh FA gene, BRCA2, are hypomorphic and lead to FA-D1. The intersection of the BRCA1/2 and FA pathways has led to increasing interest in the function of the FA "pathway" in sporadic malignancies. However, despite the very clearly interesting and dynamic protein-protein interactions, the functions of the FA proteins in the nucleus are unknown at a biochemical level. Thus, there is not yet a clear biochemical function of the FA nuclear pathway, but when it is defective cellular responses to genotoxic stress are deficient, at least in nontransformed cells.
It is unlikely that the nearly universal finding of marrow hypoplasia is related simply to intolerance of crosslinking agents or general cytogenetic instability; otherwise, other organ systems should fail as much as hematopoietic tissues. In fact, most FA cells are also intolerant of oxidative stress and at least one of the proteins (FANCC) is clearly involved in survival signaling and in modulating responses to apoptotic cytokine cues^ref. Probably as a result of loss of these additional functions of FA proteins, bone marrow progenitor cells and stem cells are pro-apoptotic in FA patients^ref. In fact, there is some evidence in humans and mice that the combination of genetic instability (loss of the nuclear function of FA proteins) and apoptotic hematopoietic stem cells (loss of the signaling functions of FA proteins) provides a selective force for the evolution of adapted hematopoietic stem cell clones that lead to leukemia and MDS^ref. Therefore, some argue that all the FA proteins will prove to be multifunctional, each having an impact on genetic stability and each enhancing stem cell survival. Furthermore, the accelerated apoptosis of hematopoietic stem cells and progenitors and a predisposition to myeloid leukemia is, to a varying degree, a consistent finding in the inherited bone marrow failure syndromes^ref. This suggests that protein multifunctionality may be a common theme.
Symptoms & signs : developmental anomalies (e.g., absent thumbs, absent radius, microcephaly, congenital eye defects, renal anomalies), short stature, abnormal skin pigmentation (café au lait and hypo- or hyperpigmented spots), a high incidence of MDS and AML and epithelial malignancies later in life, and cellular hypersensitivity to crosslinking agents. As many as half of patients with FA may not exhibit obvious developmental or skin abnormalities, and it is increasingly clear that the diagnosis should be considered in adults with bone marrow failure, MDS, or early onset epithelial malignancies. Germ-cell loss, chromosome misparing during meiosis, some perinatal lethality.
Laboratory examinations : apart from a few of those identified because they were siblings of a newly diagnosed FA patient, virtually all newly diagnosed FA patients have abnormal blood counts (initially thrombocytopenia and macrocytosis) and most have pancytopenia (marrow failure). Increases of HbF and macrocytosis are commonly noted but their absence cannot rule out the disease. Therefore, the safest operating principle is to consider this disease in all young adults and children with hypoplastic or aplastic anemia or cytopenias, unexplained macrocytosis, MDS, AML, epithelial malignancies or subtle but characteristic physical anomalies. In the proper clinical context the gold-standard screening test for Fanconi anemia is based on the characteristic hypersensitivity of FA cells to the crosslinking agents (mitomycin C, diepoxy butane [DEB], cisplatin). Culture of replicative cells (usually phytohemagglutinin [PHA]-stimulated peripheral blood lymphocytes or skin fibroblasts) in the presence of low doses of either mitomycin C (MMC) or DEB followed by examination of metaphase spreads for evidence of chromosomal breaks and radial chromosomes^ref can establish the diagnosis of FA. Mutated genes can be identified by retroviral complementation studies, by direct sequencing, or by denaturing high performance liquid chromatography (DHCLP) heteroduplex analysis.
• Laboratory of Human Genetics and Hematology at The Rockefeller University
• GeneDx
• g.pals@vumc.nl
Therapy : the median survival of patients with FA is approximately 30 years but survival is extraordinarily variable^ref. The most life-threatening early event in most complementation groups is bone marrow failure (patients with homozygous BRCA2 mutations, who seem to have early onset epithelial malignancies, may be exceptions), so management of bone marrow failure is the primary concern.
• allogeneic HSCT is the only option for establishing normal hematopoiesis. For a more comprehensive discussion of HSCT for the inherited bone marrow failure syndromes readers are referred to a recent comprehensive review (Vlachos A, Lipton JM. Hematopoietic stem cell transplant for inherited bone marrow failure syndromes. In: Mehta P, ed. Pediatric Stem Cell Transplantation. Sudbury, MA: Jones and Bartlett; 2004:281–311). There is general agreement that an otherwise healthy patient with FA and significant pancytopenia (ANC < 1000/mm³, hemoglobin < 8g/dL or a platelet count < 40–50,000/mm³) and an available HLA-matched sibling donor is an excellent candidate for hematopoietic stem cell transplantation. Given that these patients are extraordinarily sensitive to the chemotherapeutic agents and radiation ordinarily used to condition recipients, the doses of conditioning agents must be reduced to avoid fatal toxicities. Even with such reductions, there is some retrospective evidence that long-term survivors are at high risk of epithelial cancers of the head and neck. This has prompted studies on the use of nonmyeloablative preparative regimens for transplant. 5-year survival of patients receiving stem cells from HLA-identical siblings approaches 75% and in some centers 5-year survival is 58% with matched unrelated stem cell donors^ref. All probands and siblings should be HLA-typed early and sibling cord blood samples should be preserved. Reduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with ATG or alemtuzumab. GvHD prophylaxis consisted of low-dose cyclosporine alone. 8 transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of HSCs. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from MUDs. 1 patient did not engraft her first matched unrelated donor and underwent a second transplantation from another MUD, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia^ref. In 98 recipients of unrelated donor BMT, transplanted between 1990 and 2003, probabilities of neutrophil (89% vs. 69%, p=0.02) and platelet (74% vs. 23%, p<0.001) recovery were higher after fludarabine than non-fludarabine containing regimens. Risks of acute GVHD (RR 4.29, p<0.001) were higher with non T-cell depleted grafts. Day-100 mortality rate was significantly higher after non-fludarabine than fludarabine containing regimens (65% vs. 24%, respectively p<0.001). Corresponding 3-year adjusted overall survival rates were 13% vs. 52% (p<0.001). In addition, mortality was higher in recipients who were older (>10 years), CMV seropositive and received >20-blood product transfusions pre-BMT. Based on these results significant practice changes are suggested: use of a fludarabine containing conditioning regimen in the context of T cell depleted marrow allografts and earlier referral for transplantation prior to excessive transfusions in patients with marrow failure^ref.
• in vitro fertilization and pre-implantation genetic diagnosis (both to rule out FA and rule in an HLA match) has been used successfully, and in one instance the cord blood stem cells of the sibling were used successfully to transplant the proband^ref. Clearly not all patients are candidates for transplantation.
Risk of head and neck squamous cell cancer and death in patients with Fanconi anemia who did and did not receive HSCT^ref
• apart from supportive measures, androgen therapy frequently induces meaningful responses in pancytopenic patients (Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Ginsburg D, Look AT, eds. Hematology of Infancy and Childhood. Philadelphia: W.B. Saunders Co.; 2003:280–365) but androgens are usually reserved for transfusion-dependent patients or patients with platelet counts and neutrophil counts that put them at high risk for bleeding and infection
• gene therapy for FA patients is a theoretically appealing option but is currently not validated. New clinical trials of stem cell gene therapy for patients with FANCA or FANCC mutations are expected to open before January 2005
For patients with stable disease, annual surveillance exams and bone marrow aspiration biopsy (with cytogenetic studies) and bone marrow trephine biopsy (BMTB) are suggested but not evidence-based. For patients with complex cytogenetic abnormalities or MDS, closer follow-up is warranted. Finally, the treatment of malignancies that develop in patients with Fanconi anemia is extraordinarily difficult, particularly those for which the standard of care is either radiation, alkylating agents (e.g., cisplatin) or both. If FA patients are treated with full doses of alkylating agents or radiation the hypersensitivity of FA cells to such treatment will result in extraordinary morbidity and mortality. Treatment of patients with such malignancies should be carried out in collaboration with specialized centers.
Web resources :
• Fanconi Anemia Research Fund, Inc.
• Fanconi Canada
• Fanconi's anemia mutation database
• Nijmegen breakage syndrome (NBS)

Aetiology : mutations in NBS1 / nibrin
• Werner syndrome (Werner CWO. Ueber Katarakt in verbindung mit sclerodermia. Doctoral Dissertation. University of Kiel; ed.Schmidt u.Klanning 1904)

Aetiology : autosomal recessive mutations in WRN
Symptoms & signs : appearance during adolescence; scleroderma-like skin changes, involving especially the extremities, cataracts, subcutaneous calcification, early atherosclerosis, muscular atrophy, osteoporosis, hypogonadism, short stature, a tendency to diabetes mellitus, prematurely aged appearance of the face, canities and baldness, and a high incidence of neoplasm (10-14% : skin, soft tissues, thyroid, sarcomas, meningiomas). Short stature is common from childhood on; the other features usually develop during adulthood. They are of normal intelligence
Prognosis : they usually die in their 30s
• hereditary non-polyposis colorectal cancer (HNPCC) / Lynch cancer family syndrome (CFS / LCFS)^ref (2.5-7% of all CRCs) : metachronous in 24% of patients, mean age of anset = 44 years
• HNPCC1 / LCFS2 (MutS homolog 2 / MSH2) : site-specific (65% in proximal) colonic cancer; 50% risk of colon cancer in relatives
• HNPCC2 / LCSF1 (MutL homolog 1 / MLH1) (10-15%^ref) : colonic cancer in association with other forms of cancer, particularly endometrial carcinoma (40-60%), ovarian carcinoma (10-12%), but also cholangiocarcinoma / pancreatic carcinoma. Favorable clinical course (increased survival, respond better to chemo).
• HNPCC3 (PMSL1)
• HNPCC4 (PMS2)
• HNPCC5 (MSH6)
• HNPCC6 : TGFBR2
Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for HNPCC (3 colon cancers in which 2 people are first-degree relatives of the third. Cancer in 2 generations. One diagnosis before age 50. No evidence of FAP) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but individuals in AC-I families with no evidence of an MMR defect have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer^ref.
Pathogenesis : autosomal dominant, early age of onset (mean about 45 years), high risk of metachronous tumours (32 to 54% in 10 years) in proximal colon
Prevention :
• full colonoscopy q3y beginning age 20-25; annual endometrial screening age 25-35
• prophylactic total hysterectomy and bilateral salpingo-oophorectomy^ref
Web resources : International Collaborative Group on HNPCC
Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD^ref
• genodermatosis : a genetically determined disorder of the skin, usually generalized; if circumscribed, it is usually called nevus
• susceptibility to epidermodysplasia verruciformis
• Carney myxoma-syndrome^ref

Symptoms & signs : myxoma cordis, cutaneous dysfunction (as Cushing), pigmentary abnormalities (lentiginosis), fibroadenoma mammae, and endocrine cancers (pituitary, Sertoli-cell tumors of the testis,). Some variants have been reported (nevi-atrial myxoma-myxoid neurofibromata-ephelides (NAME) syndrome / lentiginous, atrial myxoma, cutaneous or subcutaneous papular myxomas, blue nevi (LAMB) syndrome)
• Carney syndrome : the triad of gastric epiheloid leioomyosarcomas, pulmonary chondromas and functional extra-adrenal paraganglioma^ref
• Ferguson-Smith syndrome : autosomal dominant condition with multiple self-healing epithelioma of the skin. Patients develop crops of raised nodules, most of which regress spontaneously and leave depressed scars.
• basal cell nevus syndrome (BCNS) / nevoid basal cell carcinoma syndrome (NBCNS) / fifith phacomatosis / Gorlin-Goltz syndrome / multiple basal cell nevi, odontogenic keratocysts, and skeletal anomalies

Aetiology : autosomald dominant mutations in PTCH
Symptoms & signs : multiple basal cell carcinomas, beginning at young age, averaging 15 years. They are more common on exposed areas. Various internal malignancies are reported; ameloblastomas of the oral cavity, ovarian fibromas, fibrosarcomas of the jaw, teratomas, cystadenomas, cerebellar astrocytomas, meningiomas, craniopharyngiomas and medulloblastomas. Gorlin also helped in the description of MEN syndrome IIB^ref
• acrokeratosis verruciformis (AKV)

Aetiology : autosomal dominant mutations in the gene encoding the SERCA2 Ca²⁺-ATPase
Symptoms & signs : dorsal aspects of the hands and feet, elbows, knees, and insteps of numerous closely grouped verrucous papules, and sometimes associated with the presence of diffuse hyperkeratosis of the palms and soles. Acrokeratosis verruciformis and keratosis follicularis frequently occur together.
• xeroderma pigmentosum (XP)

Aetiology : defective DNA repair. Many XP patients have defective NER, whereas XP variant (XPV) patients have normal NER but are defective in their replication of UV-damaged DNA because of a defect in  DNA polymerase h. Pol h can efficiently bypass a thymine thymine cis-syn cyclobutone T-T dimer in the presence of dATP. In XPV, UV-induced nucleotide damage is repaired by NER or by error-prone polymerase e. Even though pol h reads through T-T dimers without inducing errors, pol h is inaccurate when copying undamaged DNA and incorporates errosrs at a frequency of 10^-2.
• XPI / XPA
• XP II / XPB : ERCC3
• XP III / XPC
• XP IV / XPD / XP VIII / XPH
• XP V / XPE
• XP VI / XPF
• XP VII
• XP IX
• DDB1
• DDB2
• ERCC1
• ERCC2
• ERCC4
• ERCC5
• ERCC6
• autosomal dominant, mild
• with normal DNA repair rates
Symptoms & signs : 1000-fold increase in the incidence of UV-induced skin cancer
Web resources : Xeroderma Pigmentosum Society
• hamartomatosis : the development of multiple hamartomas
• juvenile intestinal poliposis / juvenile poliposis syndrome
• Peutz-Jeghers syndrome (PJS) / Hutchinson-Weber-Peutz / Peutz-Touraine syndrome / polyps-and-spots syndrome / hamartomatous intestinal polyposis : an autosomal dominant syndrome, a type of familial adenomatous polyposis (Peutz JLA. On a very remarkable case of familial  polyposis of the mucous membranes of the intestinal tract. Ned.Tijdschr.Geneersk. 10:134-146 (1921); Jeghers H., McKusick VA & Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits. NEJM 241;1031-1036 (1949))

Aetiology : germline loss-of-function mutations in the tumor suppressor gene LKB1, which activates AMPK. One such mutation, IVS2+1A>G, alters the second intron 5' splice site, which has sequence features of a U12-type AT-AC intron. We report that in patients, LKB1 RNA splicing occurs from the mutated 5' splice site to several cryptic, noncanonical 3' splice sites immediately adjacent to the normal 3' splice site. In vitro splicing analysis demonstrates that this aberrant splicing is mediated by the U12-dependent spliceosome. The results indicate that the minor spliceosome can use a variety of 3' splice site sequences to pair to a given 5' splice site, albeit with tight constraints for maintaining the 3' splice site position. The unusual splicing defect associated with this PJS-causing mutation uncovers differences in splice-site recognition between the major and minor pre-mRNA splicing pathways^ref.
Symptoms & signs : hamartomas of the small intestine (90% in ileum), nose, bladder and bronchi, rare malignant potential; excessive melanin pigmentation of the skin (fingers) and mucous (including circumanal, lips) membranes; gastrointestinal bleeding and intussusception are common complications. The risk of developing malignant tumors in some tissues (ovarian carcinoma, breast, pancreas, endometrial carcinoma) is 15-fold higher than normal (12% of patients)
• Turcot's syndrome / glioma-polyposis syndrome^ref
• type I : only siblings affected
• type II : autosomal dominant colonic polyposis in 2 or more generations
• type III : isolated non familial
Symptoms & signs : familial adenomatous polyposis of the colon (< 100) associated with malignant tumors of the central nervous system (medulloblastoma, glioblastoma, astrocytoma), café-au-lait spots, focal nodular hyperplasia of the liver, basal cell nevi and carcinoma
• Muir-Torre syndrome^{ref1, ref2}

Symptoms & signs : multiple carcinomas, primarily of the gastrointestinal tract, in association with a large number of sebaceous gland neoplasms
• Gardner's syndrome (GS)^{ref1, ref2}

Aetiology : mutations in APC gene but has variable penetrance so not all extracolonic features are present
Symptoms & signs : familial adenomatous polyposis of the colon (with malignant potential) with extrabowel tumors, especially multiple osteomas (skull, mandible, long bones), a rather characteristic retinal lesion, fibrous dysplasia of the skull, epidermal cysts, fibromatosis (usually intraabdominal after surgery), lipomas, impacted and supernumerary teeth, dental cysts, lymphoid polyps in small intestine and fundic gland polyps in stomach. 100% develop colon cancer. Other malignancies: periampullary, thyroid, adrenal.
• Oldfield syndrome : multiple sebaceous cysts associated with polyposis and adenocarcinoma of the colon^ref
• phakomatoses : neuroectodermal dysplasias with blastematous tendency; any of a group of hereditary or congenital diseases affecting the CNS and characterized by the development of hamartomas
• neurofibromatosis / multiple neuroma / neuromatosis : a familial condition characterized by developmental changes in the nervous system, muscles, bones, and skin and marked superficially by the formation of multiple pedunculated soft neurofibromas distributed over the entire body associated with areas of pigmentation.
• type I (NF1) / von Recklinghausen's disease / peripheral neurofibromatosis (von Recklinghausen F. Ueber die multipele Fibromen der Haut und ihre Bezienhung zu den multipelen Neuromen. Dissertation Berlin 1882 (ed.A.Hirschwald))

Epidemiology : 1 every 4,000 births
Aetiology : autosomal dominant mutations of the tumor suppressor neurofibromin
Symptoms & signs : developmental changes in the nervous system, muscles, bones (sphenoid dysplasia or scoliosis), and skin with > 6 café au lait spots > 5 mm in diameter in prepubertal age or > 15 mm in postpubertal age, intertriginous freckling (axillary (Crowe's sign) or inguinal freckling), Lisch nodulesin iris (seen with slit-lamp examination : 5% before age 3, 42% at age 3-4, 100% in adults), and multiple pedunculated soft tumors distributed over the entire body (> 2 neurofibromas or 1 plexiform neurofibroma, malignant schwannoma, pheochromocytoma, Wilms' tumor, renal arterial stenosis, leukemia, rhabdomyosarcoma, CNS tumors (unilateral optic gliomas (asymptomatic in 80%), cerebral gliomas, meningioma, medullary meningioma, astrocytoma) => seizure, language anomalies, macrocephalia, TIA, hemiparesis
Therapy : a study in mice suggests that HMG-CoA reductaseinhibitors (statins) could reverse neurofibromatosis. NF1 fails to produce a protein called neurofibromin, which normally keeps another protein, Ras, in check. Evidence from mouse studies suggests that an overabundance of active Ras results in abnormal nerve-cell responses in the brain. Ras also requires cholesterol compounds to function, and this led medical student Steven Kushner to wonder whether cholesterol-busting drugs could keep Ras in check, should neurofibromin not be up to the task. Mice genetically engineered to have the same defect as NF1 humans have a hard time focusing their attention on a task. In one test, for example, mice are exposed to a blinking light that appears consistently either to their left or right. If the mice learn to look in the right direction, they are rewarded for spotting the blinking light with food. Mice with NF1 only learn to watch the right spot 50% of the time. But those given statins up their learning rate to about 65% of the time. That's a 30% improvement in their ability to pay attention. Similarly, NF1 mice trained to find a dry platform in a water maze were 4 seconds faster on their 5th day of training if they had received a dose of statins^ref. The results of the recent experiment strongly suggest that this pharmacologic approach may be an effective way to treat the learning disabilities in children with NF1. But other drugs currently in trials for the treatment of NF1-associated tumours may also be useful for improving cognitive function in these people. Statins offer one distinct advantage over other drug options: people have taken these tablets for nearly two decades without toxic side effects. Researchers have received approval for three clinical trials to see if statins can reverse NF1-related learning disabilities in people. 2 trials will start shortly in the USA, the third in the Netherlands : we should know in one to two years if it works or not
Web resources : Neurofibromatosis, Inc. (NF, Inc.)
• type II (NF2) / central neurofibromatosis / bilateral acoustic neurinoma, neuroma, or neurofibromatosis :

Epidemiology : 1 every 50,000 births
Aetiology : autosomal dominant mutations in a gene on chromosome 22q that codes for the cytoskeletal protein merlin / NF2, which acts as a tumor suppressor
Symptoms & signs : usually bilateral acoustic neuromas, sometimes with skin changes like those seen in neurofibromatosis 1 (café au lait spots), central and peripheral nerve tumors, and presenile cataract
• type III (NF3), mixed central and peripheral / schwannomatosis : mutations in ? (somatic unrelated truncating NF2 gene mutations are detected in some specimens)
• type IV (NF4), of Riccardi : mutations in ?
• NF-Noonan syndrome (NFNS)
• familial spinal NF
• familial intestinal NF
• NF-pheochromocytoma-duodenal carcinoid syndrome
Laboratory examinations :
• objective and cutaneous examination
• brain CT/MRI
• oculistic examination
• genetic tree
• von Hippel-Lindau (VHL) syndrome / cerebroretinal or retinocerebral angiomatosis / angiophakomatosis (von Hippel E. Ueber eine sehr seltene Ekrankung der Netzhaut. Graefes Arch.Ophthalmol. 59:83-106 (1904); Lindau A. Studien uber Kleinhirncysten Bau, Pathogenese und Beziehunger zur Angiomatosis retinae. Acta Pathol.Microb.Scand suppl. 1-128 (1926))

Aetiology : autosomal dominant mutations in VHL
Symptoms & signs : hemangioblastoma of the retina (Von Hippel's disease), cerebellar hemangioblastoma, hemangioma of the spinal cord, pheochromocytoma (10-25%). The combination of systemic arterial hypertension with angioma may lead to subarachnoid hemorrhage. Hypernephroma-like renal tumors occur in some patients. Polycythemia may be due to either the hemangioblastoma of the cerebellum or the renal adenocarcinoma. Hemangiomas of the adrenals, lungs, and liver, and multiple cysts of the pancreas, liver, epididymus and kidneys, have been observed in some instances. Neurologic symptoms, including walking disorders, propriooceptive anomalies, urinary bladder disorders, seizures and mental retardation, may be present.
• Bourneville tuberous sclerosis (TS) / tuberous sclerosis complex (TSC) / epiloia is a multisystemic disorder primarily involving the nervous system.

Epidemiology : 1 every 60,000 births, 50-75% of cases are sporadic
Aetiology :
• TS1 / TSC1 : mutations in TSC1 (milder disease)
• TS2 / TSC2 : mutations in TSC2. The TSC1-TSC2 complex negatively regulates mTOR and HIF, but TSC2 regulates VEGF through mTOR-dependent and independent pathways
• TS3 / TSC3
• TS4 / TSC4
Pathogenesis : tubercles are proliferations of astrocytes and neurons on cerebral gyri and projecting into the cerebral ventricles
Symptoms & signs : renal angiolipoleiomyoma, pheochromocytoma, cerebral tumors, cardiac rhabdomyomas, shagreen patch or skin / peau de chagrin; 60% of patients having epilepsy, with 50% having infantile spasms, mental retardation, hypopigmented frassin-leave spots on trunk and limbs (90%), hard orange peel spot in lumbosacral region
Laboratory examinations : cerebral MRI/CT
• Sturge-Weber syndrome / encephalofacial or encephalotrigeminal angiomatosis / Sturge's or Sturge-Kalischer-Weber syndrome / Weber's disease

Epidemiology : 1 every 50,000 births
Aetiology :
Symptoms & signs : congenital unilateral port-wine stain (PWS) distributed over the trigeminal nerve accompanied by a similar vascular disorder of the underlying meninges and cerebral cortex, pharynx and oral cavity; it usually occurs unilaterally; highly vascularized leptomeninges with atrophy or calcification of the underlying brain; CNS tumors => seizures, hemiparesis, mental retardation; pheochromocytoma
• Jahnke's syndrome : a variant in which glaucoma is absent.
• Schirmer's syndrome : a variant in which glaucoma occurs early in the course of the disease
Laboratory examinations : cerebral MRI/CT
• Brushfield-Wyatt syndrome

Symptoms & signs : a congenital syndrome consisting of extensive unilateral nevus flammeus, hemianopia affecting the right or left halves of the visual fields of both eyes, contralateral hemiplegia, cerebral angioma, and mental retardation; it is probably related to the Sturge-Weber syndrome.
• neurocutaneous melanosis (NCM) is a rare phakomatosis

Symptoms & signs : congenital abnormal pigmentation of the skin and meninges. The meningeal lesions are particularly prone to malignant change => leptomeningeal melanoma (LMM)
• germline PTEN mutations in humans are associated with 3 clinically related, inherited cancer syndromes
• Cowden disease / multiple hamartoma syndrome : an autosomal dominant disorder comprising a combination of ectodermal, mesodermal, and endodermal anomalies, characterized by development of multiple hamartomatous lesions, especially in the skin (multiple facial trichilemmomas), high arched palate, acral keratoses, oral mucosa, colorectal, breast, thyroid, associated with a high incidence of malignancies in the organs involved (breast (30%), uterine and thyroid carcinomas), but not in polyps. Cowden is actually the name of the first patient described^ref.
• Lhermitte-Duclos disease (LDD)
• Bannayan-Zonana syndrome : a rare autosomal dominant syndrome characterized by hemangiomas of the trunk, cutaneous lipomas, macrocephaly, and swelling of the abdomen with angiomas.
In the mouse, Pten loss results in early embryonic death (circa day 6.5-7.5), whereas heterozygous survive into adulthood, but developing a wide spectrum of tumour types that are variably altered by the specific Pten mutation and/or genetic background
• Aetiology : mutations in TP53
• adrenal cortical carcinoma
• breast cancer
• colorectal cancer
• hepatocellular carcinoma
• histiocytoma
• Li-Fraumeni syndrome / sarcoma, breast, bone, brain, lung, larynx, leukemia, adrenal cortical tumors (SBLA) syndrome : a familial syndrome of early breast carcinoma associated with breast cancer, soft tissue sarcomas and other tumors. Can be present in the mother of some children with rhabdomyosarcoma or osteosarcoma^ref
• multiple malignancy syndrome
• nasopharyngeal carcinoma
• osteosarcoma
• pancreatic cancer
• thyroid carcinoma
• familial medullary thyroid carcinoma (FMTC)

Aetiology : autosomal dominant mutations in RET or NTRK1
Symptoms & signs :
• bilateral, multifocal MTC
• primary localized cutaneous AE amyloidosis (PLCA)
• inherited activating mutations in protooncogenes
• multiple endocrine neoplasias (MENs)
• multiple endocrine neoplasia (MEN) I / Wermer syndrome / 3 P's disease^ref : parathyroid adenomas, pancreatic islet cell adenomas, pituitary adenoma, duodenal carcinoid  (Zollinger-Ellison syndrome), bronchial carcinoid
• MEN1-Burin variant : thymic carcinoid or peripheral lung parenchyma
• multiple endocrine neoplasia (MEN) II
• multiple endocrine neoplasia (MEN) IIA / Sipple's syndrome (Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am.J.Med. 31:163-166 (1961))

Aetiology : autosomal dominant activating point mutations in exons 10 and 11 of the RET protooncogene
Symptoms & signs :
• bilateral, multifocal C cell hyperplasia (100%) => medullary thyroid carcinoma (MTC)
• asymmetric parathyroid hyperplasia (25-35% : MEN2A-1) => parathyroid adenomas (MEN2A-3)
• diffuse adrenal medullary hyperplasia => pheochromocytoma (42%: MEN2A-1, MEN2A-2 (bilateral) and MEN2A-3)
• primary localized cutaneous AE amyloidosis (PLCA) among scapulae (rare)
• hyperplastic epidermoid PCLA
• acanthosis nigricans
• lipomas
• corticoadrenal adenoma
Prevention : prophylactic thyroidectomy^{ref1, ref2}
• multiple endocrine neoplasia (MEN) IIB / III / Wagenmann-Froboese syndrome / ganglioneuromatosis of the alimentary tract :

Aetiology : autosomal dominant inherited or somatic M918T activating point mutation in the tyrosine kinase domain of the RET protoncogene (exon 16)
Symptoms & signs :
• very aggressive multifocal medullary thyroid carcinoma (MTC) within age 1 (100%) associated with bilateral cervical lymph nodal metastases
• multiple true mucosal ganglioneuromas (lips, anterior tongue, conjunctiva and nasal and laryngeal mucosa) (main criterion for differential diagnosis)
• marfanoid habitus (arachnodactyly) (75%)
• pheochromocytoma (40-50%, often bilateral, rarely extraadrenal)
• megacolon with plexus hyperplasia or neoplasm (40%) => constipation
In 42% of cases pheochromocytoma is the only sign.
Therapy : treatment of pheochromocytoma should preceed treatment of other organs, including MTC
• oculocutaneous albinism (OCA) : a rare, inherited disorder
• OCA1
• OCA2
• pink-eyed diluition
• Vici syndrome / immunodeficiency with cleft lip/palate, cataract, hypopigmentation, and absent corpus callosum
• Hermansky-Pudlak syndrome (HPS)

Aetiology : autosomal recessive mutations of the cytosolic adaptor protein 3 (AP-3) involved in lysosomal sorting
Pathogenesis : immunodeficiency due to loss of polarized secretion of enlarged lytic granules by CTLs (no movement along microtubules and no docking within the secretory domain of the immunological synapse). Although the lysosomal protein CD63 is mislocalized to the plasma membrane, perforin and granzymes are correctly localized to the in AP-3-deficient CTLs. d-storage pool defect in platelets.
Symptoms & signs : hemorrhagic diathesis
Laboratory examinations : accumulation of a ceroid-like substance in the reticuloendothelial system, oral mucosa, and urine
• Chédiak-Higashi syndrome
• albinism-deafness syndrome (ADFS)
• BADS syndrome : a syndrome of black locks, oculocutaneous albinism, and deafness of the sensorineural type
Symptoms & signs : congenital total or partial lack of melanin (skin pigment) in the skin, hair, choroid, retina and iris
• inborn errors of metabolism (IEM) / metabolic disease : general term for diseases caused by disruption of a normal metabolic pathway because of a genetically determined enzyme defect.
• point deficit in metabolism
• accumulation of substrates
• hydrosoluble :
• amino acids
• organic acids
• liposoluble : limitated accumulation (e.g. in CNS)
• accumulation of normally poorly represented metabolites (e.g. galactose => galactitol)
• lack of product :
• lack of function
• metabolic steal (e.g. deficiency of glycogen debranching enzyme => protein hypercatabolism)
• sequestration (e.g. deficiency of ornithine transporter)
• secondary metabolic consequences
• Hartnup disease

Symptoms & signs : cerebellar ataxia, a pellagra-like condition of the skin, and massive aminoaciduria involving a group of neutral monoaminomonocarboxylic amino acids sharing a common renal reabsorption mechanism; green urine
Therapy : patients respond well to prolonged oral administration of nicotinamide.
• thesaurismoses / inherited storage diseases : an IEM in which some substance accumulates or is stored in certain cells in unusually large amounts; the stored substances may be lipids, proteins, carbohydrates, or other substances
• lysosomal storage diseases (LSD) / lysosomal enzymopathies / inborn lysosomal disease : any IEM having 4 characteristics: (1) a defect in a specific lysosomal hydrolase; (2) intracellular accumulation of the unmetabolized substrate; (3) clinical progression affecting multiple tissues and organs; (4) considerable phenotypic variation within a disease. All but 2 of the LSD are of autosomal recessive inheritance. The term comprises the mucolipidoses, mucopolysaccharidoses, disorders of glycoprotein degradation, lipase deficiencies, ceramidase deficiency (Farber's disease), a-galactosidase A deficiency (Fabry's disease), lipidoses, and gangliosidoses

Epidemiology : 1 in 7,700 people
• fatty degenerations / steatoses / lipidoses / lipid storage diseases (LSD) / thesaurismoses lipoidica
• cerebrotendinous xanthomatosis

Aetiology : inherited autosomal recessive mutations in CYP27A1
Pathogenesis : defective bile synthesis => elevated plasma and tissue levels of cholestanol and , with the deposition of cholestanol in the CNS and in the myelin of peripheral nerves. The lesions contain cholesterol and dehydrocholesterol.
Symptoms & signs : tendinous xanthomas, xanthomas in the white matter of the brain, and the lungs and by spasticity, progressive cerebellar ataxia, pyramidal paresis, mental retardation, dementia, early cataracts, and atherosclerosis
Therapy : chenodeoxycholic acid
• b-sitosterolemia

Aetiology : autosomal recessive mutations in intestinal ABCG5 / sterolin 1, ABCG8 / sterolin 2 and STSL
Symptoms & signs : a rare form is associated with xanthomatosis, with tuberous xanthomas and tendinous xanthomas and atherosclerosis appearing in childhood.
Laboratory examinations : excessive levels of sitosterols in the blood, especially b-sitosterol (with normal cholesterol and triglycerids), absorbed from dietary vegetables, which leads to increased intestinal absorption and decreased biliary elimination of all sterols, particularly plant sterols; stomatocytic anemia and macrothrombocytopenia^ref.
Therapy : diet with low vegetal sterols and cholesterol content
• lipid proteinosis / hyalinosis cutis et mucosae / lipoproteinosis / Urbach-Wiethe disease : an autosomal recessive disorder of lipid metabolism

Symptoms & signs : deposition of hyaline material in the skin and mucosa of the mouth, pharynx, hypopharynx, and larynx, resulting in prolonged hoarseness, often from birth, due to infiltration of the vocal cords. Skin lesions are first manifested as recurrent pustules or bullae on the face and distal exposed surfaces of the arms and legs, which heal and leave white varioliform scars, and later by waxy yellow ivory papules, nodules, or verrucoid plaques primarily located on the face, eyelids, nape, hands, fingers, elbows, and knees
• phytanic acid storage disease / Refsum disease

Aetiology : mutations in phytanoyl-CoA hydroxylase (PAHX / PHYH) or peroxin-7 (PEX7)
• infantile form : mutation in PEX1or PEX2
Therapy : plasma exchange
• triglyceride storage diseases (TSD) / neutral lipid storage diseases
• type I : NE poorly stimulates the activity of AC in tissues, suggesting a defect either in the b-AR or in AC itself
• type II : both the b-AR and AC are intact as judged by a normal increment in tissue levels of cAMP on treatment with isoprenaline. However, cAMP does not activate triglyceride-lipase with the expected release of glycerol from the tissues
• type III / primary familial xanthomatosis / Wolman xanthomatosis or disease / cholesteryl ester storage disease (CESD) : a relatively mild LSD caused by deficiency of the lysosomal acid lipase A / lysosomal acid cholesteryl ester hydrolase, with onset in early infancy and death before one year of age.

Symptoms & signs : hepatosplenomegaly, steatorrhea, abdominal distension, anemia, inanition, and adrenal calcification; hepatomegaly may be the only clinical abnormality; hyperbetalipoproteinemia is common, and there is often severe premature atherosclerosis; patients may survive past 40
• with hypolipoproteinemia and acanthocytosis
• TSD with impaired long-chain fatty acid oxidation / Chanarin-Dorfman disease

Symptoms & signs : a rare form of nonbullous congenital ichthyosiform erythroderma (NCIE) with leukocyte vacuolation : mutation in the CGI58 gene
• sphingolipidoses
• sphingomyelinoses
• Niemann-Pick disease (NPD) / sphingolipidosis, sphingomyelin lipidosis / sphingomyelinase deficiency : a LSD due to a deficiency of sphingomyelin phosphodiesterase with sphingomyelin accumulation in the reticuloendothelial system

Symptoms & signs : there are 5 types distinguished by age of onset and by the amount of CNS involvement and of sphingomyelin phosphodiesterase activity :
• type I NPD
• type A (NPA) / classical infantile or acute neuronopathic form is the classic type, due to sphingomyelin phosphodiesterase-1 / acid sphingomyelinase (ASM) and accounting for 85% of the patients: onset is in early infancy; CNS damage is severe; death occurs by 4 years
• type B (NPB) / visceral or chronic non-neuronopathic form has onset in early infancy but does not affect the CNS or intelligence; normal life-span is possible.It is due to lack of sphingomyelin phosphodiesterase-1 / acid sphingomyelinase (ASM)
• type II NPD
• type C (NPC) / subacute or juvenile form has variable ages of onset (at 2 years or older) and of death (from age 5 to adulthood) and variable CNS involvement
• type C1 (NPDC1) or chronic neuronopathic form : mutation in the NPC1 gene
• type C2 (NPDC2) : mutation in the NPC2 gene
Therapy : a single injection of the neurosteroid allopregnanolone can delay the onset of neurological symptoms, decrease neuronal cell death and double the lifespan of mice with NPC^ref
• type D (NPD) / Nova Scotian variant / without sphingomyelinase deficiencyresembles type C : 3097G-T transversion in the NPC1 gene, resulting in a gly992-to-trp amino acid substitution
• not well-characterized
• type E (NPE) / adult, nonneuronopathic form may be a late-onset variant of type C
• type F (NPF) / thermolabile enzyme
Laboratory examinations : Niemann-Pick cells / Pick's cells (round, oval, or polyhedral cells present in the bone marrow and spleen in Niemann-Pick disease; they have foamy, lipid-containing cytoplasm, in the form of sphingomyelin, which gives a positive reaction with Sudan III and other fat stains)
• Farber's disease or lipogranulomatosis : a lysosomal storage disease of ceramide metabolism due to defective N-acylsphingosine amidohydrolase 1 (ASAH1) / acid ceramidase 1

Symptoms & signs : hoarseness, aphonia, and a brownish desquamating dermatitis beginning at about 3 months of age, followed by foam cell infiltration of bones and joints, resulting in deformations; granulomatous reaction in lymph nodes, heart, lungs, and kidneys, and psychomotor retardation.
• Gaucher's disease / glucosylceramide lipidosis : mutations in acid b-glucosidase / b-glucocerebrosidase / glucosylceramidase => glucocerebroside (glucosylceramide) accumulation in Gaucher cells, storage cells in the liver, spleen, lymph nodes, alveolar capillaries, and bone marrow.

Symptoms & signs :
• type I : chronic non-neuronopathic or “adult” type, may appear at any age and is associated with hypersplenism, thrombocytopenia, anemia, jaundice, and bone lesions
• type II : acute neuronopathic or “infantile” type, is associated with onset in infancy, hepatosplenomegaly, severe impairment of the central nervous system, and death usually within the first year
• type III : subacute neuronopathic or “juvenile” type, is the most varied, having the same clinical features as types 1 and 2 but a longer course
• Norrbottnian Gaucher disease
• Gaucher-like disease : homozygosity for a D409H mutation
Laboratory examinations : Gaucher's cell (a large and distinctive cell characteristic of Gaucher's disease, with one or more eccentrically placed nuclei and with fine wavy kerasin fibrils running parallel to the long axis of the cell, imparting a wrinkled, tissue-paper appearance to the gray or bluish opaque cytoplasm)
Therapy :
• substrate deprivation / substrate reduction therapy (SRT) aims to reduce biosynthetic capability in the cell to match the reduced lysosomal catalytic activity : orally administered ceramide glucosyltransferase inhibitor which prevents the lysosomal accumulation of glucocerebroside that occurs in patients with Gaucher's disease whose mutations don't completely destroy the enzyme activity. In noncomparative trials in patients with type 1 Gaucher's disease, miglustat (50 or 100mg 3 times daily) for 6-12 months significantly reduced baseline liver and spleen volumes. At both 6 and 12 months, the reductions in organ volumes were greater with the higher dosage. Miglustat 50 or 100mg 3 times daily for 6-12 months had no significant effect on haemoglobin concentrations. Baseline platelet counts were not significantly improved by either dosage at 6 months, although the higher dosage significantly increased platelet counts at 12 months. In an open extension phase, patients continued to show further reductions in organ volume as well as significant improvements in haematological parameters at 24 and 36 months. In a 6-month randomised study in patients with type 1 Gaucher's disease who had previously received long-term ERT, liver volume reduction was greater with miglustat plus ERT than with ERT alone. Diarrhoea and weight loss were the most frequent adverse events associated with miglustat therapy. Fine tremor has been reported in approximately 30% of miglustat-treated patients^{ref1, ref2}
• enzyme replacement therapy (ERT) (highly effective, but requires a 2-hr i.v. infusion as often as 3 times a week and costs approximately $200,000 a year).
• Anderson-Fabry disease / diffuse angiokeratoma / angiokeratoma corporis diffusum

Aetiology : an X-linked lysosomal storage disease of glycosphingolipid catabolism, resulting from a deficiency of a-galactosidase A / ceramide trihexosidase and leading to accumulation of ceramide trihexoside in the cardiovascular and renal systems
Epidemiology : there is a significant concentration of Fabry patients in Nova Scotia, all descended from an immigrant who arrived there in the late 1600s.
Symptoms & signs : telangiectases in the “bathing suit area,” corneal opacities, burning pain in the palms, soles, and abdomen, chronic paresthesias of the hands and feet, cardiopulmonary involvement, edema of the legs, osteoporosis, retarded growth, and delayed puberty. Patients usually die of renal failure (focal segmental glomerulosclerosis (FSGS)) or cardiac or cerebrovascular disease.
Therapy : a 5% level of normal enzyme activity is enough to correct the disorder
• gene therapy at birth
• recombinant human a-galactosidase A replacement therapy
Prognosis : life expectancy of only 40 to 50 years
Differential diagnosis : chloroquine-induced lipidosis^ref
• metachromatic leukodystrophy (MLD) or leukoencephalopathy / sulfatide lipidosis : an autosomal recessive disorder due to deficiency of arylsulfatase A (ARSA) / cerebroside sulfatase or sphingolipid activator protein–1 (SAP1) / saposin,

Symptoms & signs : accumulation of sulfatide in neural and nonneural tissues, with a diffuse loss of myelin in the central nervous system. There are 3 forms due to deficiency of cerebroside sulfatase, with variable age of onset, all initially presenting as mental regression and motor disturbances
• the infantile form (Greenfield's disease) usually begins in the second year of life and is additionally characterized by developmental delay, seizures, optic atrophy, ataxia, weakness, loss of speech, and progressive spastic quadriparesis
• the juvenile form (Scholz's disease) is clinically similar, but presents between the ages of 4 and 12 and progresses more slowly; a variant of the juvenile form is caused by deficiency of sphingolipid activator protein–1 (SAP1) / saposin
• the adult form (Nyssen-van Bogaert syndrome) begins after 16 years of age, generally presenting initially as dementia and disturbances in behavior and progressing more slowly to motor and posture disturbances
• GM₂ gangliosidosis
• type I / B variant / classic Tay-Sachs disease (TSD) : the most common ganglioside storage disease, occurring almost exclusively among northeast European Jews. TSD is a GM₂ gangliosidosis due to mutation in the a subunit of the hexosaminidase (HEXA) gene and specifically characterized by infantile onset (3–6 months), doll-like facies, cherry-red macular spot (> 90% of the infants), early blindness, hyperacusis, macrocephaly, seizures, and hypotonia; the children die between 2 and 5 years of age
• type II / O variant / Sandhoff's disease : mutation in the bsubunit of hexosaminidase (HEXB)
• type III / juvenile : partial deficiency of a subunit of the hexosaminidase (HEXA)
• AB variant : lack of GM₂ ganglioside activator protein
• A(M)B variant
Symptoms & signs : anterior horn cell disease (AHCD)
• Krabbe's or globoid cell leukodystrophy (GLD) / galactosylceramide lipidosis : a lysosomal storage disease due to a deficiency of galactocerebrosidase-a(GALC) leading to accumulation in oligodendrocytes of psychosine, a toxic glycolipid.

Symptoms & signs : begins in infancy with irritability, fretfulness, and rigidity, followed by tonic seizures, convulsions, quadriplegia, blindness, deafness, dysphagia, and progressive mental deterioration. Pathologically, there is rapidly progressive cerebral demyelination and large globoid bodies in the white substance
Laboratory examinations : globoid cells (an abnormal large histiocyte found in large numbers in intracranial tissues)
• ceroid storage disease (CSD) / ceroid lipofuscinosis / ceroidosis / lipofuscin storage disease
• neuronal ceroid lipofuscinosis (NCL)
• autosomal recessive
• type 1, infantile
• type 2, late infantile (LINCL) / Janský-Bielschowsky disease : the late infantile form of NCL, occurring between 2-4 years of age and characterized by abnormal accumulation of lipofuscin; it begins as myoclonic seizures and progresses to neurologic and retinal degeneration and death, usually by the age of 8 to 12 years.
• type 3, juvenile NCL (JNCL) / Batten disease
• type 4
• type 5
• type 6, late infantile
• juvenile NCL (JNCL) with granular osmiophilic deposits : mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene
• dominant : Parry type
• Haltia-Santavuori disease : rare infantile form of NCL, beginning about 1 year of age, with excessive storage of lipofuscin, failure to thrive, myoclonic seizures, muscular hypotonia, psychomotor developmental delay and deterioration, blindness with optic atrophy and cerebellar ataxia, and death within about 5 years.
• Kufs' disease : the adult form of NCL (ANCL), beginning usually before the age of 40 and characterized by progressive neurologic degeneration, excessive storage of lipofuscin in the CNS, and shortened life expectancy. Unlike other forms of NCL, it does not cause blindness. There is involvement of the muscle in neuroleptic malignant syndrome^ref
• Vogt-Spielmeyer disease : the juvenile form of NCL with onset between 5 and 10 years of age, characterized by rapid cerebroretinal degeneration, massive loss of brain substance, excessive neuronal storage of lipofuscin, and death within 10 to 15 years.
Laboratory examinations : cherry-red spot / Tay's spot or sign
• glycoproteinoses
• fucosidosis : lack of a-L-fucosidase 1
• mannosidosis
• a-mannosidase, class 2B, member 1
• b- mannosidase
• sialidosis

Symptoms & signs : focal segmental glomerulosclerosis (FSGS)
• galactosialidosis / neuraminidase deficiency with b-galactosidase deficiency / Goldberg syndrome
• mucolipidosis : any of a group of lysosomal storage diseases in which both glycosaminoglycans (mucopolysaccharides) and lipids accumulate in tissues but without excess of glycosaminoglycans in the urine.
• mucolipidosis III / pseudo-Hurler polydystrophy : a disorder similar to but milder than mucolipidosis II and thought to be due to the same enzyme deficiency but to a lesser extent
• mucolipidosis I (ML 1) / pseudo-Hurler polydystrophy / lipomucopolysaccharidosis / type I sialidosis
• mucolipidosis II (ML 2) / I-cell disease / ML 3 complementation group A (for "inclusion") : lack of catalytic subunit of N-acetylglucosamine-1-phosphotransferase : a rapidly progressing disease of young children, characterized histologically by abnormal fibroblasts containing a large number of dark inclusions which fill the central part of the cytoplasm except for the juxtanuclear zone (I-cells)

Aetiology : mutations in GNPTA => defects in the multimeric GlcNAc-1-phosphotransferase responsible for the initial step in the generation of the mannose 6-phosphate (M6P) recognition marker. M6P residues on oligosaccharides of newly synthesized lysosomal enzymes are essential for efficient receptor-mediated transport to lysosomes. The N-terminal domain of GNPTA, interrupted by a long insertion, shows similarities to bacterial capsule biosynthesis proteins^ref
Symptoms & signs : severe growth impairment, minimal hepatomegaly, extreme mental and motor retardation, and clear corneas; inherited as an autosomal recessive trait, it is caused by failure of lysosomal enzymes to be incorporated into lysosomes, due to deficiency of the enzyme UDP-N-acetylglucosamine–lysosomal-enzyme N-acetylglucosamine-phosphotransferase
Laboratory examinations : I-cell (an abnormal fibroblast containing a large number of dark inclusions that fill the central part of the cytoplasm except for the juxtanuclear zone)
• mucolipidosis III (ML 3) / complementation group B : lack of catalytic subunit of N-acetylglucosamine-1-phosphotransferase
• variant form / complementation group C : also lack of recognition subunit of N-acetylglucosamine-1-phosphotransferase
• mucolipidosis IV (ML 4) : lack of mucolipin-1 : an autosomal recessive disorder

Symptoms & signs : psychomotor retardation and severe visual impairment, initially manifest in infancy or childhood as corneal clouding. Sialic acid–containing gangliosides are accumulated due to deficient ganglioside sialidase activity; however the deficiency is not believed to be the primary defect
• mucopolysaccharidoses (MPS)
• MPS I / gargoylism : lack of a-L-iduronidase
• Pfaundler-Hurler disease (MPS IH) : the prototype of the MPS, and the gravest of the 3 allelic disorders of MPS I, specifically marked by corneal clouding and death by age 10. It is caused by deficiency of a-L-iduronidase

Symptoms & signs : onset is after the first year with progressive physical and mental deterioration. Further symptoms include gargoyle-like facies with hypertelorism, depressed nasal bridge, large tongue, and widely spaced teeth; dwarfism; severe somatic and skeletal changes, including short neck and trunk, scaphocephaly, and kyphosis with gibbus; short broad hands with short fingers; progressive opacities of the cornea; deafness; cardiovascular defects; hepatosplenomegaly; and joint contractures. Death is usually caused by respiratory infection and heart failure
Laboratory examinations : Reilly granulations
Therapy : UBSCT
• Scheie's disease or syndrome (MPS IS) : a relatively mild allelic variant of Hurler's syndrome and the mildest of the 3 allelic disorders of MPS I,

Symptoms & signs : corneal clouding, claw hand, involvement of the aortic valve, somewhat coarse facies with a broad mouth, genu valgum, and pes cavus. Stature, intelligence, and life span are normal; it is caused by a deficiency of a-L-iduronidase
• Hurler-Scheie syndrome (MPS I H/S) : one of the 3 allelic disorders of MPS I, with clinical features intermediate between the Hurler and the Scheie syndromes, caused by deficiency of a-L-iduronidase, and specifically characterized by receding chin (micrognathism)

Symptoms & signs : mental retardation, dwarfism, dysostosis multiplex, corneal clouding, deafness, hernia, stiff joints (claw hand), and valvular heart disease. Patients survive until their late teens or twenties
Therapy : enzyme replacement therapy (ERT)
• MPS II / Hunter syndrome : a MPS caused by deficiency of iduronate 2-sulfatase, characterized by excretion of dermatan sulfate and heparan sulfate in the urine

Epidemiology : there are approximately 2,000 patients worldwide afflicted with Hunter syndrome in countries where reimbursement may be possible
Symptoms & signs : differing clinically from Hurler's syndrome by (1) X-linked inheritance; (2) slower progression, less severity, and longer survival (thus resembling the Hurler-Scheie syndrome); and (3) absence of corneal clouding. 2 clinical forms exist:
• severe form has Hurler-Scheie–like symptoms with death before 15, usually from heart disease
• mild form has onset in the first decade, reduced somatic involvement, and near-normal intelligence and lifespan
The symptoms of Hunter syndrome are usually not visible at birth, but usually start to become noticeable after the first year of life. Often the first symptoms may include hernias, frequent ear infections, runny noses, and abnormal facial appearance. As the disease progresses, a variety of symptoms appear including, enlarged liver and spleen, heart failure, decreased endurance, obstructive and restrictive airway disease, sleep apnea, joint stiffness, and, in some cases, CNS involvement. If CNS involvement exists, the life expectancy for patients with Hunter syndrome is typically 10-15 years of age, however, some patients can survive into the fifth or sixth decade of life
Therapy : enzyme replacement therapy (ERT)
• MPS III / Sanfilippo's syndrome : 4 heterogeneous, biochemically distinct, but clinically indistinguishable forms of MPS characterized biochemically by excretion of heparan sulfate in the urine

Symptoms & signs : severe, rapid mental deterioration and relatively mild somatic symptoms. Onset is from 2 to 6 years of age; the head is large, height normal; Hurler-like features (dysostosis multiplex, hepatomegaly) are mild; hirsutism is generalized; death usually occurs before 20 years of age.
• MPS IIIA (the most severe) : lack of heparan N-sulfatase / sulfamidase
• MPS IIIB : lack of a-N-acetylglucosaminidase (NAGLU)
• MPS IIIC : lack of heparan-a-glucosaminide N-acetyltransferase
• MPS IIID : lack of N-acetylglucosamine 6-sulfatase
• MPS IV / Morquio's syndrome / osteochondrodysplasia / osteochondrodystrophia deformans / eccentrochondroplasia / eccentro-osteochondrodysplasia : 2 biochemically distinct, but clinically nearly indistinguishable, forms of MPS characterized by excretion of keratan sulfate in the urine.

Symptoms & signs : affecting primarily the skeletal and secondarily the nervous system, include genu valgum, pectus carinatum, progressive platyspondyly, short neck and trunk, normal but broad-mouthed facies with spacing between the teeth, progressive deafness, and very mild corneal clouding. Intelligence is normal
• MPS IVA : lack of N-acetylgalactosamine-6-sulfate sulfatase
• MPS IVB : lack of b-galactosidase
• MPS IVC / nonkeratosulfate-excreting type
• Silfverskiöld's syndrome : a form of eccentro-osteochondrodysplasia in which the skeletal changes are chiefly in the extremities and which is inherited as a dominant character.
• camptomelic syndrome : osteochondrodysplasia associated with flat facies, bowed tibiae with skin dimpling, hypoplastic scapulae, and short vertebrae.
• MPS V (?)
• MPS VI / Maroteaux-Lamy syndrome / arylsulfatase B (ARSB) deficiency : a MPS caused by deficiency of N-acetylgalactosamine-4-sulfatase (arylsulfatase B (ARSB)), and characterized biochemically by the predominance of dermatan sulfate in the urine and the presence of coarse metachromatic granules in the leukocytes

Symptoms & signs : Hurler-like signs with normal intelligence. There are 3 clinical forms:
• the severe or classic form shows Hurler-like symptoms
• the intermediate form has the same phenotype as mucolipidosis III (pseudo-Hurler polydystrophy)
• the mild form is difficult to distinguish from the Scheie syndrome
Therapy : enzyme replacement therapy
• MPS VII / Sly's syndrome : a MPS caused by deficiency of b-glucuronidase (GUSB) and characterized biochemically by excretion of dermatan sulfate, heparan sulfate, and chondroitin sulfates A and C in the urine and by granular inclusions in granulocytes

Symptoms & signs : onset is between 1 and 2 years with mild to moderate Hurler-like features including dysostosis multiplex, pectus carinatum, visceromegaly, cardiac murmurs, short stature, and moderate mental retardation. Milder forms exist
Therapy : gene therapy. Enzyme replacement therapy (ERT) effectively reverses storage in several lysosomal storage diseases. However, improvement in brain is limited by the blood-brain barrier except in the newborn period. This barrier could be overcome by higher doses of enzyme than are used in conventional trials. Immunotolerant mice given up to 5 mg/kg human b-glucuronidase (hGUS) weekly over 3 weeks had moderate reduction in meningeal storage but no change in neocortical neurons. Mice given 20-40 mg/kg three times over 1 week showed no reduction in storage in any area of the CNS except the meninges. In contrast, mice receiving 4 mg/kg per week for 13 weeks showed clearance not only in meninges but also in parietal neocortical and hippocampal neurons and glia. Mice given 20 mg/kg once weekly for 4 weeks also had decreased neuronal, glial, and meningeal storage and averaged 2.5% of wild-type hGUS activity in brain. These results indicate that therapeutic enzyme can be delivered across the blood-brain barrier in the adult mucopolysaccharidosis type VII mouse if administered at higher doses than are used in conventional ERT trials and if the larger dose of enzyme is administered over a sufficient period^ref
• MPS VIII / DiFerrante syndrome : lack of N-acetylglucosamine sulfate sulfatase
• MPS IX : lack of hyaluronidase 1
• multiple (> 9) sulfatase deficiency (MSD), associated with hemophagocytic syndrome
• unclassified types
• combined sphingolipidosis and mucopolysaccharidosis
• generalized GM₁ gangliosidosis : mutations in b-galactosidase
Therapy : substrate reduction therapy (SRT) :
• genistein (an EGFR inhibitor) inhibits synthesis of GAGs considerably in cultures of fibroblasts of MPS patients (types I, II, IIIA and IIIB were tested)^ref
• glycogen storage diseases (GSD) / glycogenoses : any of a number of rare inborn errors of metabolism caused by defects in specific enzymes or transporters involved in the metabolism of glycogen.

Cori classification :
• GSD type 0 : lack of liver glycogen synthase 2
• GSD type I / glucose-6-phosphatase deficiency: a severe hepatorenal form of the disease in which deficiency of glucose-6-phosphatase, an autosomal recessive trait

Symptoms & signs : hepatomegaly, hypoglycemia, hyperuricemia, hyperlacticacidemia, hyperlipidemia, xanthomas, bleeding, and adiposity; patients frequently survive to adulthood.
• Ia / von Gierke disease / hepatorenal : lack of glucose-6-phosphatase catalytic subunit

Laboratory examinations : hypoglycemia with low or absent response to i.v. glucagone
Therapy : gene therapy
• Ib : lack of glucose-6-phosphatase, transporter 1 (T1), responsible for transport of Glc-6-phosphate into the ER. An autosomal recessive disorder caused by a defect in the transport system for glucose 6-phosphate.

Symptoms & signs : resemble those of the type I disorder, but patients are additionally predisposed to infection related to neutropenia and to chronic inflammatory bowel disease.
• Ic : lack of glucose-6-phosphatase, translocase 2 (T2), responsible for transport of pyrophosphate into, and phosphate out of, the ER
• Id : lack of glucose-6-phosphatase, translocase 3 (T3), responsible for transport of Glc out of the ER
• GSD II / lysosomal a-1,4-glucosidase deficiency / cardiomegalia glycogenica diffusa : an autosomal recessive disorder caused by deficiency of the lysosomal enzyme glucan acid a-1,4-glucosidase / acid maltase, with accumulation of glycogen in tissues.

Symptoms & signs : in infants, it is characterized by mild hepatomegaly, mental and motor retardation, hypotonia, and cardiomegaly and cardiorespiratory failure resulting in death; the adult form is usually characterized primarily by a gradual skeletal myopathy that sometimes causes respiratory problems.
• IIa / Pompe disease / acid maltase deficienct (AMD) : lack of acid a-1,4-glucosidase / acid maltase

Epidemiology : 5,000-10,000 people worldwide.
Prognosis : children under 6 months old who fail to produce the enzyme typically do not live longer than 1 year
Therapy : enzyme replacement therapy
• IIb / Danon disease / cardiomyopathy
• Antopol disease
Therapy : gene therapy
• GSD type III / Cori-Forbes disease / limit dextrinosis / debrancher deficiency / amylo-1,6-glucosidase deficiency : an autosomal recessive disorder caused by a defect in the amylo-1,6-glucosidase, 4a-glucanotransferase / glycogen debranching enzyme in muscle, liver, or both.

Symptoms & signs :
• defects in the liver enzyme are characterized by hepatomegaly and hypoglycemia
• defects in the muscle enzyme are characterized by progressive muscle wasting and weakness
Heart and skeletal muscle are also frequently affected
Laboratory examinations : double glucagon test : glucagon is administered after a 12 hour fast and again shortly after a meal; if the blood sugar fails to rise after the first administration but has a normal rise after the second, the test is positive.
• GSD type IV / Andersen disease / amylopectinosis / brancher enzyme deficiency : an autosomal recessive disorder caused by a defect in the glycogen branching enzyme 1,4-a-glucan branching enzyme

Symptoms & signs : the most severe abnormalities are in the liver, with hepatosplenomegaly, early cirrhosis with portal hypertension, liver failure, and death in childhood. Neuromuscular abnormalities are also present
• GSD type V / McArdle-Schmidt-Pearson disease / muscle phosphorylase deficiency: an autosomal recessive disorder caused by a defect in the skeletal muscle isozyme of glycogen phosphorylase / myophosphorylase

Symptoms & signs : muscle cramps and fatigue during exercise.
• GSD type VI / Hers disease / hepatic phosphorylase deficiency : an autosomal recessive disorder caused by deficiency of the liver isozyme of glycogen phosphorylase

Symptoms & signs : hepatomegaly, mild to moderate hypoglycemia, and mild ketosis. GSD type 8 was previously included in this type by some authors.
• GSD type VII / Tarui disease / muscle phosphofructokinase deficiency : an autosomal recessive disorder caused by deficiency of the muscle isozyme of 6-phosphofructokinase

Symptoms & signs : muscle weakness and cramping after exercise. Activity of the erythrocyte isozyme is also decreased, causing increased hemolysis.
• GSD type VIII : lack of liver a₂-subunit of glycogen phosphorylase kinase
• GSD type IX : lack of heart a₂-subunit of glycogen phosphorylase kinase
• GSD type X (?)
• GSD type XI / hepatorenal glycogenosis with renal Fanconi syndrome / Fanconi-Bickel syndrome : lack of GLUT-2
• fatal congenital nonlysosomal heart glycogenosis (FCNHG) : children with this disease have a dramatically enlarged heart (5 times the normal weight) and arrhythmia, and die from heart failure and respiratory complications at a few weeks of age.

Aetiology : heterozygous R531Q missense mutations of the PRKAG2 gene, which encodes the gamma 2-subunit of AMP-activated protein kinase, a key regulator of energy balance, previously attributed to a subtype of phosphorylase kinase deficiency^ref. Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal cardiac glycogenosis seems to be genetically heterogeneous.
Therapy :
• replacement therapy
• substrate balance therapy (SBS)
Web resources : Storage disorders by K.G.Braund
• congenital disorders of glycosylation (CDG) / carbohydrate deficient glycoprotein syndromes (CDGS) / Jaeken's syndrome

Laboratory examinations : normal transferrin has 2 fully occupied N-glycosylation sites and is a relatively homogeneous glycoprotein with > 80% of its oligosaccharides being sialylated stucture with 2 antennae. This high level of homogeneity permits meaningful ES-MS analysis on the intact glycoportein. Alterations in the oligosaccharide structures are readily revealed by shifts in molecular weight (tetrasialotransferrin deficiency and increased disialotransferrin in serum)
• CDG type I : impaired lipid-linked oligosaccharide (LLO) assembly and transfer, leading to insufficient biosynthesis of the oligosaccharide precursor required for N-oligosaccharide biosynthesis. 3 major molecular species are detected with ES-MS. The first has the correct mass for normal transferrin [mass-to-charge ratio (m/z) 79,570], whereas the others (m/z 77,364 and 75,157) are smaller by the masses of 1 and 2 biantennary sialylated structures, respectively.
• CDG type Ia
• CDG type Ib (CDG1b) : lack of phosphomannose isomerase, an enzyme that converts Frc-6P to Man-6P. The mannose compound is a critical intermediate needed to synthetize N-linked glycosylated proteins, which are involved in myriad biochemical functions.

Symptoms & signs : chronic gastrointestinal problems, including vomiting, diarrhea, bleeding, and blood clot formation
Therapy : mannose to allow cells to use an alternative route for making Man-6P
• CDG type Ic
• CDG type Id
• CDG type Ie
• CDG type Ig
• CDG type Ix
• CDG type I/IIx
• CDG type II : affect trimming of the protein-bound oligosaccharide or the addition of sugars to it. ES-Ms detects a major molecular ion at m/z 78,247 in the serum transferrin spectrum, consistent with 2 sites being occupied with structures having only 1 antenna
• CDG type IIa
• CDG type IIb
• CDG type IIc
• CDG type II
• congenital nephrosis 1, Finnish type : nephrin in podocytes
• progressive familial intrahepatic cholestasis
• type 1
• type 2 / severe bile salt export pump (BSEP) deficiency

Aetiology : recessive mutations in ABCB11, the gene encoding BSEP^{ref1, ref2}. BSEP is expressed at the canalicular membrane of the hepatocytes and transports bile acids into the canalicular space, using ATP as an energy source^ref. Hepatocyte canaliculi in most patients carrying ABCB11 mutations express little or no detectable BSEP^ref. Children with severe BSEP deficiency typically have jaundice and pruritus within the first few months of life. Early-onset cholestasis progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease^ref. Affected children are also at increased risk for liver cancer^{ref1, ref2}. Biochemical and histopathological features of this disorder include elevated serum concentrations of bile acids, intrahepatic cholestasis, and often, giant-cell transformation. Serum values of gGT activity are normal, despite the degree of conjugated hyperbilirubinemia^{ref1, ref2, ref3}.9,10,11 Liver disease caused by severe BSEP deficiency is usually resistant to medical treatment; therefore, for most patients, transplantation becomes necessary^{ref1, ref2}. Rare phenotypic recurrences of BSEP deficiency that takes place after liver replacement correlate with the presence in serum of blocking antibodies against BSEP^ref.
• Alport's syndrome : a hereditary disorder

Symptoms & signs : progressive sensorineural hearing loss, progressive pyelonephritis or glomerulonephritis, and, occasionally, lenticonus.
• X-linked : collagen type IV, a₅ chains => progressive impairment of renal function
• autosomal recessive
• autosomal dominant
• with mental retardation, midface hypoplasia, and elliptocytosis (AMME) complex
• with macrothrombocytopenia (Epstein syndrome)
Therapy : kidney transplantation
• Usher syndrome : an autosomal recessive syndrome

Symptoms & signs : congenital deafness is accompanied by retinitis pigmentosa, often ending in blindness; sometimes mental retardationand disturbances of gait also occur
• type IA
• type IB
• type IC
• type ID
• type IE
• type IF
• type IG
• type IIA
• type IIB
• type IIC
• type III
• fragile site mental retardation (FMR)

Aetiology : mutations in FMR1 / FRAXA : an X-linked recessive syndrome associated with fragile site on the long arm of the X chromosome at q27.3,. In some families there have been unaffected transmitting males. Men inherit premutation expansions from their mothers and pass them along to their daughters, all of whom have the abnormal gene : the expansion can grow in size when the daughters pass it along to their own offspring causing fragile X syndrome
• fragile X-associated tremor/ataxia syndrome (FXTAS)

Epidemiology : 1 in 259 women and 1 in 813 men in the USA
Aetiology : 55-200 repeats (premutation)
Symptoms & signs : high intelligence and achievement in early and mid-life : but starting in their 50s and beyond as many as 30% of men with premutation expansions of their fragile X protein gene may develop FXTAS (moderate to severe intention tremors, balance problems, dementia ) (RR = 13) -- the result, apparently, of tiny pearl-like protein clusters that accumulate in their neurons -- while women with the gene expansions didn't seem to be prone to FXTAS, probably because they have another X chromosome to compensate for the defective one. While just 17% of men in their 50s had FXTAS, the percentage of men with tremors and balance problems who had the mutation increases with each decade of life (75% at age 80). As many as 10% of patients diagnosed with atypical Parkinson's disease (PD) might actually have FXTAS^ref
• FMR1 / fragile X syndrome

Epidemiology : 1 in 3,600 men and 1 in 4,000 to 6,000 women
Aetiology : > 200 repeats cause loss of an RNA-binding protein called FMRP (for fragile X mental retardation protein). FMRP seems to influence synaptic plasticity through its role in mRNA transport and translational regulation. Recent advances include the identification of mRNA ligands, FMRP-mediated mRNA transport and the neuronal consequence of FMRP deficiency. FMRP was also recently linked to the microRNA pathway^ref.
Symptoms & signs : mental retardation, macroorchidism, macrotia, high forehead, prominent jaw and ears, and high-pitched jocular speech in most males and mild mental retardation in many heterozygous females . In women, retardation may be accompanied by premature menopause (25%)
Web resources : National Fragile X Association
• FMR2

Aetiology : mutations in FMR2 / FRAXE
• chromosomal aberrations


• deletions
• Wolf-Hirschhorn syndrome : a syndrome associated with partial deletion of the short arm of chromosome 4

Symptoms & signs : microcephaly, ocular hypertelorism, epicanthus, cleft palate, micrognathia, low-set ears simplified in form, cryptorchidism, and hypospadias.
• cri du chat syndrome / cat's cry syndrome : a hereditary congenital syndrome

Symptoms & signs : hypertelorism, microcephaly, severe mental deficiency, and a plaintive catlike cry, due to deletion of part of 5p
• aneuploidies
• monosomy : the absence of one chromosome of a homologous pair in the complement of an otherwise diploid cell (2n-1)
• monosomy 9p- syndrome : a rare chromosomal disorder in which a piece of the short arm of the ninth chromosome is broken and often lost.

Symptoms & signs : mental retardation, a triangular head with forward angulation of the frontal bone, and various other physical deformities
• Turner's syndrome (TS) / Ullrich syndrome / gonadal dysgenesis

Aetiology :
• 45,X0 karyotype (50% : 99% of fetuses with this anomalies are aborted ?)
• mosaicism (e.g., 46,XX/45,X0 or 45,X0/47,XXX) (25%)
• structural abnormality of one X chromosome with or without mosaicism (25%)
• additional Y chromosome (clitoris hypertrophy and gonadoblastoma)
Epidemiology : 1 every 3,000 female newborns, 0.8% of zygotes (the most common human chromosomal anomaly)
Symptoms & signs : phenotypically female, bilateral undifferentiated (streak) gonads => primary amenorrhea (although 2% of 45,X0 and 12% of mosaicism have menses and some pregnancies are reported in literature, despite the low fertility period), immature female external genitalia, no breast, dwarfism (average adult hieght < 150 cm), pterygium colli, micrognathia, epicanthic fold, macrotia, broad chest, horseshoe kidneys, cardiovascular abnormalities, low posterior hair line, bilateral cubitus valgus, short forth metacarpal (50%), aorta coartaction (10-20%), pigmented nevi, hypoplastic nails, cheloids, perceptive hearing loss, essential systemic arterial hypertension, IGT, autoimmune thyroid diseases.
Laboratory examinations : low [estrogens and progesterone]_plasma => lack of negative feedback on hypothalamus => high [FSH and LH]_plasma
Secondary prevention :
• Triplo testat pregnancy wk 15-17
• geentic echography at pregnancy wk 20-22 (30% have an echographically distinguishable malformation at this age)
Therapy : atients undergo feminizing puberty with estrogen replacement therapy.
• trisomies : the presence of an extra chromosome of one type in an otherwise diploid cell (2n +1).
• trisomy 8 syndrome / trisomy C syndrome : a syndrome associated with an extra chromosome 8, usually mosaic (trisomy 8/normal)

Symptoms & signs : mild to severe mental retardation, prominent forehead, deep-set eyes, thick lips, prominent ears, and camptodactyly
• trisomy 11q syndrome : a syndrome resulting from the presence of an extra long arm of chromosome 11

Symptoms & signs : because different segments may be involved, the associated anomalies are highly variable and include preauricular fistulas, hypoplasia of the gallbladder, micropenis, bicornuate uterus, microphthalmos, malformations of the heart, lung, and brain, seizures, and recurrent infection.
• trisomy 13 syndrome / trisomy D syndrome / Bartholin-Patau syndrome : a chromosome aberration in which an extra chromosome 13

Symptoms & signs : central nervous system defects (holoprosencephaly, microcephaly, ocular anomalies, hypotelorism, deafness, convulsions) and mental retardation, together with low-set ears, bilateral cleft palate and lip, polydactyly, dermal pattern anomalies, ventricular septal defects, and abnormalities of genitalia
• trisomy 18 syndrome / trisomy E syndrome / Edwards syndrome

Symptoms & signs : mental retardation, scaphocephaly or other skull abnormality, micrognathia, blepharoptosis, low-set ears, corneal opacities, deafness, pterygium colli, short digits, ventricular septal defects, Meckel's diverticulum, and other deformities. It is due to the presence of an extra chromosome 18.
• trisomy 21 syndrome / Down syndrome (DS) / mongolism
• translocation Down syndrome : Down syndrome in which the excess chromosomal material (the long arm of chromosome 21) is translocated to another acrocentric chromosome (in standard trisomy 21 there is an additional chromosome 21). A carrier of the translocation chromosome has 45 chromosomes including the translocation chromosome and may be at increased risk of having a child with Down syndrome.
Epidemiology : DS is the most common congenital chromosomal disorder in humans, with an estimated incidence of 1/660 to 1/1,000 live births. The risk of bearing a trisomy 21 child increases with maternal age and is more than 1 in 50 after the mother reaches age 35. Approximately 4 million live births occur each year in the USA, and > 4,000 of these infants have DS. As most births occur before maternal age 35, 60-70% of all newborns with Down's syndrome have been delivered by mothers aged < 35 yrs.
Aetiology : trisomy of chromosome 21 associated with late maternal age ; despite long believed due to triplication of a 'critical region' of chromosome 21, which contains just 30 or so genes, mice with 3 copies of the critical region did not look significantly different from mice with only one or two copies of these genes and the disease is likely to be caused by complex genetic interactions between much larger numbers of tripled genes^ref
Symptoms & signs : small, anteroposteriorly flattened skull, short, flat-bridge nose, epicanthal fold, Brushfield's spots, short phalanges, widened spaces between the first and second digits of hands and feet (Goldstein's sign : wide space between the great toe, and the adjoining toe seen also in cretinism), Siegert's sign (the little fingers are short and curved inward), Sydney line (a palmar crease correlated with an increased risk for leukemia and other malignancies in children), simian crease or line (a single transverse palmar crease formed by fusion of the proximal and distal palmar creases; frequently seen in congenital disorders such as DS and rarely in normal persons), early decline in immune function, OSAS, and moderate to severe mental retardation, with early-onset Alzheimer's disease developing in the fourth or fifth decade. There is a 15- to 20-fold increased risk of leukemia : the most common type of leukemia to occur in patients with DS during the first few years of life is acute myelocytic leukemia (AML). However, after these patients reach age 5, the ratio of AML-to-acute lymphocytic leukemia (ALL) approaches that for children without DS. Transient myeloproliferative disorder (TMD) associated with pancytopenia, hepatosplenomegaly, and circulating immature WBCs, is found almost exclusively in DS infants with an incidence of approximately 10%. In most cases, TMD regresses spontaneously within the first 3 months of life, but in some children, it can be life threatening or even fatal. Despite the high rate of spontaneous regression, TMD can be a preleukemic disorder in 20-30% of children with DS. The types of malignancy, response to therapy, and clinical outcome in children with DS are also unique. There is an increased risk of leukemia with an equal incidence of lymphoid and myeloid leukemia. Acute megakaryocytic leukemia (AMKL) subtype is the most common form of AML in this setting, and is uncommon in children without DS. Somatic mutations of the gene encoding the hematopoetic growth factor GATA1 have been shown to be specific for TMD and AMKL in children with DS. Myelodysplastic syndrome can precede AML. Children with DS and leukemia are more sensitive to some chemotherapeutic agents such as methotrexate than other children which requires careful monitoring for toxicity. Although the risk for leukemia is higher in individuals with DS, these patients have a lower risk of developing solid tumors, with the exception of germ cell tumors, and perhaps retinoblastoma and lymphoma^ref. Reduced risk for developing atherosclerosis due to overexpression of Down syndrome critical region 1 (DSCR-1)
Laboratory examinations :
• first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free b-hCG subunit at 10 weeks 3 days through 13 weeks 6 days of gestation) at 11 weeks of gestation is better than second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation) but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening (risk results provided after each test) and fully integrated screening (single risk result provided) have high rates of detection of Down's syndrome, with low false positive rates^ref.
• increased erythrocyte mean corpuscular volume (MCV) is frequently found among DS infants and remains elevated throughout life in two-thirds of patients, making interpretation of red cell indices for diagnosis of nutritional anemias or bone marrow failure disorders more challenging.
Web resources :
• National Down Syndrome Society (NDDS)
• Growth charts for children with Down syndrome by Greg Richards
• trisomy 22 syndrome : a syndrome due to an extra chromosome 22, characterized typically by growth retardation, mental retardation, microcephaly, low-set or malformed ears, micrognathia, long philtrum, preauricular skin tag or sinus, and congenital heart disease. In males, there is small penis and/or undescended testes.
• Hutchinson-Gilford progeria syndrome (HGPS)

Epidemiology : 1-2 in every 8 million births. Since it was first described in 1886, > 100 cases have been reported worldwide.
Aetiology : germinal mutations in codon 608 (G608G) of LMNA / progerin (the gene for prelamin A and lamin C), which activates a cryptic splice site resulting in the in-frame loss of 150 nucleotides from the lamin A message and in the deletion of 50 aa within prelamin A. In normal cells, prelamin A is a "CAAX protein" that is farnesylated and then processed further to generate mature lamin A, which is a structural protein of the nuclear lamina. The mutant prelamin A in HGPS, which is commonly called progerin, retains the CAAX motif that triggers farnesylation, but the 50-aa deletion prevents the subsequent processing to mature lamin A. The deleted region includes a protein cleavage site that normally removes 15 amino acids, including a CAAX box farnesylation site, from the lamin A protein. The presence of progerin adversely affects the integrity of the nuclear lamina, resulting in misshapen nuclei and nuclear blebs.
Symptoms & signs : sufferers seem to age up to 10 times faster than normal. Children develop ...
• pinched and wrinkled skin
• alopecia
• growth retardation
• atherosclerosis
• lipodystrophy
• arthritis
• severe myalgia
• hip dislocations
• normal intelligence
By the time they are 4-5 years old, they look like wizened old people. Most die of severe premature atherosclerosis at an average age of 13 years, usually from a heart attack or stroke. HDL-Ch and adiponectin concentrations decreased significantly with increasing age in HGPS but not in control children. Mean T-Ch, LDL-Ch and HDL-Ch, triglyceride, and median CRP levels were similar between HGPS and control children. Declining HDL-Ch and adiponectin with advancing age may contribute to accelerated atherosclerotic plaque formation in HGPS. Several factors frequently associated with CVD risk in normal aging (elevated CRP, T-Ch and LDL-Ch) showed no difference and are unlikely to influence CVD risk in HGPS. HDL-Ch and adiponectin may represent significant mediators and potential therapeutic targets for atherosclerosis in HGPS^ref.
Therapy :
• farnesyl transferase inhibitors block the targeting of progerin to the nuclear envelope, and the mislocalization of progerin away from the nuclear envelope improves the nuclear blebbing phenotype^{ref1, ref2}; alendronate may help treat progeria by interfering with the faulty protein, and as yet unpublished experiments have shown it also improves the misshapen nucleus. To determine whether an FTI would ameliorate disease phenotypes in vivo, a gene-targeted mice was created with an HGPS mutation (LmnaHG/+) and then the effect of an FTI on disease phenotypes was examined. LmnaHG^/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness^ref
• RNAi might also work.
Web resources : Progeria Research Foundation (PRF)
• Canavan disease

Aetiology : mutations in aspartoacylase (ASPA), which acts to hydrolyze N-acetylaspartate (NAA) into L-aspartate and acetate, important for the increased cerebroside and sulfatide synthesis that occurs during postnatal CNS myelination^ref.
Therapy : gene therapy
• Noonan syndrome
• 1
• 2
Symptoms & signs : dwarfism, palpebral ptosis, pterygium colli, pulmonic valve stenosis, gonadotropic hypopituitarism, thyroiditis, primitive gonadal failure

• mitochondrial DNA mutations are quite a common cause of human genetic disease. Estimates of prevalence vary; established cases occur at a frequency of about 1 per 10 000 population. This rate, however, is likely to be a substantial underestimation. For instance, the prevalence of one mutation (A3243G) has been estimated at 1·6 per 10 000. Inevitably, in addition to underdiagnosis, there is a high rate of asymptomatic carriers. Mutations of the mitochondrial genome contribute substantially not only to mitochondrial encephalomyopathies, but also to conditions such as diabetes, deafness, and cardiomyopathy.
• MELAS syndrome
• MERFF syndrome
Therapy : palliative therapy; removal of noxious metabolites; administration of artificial electron acceptors, metabolites, and free radical scavengers; genetic counseling; and gene therapy
Experimental animal models : transfer of species-specific mitochondria into mouse embryos using mitochondrial DNA–depleted embryonic stem cells and cytoplast fusions that results in homoplasmy for the introduced mitochondrial background. Only a few homoplasmic offspring survive, and these are only male mice : the mitochondrial line is effectively extinguished in these offspring, as males cannot transmit the mitochondrial phenotype^ref

• preimplantation genetic diagnosis (PGD)
• predictive medicine : at-home genetic testing.
• DNA Direct currently offers genetic testing, a la carte with prices ranging from $199 to $380, for a predisposition to cystic fibrosis, blood clotting, iron overload and a heightened risk for lung and liver diseases. DNA Direct's breast cancer testing plans are modest. Initially, it will offer 2 of Myriad Genetics's less-complicated tests launched in 1996, which screen for only a few mutations on the key genes. DNA Direct expects the tests to cost roughly $300 each. Until DNA Direct came along, Myriad made the breast cancer test available only to patients who visited a doctor's office or a cancer clinic. Because DNA Direct employs doctors and genetic counselors to advise its customers, Myriad insists its deal with the company is no different from its traditional arrangements. Myriad still requires a doctor's order and a signed "informed consent" form for each test it processes. Skeptics fret that the online companies don't have the expertise to properly explain the often complicated results. There are only about 2,000 genetic counselors in the United States, the majority of whom work with pregnant women. A Centers for Disease Control and Prevention study last year found that primary care doctors in Atlanta and Denver were largely ill-prepared to handle a surge in demand for Myriad's tests after the company tested a $3 million direct-to-consumer advertising blitz in those two cities between September 2002 and February 2003

• The Association of Genetic Support of Australasia (AGSA)
• European Organisation for Rare Diseases (EurORDis)
• European Rare Diseases Therapeutic Initiative (ERDiTI)

• Genes and Disease [free at NCBI BookShelf !]

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