clinical genetics : the study of the possible genetic factors influencing
the occurrence of clinical disorders.
The major impact of the completion of the human
genome sequence is the understanding of molecular pathophysiology of the
different syndromes, from which etiologic therapy will derive. In fact
every gene, when mutated, is a potential disease gene, and we end up the
new concept of "reverse medicine" (the opposite of reverse
genetics / positional cloning : the indirect exploration of a genetic
disease by learning the location of the responsible gene, isolating and
cloning its DNA, and translating the DNA to determine the protein product.
By comparing this product with the product of the normal allele, one can
also analyze the nature of the normal protein altered by the mutation),
by which we will derive new morbid entities and pathogenic pathways from
the knowledge of the structure and function of every gene. Regardless
of the strategy used, the ultimate validation relies on the finding of
pathogenic mutations in the suspected gene. The catalog of monogenic ("Mendelian")
diseases should be easily completed through simple computer interrogation
(in silico cloning). The major challenge today is to decipher the
polygenic and multifactorial etiology of common diseases. Anyway apart
from environmental influences, there are endogenous factors encrypted in
the genome itself, such as modifying genes, or polymorphisms in both coding
and non-coding sequences, and some so-called neutral alleles may modulate
the expresion of a key protein : it is now clear that monogenic diseases,
in which only one gene is affected by an etiological mutation, can no longer
be considered as monofactorial disorders. Some genetic diseases do not
follow a simple pattern of inheritance and exhibit phenotypic variation.
This can be explained as a monogenic disorder that is being affected by
the action of nonlinked genetic modifiers, e.g. :
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.
From an etiological standpoint, both phenotypic
and genetic heterogeneity invalidate the classical nosology, based upon
anatomoclinical criteria. Predictive
medicine (expecially referring to that arising from knowledge of intrinsic
aetiology) is a double-edged sword : beneficial if prevention or cure is
possible, detrimental if no action at all can be done !
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 brainref.
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 oneref.
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 estimatedref1,
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 replicationref.
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 studyref.
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 replicatedref.
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. Pokémonref).
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
connotationsref,
researchers need to be mindful when naming genes and syndromesref.
General resources
On-line Mendelian Inheritance in Men (OMIM)
database by Victor A.McKusick at Johns Hopkins University
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) :
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
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.
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 morphantsref Symptoms & signs : mental
retardation,
retinitis
pigmentosa,
obesity,
polydactyly,
and hypogonadism
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 syndromeref
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
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 proteinsref.
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 ileusref 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 potentialref 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,
Staphylococcus
aureus,
Haemophilus
influenzae,
and Burkholderia cepacia
complexref1,
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 clarifiedref1,
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
mannitolyticaref,
Pandoraea
ssp.ref,
Cupriavidus
respiraculiref,
Bordetella
bronchisepticarefand
Inquilinus
limosusref Laboratory
examinations :
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 diseaseref1,
ref2
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 CFref1,
ref2
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 3-8055-7960-8ref
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
leukodystrophy : disturbance of the
white substance of the brain due to defect in the formation and maintenance
of myelin in infants and children.
Hallervorden-Spatz disease
/ status dysmyelinatus / status dysmyelinisatus
: a hereditary disorder
characterized by marked reduction in the number of myelin sheaths of the
globus pallidus and substantia nigra, with accumulations of iron pigment,
progressive rigidity
beginning in the legs, choreoathetoid movements,
dysarthria,
and progressive mental deterioration. Transmitted as an autosomal recessive
trait, it usually begins in the first or second decade, with death usually
occurring before the thirtieth year.
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.
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 abnormalitiesref.
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-ALDref
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
spongy degeneration
of central nervous system / spongy degeneration of white matter / Canavan-van
Bogaert-Bertrand disease : a rare, autosomal recessive form of leukodystrophy,
characterized by 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
hereditary adult-onset
leukodystrophy : an autosomal dominant leukoencephalopathy characterized
by degeneration of the white matter, beginning at the frontal lobes and
extending to the centrum semiovale and cerebellum. Symptoms 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.
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)
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
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
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
hyperphenylalaninemia : any
of several autosomal recessive defects in the hydroxylation of phenylalanine
resulting in accumulation and excretion of dietary phenylalanine.
(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
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.
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)
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 performedref.
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 : a hereditary disorder of metabolism
transmitted as an autosomal recessive trait, involving a defect in dibasic
amino acid transport and resulting in a lack of sufficient ornithine to
support activity of ornithine transcarbamylase, an intramitochondrial urea
cycle enzyme, in the liver. It is characterized by growth retardation,
episodic hyperammonemia, seizures, mental
retardation,
hepatomegaly, muscle weakness, and osteopenia and is treated by 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
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.
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 generef
is characterized by ocular hypertelorism, anteverted nostrils, broad upper
lip, peculiar scrotal “shawl” above the penis, and small hands.
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 mutations
in AGS on chromosome 3p21 (AGS1)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 infectionsref.
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 diseaseref.
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 conditionref
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.
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.
Epidemiology : prevalence = 1 in 13,000
(higher in children born via FIVETref)
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
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
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
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 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 HRASref Symptoms & signs : mental
retardation
syndrome characterized by coarse face, loose skin, cardiomyopathy and predisposition
to tumors
Cree encephalitis : in 1988, Black
et alref
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 populationref1,
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 disorderref.
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 tumorsref
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
syndromeref
(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 sequencesref
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
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
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 phenotypesref.
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 sporadicref.
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 erythropoiesisref.
There is recent direct evidence in studies on knockout mice that complete
deficiency of RPS19 is lethalref.
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
Canadaref.
Phenotypic
heterogeneity is common in DBA : even within families, the degree of
anemia, response to treatment, and presence of congenital anomalies can
varyref
:
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 sarcomaref.
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 cancersref.
Furthermore instances of significant cytopenias, including aplastic anemia,
are emergingref.
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 erythrocyte adenosine deaminase (eADA) activity found in
approximately 85% of patientsref
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 DBARref,
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 wellref
(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 cellsref.
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).
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 dyskerinref.
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 / DKC2ref
on chromosome 3q. Disease anticipation is observed in families with this
disease and this is associated with progressive telomere shorteningref.
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 generationsref.
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 heterozygotesref.
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
reportref
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 ageref.
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 malignanciesref.
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 deficiencyref.
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 DCref.
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.
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 riskref.
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 :
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 bridgeworkref
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 : 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 flowref
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
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
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 tumorigenesisref
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; OMIM 180920
and OMIM 103420) 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 ALSGref.
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
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
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 ciliopathiesref Symptoms & signs : partial or complete
agenesis of the cerebellar vermis, with hypotonia, episodic hyperpnea,
mental
retardation,
nephronophthisisref,
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 syndromesref
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)
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 humansref.
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
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 GaS
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
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 meckelinref)
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
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.
Symptoms & signs : extensive facial
and limb defects, characterized by malar hypoplasia, downslanting palpebral
fissures, micrognathia, cleft lip and palate, cup-shaped ears, lower lid
ectropion, postaxial limb deficiencies, and syndactyly. Less frequently
present are heart defects and hearing loss
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
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.
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
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 presentref
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.
pancreatic and cerebellar
agenesis
Aetiology : 705insG and C886T mutations
in PTF1A cause truncation of the expressed PTF1A protein C-terminal to
the bHLH domainref
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 syndromeref
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).
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
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
diagnosisref.
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
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.
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.
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 SLSNref
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
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 7q11ref.
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 processingref1,
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 AMLref.
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 liferef,
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 fMLPref 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 85ref.
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 20ref.
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 cloneref.
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.
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
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 correlationsref 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
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 patientsref1,
ref2.
This deletion removes 24 genes, of which TBX1
seems the most important, causing a decrease in VEGF164 levels.
Other deleted genes are :
In rare instances, patients are hemizygous for 10p13, which encodes DGS2ref.
Deletion in the UFD1L gene at 22q11 has been describedref.
The term complete DiGeorge syndrome is used to describe patients
with the syndrome who have profound T-cell deficiencyref1,
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 infectionsref.
Therapy :
in a few cases, transplantation of fetal thymus was followed by immune
reconstitutionref1,
ref2,
ref3,
ref4.
However, some of those patients had partial DiGeorge syndrome with detectable
T-cell function before transplantation and might have improved without
therapyref1,
ref2.
Most published trials of postnatal thymus transplantation have been unsuccessfulref1,
ref2,
ref3.
Transplantation of bone marrow stem cells has not been successfulref
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 reconstitutionref
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
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 mutationref.
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
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 generated
in 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
leukodystrophyref.
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
replicationref.
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 MRIref
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 functionref
Wolfram syndrome /
DIDMOAD syndrome : an autosomal recessive syndrome, first evident in
childhood,
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)
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 :
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 III / osteogenesis imperfecta, progressively deforming, with normal
sclerae : the progressive deforming type, may be autosomal recessive
or a new mutation
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.
Aetiology : autosomal dominant mutations
in fibrillin
1 => dysregulation of either the gene for TGF-b
receptor 1
or 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
Epidemiology : late-onset homozygous cases
have been reportedref 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)
:
50% of patients present with hepatic disturbanceref.
Acute hepatic failure tends to be fulminant when it is associated with
Coombs-hemolytic
anemiaref;
patients can survive for only days or weeks unless liver
transplantation
is performedref.
Plasma
exchange
has proven effectiveref
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 alref
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 experienceref1,
ref2
nor autopsy seriesref1,
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 ageref.
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
studyref1,
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 studyref
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 populationref
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 controlsref.
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 numberref1,
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 illnessref1,
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 alref)
:
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 diagnosisref1,
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 studyref1,
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 comparisonsref.
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. Olynykref
reported that of 16 homozygotes (of whom two refused biopsy) 3 had fibrosis,
and one alcoholic subject had cirrhosis (25%). Bulajref
found 16 patients with cirrhosis and 17 with fibrosis out of 210 homozyotes
(15%), and Åsberg et alref
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
controlsref),
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
genotyperef.
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 diabetesref1,
ref2,
heart diseaseref1,
ref2,
and cancerref1,
ref2.
None of these claims has been widely substantiatedref1,
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 tardaref1,
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 womenref1,
ref2.
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
4 (HFE4) : an autosomal dominant disorder caused by mutation in the
SLC11A3
/ ferroportin
(includes some cases of African iron overloadref1,
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 phenotypesref.
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.
cancer
syndromes : 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.
inheritedautosomal 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
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
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 Bref
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
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 stressref1,
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 cuesref.
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 patientsref.
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 MDSref.
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
syndromesref.
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 chromosomesref
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.
Therapy : the median survival of patients
with FA is approximately 30 years but survival is extraordinarily variableref.
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 donorsref.
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 anemiaref.
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 probandref.
Clearly not all patients are candidates for transplantation.
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 :
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
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 cancerref.
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
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
ATLDref
genodermatosis : a genetically determined
disorder of the skin, usually generalized; if circumscribed, it is usually
called nevus
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
paragangliomaref
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.
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
IIBref
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.
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 pathwaysref.
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)
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
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 colonref
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.
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 statinsref.
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.)
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
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 :
TS2
/ TSC2 : mutations in TSC2.
The TSC1-TSC2 complex negatively regulates mTOR
and HIF,
but TSC2 regulates VEGF through mTOR-dependent and independent pathways
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
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 describedref.
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 : 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)
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
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)
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
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
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
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 macrothrombocytopeniaref.
Therapy : diet with low vegetal sterols
and cholesterol content
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
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
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
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 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
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 NPCref
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)
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
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
patientsref1,
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).
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
Prognosis : life expectancy of only 40
to 50 years
Differential diagnosis : chloroquine-induced
lipidosisref
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
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)
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.
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 syndromeref
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.
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
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 proteinsref 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)
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
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
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 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
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
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 periodref
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.
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.
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.
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.
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
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.
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
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 deficiencyref.
Since not all cases displayed PRKAG2 mutations, fatal congenital nonlysosomal
cardiac glycogenosis seems to be genetically heterogeneous.
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 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 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
Symptoms & signs : congenital deafness
is accompanied by retinitis pigmentosa, often ending in blindness; sometimes
mental
retardationand
disturbances of gait also occur
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
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 FXTASref
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
pathwayref.
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
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
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 genesref 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; transient
myeloproliferative disorder (TMD)
(1-10%). Children and adolescents with DS have a 15- to 20-fold greater
risk of leukemia than do normosomic individuals. The most common type of
leukemia to occur in patients with DS during the first few years of life
is AML. However, after these patients reach age 5, the ratio of acute
myelocytic leukemia (AML)-to-acute
lymphocytic leukemia (ALL)
approaches that for children without DS. AML-M7, which arises from megakaryocytic
precursors in the bone marrow, is the most common subtype of AML seen in
young children with DS. Reduced risk for developing solid
tumors
and 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 ratesref.
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.
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.
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
(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 ...
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 HGPSref.
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
phenotyperef1,
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.
RNAi might also work
Web resources : Progeria
Research Foundation (PRF)
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 myelinationref.
Therapy : gene
therapy
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.
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 phenotyperef
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
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