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
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
aeruginosaref,
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.
Elastase and neutrophil counts were able to explain the majority
of variation in FEV1. Elastase was further shown to
have a significant longitudinal association with FEV1,
specifically a -2.9% decline in FEV1 (95% CI:
-5.0,-0.9) per 1 log increase in elastase. Although correlated
with FEV1, bacterial densities were unable to explain
clinically meaningful differences in FEV1 within and across
patientsref.
Rapid IL-1 release and signaling through the IL-1R represent key
steps in the innate immune response to P. aeruginosa
infection, and this process is deficient in cells lacking
functional CFTRref.
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
DF508 CFTR correctors
:
MPB-07ref
produces an anti-inflammatory effect in CF bronchial cells
exposed to P.aeruginosa in vitroref
VX-770 (Vertex Pharmaceuticals)
VX-809
ataluren / PTC124 (PTC Therapeutics) is an oral
drug that permits ribosomes to read through premature stop
codons in mRNA to produce functional protein in children
with nonsense mutations (10%)
activators of alternate (non-CF transmembrane regulator
[CFTR]) chloride channels
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
newborn screening was associated with improved growth,
reduced morbidity, and reduced therapy, yet generated
equivalent pulmonary outcome compared with late clinical
diagnosis, suggesting that newborn screening may slow cystic
fibrosis lung disease progressionref
maintenance azithromycin
therapy in patients with CF leads to macrolide resistance in
nearly all S. aureus carriers. Pulmonary function
improvement after initiation of azithromycin therapy seems
to be temporary and appears not to be related to macrolide
resistance of S. aureusref.
Photodynamic antimicrobial chemotherapy (PACT) could be one
potential alternative antimicrobial method. As
photosensitisers could be delivered to the lungs of CF
patients via inhalation, the current in vitro study
investigated the potential use of PACT in the treatment of P.
aeruginosa CF pulmonary infection. Delivery of red
light (635 nm) and 2 photosensitisers (toluidine blue O
(TBO) and m-tetra (N-methyl-4-pyridyl) porphine
tetra tosylate (TMP)) across artificial CF mucus was
successfully achievedref.
Biofilm formation in the CF lung likely occurs under
anaerobic conditions, is controlled by bacterial
quorum-sensing mechanisms, and is enhanced by environmental
components in the CF airway. P. aeruginosa possesses
regulatory pathways that recognize environmental cues to
favor either acute infection or chronic colonization. P.
aeruginosa that inhabit the respiratory tract
accumulate mutations favoring chronic colonization.
Azithromycin, a macrolide with clinical benefit in CF,
alters P. aeruginosa biofilm formation. Promising new
therapies that target biofilm formation include molecules
that disrupt quorum sensingref.
Prognosis : the median survival is
only about 35 yearsref
Web resources :
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
infantile
neuroaxonal
dystrophy
(INAD) / Seitelberger disease : symptoms start by age 2
and worsen over time, and include loss of head control and the
ability to sit, crawl or walk, as well as deteriorating vision
and speech. PLA2G6's discovery means a clinical test can be
developed to help families determine their chances of passing
the disorders to their children. PLA2G6 is among 18
lipid-metabolizing genes in a protein family known as
phospholipase A2 (PLA2), and INAD is the first inherited
disorder associated with mutations in one of these genes. Its
discovery "unequivocally" links PLA2 defects to
neurodegeneration, which is significant because similar lipid
metabolism changes are seen in neurodegeneration associated
with ischemia from stroke, spinal cord trauma, head injury and
Alzheimer's disease, making this metabolic pathway a potential
drug target.
leukodystrophy :
disturbance of the white substance of the brain due to defect
in the formation and maintenance of myelin in infants and
children.
neurodegeneration
with
brain iron accumulation (NBIA) / Hallervorden-Spatz
syndrome / status dysmyelinatus / status dysmyelinisatus
Epidemiology : incidence is 1 in
500,000 to 1 million.
Aetiology : recessive
Pathogenesis : marked reduction in the number of myelin
sheaths of the globus pallidus and substantia nigra, with
accumulations of iron pigment
Symptoms & signs : usually
begins in the first or second decade, with death usually
occurring before the thirtieth year; involuntary muscle
contractions, rigidity and spasms beginning in the legs, face
and torso, as well as confusion, disorientation, seizures,
stupor and dementia, choreoathetoid
movements, dysarthria.
Rapid deterioration, punctuated by stable periods, lasts 1-2
months, with the rate of progression correlating with the
patient's age – the later the onset, the better the patient
fares
Therapy : there is no cure
Alexander's disease
: an infantile form of leukodystrophy, characterized
histologically by the presence of eosinophilic material at
the surface of the brain and around its blood vessels,
resulting in brain enlargement.
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
Aetiology : autosomal recessive
Symptoms & signs : early
onset, widespread demyelination and vacuolation of the
cerebral white matter that gives rise to a spongy appearance,
severe mental
retardation,
megalocephaly, atony of the neck muscles, spasticity
of the arms and legs, and blindness, with death usually
occurring at about 18 months of age
adult-onset
autosomal
dominant
leukodystrophy (ADLD)is a slowly progressive
neurological disorder characterized by symmetrical
widespread myelin loss in the central nervous system, with a
phenotype similar to chronic progressive multiple sclerosis.
Aetiology : autosomal dominant
extra copy of the gene for the nuclear laminar protein lamin B1, resulting in
increased gene dosage in brain tissue from individuals with
ADLD. Increased expression of lamin B1 in Drosophila
melanogaster resulted in a degenerative phenotype. In
addition, an abnormal nuclear morphology was apparent when
cultured cells overexpressed this protein. This is the first
human disease attributable to mutations in the gene encoding
lamin B1. Antibodies to lamin B are found in individuals with
autoimmune diseases, and it is also an antigen recognized by a
monoclonal antibody raised against plaques from brains of
individuals with multiple sclerosis. This raises the
possibility that lamin B may be a link to the autoimmune
attack that occurs in multiple sclerosisref
Pathogenesis : degeneration of
the white matter, beginning at the frontal lobes and extending
to the centrum semiovale and cerebellum
Symptoms & signs : first
appear in the fourth, fifth, or sixth decade and include motor
disturbances, bowel and urinary
incontinence,
and orthostatic
systemic
arterial
hypotension;
mental acuity is often retained. Death occurs about 20 years
after the appearance of symptoms.
Aetiology : autosomal recessive
F382L amino acid substitution in SEC23A
on chromosome 14q13–q21. SEC23A is an essential component of the
COPII-coated vesicles that transport secretory proteins from the
endoplasmic reticulum to the Golgi complex. Electron microscopy
and immunofluorescence show that there is gross dilatation of
the endoplasmic reticulum in fibroblasts from individuals
affected with CLSD. These cells also exhibit cytoplasmic
mislocalization of SEC31. Cell-free vesicle budding assays show
that the F382L substitution results in loss of SEC23A function.
A phenotype reminiscent of CLSD is observed in zebrafish embryos
injected with sec23a-blocking morpholinosref
Symptoms & signs : late-closing
fontanels, sutural cataracts, facial dysmorphisms and skeletal
defects
pseudohypophosphatasia
: a condition resembling hypophosphatasia, characterized by
osteopathy of the skull and long bones, muscular hypotonia,
hypercalcemia, and increased urinary excretion of
phosphoethanolamine. It is distinguished by normal alkaline
phosphatase activity
acatalasia
Epidemiology : rare, observed
mainly in Japan and Switzerland
Aetiology : autosomal recessive
disorder due to virtual absence of catalase activity
Symptoms & signs :
hypocatalasia : an
asymptomatic variant of acatalasia in which some catalase
activity is present; it occurs in some heterozygotes
(usually)
Takahara's disease : oral ulcerations and
gangrene (approximately 50% of the Japanese cases)
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.
Aetiology : autosomal recessive
mutations in dibasic amino acid transport (SLC7A7)
Pathogenesis : lack of sufficient
ornithine to support activity of ornithine transcarbamylase,
an intramitochondrial urea cycle enzyme, in the liver
Symptoms & signs : growth
retardation, episodic hyperammonemia,
seizures, mental
retardation,
hepatomegaly, muscle weakness, hemophagocytic
syndrome
and osteopenia
Therapy : citrulline
supplementation.
carbohydrate
intolerance : inability to properly metabolize one or
more carbohydrate(s), as in
glucose intolerance : inability to properly
metabolize glucose, a type of carbohydrate intolerance; see
also impaired glucose tolerance, under tolerance, and
diabetes mellitus
hereditary fructose intolerance : an autosomal
recessive type of carbohydrate intolerance due to deficiency
of fructose bisphosphate aldolase, isozyme B, with onset in
infancy; it is characterized by hypoglycemia, with variable
manifestations of fructosuria, fructosemia, anorexia,
vomiting, failure to thrive, jaundice, splenomegaly, and an
aversion to fructose-containing foods. If untreated, it may
be fatal
disaccharide intolerance : inability to properly
metabolize one or more disaccharide(s), usually due to
deficiency of the corresponding disaccharidase(s), although
it may have other causes such as impaired absorption. The
results are a complex of symptoms seen after ingestion of
the disaccharide, particularly abdominal symptoms such as
diarrhea, flatulence, borborygmus, distention, and pain
disaccharidase
deficiency : less than normal activity of
disaccharidases of the intestinal mucosa; it usually
denotes a generalized deficiency of all such enzymes
secondary to a disorder of the small intestine, which
clinically may be manifest only as a deficiency of
lactase activity, but is sometimes used to denote
deficiency of a single enzyme or enzyme complex, e.g.,
lactase, sucrase-isomaltase, or trehalase
congenital or intestinal sucrase-isomaltase (sucrase-a-dextrinase) deficiency /
disaccharide intolerance I :
congenital sucrose intolerance : a disaccharide
intolerance specific for sucrose, usually due to a
congenital defect in the sucrase-isomaltase enzyme complex
sucrase-isomaltase deficiency : a
disaccharidase deficiency in which deficient activity of
the sucrase-isomaltase complex of the intestinal mucosa
results in malabsorption of sucrose and starch dextrins;
it is characterized by watery, osmotic-fermentative
diarrhea, sometimes leading to dehydration and
malnutrition, manifest in infancy (congenital sucrose
intolerance). While sucrase activity is always absent, a-dextrinase (isomaltase) activity
may be either greatly reduced or relatively normal
lactose intolerance : a disaccharide intolerance
specific for lactose, usually due to an inherited deficiency
of lactase activity in the intestinal mucosa; see also
lactase deficiency.
congenital lactose intolerance : 1. lactose
intolerance present at birth, due to deficiency of lactase
activity; see lactase deficiency. 2. a severe
autosomal dominant disorder with vomiting, dehydration,
failure to thrive, disacchariduria (including lactosuria
and aminoaciduria), and cataracts; it is probably due to
abnormal permeability of the gastric mucosa.
glutaricaciduria :
an autosomal recessive aminoacidopathy characterized by
accumulation and excretion of glutaric acid and occurring in 2
types:
type I is due to deficiency of glutaryl-CoA
dehydrogenase and is characterized by excretion also of
3-hydroxyglutaric acid, progressive dystonia and dyskinesia,
hypoglycemia, mild ketosis and acidosis, opisthotonus,
choreoathetosis, motor delay, mental
retardation,
hypotonia, and death within the first decade
type II / multiple acyl CoA dehydrogenation
deficiency (MADD) is due to deficiency of either
electron transfer flavoprotein (a-subunit) or electron
transfer flavoprotein:ubiquinone oxidoreductase and is
characterized by accumulation and excretion of glutaric and
2-hydroxyglutaric acids as well as multiple organic acids
normally oxidized by mitochondrial flavin-containing
acyl-CoA dehydrogenases, which require both proteins for
activity. Additional manifestations include hypoglycemia
without ketosis, metabolic acidosis, and a spectrum of
phenotypic manifestations varying with the particular
defect. Increasing age of onset is correlated with
decreasing severity; when of neonatal onset it may be
accompanied by congenital anomalies and is rapidly fatal
molybdenum
cofactor deficiency : an autosomal recessive disorder in
which deficiency of the molybdenum cofactor causes deficiency
of the molybdoenzymes sulfite oxidase, xanthine dehydrogenase,
and aldehyde oxidase, resulting in severe neurologic
abnormalities, dislocated ocular lenses, mental
retardation,
xanthinuria, and early death
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.
type I
interferonopathies
Aicardi-Goutieres
syndrome (AGS)
Epidemiology : in 1984, Jean
Aicardi and Françoise Goutiéres described 8 children
Aetiology :
mutations in IFIH1, the gene encoding MDA5, a protein
that responds to cytosolic viralref
autosomal recessive loss-of-function mutations in AGS1 /
TREX1, encoding the major mammalian 3' => 5' DNA
exonuclease on chromosome 3p21ref1,
ref2.
AGS can result from mutations in the genes encoding any
one of the 3 subunits of the human ribonuclease H2 enzyme
complex, explaining why clinical and immunological
features of AGS parallel those of transplacentally
acquired congenital viral infectionref
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
STING-associated
vasculopathy with onset in infancy (SAVI)
Aetiology :
gain-of-function mutations in STING / TMEM173 leading to a
chronic induction of type 1 interferon signalingref
Symptoms & signs :
neonatal-onset systemic inflammation with an elevated
erythrocyte sedimentation rate and elevated levels of
C-reactive protein, a severe cutaneous vasculopathy leading to
extensive tissue loss, and in three patients, major
interstitial lung disease. In the skin, there were features of
a dense neutrophilic inflammatory infiltrate with blood-vessel
damage, and lung biopsies from two patients revealed a
lymphocytic inflammatory infiltrate resulting in interstitial
fibrosis and emphysematous changes. The authors found that
STING was widely expressed, including in endothelial cells and
alveolar cells, and that vascular endothelial cells in biopsy
samples from lesional skin expressed markers of inflammation.
In contrast to the majority of patients with the
Aicardi–Goutičres syndrome, brain involvement was not noted in
patients with SAVI.
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.
leukocyte subset flow FISH telomere length measurement :
diagnostic sensitivity and specificity of very short
telomeres for DC were >90% for total lymphocytes, CD45RA+/CD20-
naive T-cells, and CD20+ B-cells.
Granulocyte and total leukocyte assays were not specific;
CD45RA- memory T-cells and CD57+
NK/NKT were not sensitiveref
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) 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.
hypertrichosis
cubiti
(HC)
/ hairy elbow syndrome consists of a localised
form of long vellus hair on the extensor surfaces of the
distal third of the upper arm and the proximal third of the
forearm bilaterally, or occasionally on other parts of the
body. In the 28 cases reported in the literature so far the
elbow hair abnormality was either isolated or associated with
short stature or other physical abnormalities. Most of these
cases were sporadic, but autosomal dominant as well as
autosomal recessive inheritance patterns have been postulatedref
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.
inherited defect in cholesterol and nonsterol isoprene
biosynthesis
Aetiology : autosomal recessive
disease is caused by a severe deficiency of mevalonate kinase
(residual activity, <1%) that results from a mutation in
the mevalonate kinase generef.
Mevalonate kinase is ubiquitously expressed and plays a
crucial role in the early stages of the isoprenoid
biosynthesis pathway. The enzyme catalyzes the phosphorylation
of mevalonic acid to 5-phosphomevalonate. The main end
products include prenylated proteins, heme A, dolichol,
ubiquinone (coenzyme Q-10), and cholesterol. As a result of
mevalonate kinase deficiency, mevalonic acid accumulates and
is excreted in the urine. Mutations in the same gene are also
responsible for the hyperimmunoglobulinemia
D
and
periodic fever syndrome (HIDS)ref1,
ref2,
an autosomal recessive disorder characterized by recurrent
febrile attacksref.
Classically, HIDS is not associated with dysmorphic features
or neurologic impairment. In addition, mevalonic acid is
excreted in the urine only during febrile attacks, and
mevalonate kinase activity is less severely impaired in HIDS
than in mevalonic aciduria (residual activity, >1%)ref1,
ref2.
In a subgroup of patients with HIDS, neurologic abnormalities
(e.g., mental retardation, ataxia, and epilepsy) may develop
with increasing ageref1,
ref2.
These findings suggest a continuum between mevalonic aciduria
and HIDS. The two syndromes belong to the group of
autoinflammatory syndromes, all of which are characterized by
recurrent episodes of inflammation without major involvement
of the adaptive immune system.
Symptoms & signs : the
clinical manifestations of mevalonic aciduria are diverseref.
Severely affected patients present from birth with failure to
thrive, microcephaly, dysmorphic features, and neurologic
involvement, including psychomotor retardation, cerebellar
atrophy, ataxia, and progressive myopathy. A periodic fever
syndrome with hepatosplenomegaly, lymphadenopathy, arthralgia,
and rashes dominates the clinical picture from infancy. Severe
polyarthritis and ocular involvement with retinal dystrophy
and cataracts develop in some patientsref.
Laboratory examinations : during
the febrile episodes, the erythrocyte sedimentation rate,
blood leukocyte counts, serum C-reactive protein levels, IgD
and IgA1 levels, and urinary leukotriene excretion
are greatly increased. Despite a lack of residual mevalonate
kinase activity in cultured cells from affected patients,
plasma levels of cholesterol lipoprotein, apolipoproteins,
steroid hormones, and primary bile acids are normal in most
patients. This paradox is related to
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and
the LDL cholesterol receptor, which are key regulatory sites
in the cholesterol pathway. In cultured skin fibroblasts from
patients with mevalonic aciduria, the activities of HMG-CoA
reductase and LDL cholesterol receptors are up-regulated,
apparently as compensatory responses that ensure sufficient
production of mevalonic acid and thus almost normal function
of the pathway. The biosynthesis of coenzyme Q10, by contrast,
is decreased in patients' fibroblasts, and there are decreased
levels of coenzyme Q10 in plasma. These findings suggest that
farnesyl pyrophosphate, an important intermediate at the
branch point between sterol and isoprenoid biosynthesis, is
shuttled toward cholesterol synthesis at the expense of
isoprene biosynthesis. The cause of the inflammatory attacks
is unclear. Mevalonic aciduria and HIDS trigger a dominance of
Th2, resulting in
elevated levels of IL-4, IL-5, and IL-6, TNF-a, and immunoglobulins (hyper-IgD or
hyper-IgE). Potential mechanisms by which mevalonate kinase
deficiency might induce a Th2 bias may reside
within cell-signaling proteins and lipid rafts — assemblages
of cholesterol and sphingolipids in the lipid bilayer.
Recently, a link was shown between apoptosis and aberrant
isoprenylation of proteins involved in cell-cycle regulation:
the apoptosis that statin-induced mevalonate depletion induces
in cultured cells could be inhibited with the addition of
farnesyl diphosphate or geranylgeranyl diphosphate, both of
which are cell-permeable isoprenoid analoguesref.
Urinary excretion of LTE4 is elevated in most
patients with mevalonic aciduria, and there is a positive
linear correlation between this elevation and increased
excretion of mevalonic acid. Increased urinary LTE4
excretion suggests that there is increased total systemic
cysteinyl leukotriene synthesisref.
The cysteinyl leukotrienes — LTC4, LTD4,
and LTE4 — are lipid mediators that are generated
in the 5-lipoxygenase pathway from arachidonic acid. The
cysteinyl leukotrienes are believed to increase vascular
permeability through the contraction of endothelial cells,
which results in edema and hemoconcentration.
Prognosis is poor; > 50% of
patients die during an inflammatory crisis in infancy or early
childhood, and very few survive to adolescenceref.
Treatment is mainly supportive.
in patients with mevalonic aciduria, the attacks can be
influenced only marginally, and the overall prognosis remains
poor. Direct replacement of the end product (coenzyme Q10 or
cholesterol) has failed to control the syndrome.
Corticosteroid treatment is effective in diminishing the
severity of attacks but cannot prevent crises. Treatment with
simvastatin (an inhibitor of
hydroxymethylglutaryl coenzyme A reductase, the enzyme that
catalyzes the formation of mevalonic acid) worsened the
clinical status of two patients with mevalonic aciduriaref.
The drug has also been tested recently in 6 patients with
HIDS, 5 of whom had a reduction in the number of febrile daysref.
Anakinra, an
interleukin-1–receptor antagonist, and TNF-a
antagonists (e.g., etanercept) have also been
used with a degree of success in patients with HIDSref.
The mechanism by which mevalonate kinase deficiency causes
recurrent episodes of fever and inflammation is unclear. Serum
levels of proinflammatory cytokines increase during attacks,
and mononuclear cells from patients with HIDS produce high
levels of interleukin-1 after in vitro stimulationref.
A 3-year-old boy with mevalonic aciduria whose condition had
failed to improve with antiinflammatory treatment underwent allogeneic HSCT
from an HLA-identical sister who was a heterozygous carrier of
the mutant gene. Successful donor lymphohematopoietic
engraftment resulted in correction of the immune function and
in a clear decrease in inflammatory cytokines, a reduction in
mevalonate excretion, and most important, a cessation of
febrile attacks during a 15-month follow-up periodref.
The marked enlargement of the liver and the spleen resolved
after the procedure, indicating that the hepatosplenomegaly
was an effect of extramedullary hematopoiesis rather than a
primary process in those organs. Although the results reported
by Neven et al. are encouraging, and bone marrow
transplantation may become an important therapeutic option for
patients with mevalonic aciduria who have primarily
inflammatory disease, important questions remain. Since the
excretion of mevalonate derived from extramedullary sources
remained high after the transplantation, it will be most
important to know whether further neurologic disease, such as
cerebellar atrophy or myopathy, develops. Concentrations of
coenzyme Q10 and other isoprenoid derivatives may not increase
sufficiently in other body tissues.
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. This chromosomal abnormality has been reported
also in human germ cell tumors and a patient with
Pallister-Killian syndrome and pineal tumor has been reportedref
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-Lefčvre
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
Tonoki syndrome
Symptoms & signs :
microcephaly, short stature, type B brachydactyly, nail
dysplasia, skeletal anomalies, and mental retardation.ref
Townes' syndrome : an
autosomal dominant syndrome
Symptoms & signs : auricular
anomalies, anal defects, limb and digit—particularly
thumb—anomalies, and renal deficiencies; it occasionally
includes cardiac disease, deafness, or cystic ovary.
trichorhinophalangeal
syndrome
: an autosomal recessive syndrome
Symptoms & signs : sparse,
slowly growing hair, pear-shaped nose with high philtrum, and
brachyphalangia with deformity of the fingers and wedge-shaped
epiphyses. Up to 50% of individuals may have Perthes-like hip
changes
trismus-pseudocamptodactyly
syndrome
: a rare autosomal dominant disorder
Symptoms & signs : inability to
open the mouth fully, facultative camptodactyly resulting from
shortened finger-flexor tendons, and short
stature.
Ullrich-Feichtiger
syndrome
Symptoms & signs : a condition
of micrognathia, hexadactyly, and genital abnormalities, with
depressed nose, small eyes, hypertelorism, and protuberant ears,
along with other defects.
Van der Woude's
syndrome : an autosomal dominant syndrome
Symptoms & signs : cleft lip
with or without cleft palate, with cysts of the lower lip.
DiGeorge syndrome
(DGS) / thymic aplasia or hypoplasia and pharyngeal pouch
syndrome (DiGeorge AM. Congenital absence of the thymus
and its immunological consequences concurrence with congenital
hypoparathyroidism. Birth Def.Orig.Abstr.Ser 4:116-121 (1968)ref1,
ref2)
Aetiology : a hemizygous deletion
in chromosome 22q11.2 is found in 60-70% of 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
Duane
retraction
syndrome is a congenital disorder of ocular
motility characterized by limited abduction, adduction or
both. It is unilateral in 80% of cases.
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 generatedin vitro. In contrast, few GFAP+
astrocytes were present in primary cultures, induction of
astrocytes was severely compromised, and the few astrocytes
generated showed abnormal morphologies and antigenic
phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi
targeting of EIF2B5 severely compromised the induction of
GFAP+ cells from normal human glial progenitors. This raises
the possibility that a deficiency in astrocyte function may
contribute to the loss of white matter in VWM 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 1or
that for TGF-b receptor 2
Symptoms & signs :
dolichostenomelia and arachnodactyly, as
well as the pectus excavatum and pectus carinatum (due to
represent excessive longitudinal growth of tubular bones in
the limbs, fingers, and ribs), subluxation of the lens,
cardiovascular abnormalities (commonly aneurysm
of
the
ascending aorta),
vertebral column deformity (scoliosis and thoracic lordosis),
wide-set eyes, a cleft
palate or
split uvula. In these patients, the aorta breaks at a much
smaller size than it does in people with Marfan syndrome or
other causes of aneurysm, making identifying these patients
critical. The syndrome-defining traits can have a wide range
of severity, and some other abnormalities, including
congenital heart and brain defects and skeletal abnormalities
such as early fusion of the bones of the skull or curvature of
the spine
Web resources : The
William
S. Smilow Center for Marfan Syndrome Research at the
Johns Hopkins University School of Medicine
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 Ĺsberg 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 Ĺsberg 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.
Pathogenesis : HFE C282Y is an
example of a mutant protein that does not fold correctly, is
retained in the endoplasmic reticulum, and was found
previously to diminish surface expression of MHC class I
(MHC-I). We now show that its expression in 293T cells
triggers an unfolded protein response (UPR), as revealed by
the increased levels of H chain binding protein, GRP94, and
C/EBP homologous protein. Elevated levels of these proteins
were also found in HFE C282Y homozygous PBMCs. Following the
UPR induction, a decrease in MHC-I cell surface expression was
observed. This defect in MHC-I could be mimicked, however, by
overexpression of transcriptionally active isoforms of
activating transcription factor-6 and X box-binding protein-1,
which induced the UPR, and reversed in HFE C282Y-expressing
cells by using dominant-negative constructs that block UPR
signaling. The present results provide evidence to the finding
that stimulation of an UPR affects MHC-I expressionref
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.
Aetiology
: a deficiency of the enzyme flavin-containing
monooxygenase 3 (FMO3) in the liver, which oxidises the odorous
trimethylamine (TMA) into its nonodorous N-oxide (TMA N-oxide) Pathogenesis : large
amounts of trimethylamine in urine, sweat and breath Symptoms & signs: aroma of fish,
which had a profound influence on his life
Laboratory examination : ratio of TMA-N-oxide to (TMA+TMA-N-oxide)
in urine < 1 Treatment : strict
diet. TMA-N-oxide is present in considerable amounts in marine
fish and after death is converted to TMA by bacteria resulting in
the characteristic smell of rotting
fish
cancersyndromes : early
onset, multifocal, bilateral. TGFBR1*6A gene is prevalent in around
15-16% of the cancer patients and is found in around 10% of
the general population. People with 2 copies of the mutated
gene have double this risk. By contrast BRCA1 and BRCA2, which
are thought to account for between 5% and 10% of breast cancer
cases, are found in 1 in 500 people. In normal cells it
inhibits their growth : however, once a cell becomes cancerous
it accelerates their growth. TGFRB1-6A gene may be to blame
for 7% of all breast cancers, nearly 11% of all ovarian
cancers and 5.5% of all colon cancers. It is less commonly
involved in a range of other cancers.
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 ŕ
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 98 recipients of unrelated donor BMT, transplanted
between 1990 and 2003, probabilities of neutrophil
(89% vs. 69%, p=0.02) and platelet (74% vs. 23%,
p<0.001) recovery were higher after fludarabine
than non-fludarabine containing regimens. Risks of
acute GVHD (RR 4.29, p<0.001) were higher with non
T-cell depleted grafts. Day-100 mortality rate was
significantly higher after non-fludarabine than
fludarabine containing regimens (65% vs. 24%,
respectively p<0.001). Corresponding 3-year
adjusted overall survival rates were 13% vs. 52%
(p<0.001). In addition, mortality was higher in
recipients who were older (>10 years), CMV
seropositive and received >20-blood product
transfusions pre-BMT. Based on these results
significant practice changes are suggested: use of a
fludarabine containing conditioning regimen in the
context of T cell depleted marrow allografts and
earlier referral for transplantation prior to
excessive transfusions in patients with marrow failureref.
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.
Risk of head and neck squamous cell cancer and death in
patients with Fanconi anemia who did and did not receive
HSCTref
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; green
urine
Therapy : patients respond well
to prolonged oral administration of nicotinamide.
thesaurismoses
/
inherited storage diseases : an IEM in which some
substance accumulates or is stored in certain cells in
unusually large amounts; the stored substances may be
lipids, proteins, carbohydrates, or other substances
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
recombinant human a-galactosidase A replacement
therapy
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
type 2 / severe bile salt export pump (BSEP)
deficiency
Aetiology : recessive mutations
in ABCB11, the gene encoding BSEPref1,
ref2.
BSEP is expressed at the canalicular membrane of the
hepatocytes and transports bile acids into the canalicular
space, using ATP as an energy sourceref.
Hepatocyte canaliculi in most patients carrying ABCB11
mutations express little or no detectable BSEPref.
Children with severe BSEP deficiency typically have jaundice
and pruritus within the first few months of life. Early-onset
cholestasis progresses to hepatic fibrosis, cirrhosis, and
end-stage liver diseaseref.
Affected children are also at increased risk for liver cancerref1,
ref2.
Biochemical and histopathological features of this disorder
include elevated serum concentrations of bile acids,
intrahepatic cholestasis, and often, giant-cell
transformation. Serum values of gGT
activity are normal, despite the degree of conjugated
hyperbilirubinemiaref1,
ref2,
ref3.9,10,11
Liver
disease
caused by severe BSEP deficiency is usually resistant to
medical treatment; therefore, for most patients,
transplantation becomes necessaryref1,
ref2.
Rare phenotypic recurrences of BSEP deficiency that takes
place after liver replacement correlate with the presence in
serum of blocking antibodies against BSEPref.
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. There is a 15- to
20-fold increased risk of leukemia : the most common type of
leukemia to occur in patients with DS during the first few
years of life is acute
myelocytic
leukemia (AML).
However, after these patients reach age 5, the ratio of
AML-to-acute
lymphocytic leukemia (ALL) approaches that
for children without DS. Transient
myeloproliferative
disorder
(TMD)
associated with pancytopenia, hepatosplenomegaly, and
circulating immature WBCs, is found almost exclusively in DS
infants with an incidence of approximately 10%. In most
cases, TMD regresses spontaneously within the first 3 months
of life, but in some children, it can be life threatening or
even fatal. Despite the high rate of spontaneous regression,
TMD can be a preleukemic disorder in 20-30% of children with
DS. The types of malignancy, response to therapy, and
clinical outcome in children with DS are also unique. There
is an increased risk of leukemia with an equal incidence of
lymphoid and myeloid leukemia. Acute megakaryocytic leukemia
(AMKL) subtype is the most common form of AML in this
setting, and is uncommon in children without DS. Somatic
mutations of the gene encoding the hematopoetic growth
factor GATA1 have been shown to be
specific for TMD and AMKL in children with DS.
Myelodysplastic syndrome can precede AML. Children with DS
and leukemia are more sensitive to some chemotherapeutic
agents such as methotrexate than other children which
requires careful monitoring for toxicity. Although the risk
for leukemia is higher in individuals with DS, these
patients have a lower risk of developing solid tumors, with the
exception of germ
cell tumors,
and perhaps retinoblastoma
and lymphomaref.
Reduced risk for developing atherosclerosis
due to overexpression of Down
syndrome
critical
region 1 (DSCR-1)
Laboratory examinations :
first-trimester combined screening (measurement of
nuchal translucency, pregnancy-associated plasma protein
A [PAPP-A], and the free b-hCG
subunit at 10 weeks 3 days through 13 weeks 6 days of
gestation) at 11 weeks of gestation is better than
second-trimester quadruple screening (measurement of
alpha-fetoprotein, total human chorionic gonadotropin,
unconjugated estriol, and inhibin A at 15 through 18
weeks of gestation) but at 13 weeks has results similar
to second-trimester quadruple screening. Both stepwise
sequential screening (risk results provided after each
test) and fully integrated screening (single risk result
provided) have high rates of detection of Down's
syndrome, with low false positive 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 / progerin
(the gene for prelamin A and lamin C), which activates a cryptic
splice site resulting in the in-frame loss of 150 nucleotides
from the lamin A message and in the deletion of 50 aa within
prelamin A. In normal cells, prelamin A is a "CAAX protein" that
is farnesylated and then processed further to generate mature
lamin A, which is a structural protein of the nuclear lamina.
The mutant prelamin A in HGPS, which is commonly called
progerin, retains the CAAX motif that triggers farnesylation,
but the 50-aa deletion prevents the subsequent processing to
mature lamin A. The deleted region includes a protein cleavage
site that normally removes 15 amino acids, including a CAAX box
farnesylation site, from the lamin A protein. The presence of
progerin adversely affects the integrity of the nuclear lamina,
resulting in misshapen nuclei and nuclear blebs.
Symptoms & signs : sufferers
seem to age up to 10 times faster than normal. Children develop
...
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. To determine whether an FTI would
ameliorate disease phenotypes in vivo, a
gene-targeted mice was created with an HGPS mutation
(LmnaHG/+) and then the effect of an FTI on disease
phenotypes was examined. LmnaHG/+ mice exhibited
phenotypes similar to those in human HGPS patients,
including retarded growth, reduced amounts of adipose
tissue, micrognathia, osteoporosis, and osteolytic lesions
in bone. Osteolytic lesions in the ribs led to spontaneous
bone fractures. Treatment with an FTI increased adipose
tissue mass, improved body weight curves, reduced the number
of rib fractures, and improved bone mineralization and bone
cortical thicknessref
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
cell-free
DNA-based noninvasive prenatal screening / noninvasive
prenatal diagnosis /noninvasive prenatal testing:
higher detection rates for trisomy 21 (Down's syndrome)
(99.0%), trisomy 18 (96.8%), and trisomy 13 (92.1%) than
previous noninvasive prenatal screening methods. Circulating
cell-free DNA is derived from both maternal and placental
tissues, so intrinsic biologic factors can influence the
accuracy :
As recommended by the American College of
Obstetricians and Gynecologists and the Society for
Maternal-Fetal Medicineref3, positive findings on noninvasive
prenatal screening must be followed by invasive prenatal
diagnostic testing before any irreversible decisions are maderef
at-home genetic testing.
DNA Direct
currently offers genetic testing, a la carte with prices
ranging from $199 to $380, for a predisposition to cystic
fibrosis, blood clotting, iron overload and a heightened
risk for lung and liver diseases. DNA Direct's breast cancer
testing plans are modest. Initially, it will offer 2 of Myriad Genetics's
less-complicated tests launched in 1996, which screen for
only a few mutations on the key genes. DNA Direct expects
the tests to cost roughly $300 each. Until DNA Direct came
along, Myriad made the breast cancer test available only to
patients who visited a doctor's office or a cancer clinic.
Because DNA Direct employs doctors and genetic counselors to
advise its customers, Myriad insists its deal with the
company is no different from its traditional arrangements.
Myriad still requires a doctor's order and a signed
"informed consent" form for each test it processes. Skeptics
fret that the online companies don't have the expertise to
properly explain the often complicated results. There are
only about 2,000 genetic counselors in the United States,
the majority of whom work with pregnant women. A Centers for
Disease Control and Prevention study last year found that
primary care doctors in Atlanta and Denver were largely
ill-prepared to handle a surge in demand for Myriad's tests
after the company tested a $3 million direct-to-consumer
advertising blitz in those two cities between September 2002
and February 2003