2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
Recent mutation reports indicate that mid-size gene deletions might
be a rather frequent cause of ARS. Therefore, analyses for mid-size
gene deletions should be routinely performed in mutation screenings
in ARS patients.
P02.014
Abnormal Expression of p63 (tP73L) in Bladder Exstrophy-
Epispadias complex
B. Ching 1 , G. Yagnik 1 , L. Qi 2 , A. Hata 1 , M. Ludwig 3 , H. Reutter 4 , C. Naidenov 5 , J.
P. Gearheart 6 , S. A. Boyadjiev 1 ;
1 Section of Genetics, University of California Davis, Sacramento, CA, United
States, 2 Rowe Program in Human Genetics, Sacramento, CA, United States,
3 Department of Clinical Biochemistry, University of Bonn, Germany, 4 Department
of Human Genetics, University of Bonn, Germany, 5 Department of Chemistry
and Biochemistry, Medical Academy, Sofia, Bulgaria, 6 Department of Urology,
The James Buchanan Brady Urological Institute, Johns Hopkins University,
Baltimore, MD, United States.
The bladder-exstrophy-epispadius-complex (BEEC) is a spectrum of
congenital anomalies of the lower abdominal wall, bladder, anterior
bony pelvis, and external genitalia, ranging from isolated epispadius
(EP), to classic bladder exstrophy (CBE), to cloacal exstrophy (CE;
its most severe form). The etiology of BEEC is unknown but there is
clear indication of genetic factors contributing to this birth defect. p63,
a p53 homolog located at chromosome 3q27-q29, was found to result
in a range of developmental defects of the skin and limbs as well as
bladder exstrophy in knockout p63-/- mice. Furthermore, p63 gain of
function mutations in humans cause genetic syndromes that frequently
present with urogenital anomalies. Although obvious mutations were
not detected, global dysregulation of variable p63 isoforms is apparent
in our results. Our data conclusively implicates p63 in the etiology of
BEEC. In eight out of 14 samples, we demonstrate expression differences
among p63 isoforms, including a total subclass of isoforms.
Direct sequencing is in progress to rule out regulatory region mutations.
We also identified a set of genes that are differentially expressed
(DE) between normal and exstrophic bladders, one of which is p63
(significantly underexpressed in BEEC bladder). p63 downstream effector,
Perp, is an integral part of desmosome and many other genes
in the DE set (~30%) were also found to play a role in desmosomal
assembly and/or cell-cell connectivity. Consistent with the suggested
multifactorial inheritance of this birth defect, we propose that abnormal
p63 expression is one of the etiologic factors for this condition.
P02.015
BPEs syndrome Ohdo type in child - case report
T. Marcovici1,2 , I. Sabau1,2 , I. Simedrea1,2 , O. Marginean1,2 , O. Belei1,2 , M.
Puiu1,2 ;
1 2 University of Medicine and Pharmacy, Timisoara, Romania, ”Louis Turcanu”
Children’s Emergency Hospital, Timisoara, Romania.
Background: BPES (Blepharophimosis-Ptosis-Epicantus inversus
Syndrome) is an autosomal, rare and complex dominant malformation
of the eyelids that may severely impair visual function. BPES locus
was assigned to 3q23. BPES syndrome Ohdo type is extremely rare.
It is characterized by BPES anomalies and in addition neurological
anomalies, growth retardation, congenital heart disease, abnormal
ears and clynodactily of fifth fingers are noticed.
Material and methods: We present a five-year and four months old
male infant admitted for abnormal phenotype. The patient underwent a
complete pediatric, ophthalmologic and neurologic evaluation.
Results: No similar case was known in the family. Pregnancy was
uncomplicated and the child was born at 38 weeks of gestation with
normal weight and length. In the first year of life seizures are mentioned.
The following facial characteristic features were noticed at clinical
examination: short eyelids, blepharophimosis, ptosis of the upper
eyelids, epicantus inversus, telecantus, arched eyebrows, flat, broad
nasal bridge, protruding ears. Limbs defects: clynodactily of fifth fingers,
flatfeet and genu valgum were present. Systolic cardiac murmur,
mild mental retardation and growth delay (15 kg weight, 100 cm height
and 50 cm occipito-frontal circumference) were determined. Cardiac
sonography found atrial septal defect. Ocular ultrasound was normal.
MLPA analysis with P036C&P070 kit didn’t find major mutations.
Conclusions: Child’s phenotype probably represents variable expression
of the Ohdo syndrome. Typical clinical features lead to establishing
the diagnosis and permit the surgical treatment of eyelids altera-
tions. The prevention of visual impairment is a very important goal in
this case.
P02.016
An unusual case with camptodactyly, thenar, hypothenar muscle
atrophy, spasmotic pains, excessive sweating and minor facial
anomalies
O. Kirbiyik, O. Cogulu, B. Durmaz, F. Ozkinay;
Ege University Faculty of Medicine, Izmir, Turkey.
An unusual case with camptodactyly, thenar, hypothenar muscle
atrophy, spasmotic pains, excessive sweating and minor facial
anomalies
Ozgur Kirbiyik, Ozgur Cogulu, Burak Durmaz, Ferda Ozkinay
We present a fifteen years old girl with deformities in her hands and
pain in the lower extremities. She was born to a consanguineous parents
at term. She had minor dysmorphological features such as hypertelorism,
epicanthus, long philtrum. She had a history of inguinal hernia
operation when she was 5 years old. The deformities started at age 11
years old, particularly in the hands, continued with stiffness and pain in
the hands and in the lower extremities. She had stiff skin, camptodactyly,
weak palmar crease pattern, abnormal dermatoglyphics, thenar
and hypotenar atrophy, excessive sweating. X-Rays showed flexion
contractures on her fingers but no erosion was noted. No laboratory
investigation was suggestive for scleroderma. Autoantibodies for rheumatoid
diseases were negative. Mutation analysis for both Crisponi
syndrome and camptodactyly-arthropathy-coxa vara-pericarditis syndrome
were negative.
P02.017
congenital heart defects in cHARGE syndrome patients with
cHD7 mutation
P. Parisot 1 , F. Bajolle 1 , T. Attié-Bitach 2,3 , S. Thomas 2 , G. Goudefroye 2 , V. Abadie
4 , S. Lyonnet 2,3 , D. Bonnet 1 ;
1 Centre national de référence Malformations cardiaques Congénitales Complexes
- M3C, Hôpital Necker-Enfants Malades, AP-HP, Université Paris Descartes,
Paris, France, 2 INSERM U781, Université Paris Descartes, Paris, France,
3 Department of genetics, Hôpital Necker-Enfants Malades, AP-HP, Paris,
France, 4 Department of pediatrics, Hôpital Necker-Enfants Malades, AP-HP,
Paris, France.
Background: CHARGE syndrome (MIM 214800) consists of a combination
of congenital malformations including Coloboma, Heart defects,
Atresia of choanae, Retardation of growth and developmental delay,
Genital anomalies and Ear anomalies. Diagnosis criteria have been recently
refined and several other features have been described such as
semi-circular canals and cranial nerve anomalies. A CHD7 gene mutation
is found in 60 % of patients with a clinical diagnosis of CHARGE
syndrome. Although frequently found, cardiovascular malformations
(CVM) are not specific.
Methods: In our series, 85% of CHARGE patients with CHD7 mutation
have a CVM. We report on the spectrum of CVM in 65 CHD7 mutated
patients (including 15 fetuses). All patients were precisely assessed for
their cardiac phenotype by echocardiography, CT scan or pathology.
Results: Conotruncal malformations (n=16), aortic arch anomalies
(n=10) and atrioventricular septal defects (n=15), were the most frequent
CVM. A rare association of atrioventricular septal defect and
transposition of the great arteries was described in one patient. Despite
the small number of mutated cases, our data suggest that hypomorphic
mutations (missense, splice sites) are less frequently associated
to a heart defect than nonsense and frameshift mutations.
Conclusions: Although being a minor criteria because of lack of specificity,
CVM proved to be very frequent in CHD7 mutated CHARGE patients.
The neural crest cells origin hypothesis of the CVM cannot account
for all observed defects. Cardiac progenitor cells of the second
heart field might be implicated in embryological mechanisms leading
to CVM in CHARGE syndrome.