2008 Barcelona - European Society of Human Genetics

Clinical genetics
trasound were normal . A small isolated notch was noted on the right
pinna .
At age 4, right sensorineural deafness was found and cranial imaging
revealed bilateral middle and internal ear abnormalities (Mondini
defect, bilateral semicircular canal agenesis, large sacculus, ossicular
chain ankylosis), and hypoplastic olfactive tractus, without median line
defect .
At age 10, anosmia was diagnosed . Growth was conserved, except for
delay due to absence of puberty, and he performed well at school .
At age 13, screening of CHD7 by heteroduplex and sequence analysis
detected a c .6290A>G (p .Asp2097Gly) heterozygous mutation . Parents
have not yet been tested but different models predict a probable
pathogenic effect of this substitution .
Conclusions: This presentation suggests that CHARGE syndrome
(MIM 214800) has to be evoked in children with apparently isolated
sensorial deficiencies, and certainly in those with unilateral deafness
and inner ear radiological abnormalities, in agreement with recent clinical
criteria (Verloes) . CHD7 mutation screening would be helpful for
better characterization of these “predominantly sensorial” forms, and
if confirmed, could allow a more specific work-up and management,
with regards to the expanding knowledge on CHD7 disease spectrum
(neurological, mainly rhombencephalic, endocrinological and immunological
deficiencies).
P01.121
clinical and molecular characterisation of a cohort of
Portuguese cHARGE patients
A. B. Sousa 1 , A. Medeira 1 , D. Johnson 2 , A. B. Salgueiro 3 , H. G. Santos 4 , I.
Cordeiro 1 ;
1 Serviço de Genética do Hospital de Santa Maria, Lisboa, Portugal, 2 Duncan
Guthrie Institute, Yorkhill, Glasgow, United Kingdom, 3 Serviço de Pediatria do
Hospital Fernando da Fonseca, Lisboa, Portugal, 4 GenoMed, Lisboa, Portugal.
CHARGE is an acronym standing for Coloboma, Heart malformation,
choanal Atresia, Retardation of growth and/or development, Genital
anomalies and Ear anomalies . Since the original description, other
clinical features have been added to the CHARGE spectrum of anomalies,
namely rhombencephalic dysfunction, hypoplasia of the semicircular
canals and arhinencephaly . The diagnostic criteria now stress
the importance of the 3C triad (Coloboma, Choanal atresia, abnormal
semicircular Canals). Additionally, patients are classified as typical (3
major or 2 major and 2 minor criteria), partial or incomplete (2 major
and 1 minor criteria), or atypical (2 major or 1 major and 2 minor criteria)
. CHARGE was considered an association until recent years, when
CHD7 mutations were identified in approximately 2/3 of patients.
We reviewed the patients with a clinical diagnosis of CHARGE syndrome
who visited our Genetics Clinic . 10 patients met the most recent
diagnostic criteria. 5 cases could be classified as typical CHARGE and
5 cases were atypical . However, 3/5 of the latter were not checked
for hypoplasia of the semicircular canals, which could well alter their
status .
CHD7 mutation detection studies were undertaken in all these patients,
except for one of the typical CHARGE cases who died in the
neonatal period. Highly likely causative mutations were identified in
7 patients overall, 3/4 typical and 4/5 atypical cases . In the remaining
atypical CHARGE patient a sequence change of unknown clinical
significance was found. This variant was also present in the patient’s
mother, who has subtle facial asymmetry and anisocoria, complicating
result interpretation .
P01.122
A prenatal diagnosis of cHARGE syndrome
W. Courtens 1 , P. Clapuyt 2 , C. Barrea 3 , N. Revencu 1 , Y. Gillerot 1 , T. Detaille 4 , P.
Bernard 5 , J. Biard 6 ;
1 Center of Human Genetics UCL, Cliniques Universitaires St-Luc, 1200 Brussels,
Belgium, 2 Dept of Pediatric Radiology, Cliniques Universitaires St-Luc,
1200 Brussels, Belgium, 3 Dept of Cardiology, Cliniques Universitaires St-Luc,
1200 Brussels, Belgium, 4 Dept of Pediatrics, Cliniques Universitaires St-Luc,
1200 Brussels, Belgium, 5 Dept of Obstetrics,Cliniques Universitaires St-Luc,
1200 Brussels, Belgium, 6 Dept of Obstetrics, Cliniques Universitaires St-Luc,
1200 Brussels, Belgium.
We report on a female foetus in whom a CHARGE syndrome was
diagnosed at 31 weeks of gestation . A Fallot tetralogy and a cleft lip
and palate were observed at a fetal ultrasound examination performed
at ~23 weeks of pregnancy . Amniocentesis, performed in another hospital,
revealed a normal female karyotype . A control of the ultrasound
examination at 29 weeks’ gestation showed, in addition, the presence
of dysplastic cup-shaped ears, especially at the right side, evoking the
diagnosis of CHARGE syndrome . Fetal brain magnetic resonance was
suggestive for the presence of hypoplastic semi-circular canals, a finding
that was confirmed by a fetal CT scan of the inner ear.
The parents were young, healthy and non-consanguineous . Family
history was unremarkable, except for the presence of miscarriages .
The parents were informed about CHARGE syndrome and decided
to continue the pregnancy . The child, born at 37 5/7 weeks, had a
left-sided cleft lip and palate, a heart murmur 3/6, a facial asymmetry
(with right eye being smaller than the left eye) and typical CHARGE
ears . She had major cardio-respiratory problems and died soon after
birth . The parents refused post-mortem examination, but a cerebral
brain MRI could be performed post-mortem and showed a coloboma
of the left retina and absent olfactory bulbs . Blood analyses for CHD7
mutational screening are ongoing .
This case illustrates the use of both fetal brain MRI and CT scan of the
inner ear in establishing a prenatal diagnosis of CHARGE syndrome .
P01.123
A novel sOX9 mutation in a case with camptomelic dysplasia
L. Grozdanova 1 , M. Krasteva 2 , G. Scherer 3 , R. Stoeva 4 , E. Bausch 3 , I. Stoev 4 ,
T. Krastev 4 , A. Linev 4 , M. Stefanova 4,5 ;
1 Departmant of Medical Genetics, University Hospital, Plovdiv, Bulgaria,
2 Department of Obstetrics and Gynaecology, Medical University, Plovdiv, Bulgaria,
3 Institute of Human Genetics and Anthropology, University of Freiburg,
Freiburg, Germany, 4 Departmant of Pediatrics and Medical Genetics, Medical
University, Plovdiv, Bulgaria, 5 Center for Human Genetics, Free Flamish University
Hospital, Brussels, Belgium.
Camptomelic dysplasia (CD, MIM 114290)) is a rare, often lethal, dominantly
inherited, congenital osteochondrodysplasia, associated with
male-to-female autosomal sex reversal in two-thirds of the affected
karyotypic males . Prominent features are bowing and angulations of
long bones, Robin sequence, pelvis, chest and rib abnormalities . De
novo mutations of the SOX9 gene, a tissue-specific transcription factor
gene involved both in skeletogenesis and male sexual differentiation,
are known to be responsible for both CD and XY sex reversal . Here we
present a 4-month-old infant of young non-consanguineous parents
out of the Turkish minority group in Bulgaria . Femoral malformations
and macrocephaly were detected prenatally . The newborn was delivered
at term and presented with an extremely short birth length, below
-7 SD, dysmorphic facial features, median cleft palate, remarkably
bowed and short limbs, narrow asymmetric thorax, club feet, short deformed
toes, and radiographic features characteristic for camptomelic
dysplasia . Male pseudohermaphroditism with female external genitalia,
enlarged clitoris, and male karyotype was found . DNA analyses
revealed a novel de novo mutation of the SOX9 gene, Q401X . A similar
nonsense mutation, Y400X, has been described previously (Hum Mol
Genet 6:91, 1997) . In both cases, a truncated SOX9 protein results
that completely lacks the C-terminal transactivation domain (residues
402-509) . The Q401X mutant SOX9 protein will still be able to bind to
DNA, as it still retains the DNA-binding domain, but will be unable to
activate transcription of the genes that are regulated by this transcription
factor .
P01.124
Opsismodysplasia with renal agenesia: A case report
M. Mihaescu1,2 , G. Olaru2 , I. Sas2 , D. Navolan1,2 , D. Chiriac1,2 , E. Taurescu1,2 ,
D. Citu1,2 ;
1 2 University of Medicine, Timisoara, Romania, Hospital “dr. Dumitru Popescu”,
Timisoara, Romania.
Opsismodysplasia is a rare chondrodysplasia clinically characterised
by micromelia, respiratory distress, and major delay in skeletal ossification
.
We present a novel case of opsismodysplasia in a foetus after termination
of pregnancy at 30 weeks of gestation . Prenatal was diagnosed
during ultrasound in our clinic with shortness of the long bones and
short extremities, depressed nasal bridge, narrow thorax . The parent’s
rroms ethnic, delivered no information about the family consanguinity .
After termination of pregnancy the female new born lived only 30 minutes
. She was at birth: the weight 840g, the length 29 cm, PC 25 cm