2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.257
s248F mutation in cHNRA4 gene has a pathogenic role in
autosomal dominant nocturnal frontal lobe epilepsy
A. Zuniga, E. Pineda, I. Pitarch, A. Guerrero;
Hospital de la Ribera, Alzira (Valencia), Spain.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, OMIM
600513) has long been misdiagnosed as nocturnal paroxysmal dystonia,
parasomnias, or psychiatric disturbances . It is characterized by
clusters of brief nocturnal motor seizures, which originate in the frontal
cortex . The results of interictal electroencephalogram are usually normal,
as are computed tomographic scans and magnetic resonance images
. Seizures are usually well controlled by carbamazepine; however,
the recurrence risk after drug withdrawal often persists for life . This
syndrome is inherited as an autosomal dominant disorder with a penetrance
of 70% to 80% . Mutations in the alfa-4 subunit of the neuronal
nicotinic acetylcholine receptor gene (CHRNA4) has been described in
several families as responsible of ADNFLE .
We have studied a family with ADNFLE from the east of Spain . The
clinical appearance of the disease in this family was very similar to previously
described cases in which mutations in exon 5 of the CHRNA4
gene were found . So, the exon 5 of the CHRNA4 gene was amplified
between nucleotides 535 and 825 and polymerase chain reaction
products were purified and sequenced directly. We have identified in
three affected members of family a identify a C-to-T transition in the
CHRNA4 gene, resulting in a Ser-248-to-Phe (S248F) substitution in
the sixth amino acid position of the transmembrane domain 2 (M2) .
Some authors have suggested that the mutation caused reduced receptor
function . These data support the hypothesis that the phenotypic
expression of autosomal dominant nocturnal frontal lobe epilepsy is
caused by mutations in the CHRNA4 gene .
P01.258
Further delineation of the partial trisomy 3q phenotype
D. Mueller1 , W. Mueller2 , F. Fresser1 , G. Utermann1 , D. Kotzot1 ;
1 2 Division for Clinical Genetics, Innsbruck, Austria, Department of Pediatrics,
Reutte, Austria.
Partial trisomy 3q is characterized by postnatal growth retardation, microcephaly,
developmental delay, and distinct facial dysmorphisms .
Here, we report on a 3 years and 7 months old girl with minor dysmorphic
features (high frontal hairline, down-slanting palpebral fissures,
telecanthus, epicanthus, bulbous nasal tip, long philtrum, tapering
fingers, and short 5th fingers) and language accentuated development
delay due to partial trisomy 3q and partial monosomy 4p born to
healthy parents (mother 20 years, father 33 years) . After an unremarkable
pregnancy, she was spontaneously delivered at term . Weight was
3920g (>90th percentile), length was 51cm (50-75th percentile), and
OFC was 36 .5cm (>90th percentile) . At the age of 39 months height
was 100cm (50-75th percentile), weight was 17 .3kg (90-97th percentile),
and OFC was 52cm (97th percentile) .
GTG-banding and FISH with subtelomeric probes (Total Telomer Probe
Panel, Vysis ® ) and a probe specific for the Wolf-Hirschhorn syndrome
critical region (WHSCR) were performed according to standard procedures
and revealed a de novo trisomy 3q27->qtel and monosomy
4p16->ptel with a breackpoint distal to the WHSCR and proximal to
the subtelomeric 4p probe (karyotype: 46,XX,der(4)t(3;4)(q27;p16) .ish
der(4)(t(3;4)(D3S4560+;D4S3359-,WHSC1+CEP4+)) . For a more exact
breakpoint determination SNP-array analysis is underway .
In accordance with the cytogenetic results the girl shows no clinical
features of WHS, but facial dysmorphisms clearly resembling partial
trisomy 3q . The lack of postnatal growth retardation, microcephaly, and
malformations in our patient will help to improve genotype-phenotype
correlation in partial trisomy 3q .
P01.259
Optimizing clinical diagnosis for some genetic syndromes with
cleft lip and/or palate (Iasi Medical Genetics Center’s experience)
E. Braha, M. Volosciuc, C. Rusu, M. Covic;
University of Medicine and Pharmacy, Iasi, Romania.
Clefts of the lip (CL) and/or palate (CP) are among the most common
birth defects and require multidisciplinary approach for diagnosis and
treatment . The purpose of this report is to optimizing the clinical diagnosis
of some genetic syndromes for the patients with CL/P . We selected
106 patients (58 boys and 48 girls) with CL/P from the 8615 total
patients evaluated in Iasi Medical Genetics Centre in 2000-2004 . The
most patients (47 .2%) had CLP (19 .8% bilateral) or a CP (47 .2%); only
5 .66% had CL . We look at other anomalies associated with CL/P, associations
which have a high power to suggest the diagnosis . We used
diagnosis algorithms and POSSUM, OMD databases .The 52 .83% (56
patients) had CL/P associated with syndromes that include anomalies
involving multiple organs . Only 47 .17% were non-syndromic . Base on
evocative signs the syndromes diagnosed in our selected cohort were:
oculo-auriculo-vertebral spectrum (6), velocardiofacial syndrome (6),
chromosomal anomalies (5), amniotic bands (3), Smith Lemli Opitz (3),
EEC (3), holoprozencephaly (2), fetal alcohool (2), Aarskog (2), other
rare syndromes (18) . For accurate assessment, correct diagnosis, and
management, the patients should be dealt with in a team approach .
CL/P are frequent associated with others anomalies which emphasize
the importance of plurimalformative syndromes identification. Clinical
proper diagnosis is essential to initiate genetic test, the correct management
and genetic counselling .
P01.260
Bannayan-Riley-Ruvalcaba syndrome confirmed by mutation in
PTEN gene
R. Zordania, A. Lehtmets, H. Põder, K. Joost;
Tallinn` Children`s Hospital, Tallinn, Estonia.
Bannayan-Riley-Ruvalcaba (BRRS) and Cowden (CS) syndromes are
autosomal dominant allelic multiple hamartoma syndromes, both in
60-80% cases due to germline mutations in tumor supressor PTEN
gene . Clinical signs in childhood have many similarities, early diagnosis
using molecular genetic analysis is important as syndromes give
increased risk for different tumors .
We describe a family, where both young parents of our index patient
were treated due to tumors- mother had bladder carcinoma, treated
during pregnancy and father was treated due to embryonal testicular
carcinoma .
Proband is the first and only child in the family. His birth anthropometry
(4020g/52cm, OFC 41cm) was above 97th centile. During the first
two years of his life he had psychomotor developmental problems,
hypotonia, seizures with EEG changes, autistic features, unilateral hydrocele
and macrocephaly . Metabolic workshop excluded metabolic
disorders .
At the age of three years three lipomas were (histologically
proved)diagnosed- two subcutaneous and one pancreatic . The patient
had different skin symptoms, no pigmentation of the glans penis . He
had macrocephaly and mild mental retardation and some autistic features
and speech problems .
Mutation analysis of PTEN gene was performed by Dr .D .O .Robinsin
(Salisbury Health Care NHS Trust) . The patient is carring a C>A substitution
at base 144, in exon 2 of the PTEN gene . This mutation impairs
the function of PTEN and is the cause of the patient`s symptoms .
conclusion: clinical, pedigree data and results of moleculargenetic
investigations of the patient having Bannayan-Riley-Ruvalcaba syndrome
are presented. This is the first case of this syndrome in Estonia
confirmed PTEN gene mutation .
P01.261
Report of cockayne syndrome from iranian families
F. Afroozan, N. Almadani, Y. Shafeghati, M. H. Kariminejad;
Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Islamic Republic
of Iran.
Cocakyne Syndrome is an autosomal recessive multisystemic
condition,characterized by usually senile-like changes beginning ininfancy
.
Retinal degeneration,Impaired hearing and photosensitivity of thinskin
.
The disease is known to be genetically heterogeneous for which 3different
Loci have been identified on chromosomes 10,12,13.We have
studied five Iranian families,each with one affected child(threemale,two
female) .three of these cases are results of cansanguineous marrige
and the parents of the two cases are offspring of unrelated
couples .Their features and radiology were compatible with Cockayne
Syndrome .
The opthalmologist showed salt&pepper retinal pigmentation for two
ofthe affected children and optic atrophy for other three cases .
Assayes of DNA repair are performed on skin fibroblasts.The most-