2008 Barcelona - European Society of Human Genetics

Cytogenetics
We herewith report two cases of Angelman syndrome with different
phenotypes .
First case, a 12 year-old girl, was admitted in our department for neurological
evaluation because of severe progressive toraco-lumbar scoliosis,
which occurred at the age of five. She also presented severe
mental retardation, absence of speech, autistic features, gait difficulties
with ataxia, hyperventilation episodes, and epileptic seizures . The
second case, a 4 year-old boy, was referred to our department for psychomotor
retardation . He had “happy-puppet” appearance, ataxic gait,
and severe mental retardation . Both children were born from healthy
non-consanguineous parents .
Clinical investigations included neurological evaluation, EEG, and
MRI .
Chromosomal studies were performed on peripheral blood lymphocytes,
by GTG banding. Locus specific BAC probes for critical region
15q11-13 and control probes were used for FISH analysis .
Normal karyotype, and 15q microdeletion was demonstrated in both
cases .
In the second case, the phenotype was highly suggestive for Angelman
syndrome, while in the first case, a differential diagnosis with Rett
syndrome was considered, especially because of the severe vertebral
scoliosis .
A diagnosis of Angelman syndrome should be considered in patients
with Rett-like phenotype. Molecular investigation of specific genetic
defect allowed, in our cases, the refinement of clinical diagnosis.
Financial support: CEEX (Project 150/2006) .
Acknowledgements: The authors thank Prof . Jean-Michel Dupont and
Mrs . Dominique Blancho for kindly providing BAC probes and Mrs .
Marioara Cristea for technical assistance .
P02.052
supravalvular aortic stenosis and Williams syndrome
G. S. Doros, M. Gafencu, A. Popoiu, B. Zoica, J. Puiu;
Victor Babes University of Medicine and Pharmacy, Timisoara, Romania, Timisoara,
Romania.
Aim: To present two cases of supravalvular aortic stenosis, selected
from the group of aortic stenosis children, admitted in the IIIrd Paediatric
Clinic in 2007, considered to be Williams syndrome . Williams
syndrome is caused by the deletion of genetic material from the region
q11 .2 of chromosome 7, including more than 20 genes, several of
these contributing to the characteristic features of this disorder .
Material and method: The patients were young children, one girl and
one boy, extremly friendly, with moderate mental retardation, short
stature, characteristic elfin face, joint laxity, systolic murmur and atraction
to music . They performed clinical examination, ECG, echocardiography,
cardiopulmonary X ray and angio CT, and after that they were
refered to the genetician, ENT and ophtalmologic department .
Results: Supravalvular aortic stenosis was confirmed in both cases,
associated with hypolasia of aortic arch and large coarctation of the
aorta in girl . She had from birth irreductible inguinal hernia, operated in
newborn period, followed by cardiopulmonary arrest, resuscitated . The
inghinolabial hernia reoccur . She also still have feeding problems for
semisolid food . Barium examination reveal large esofageal stenosis in
the 1/3 inferior part . Both of them have proeminent lips with an open
mouth, defective tooth enamel and spaced teeth . The girl associated
hypercalcemia .
Conclusions: After examinations, both patients are able to be considered
Williams syndrome. The FISH test to confirm this syndrome
has to be done . They are in follow up programe and we intend, after
confirmation of the genetic FISH test, to introduce them in Williams
Syndrome Children Association .
P02.053
clinical and molecular characterization of a cohort of 49 children
affected by Beckwith-Wiedemann syndrome and related
congenital defects
A. Mussa 1 , G. Baldassarre 1 , C. Molinatto 1 , L. Peruzzi 2 , E. Pepe 3 , A. Riccio 4 , M.
Cirillo Silengo 1 , G. B. Ferrero 1 ;
1 Department of Paediatrics, Torino, Italy, 2 Division of Nephrology , Regina Margherita
Children’s Hospital, Torino, Italy, 3 Department of Surgery, Regina Margherita
Children’s Hospital, Torino, Italy, 4 Dipartimento di Scienze Ambientali,
University of Napoli, Caserta, Italy.
The Beckwith-Wiedemann syndrome (BWS) is a paradigmatic condition
of overgrowth, characterized by macrosomia, congenital malformations,
neonatal metabolic anomalies, and predisposition to embryonal
malignancies, and a complex pattern of inheritance . Imprinting
defects in 2 gene clusters located at 11p15.5 have been identified in
about 75% of the cases . We report the clinical and molecular characterization
of a cohort of 49 patients (27 M, 22 F) presenting a classic
BWS (34) or a BWS-like phenotype (15) . A molecular lesion has
been identified in 16 out of the 39 patients analyzed (41%): KvDMR
hypomethylation in 7 (17 .9%), paternal uniparental disomy (UPD) in 6
(15 .4%), partial deletion of the IGF-2/H19 imprinting center in 3 (7 .7%),
2 maternally inherited and 1 de novo . All the patients presenting a genetic/epigenetic
lesion were affected by a classic BWS phenotype .
Seven children of the cohort (14 .3%) developed an embryonic neoplasm,
5 Wilm’s tumors and 2 hepatoblastomas; all neoplasms were
detected in patients presenting hemihyperplasia, and two of them were
diagnosed as affected by BWS only after the onset of the embryonic
tumor. We confirm the complex genotype-epigenotype/phenotype correlation
in BWS, describing three cases of the rare partial deletions of
the IGF/H19 imprinting center, documenting a high incidence of cancer
in our cohort, occurring even in children with an extremely mild expression
of the overgrowth syndrome
P02.054
molecular defects in patients with clinical symptoms of
Angelman syndrome
M. Gos1,2 , E. Obersztyn1 , M. Nawara1 , J. Bal1 , T. Mazurczak1 , A. Szpecht-Potocka1
;
1 2 Institute of Mother and Child, Warsaw, Poland, MSCM Cancer Center and
Institute of Oncology, Warsaw, Poland.
Angelman syndrome (AS) is a rare complex neurobehavioral disorder
that is due to defects in parental genetic imprinting at the 15q11-q13
region resulting in the aberrant expression of genes located within this
region . It was also suggested that mutations in UBE3A gene might be
responsible for AS .
We included 206 patients with clinical symptoms of AS in our study .
First, the analysis of methylation status was performed with MS-PCR
method using primers specific for SNRPN locus . The abnormal (paternal
only) methylation pattern was found in 23 patients and in several
cases it was due to the deletion in 15q11-q13 region as shown by
Methylation Specific Multiplex Ligation-dependent Probe Amplification
technique .
Patients with the normal methylation pattern were qualified to the
analysis of UBE3A coding sequence . Three missense (c .1291G>A -
p .Gly192Ser, c .1249G>A - p .Ala178Thr, c .1643A>G - p .Asn309Ser),
two frameshift (c .3228-3231del4 and c .1683-1689del7) and one
splice-site (c .2616A>G) mutations were found in our group . Moreover,
a 14bp deletion (c .3298-3311del14) in 3’UTR and stop codon change
(c .3275A>G) were detected in 2 and 3 patients, respectively . In 32
(15 .5%) patients, a small insertion in intron 6 (c .678 -48insT) always
linked to small deletion in intron 7 (c .720 -66_68delGAT) was identified.
Therefore, the molecular analysis confirmed the clinical diagnosis
of AS in 29 (14 .1%) examined cases .
However, defects in other genes e .g . MECP2, ATP10C or CDKL5/
STK9 might be responsible for AS specific phenotype. After careful
examination of clinical symptoms selected patients would be qualified
to further molecular analysis .
The study was supported by grant PBZ-KBN-122/P05/01-4 .
P02.055
Hypomethylation gradient at the 11p15 Different methylated
Region 2 (DmR2) in BWs patients
V. Romanelli 1,2 , L. Magano 1,2 , L. Fernández 1,2 , P. Arias 1,2 , I. Incera 1,2 , R. Gracia
Bouthelier 3 , P. Lapunzina 1,2 ;
1 Servicio de Genética Medica y Molecular, Hospital Universitario La Paz, Madrid,
Spain, 2 CIBERER, Centro de Investigación Biomédica en Red de Enfermedades
Raras, Madrid, Spain, 3 Servicio de Endocrinología Infantil, Hospital
Universitario La Paz, Madrid, Spain.
Beckwith-Wiedemann syndrome (BWS) is a genetic disease characterised
by somatic overgrowth, macroglossia, abdominal wall defect
and a variety of other findings including predisposition to embryonal
tumours .