2008 Barcelona - European Society of Human Genetics

Cytogenetics
the ears, camptodactyly, and abnormal genitalia . Genetic counselling
was given .
Although 4p-syndrome is a distinct entity, it can not be recognized
without cytogenetic evaluation as the features are variable sometimes
very mild .
P02.047
clinical and cytogenetic characteristics in Wolf-Hirschhorn
syndrome - considerations on five cases
E. Gorduza1 , M. Covic1 , M. Volosciuc1 , E. Braha1 , M. Gramescu1 , L. Butnariu1 ,
O. Bartsch2 ;
1 2 University of Medicine and Pharmacy Iasi, Iasi, Romania, Institute of Medical
Genetics, Mainz, Germany.
Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disease
(1/50.000 new-borns) generated by a 4p deletion. We present five
cases of WHS diagnosed in our service in last 10 years . In all cases we
discovered the following features of WHS: marked growth deficiency,
microcephaly, facial dysmorphism (ocular hypertelorism, down turned
“fishlike” mouth, short upper lip and philtrum). We found cardiac anomalies
in 4 cases, ocular abnormalities in 3 cases, cleft lip in 1 case and
talipes in 1 case . Chromosomal analysis was performed in all 5 cases .
At 3 patients, karyoptype revealed 4p deletion specific to WHS. In last
2 cases karyotype was normal and we made FISH analysis in Clinical
Genetic Institute in Dresden (Germany) . In both cases was found a
4p16 .3 microdeletion . In the last case, because of abnormal reproductive
history of mother (2 spontaneous abortions, and 1 child death in
neonate) the FISH analysis was made also in mother and indicated a
t(4;20)(p16;p13) translocation . In this situation our patient presented in
fact an association between a 4p partial monosomy and a small 20p
partial trisomy . In the last case we estimate a recurrence risk about
10% . Our study reveals the importance of clinical examination in WHS,
in all our cases clinical suspicion being confirmed. In addition, classical
chromosomal analysis is not sufficient for confirmation of diagnosis.
Thus, in all cases with strong evidences for WHS, but with normal
karyotype are required a FISH analysis . Also, genetic counselling is
difficult in some rare cases.
P02.048
Prenatal diagnosis of simultaneous Wolf-Hirschhorn and
deletion 4q syndromes in a ring chromosome 4
M. J. Gómez-Rodríguez1 , A. Moreno-Izquierdo1 , F. Fernández-Martínez1 , M.
Martín-Ramos1 , A. Galindo2 , A. Grañeras3 , E. Barreiro1 ;
1 2 Department of Genetics, Madrid, Spain, Department of Fetal Physiopathology,
Madrid, Spain, 3Department of fetal Physiopatholgy, Madrid, Spain.
The phenotypes in patients with segmental aneuploidy are syndromes
which often vary in their clinical manifestation depending on the size of
the chromosomal region involved .
Formation of a ring chromosome 4, often involves loss of 4p and 4q
telomeres and of more proximal regions on either or both chromosome
arms . Deletions of the distal short arm of one chromosome 4 involving
parts of 4p16 cause the Wolf-Hirschhorn (4p-) syndrome and deletions
on chromosome region 4q33-4qter have also been recognised as a
distinctive malformation syndrome .
To date, at least 17 cases with ring chromosome 4 have been described,
but only two cases were prenatally diagnosed .
We report a case of prenatal diagnosis corresponding to the pregnancy
of a 27 year old woman, which was referred for amniocentesis at 24
weeks of gestation because of intrauterine growth restriction (IUGR)
showing a foetal biometry corresponding to a 18 weeks of gestation .
Moreover, the fetus showed complex cardiac malformations .
Cytogenetic and molecular cytogenetic analysis of the cultured
amniocytes revealed mosaic for a de novo ring chromosome 4:
46XY(10),45XY,-4(10),46XY,r(4)(p16,q35)(16) .
The ring chromosome 4 was further characterized by fluorescence in
situ hybridization (FISH) using WCP 4, CEP 4 , tel 4q, tel 4p and the
Wolf-Hirschhorn syndrome (WHS) .
The prenatal and postnatal clinical features are well correlated with
those described for simultaneous Wolf-Hirschhorn and deletion 4q
syndromes .
P02.049
Evidence for epigenetic regulation of CDKN A in normal human
placenta
E. N. Tolmacheva, A. A. Kashevarova, I. N. Lebedev;
Research Institute of Medical Genetics, Tomsk, Russian Federation.
Placental development and trophoblast differentiation share many similarities
with the process of tumorigenesis . These are rapid proliferation,
invasiveness and gene expression profiles. It is possible, that this
analogy might provided by epigenetic mechanisms . To test this hypothesis
methylation status of four tumor suppressor genes in the normal
human placentas was investigated . Promoter methylation of p14ARF,
CDKN2A, CDKN2B and RB1 genes was analyzed by methyl-specific
and methylation-sensitive PCR in the cytotrophoblast and extraembryonic
mesoderm of 32 first-trimester induced abortions. Studied tissues
have different dynamics of epigenetic genome reprogramming and
level of methylation . No methylated alleles of p14ARF, CDKN2B and
RB1 genes were detected in normal extraembryonic tissues . However
aberrant methylation of the CDKN2A promoter was observed in 78%
of cases in both placental tissues . Heretofore aberrant methylation of
CDKN2A gene was frequently observed in different human cancers as
well as in 20% of hydatidiform moles, 40% of chorioncarcinomas (Xue
et al ., 2004) and even up to 14% cases of spontaneously aborted embryos
with normal karyotype (Park et al., 2008). Our data for the first
time have demonstrated that hypermethylation of CDKN2A with high
frequency can occur in normal human placenta . Tendency of decreasing
in mean gestational age between embryos with (8 .4 weeks, n=7) or
without methylation (10 .2 weeks, n=25) was found . It is possible, that
several cell populations with epigenetic inactivation of the cell-cycle
checkpoint genes can exist in placental tissues during some periods of
its development providing evidence for a new unresolved mechanism
of successful placentation .
P02.050
screening for 22q13 deletion syndrome in 40 patients with
clinical feautures suggestive of Angelman syndrome and normal
methylation test
F. García-Santiago 1,2 , M. Palomares 1,2 , L. Fernández 1,2 , P. Lapunzina 1,2 , V. F.
Montaño 1 , A. Delicado 1,2 ;
1 Servicio de Genética Hospital Universitario La Paz, Madrid, Spain, 2 Centro de
Investigación Biomédica en Red de Enfermedades Raras (CIBERER). ISCIII,
Madrid, Spain.
The 22q13 deletion syndrome has been associated with neonatal
hypotonia, developmental and mental delay, abscent or severe expressive
language delay, autistic-like behaviour and subtle facial dysmorphisms
. As some of those features are suggestive of Angelman
Syndrome (AS), testing for 22q13 .3 deletion in patients with AS features
without the characteristic molecular 15q abnormalities has been
suggested .
Forty patients with mental retardation, who had been previously referred
with a clinical diagnosis of AS and a normal methylation test
result, were included in the study . Patients had not been screened
for UBE3A mutations (about 10%) . Screened for 22q13 deletions appliying
the SALSA P188 MLPA kit contains 37 probes detecting sequences
on chromosome 22q13 . This kit including four probes in the
SHANK3 gene, which is thought to be responsible for at least part of
the phenotype, in particular the neurological symptoms .
A 22q13 deletion was discarted in 39/40 patients (97 .5%) because no
deletions were detected by MLPA analysis . Only one patient showed
an abnormal result consisting in a deletion of the probe located in exon
9 of SHANK3 gene, but this result needs to be confirmed.
This study confirms the findings of Vries (2002) et al. suggesting that
patients with an “Angelman phenotype” are not more likely to have a
22q13 .3 deletion than other individuals with mental retardation .
P02.051
Phenotypic variability in Angelman syndrome - report of two
cases
M. Budisteanu1,2 , A. Arghir2 , G. Cardos2 , S. Chirieac2 , S. Magureanu1 , A. Lungeanu2
;
1Clinical Hospital of Psychiatry “Prof. Dr. Al. Obregia”, Bucharest, Romania,
2 ”Victor Babes” National Institute, Bucharest, Romania.
Angelman syndrome is a complex neurodevelopmental disorder with a
difficult clinical diagnosis and heterogeneous genetic basis.