2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.325
mowat-Wilson syndrome in a patient with severe eye anomalies
A. Medeira1 , G. Black2 , E. Seabright2 , I. Cordeiro1 ;
1Serviço de Genética Médica, Hospital de Santa Maria, Lisboa, Portugal,
2Department of Clinical Genetics, St. Mary’s Hospital, Manchester, United Kingdom.
Mowat-Wilson Syndrome (MWS) is a mental retardation syndrome
associated with distinctive facial features, frequent microcephaly and
epilepsy, and a variable spectrum of congenital anomalies, including
Hirshprung disease (HSCR), corpus callosum agenesis, genitourinary
and heart defects . Eye anomalies such as strabismus, microphtalmia,
colobomas, have been reported in a few patients .
Heterozygous mutations or deletions involving the zinc finger homeobox
1B gene (ZFHX1B) cause MWS
We report a 5 years old female patient with severe psychomotor delay,
epilepsy, microcephaly, deep set eyes, left eye anophtalmia , right eye
severe microphtalmia with retinal and optic nerve colobomas, broad
nose with long columella , short nasolabial distance, large mouth,
prominent chin, large ears with fleshy uplifted lobes, septo-optic dysplasia,
corpus callosum hypoplasia, HSCR, ventricular septal defect .
Mutation analysis of ZFHX1B gene identified a truncating mutation
c .2083C>T[p .Arg695X] .
MWS was originally reported as a syndromic form of HSCR . It is now
known that it frequently occurs without HSCR and can be recognized
by a consistent facial phenotype associated with severe mental retardation
. MWS and Goldberg-Shprintzen may overlap features but
faces are distinct . Some MWS patients have an ataxic gate and smiling
personality suggesting Angelman, but the caracteristic facial features
of MWS and the presence of other congenital anomalies usually
distinguish these conditions . The patient that we report presents the
main manifestations described in MWS including facial phenotype .
Eye anomalies have been reported in MWS, but not as severe as in
our patient . As far as we are aware this is the only MWS patient with
anophtalmia .
P01.326
Recurrence of mowat-Wilson syndrome in two siblings carrying
a novel mutation in the ZEB gene
M. Cecconi 1 , F. Forzano 1 , L. Garavelli 2 , M. Grasso 1 , E. Di Maria 1,3 , F. Faravelli 1 ;
1 Galliera Hospital, Genova, Italy, 2 Clinical Genetics Unit, S. Maria Nuova Hospital,
Reggio Emilia, Italy, 3 Dept. of Neuroscience, Ophthalmology and Genetics,
University of Genova, Genova, Italy.
The eponym Mowat-Wilson syndrome (MWS, OMIM #235730) designates
a multisystem congenital disease caused by heterozygous mutations
in the ZEB2 gene . Molecular diagnosis has helped to delineate
the cardinal signs (facial gestalt and delayed psychomotor development)
as well as several variously associated congenital disorders . To
date, literature describes approximately 180 patients with MWS . Only
three cases of recurrence in siblings were reported .
We describe two sisters with clinical features of MWS . Antenatal scanning
in the first sibling had revealed corpus callosum agenesis. Hypotonia
and feeding difficulties were present in the neonatal period. The
psychomotor development was delayed . US scans of the heart and
abdomen were normal . At our evaluation (5 years of age), facial dysmorphisms
strongly suggestive of MWS were noted . The second born
had a congenital complex heart disease . The surgical interventions
on heart defects were complicated by renal failure, airways infection,
denutrition and a cardiac arrest . At our evaluation (3 yrs .), she presented
microcephaly and facial dismorphisms, and with the sequelae
of cerebral anoxia .
Direct sequencing of ZEB2 revealed in both patients a novel heterozygous
c .310C>T transition, resulting in a stop codon (p .Q104X) . The
nucleotide substitution was not found in both parents, as well as in 94
unrelated control individuals . No evidence of somatic mosaicism was
found in the parents .
In light of this and previous reports, the recurrence risk provided to
families with an isolated MWS case should be frequently revisited .
Genetic counselling should consider intrinsic clinical variability, risk of
complications and still inaccurate empiric risk of recurrence .
P01.327
the placenta as the main clue to the diagnosis in a patient with
recurrent nonimmune hydrops fetalis
A. Moresco1 , N. Mazzitelli2 , N. Ronaldo3 , D. Caceres3 ;
1 2 Centro Nacional de Genética Médica, Buenos Aires, Argentina, Unidad de
Patología. Hospital Materno Infantil Ramón Sardá, Buenos Aires, Argentina,
3Servicio de Neonatología. Hospital Materno Infantil Ramón Sardá, Buenos
Aires, Argentina.
Introduction: Nonimmune hydrops fetalis (NIHF) usually carries a poor
prognosis and can have diverse causes . Lysosomal storage diseases
(LSD) are among the causes of NIHF .
Objective: Report a case of recurrent NIHF where the placental histology
lead to the investigation of Mucopolysaccharidosis VII (MPS VII) .
Materials and methods: Histopathological examination of the placenta
and serum beta-glucuronidase (GUSB) activity were performed .
Case report: In the second pregnancy of non-consanguineous parents
fetal hydrops was detected by an ultrasound scan at 22 weeks of gestation
. An earlier pregnancy resulted also in an hydropic fetus . There
was no evidence of immune hydrops, congenital infection or cardiovascular
abnormalities and a normal karyotype (46,XY) was obtained .
The pregnancy resulted in a depressed, hydropic infant, which despite
of intensive care died at 3 days of age .
The histopathological examination of the placenta, presented vacoulated
Hofbauer cells, which were possitive stained with Alcian Blue and
negative to PAS reaction . A normal appearence of the cytotrophoblast
was noted. The electron microscopic reflected the empty appearence
of the vacuoles . This features suggested a LSD with accumulation of
an acid mucopolysaccharide probably MPS- VII . The diagnosis was
confirmed GUSB activity that was neglible.
Conclusion: The placental histopathological examination performed
in this case of recurrent NIHF led to the suspicion of MPS-VII . The
diagnosis necessary had to be confirmed with the quantification of enzyme
activity . The placental proved to be an useful tool, in order to
limit the diagnostic resources . The accurate diagnosis is important for
adequate genetic counselling .
P01.328
Novel mutation in epithelial sodium channel alfa subunit
(SCNN1A) in a patient with a cystic fibrosis-like syndrome.
M. Bernal1 , F. Mora1 , J. F. Rodríguez-Gutiérrez1 , N. Hernández-Trujillo2 , J. A.
Brieva1 , A. Sampalo1 , A. Nieto1 ;
1Laboratorio de Diagnostico Molecular. Hospital Puerta del Mar, Cádiz, Spain,
2Servicio de Pediatría. Hospital Puerta del Mar, Cádiz, Spain.
A six months old girl clinically diagnosed of cystic fibrosis was admitted
for molecular study of CFTR gene . No mutations were detected using
Inno-Lipa CFTR19 and CFTR17+Tn kits . A subsequent complete
screening using DGGE and SSCP/HD was also negative (detection
level of 97%) . In the search for an alternative diagnosis, an extremely
high aldosterone and renin activity levels were found suggesting the
diagnosis of a multisystem primary type I pseudohypoaldosteronism .
This is a rare autosomal recessive disease that results from mutations
in the genes encoding epithelial sodium channel subunits (alfa, beta,
gamma) . Most mutations have been described in the alfa subunit gene
(SCNN1A) . This gene was sequenced in the patient and her parents .
A C>A substituion at position 301 resulting in a change of glutamine for
lysine at amino acid 101 (Q101K) was found . The patient was homozygous
for the mutation while parents were both heterozygous . This mutation
has not been reported to date. Residue 101 is at the first membrane-spanning
segment of the channel inside a structural motif that
has been shown to be essential to proper channel folding or assembly .
In addition the 101Q residue is highly evolutionarily conserved . This
data strongly suggest that Q101K mutation affects channel function
and support the diagnosis of multisystem primary pseudohypoaldosteronism
in this patient .
P01.329
mulvihill-smith syndrome - case Report
L. Caba, C. Rusu, A. Sireteanu, M. Covic;
University of Medicine and Pharmacy - Department of Medical Genetics, Iasi,
Romania.
Mulvihill-Smith syndrome is a very rare autosomal dominant disorder,
defined by low birth weight, dwarfism, a prematurely aged facial appearance,
pigmented naevi, hearing impairment and mental retardation .
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