2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.253
The first case of Berardinelli-Seip congenital lypodystrophy
reported in Lithuania
L. Cimbalistienė 1 , V. Černiauskienė 2 , V. Kučinskas 1 ;
1 Department of Human and Medical Genetics of Vilnius University, Vilnius,
Lithuania, 2 Vilnius University Children’s Hospital, Vilnius, Lithuania.
Berardinelli-Seip congenital lypodystrophy (BSCL) syndrome is a extremely
rare autosomal recessive disorder, with estimated prevalence
of 1 in 10 million population . Two genes are known to be associated
with BSLC: AGPAT and BSCL2 . Individuals with mutations in BSCL2
include whites of varying ethnicities originated mostly from Europe and
Middle East, and with muations in AGPAT2 typically originate from
sub-Saharan Africa and Maghreb .
case report. Our presented patient, male, was the first child of non
consanquineous parents Lithuanian origin . BSCL syndrome was diagnosed
one month after birth by the phenotypic characteristics
of the syndrome . At the age of the 9 years patient had total loss of
subcutaneous fat, muscular hypertrophy, long extremities, acromegalic
appearance, dry and curly hair, umbilical hernia, hyperhidrosis,
distinct acanthosis nigricans, marked hepatosplenomegaly, divergent
alternant strabismus, hypermethropia, slight mental retardation . Patient’s
pubertal status was stage 2 according to Tanner’s charts, the
bone age was of 14 years . His blood pressure was slightly increased,
he had increased fasting glucose, dyslipidemia, mild proteinuria,
marked hyperinsulinemia, increased hepatic enzymes, signs of left
ventricular hypertrophy . Liver biopsy showed steatohepatitis of low
activity and hepatic fibrosis. Mutation analysis revealed that our patient
was compound heterozygous for two mutations of BSCL2 gene
[c .458C>A]+[c .412C>T] (testing was performed in Belgium, Loverval,
Human Genetic Centre). The results confirmed the clinical diagnosis of
BSCL and allowed assignment to type 2 . To our knowledge this is the
first report of Berardinelli-Seip syndrome in Lithuania.
P01.254
Biallelic BRCA2 -the first Greek Cypriot Family reported
V. C. Anastasiadou 1 , E. S Aristidou 1 , A. Kotti 2 , T. Delikurt 1 , D. Georgiou 3 , A.
Hadjisavvas 4 , K. Kyriacou 4 ;
1 Clinical Genetics Service, Cyprus Institute of Neurology and Genetics, Nicosia,
Cyprus, 2 Clinical Genetics Service, Makarios Medical Centre, Nicosia, Cyprus,
3 Department of Cytogenetics, Makarios Medical Centre, Nicosia, Cyprus, 4 Department
of Electron Microscopy and Molecular Pathology, Cyprus Institute of
Neurology and Genetics, Nicosia, Cyprus.
MM was born with multiple congenital anomalies, affecting mainly her
growth, limbs, digits and kidneys . She also had short stature, microcephaly
and dysmorphic facial features . Her right thumb was ectopic
whereas her left thumb was absent . Fanconi anemia (FA) was suggested
.
Chromosomal examination revealed anomalies (end to end fusion,
deletions and chromatid breaks) also compatible with the clinical diagnosis
of FA . MM was diagnosed with metastatic neuroblastoma at six
months of age and passed away a month later .
Parents had three miscarriages. At the 24th week of their fifth pregnancy
(in vitro fertilization) fetus was found to be microcephalic and were
referred back for genetic counselling . Based on family history of breast
cancer both parents were tested for BRCA mutations and found to be
positive for the BRCA2 mutation 8984DelG which has been reported
as a founder mutation among Greek Cypriots . DNA stored from MM
was tested and found homozygous for BRCA2 alleles . The FA phenotype
related to biallelic BRCA2 is associated with high spontaneous
chromosome aberration rate , less frequent bone marrow suppression
and a different spectrum of childhood cancers . Cancer risk for children
with biallelic BRCA2 mutations may be very high. This is the first family
diagnosed among Greek Cypriots with biallelic BRCA2 mutations
manifesting breast cancer and FA .
P01.255
Expansion and diversity of the phenotype and results of
molecular studies in patients with blepharocheilodontic
syndrome
A. Maat-Kievit1 , J. Hoogeboom1 , M. Whiteford2 , A. de Klein1 ;
1 2 Dept of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands, Ferguson-Smith
Centre for Medical Genetics, Glasgow, United Kingdom.
Blepharocheilodontic (BCD) syndrome is one of the at least 400 orofacial
clefting syndromes known, first described by Elschnig in 1912
and recognised as a syndrome and named by Gorlin in 1996 . It is a
rare, but possibly underdiagnosed, autosomal dominant condition with
variable expressivity in which the main clinical features are orofacial
clefts, ectodermal defects and ocular abnormalities . The ectodermal
defects are mainly oligodontia, delayed dentition, conical crown form,
hair abnormalities (pili torti, sparse hair, eyebrows and eyelashes) and
hypo/dysplastic nails . The ocular abnormalities comprise ectropion of
the lower eyelid, distichiasis of the upper eyelid, euryblepharon and
lagophthalmos . Other dysmorphic features have been described in
BCD patients, like hypertelorism, ptosis, broad forehead with high
frontal hairline, dysplastic ears, clinodactyly and syndactyly . Also ankyloblepharon,
hypothyroidism, dermoid cysts and membranous imperforate
anus were suggested to be part of the spectrum .
While BCD and lagophthalmos syndrome are a continuum, as suggested
by Gorlin, BCD syndrome shows clinical overlap with ectrodactyly-ectodermal
dysplasia-cleft lip/palate (EEC) syndrome, ankyloblepharon-ectodermal
defects-cleft lip/palate (AEC) or Hay Wells
syndrome and van der Woude/popliteal pterygium syndrome . A gene
for BCD syndrome has not yet been identified and might be involved in
neural crest and/or branchial arch development .
The variable clinical features of two families comprising nine patients
and three other sporadic patients with BCD syndrome will be presented
and compared to the patients described before . It will be discussed
if the phenotype can be expanded with neural tube defects . Also the
results of molecular studies in these patients will be shown .
P01.256
A three generation Serbian family with C263T mutation in MPZ
gene
M. P. Keckarevic-Markovic1 , J. Dackovic2 , J. Mladenovic3 , M. Kecmanovic1 , D.
Keckarevic1 , V. Milic-Rasic3 , S. Romac1 ;
1 2 Faculty of Biology, Belgrade, Serbia, Institute of Neurology, Belgrade, Serbia,
3Institute of Child Neurology and Psychiatry, Belgrade, Serbia.
The myelin protein zero (MPZ) gene encodes an integral membrane
protein with immunoglobulin-like extracellular domain . MPZ is expressed
only in peripheral nerves, and is localized in compact myelin .
Mutations in MPZ gene are the common cause of peripheral neuropathies
. Depending on the location and type of the mutation, MPZ is associated
or with demyelinating either with axonal phenotypes . Mostly,
mutations that lie in extracellular domain of MPZ and affect tertiary
structure of the protein important for myelin sheet formation lead to demyelinating
neuropathies, and mutations affecting myelin-axon communication
induce axonal degeneration .
Here we present a three generation family with C263T mutation that
affects extracellular domain of MPZ .
Clinical features are listed in a table:
Patient Age (years) Gender
Age at onset of
symptoms of
weakness (years)
Motor nerve conduction
velocity (MNCV) for
median nerve (m/s)
II1 65 F Unknown Not done
II2 47 F >40 22
III1 40 M 11-20 35 .7
III2 38 F 6-10 17 .6
III3 20 F 11-20 22
IV1 7 F / 18 .5
Mutations causing peripheral neuropathies show intra- and interfamilial variability.
In presented family MNCVs are severely reduced, except for the only male patient,
whose MNCV is 35.7 m/s and could fit even in a group of axonal neuropathies. There
is no extensive intrafamilial variability in this family, but, the only male patient displays
milder symptoms then other, female patients.
Although, there were no previously reported association between MPZ gene mutations,
sex and the severity of the disease, cases like this should be recognized in order
to remind us that our knowledge of biology of myelin sheet and peripheral nervous
system is limited and, probably, more complex then we assume.