2008 Barcelona - European Society of Human Genetics

Clinical genetics
University Hospital Center Zagreb, Zagreb, Croatia, 5 University Hospital for
Infectious Diseases Dr. Fran Mihaljević, Zagreb, Croatia, 6 Institute of Human
Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United
Kingdom.
Due to ubiquitous nature of oxidative phosphorylation and dual genetic
origin of respiratory chain enzymes (nuclear and mitochondrial DNA)
their deficiencies can produce any symptom in any organ. However,
the involvement of the immune system in mitochondriopathies is rare .
We report a girl aged 20 months with combined respiratory chain defect
and immunologic impairment that includes T-cell immunodeficiency
and autoimmune reactions. Main clinical findings were generalized
hypotonia, rotatory nystagmus, failure to thrive and respiratory deficiency
due to persistent lung infections . In trachea a large spectrum of
bacteria and fungi (mostly Aspergillus fumigatus) has been detected .
Cytomegalovirus infection was permanent with up to 240,000 copies of
CMV DNA/ml of blood despite one year ganciclovir treatment . She had
crises with fever, tachycardia and facial blushing. Laboratory findings
pointed to autoimmune processes (positive anticardiolipin antibodies,
positive direct and indirect Coombs test and positive antiplatelet antibodies,
hypergammaglobulinemia) and immunodeficiency. The clinical
impression of an immunodeficiency was supported by repeatedly
increased CD4/CD8 ratio (6.3; normal 0.97-2.3) with significant decrease
of CD8 T cells (9%) . Flow cytometric analysis of intracellular
staining of IFN-gamma and IL-4 in CD4 and CD8 T cells showed three
times very low IFN-gamma in CD8 T cells (0 .5-1%; reference range
2-7%) .
The severely reduced activity of respiratory chain complexes I (3 .0
U/gNCP; normal 15 .8-42 .8) and IV (53 .6 U/gNCP; normal 112-351) in
skeletal muscle suggested mitochondrial etiology . Sequencing of the
mtDNA tRNA genes did not reveal pathogenic mutations and mtDNA
depletion was excluded by real-time PCR suggesting a mitochondrial
translation defect .
P01.356
Horizontal gaze palsy with progressive scoliosis can result from
new missens mutation in ROBO gene in Russian family
V. A. Galkina, A. Kalygina, O. A. Schagina, A. V. Polyakov;
Research Centre for Medical Genetics, Moscow, Russian Federation.
Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal
recessive disorder characterized by congenital absence of horizontal
gaze, progressive scoliosis, and failure of the corticospinal and
somatosensory axon tracts to decussate in the medulla . The reasons
of disease are various homozygous or compound heterozygous mutations
in the axon guidance molecule ROBO3 .
Two sisters seven and ten years old from Armenian family with short
stature non-proportional because of spine deformity were examined
by us . Both of them has progressive scoliosis (the oldest sister has
right-sided scoliosis and younger has left-sided one) . Now both girls
have severe thorakolumbar scoliosis . Two girls have congenital external
ophtalmoplegia, gorisontal gaze palsy, which at birth onset .
DNA was extracted from a blood sample from each participant using
a standard protocol, and the coding exons of ROBO3 were amplified
and sequenced .
Two sibs with horizontal progressive external ophthalmoplegia unique
and scoliosis have c .290G>C (Trp97Ser) mutation in homozygous
state in ROBO3 gene . Each of their parents was the heterozygotic carrier
of this mutation . This mutation was not previously described .
P01.357
An unusual case of sirenomelia and a review of the casuistic of
the Perinatal Genetic Program, UNicAmP, Brazil
D. P. Cavalcanti 1 , P. L. P. Rojas 1,2 ;
1 UNICAMP, Campinas, Brazil, 2 Universidad Javeriana, Bogotá, Colombia.
Sirenomelia sequence is a rare and etiologically unknown anomaly,
which is considered as a primary defect of the blastogenesis . The purposes
of this presentation is, first, reporting a case of sirenomelia associated
with a unique constellation of malformations, and, second,
exploring the casuistic of this anomaly in the Perinatal Genetic Program
during a twenty years period . The case reported is the product
of the first gestation of young and non consanguineous parents. Family
history was unremarkable . Gestational period was also uneventful,
except for prenatal ultrasonographic evaluation that revealed bilateral
renal agenesis, absence of the left lower limb and the right fibula, and
vertebra malformations. At birth, besides the findings of sirenomelia
sequence with footless, the fetus also presented bilateral anotia, an unusual
cleft palate, and also an unusual phallic structure on the genital
region . The review of 7 cases occurring at the same hospital showed
a high prevalence (1 .2 cases per 10,000 births) of sirenomelia, probably,
due to the prenatal diagnosis . All are single cases . The maternal
diseases referred by these respective mothers were hypotiroidism, depression
and arterial hypertension . The main medicines used by them
were l-thyroxine, fluoxetine, captopril, and amphetamines. Although
the sonographic evaluation performed at the first trimester has been
made in two cases, sirenomelia was never referred at prenatal time .
In conclusion, besides the case with a rare pattern of sirenomelia associated
with other no related defects, the review of seven new cases
shows the inability of sonographists to make diagnosis of sirenomelia .
P01.358
sirenomelia sequence: clinical, radiological and postmortem
findings
S. Balci 1 , G. Altinok 2 ;
1 Hacettepe University, Department of Pediatrics, Clinical Genetics (Emeritus
Member), Ankara, Turkey, 2 Hacettepe University, Department of Pathology,
Ankara, Turkey.
Sirenomelia is a Greco-Roman mythical creature with the tail of a fish
and a human upper body . Similarly, Sirenomelia Sequence is characterised
by fusion and reduction of lower extremities; renal and sacral
agenesis; imperforate anus; absence of rectum and bladder . It is
indeed an “orphan” malformation since it is not even recognised as
a separate entity in the OMIM cataloque . Here, we report a total of
five cases, including a pair of twin sibs, who were classified according
to Stocker classification as type I, VI and VII (N=1 each) and type
II (N=2) . All patients had a single umbilical artery; imperforate anus
, oligo hydramnion; Potter facies; congenital heart diseases; gastrointestinal
and genitourinary abnormalities . One of the twins had full
blown expression of Sirenomelia, whereas the other had imperforate
anus only (Clinical Dysmorphology 2000; 9:227) . Maternal diabetes
was associated with Sirenomelia in one patient (Turkish Journal of
Pediatrics 1996; 38: 393) . The earliest age of prenatal diagnosis was
fourteen weeks based on the observation of severe oligohidramnion
and a single lower extremity at ultrasonography. Postmortem findings
of this case revealed a blind end of the abdominal aorta, a single femur
and hypoplastic fused tibiae, renal agenesis, a dysplastic kidney, a hypoplastic
bladder, genital organ agenesis, colon abnormalities, hypoplasia
of the cerebellum and the posterior fossa . Severe maternal B12
and Folic Acid deficiency were present in this case. These etiological
factors have not been reported previously although various teratogenic
events have frequently been associated with Sirenomelia .
P01.359
sirenomelia with a de novo balanced translocation 46,XX,t(X;16)
(p11.3;p12.3)
K. Kurosawa, M. Takei, N. Furuya, H. Yoshihashi, M. Yamanaka;
Kanagawa Children’s Medical Center, Yokohama, Japan.
Sirenomelia is a rare developmental abnormality, characterized by the
fused lower limbs, and abnormalities in the caudal abdomen and pelvis.
Most cases are sporadic and specific causes and early pathogenetic
events leading to sirenomelia are unknown . We report a singleton
female fetus with sirenomelia with 46,XX t(X;16)(p11 .3;p12 .3)dn .
The pregnancy was electively terminated at 21 weeks gestation after
prenatal ultrasound examination . The birth weight was 294g, and
length 25 .5cm . The external genitalia was ambiguous and anal atresia
was noted. At autopsy, anatomical findings included absence of
bilateral kidney and bladder, hypoplastic or absence of renal artery
and inferior mesenteric artery . Unfortunately the results of karyotype
were revealed after autopsy . The cytogenetic analysis of breakpoints
was so limited . FISH experiments with BACs were employed for narrowing
of the breakpoint regions . On chromosome 16, the breakpoint
was mapped between RP11-347K10 (16p12 .3, 17 .55Mb from pter)
and RP11-167K14 (16p12 .2, 20 .87Mb from pter) . On chromosome X,
the breakpoint was mapped between RP11-245M24 (Xp11 .3, 45 .36Mb
from pter) and RP11-416B14 (Xp11 .23, 48 .46 Mb from pter) . Abnormal
phenotype, present in balanced translocation, was caused by deletion
or breakage of dosage-sensitive genes of breakpoint, or disruption
of an imprinted gene . In addition, cases with balanced translocations