2008 Barcelona - European Society of Human Genetics

Clinical genetics
ity of the endplates of the vertebral bodies, narrowed intervertebral
space and small and irregular epiphyses as described by Rajab et al .
(Am J Med Genet 2004;126:413) in Omani family . When compared
phenotypicaly to Omani’s family, all our patients had also minor facial
changes and most importantly they all had a cardiac involvement like
mitral, tricuspid and aortal regurgitations, which were not described .
The differences in clinical outcome are likely to be due to differences
in the nature of the mutation . The original SED Omani mutation resulted
in a complete loss of function whereas T141M appears to have
residual function .
P01.148
tibial Developmental Field Defect is the most common Lower
Limb malformation Pattern in VActERL Association
M. Castori1 , R. Rinaldi1 , S. Cappellacci1 , P. Grammatico1,2 ;
1 2 San Camillo-Forlanini Hospital, Rome, Italy, La Sapienza University of Rome,
Rome, Italy.
VACTERL association is one of the most common recognizable patterns
of human malformation and has been recently defined as a
multiple polytopic developmental field defect. Limb anomalies are
a key component of this condition and characteristically reflect perturbation
of radial ray development . However, the pattern of appendicular
malformations in VACTERL association is wider and includes
a broad spectrum of additional and apparently unspecific anomalies.
We report on the sporadic case of a 4-10/12-year-old boy presenting
with multiple costo-vertebral defects, dextrocardia, bilateral radial ray
hypo/aplasia, unilateral kidney agenesis and anal atresia . Homolaterally
to the more severe radial ray defect and kidney aplasia, he also
has a complex lower limb malformation, consisting of distal tibial aplasia,
clubfoot, hallucal deficiency and preaxial polydactyly. Literature
review identifies 24 additional patients with VACTERL manifestations
and lower limb malformations (excluding cases with isolated secondary
deformations) . Tibial hypo/aplasia with or without additional tibial
field defects, reported in about 2/3 (68%) of the patients, represents
the most common finding, while involvement of the fibular ray is rare
(20%) and very often accompanies tibial anomalies . The relatively high
frequency of tibial ray anomalies in VACTERL patients could easily
be explained by the principle of homology of the developmental field
theory . Careful search of lower limb anomalies of the “tibial type” is,
therefore, indicated in all patients with multiple polytopic developmental
field defects.
P01.149
Hypoplasia of tibia with polysyndactyly (Werner syndrome) is
allelic to preaxial polydactyly ii (PPD2) and caused by a point
mutation in the distant sonic Hedgehog (sHH) cis-regulator
(ZRS)
D. Wieczorek 1 , B. Pawlik 2 , N. A. Akarsu 3 , G. Gillessen-Kaesbach 1,4 , Y. Hellenbroich
1,4 , S. Lyonnet 5 , F. R. Vargas 6 , B. Wollnik 2 ;
1 Institut für Humangenetik, Essen, Germany, 2 Institut für Humangenetik, Köln,
Germany, 3 Hacettepe University Pediatric Hematology Gene Mapping Laboratory,
Ankara, Turkey, 4 Institut für Humangenetik, Lübeck, Germany, 5 Département
de Génétique et Unité INSERM, Paris, France, 6 Centro de Genetica
Medica, Rio de Janeiro, Brazil.
Tibial hypoplasia, preaxial polydactyly of hands and feet and/or a fivefingered
hand with absence of thumbs was first described by Werner
in 1915 (MIM 188770) . This autosomal dominant condition is variable
and no causative mutations have been described so far .
Here we describe an adult Turkish patient with short stature, shortening
of forearms, and preaxial polydactyly of hands . His femora are
mildly and his lower legs are severely shortened . He had preaxial polydactyly
of feet, the supernumerary toe was surgically removed . The
clinical diagnosis hypoplasia of tibia with polysyndactyly was established
. The patient’s father has a preaxial polydactyly of his right hand .
We performed mutational analysis in the Sonic Hedgehog (SHH) gene
and SHH regulatory region (ZRS) located in intron 5 of the LMBR1
gene . A transition (G>A) at position 404 of the ZRS, which was previously
reported as the Cuban mutation of the preaxial polydactyly type
II (PPD2)-phenotype (Zguricas et al ., 1999; Lettice et al ., 2003) was
identified in the patient and his father. Single nucleotide substitutions
in the ZRS regulatory region, also described in the Hemingway’s Cats,
operate as gain-of-function mutations that activate Shh expression at
an ectopic embryonic site (Lettice et al ., 2007) . Currently, molecular
studies including copy number analysis of the ZRS and SHH regions
are done in additional families with Werner syndrome, triphalangeal
thumb-polysyndactyly syndrome and polysyndactyly type Haas .
In summary, we identified the molecular cause of Werner syndrome
in our patient and confirmed the previously suggested hypothesis that
Werner syndrome is allelic to PPD2 .
P01.150
Fetal phenotype of three cases of campomelic dysplasia
harbouring novel mutations of sOX9 gene
B. Gentilin 1 , F. Forzano 2 , F. Faravelli 2 , M. Bedeschi 1 , M. Baffico 2 , M. Lituania 3 ,
P. Ficarazzi 4 , T. Rizzuti 5 , P. Bianchi 6 , F. Lalatta 1 ;
1 UOS Dipartimentale di Genetica Medica, Fondazione IRCSS Ospedale Maggiore
Policlinico, Mangiagalli e Regina Elena, Milano, Italy, 2 Medical Genetics
Unit; E.O.Ospedali Galliera, Genova, Italy, 3 Fetal Medicine Unit; E.O.Ospedali
Galliera, Genova, Italy, 4 Obstetric and Gynaecologic Unit; Fondazione IRCSS
Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy, 5 Pathological
Unit, Fondazione IRCSS Ospedale Maggiore Policlinico, Mangiagalli
e Regina Elena, Milano, Italy, 6 Neonatal Intensive Care Unit, Ospedali Riuniti di
Bergamo, Bergamo, Italy.
Campomelic dysplasia (CD) is a rare congenital skeletal disorder characterized
by bowing of the long bones and a variable association of
other skeletal and extraskeletal defects, with or without XY sex reversal
.
CD is caused by mutations in the SRY-box 9 gene (SOX9), a dosage-sensitive
gene expressed in chondrocytes and other tissues and
located at 17q24 . The correlation between the campomelic dysplasia
genotype and phenotype is still unclear .
In the prenatal period the most characteristic sign of campomelic dysplasia
is the shortening and marked anterior bowing of long bones,
particularly of femur and tibia . Narrow chest, scoliosis, talipes equinovarus,
and flat facial profile are other sonographic features commonly
present . Increased nuchal translucency, polyhydramnios, and anomalies
of the central nervous, cardiac, and renal systems have also been
described .
We report three cases of campomelic dysplasia suspected in the first
or second trimester of pregnancy by prenatal ultrasound . The pregnancies
were all terminated and the diagnosis of campomelic dysplasia
has been confirmed on clinical and radiographic examination of
the fetuses .
In the three cases molecular analysis detected three novel mutations
in the SOX9 gene which occurred de novo .
The protocol which allowed the specific diagnosis of this rare condition
will be presented .
P01.151
Prenatal diagnosis and management of a patient affected by
Kniest dysplasia.
M. F. Bedeschi 1 , V. Bianchi 1 , L. Colombo 2 , F. Natacci 1 , S. Giglio 3 , E. Andreucci 3 ,
L. Trespidi 4 , B. Acaia 4 , G. Canepa 1 , F. Lalatta 1 ;
1 Clinical Genetics Unit, Fondazione IRCCS, Ospedale Maggiore Policlinico,
Mangiagalli e Regina Elena, Milano, Italy, 2 Neonatal Intensive Care Unit, Fondazione
IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena,
Milano, Italy, 3 Department of Clinical Pathophysiology and Medical Genetics
Unit, AOU Meyer, University of Florence, Firenze, Italy, 4 Obstetrics and Gynecology
Clinic I, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena,
Milano, Italy.
Patients affected by rare skeletal dysplasias may remain undiagnosed
for a long time, until adulthood . In these cases a pregnancy might disclose
several unexpected problems and special needs . We present the
case of a 28 year old primigravida who was referred to our centre at 17
weeks of gestation with an undiagnosed skeletal dysplasia . Her clinical
and radiological examination showed severe dwarfism characterized
by spinal curvature anomalies including dorsal scoliosis, lumbar
lordosis, platyspondyly, bell-shaped chest, pectus carinatum, drooping
ribs, suggesting the diagnosis of Kniest dysplasia (MIM 156550) which
is a rare, severe, chondrodysplasia characterized by short trunk and
limbs, kyphoscoliosis, midface hypoplasia, severe myopia and hearing
loss . The woman was then informed about the recurrence risk and
offered ultrasound prenatal diagnosis . Ultrasound examination at 17-
18-20 weeks revealed fetal macrocephaly, narrow thorax, shortening
and bowing of long bones . Parents decided to continue the pregnancy
informed about the clinical features of the fetus . The baby was deliv-