European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
P0152. Kabuki syndrome - clinical study of six cases.
R. Zordania1 , O. Kostina2 , K. Joost1 ;
1 2 Tallinn Children`s Hospital, Tallinn, Estonia, Institute of General and Molecular
Pathology Tartu University, Tartu, Estonia.
Kabuki syndrome (KS) (OMIM 147920) is a syndrome, estimated at
1:32000 births. KS is a complex disorder characterized by distinctive
facial features, dermatoglyphic abnormalities, short stature and mental
retardation. Some cases associate congenital anomalies of heart,
kidneys, cleft palate and/or lip and recurrent infections. The underlying
genetic mechanism of KS remains unknown. Most cases are sporadic.
KS diagnosis is based on phenotypical signs and clinical investigations.
We focus on the medical data and present clinical data of six children
diagnosed Kabuki syndrome (five boys and one girl), at the age of
7-17 years. All the patients had specific ocular and auricular defects:
long palpebral fissures, eversion of lower lateral eyelid, arched eyebrows,
long eyelashes and large/prominent ears, fetal pads at fingertips
and mental retardation. Two children were born praematurely with
antenatal hypotrophy, three patients had short stature (< 2 SD) during
investigation. Congenital anomalies were diagnosed in five patientshorseshore
kidney (one child), thoracolumbal scoliosis (two children),
thoracal kyphosis (one child), pectus excavatum (one child). None of
our patients had congenital heart defect, none had microcephaly.
Kabuki syndrome is a complex condition, guidelines for preventive
managment are given: 1.growth and development should be monitored,
2.overweight can occur in early puberty, 3.recurrent ear infections
and possible hearing loss are important issues.
P0153. Benign lymphoepithelial lesion of parotid gland in a
patient with Keutel syndrome and her two sibs with classic
Keutel syndrome
A. Yüksel 1 , G. Acar 2 , E. Karaca 1 , B. Tüysüz 1 , S. Boyd 3 ;
1 Istanbul University, Cerrahpasa Medical School, Medical Genetics, İstanbul,
Turkey, 2 Istanbul University, Cerrahpasa Medical School, department of Otorhinolaryngology,
İstanbul, Turkey, 3 Children’s Miracle, Network Endowed Chair,
MIND Institute, UC, CA, United States.
Keutel syndrome is a rare autosomal ressesive disorder that mainly
consists of abnormal cartilage calcification, sensorineural hearing
loss, peripheral pulmoner stenosis, brachiotelephalangism and maxillar
hypoplasia. The molecular etiology of disorder was shown with the
mutation in human matrix GLa protein gene. Defect in this gene is
thoughted to be responsible for this disase. We report 3 sibs with Keutel
syndrome. One of them with Keutel syndrome findings and she also
has a recurrent benign lymphoepithelial lesion of the left parotid gland.
In this patient we identified a new nonsense mutation in exon 2 (at c.
79C>T causing termination codon at aminoacid position 27). Other two
sibs had classic Keutel syndrome whose parents were first cousins.
P0154. Molecular and clinical findings of Larsen syndrome in a
large Iranian family caused by a mutation in FLNB gene.
Y. Shafeghati1 , N. Al-Madani2 , M. H. Karimi-Nejad2 , K. Azadbakht3 , L. S. Bicknell4
, S. P. Robertson5 ;
1 2 Genetics Research Center, Tehran, Islamic Republic of Iran, Karimi-Nejad
Najmabadi Genetics Centre, Tehran, Islamic Republic of Iran, 3Science and
Research Unit, Azad university, Tehran, Islamic Republic of Iran, 4Department of Paediatrics and Child Health, University of Otago, Otago, New Zealand,
5Department of Paediatrics and Child Health, University of Otago, Dunedin,
New Zealand.
Larsen syndrome (LS) is an autosomal dominant osteochondrodysplasia
characterised by
large joint dislocations and craniofacial anomalies such as cleft palate
and midface
hypoplasia. Recently LS was shown to be caused by missense mutations
or small in-frame deletions in FLNB gene, encoding the cytoskeletal
protein filamin B.
We found a large Iranian family with at least 30 affected members.
Clinical findings were typical. Cardinal features were: short stature,
multiple joints dislocation or subluxation, prominent forehead, midface
hypoplasia, hypertelorism, depressed nasal bridge, carpal, tarsal,
phalyngeal bone abnormalities, and spatulate fingers. Cleft palate was
detected only in one case. Most of them were suffering from deafness,
but none was mentally retarded. Club feet was common. A wide
range of skeletal abnormalities such as craniofacial, distal humeral hy-
poplasia, supernumerary carpal and tarsal ossification centers, distal
phalyngeal, cervical vertebral anomalies, and thoracolumbar scoliosis
all were common findings in our patients.
Patients were evaluated clinically and radiographically. After ascertainment
they screened for mutations in FLNB gene, using a combination
of dHPLC, direct sequencing and restriction endonuclease digestion.
In this large family intrafamilial phenotypic variations for LS was studied
and segregation of a recurrent mutation 679G>A, leading to the
substitution of E227K was detected. Recent molecular studies showed
that distribution of mutations within the FLNB gene is non-random. Our
findings in this large family collectively show an autosomal dominant
Larsen syndrome and demonstrate causative mutation in FLNB gene.
So we can provide accurate genetic counseling and prevent further
cases in future pregnancies.
P0155. A novel mutation in SURF1 gene in Russian patient with
Leigh syndrome
E. Y. Zakharova 1 , P. G. Tsygankova 1 , I. D. Fedonyuk 2 , E. S. Il’ina 2 ;
1 Research Center for Medical Genetics, Moscow, Russia, Moscow, Russian
Federation, 2 Russian Child Hospital, Moscow, Russia, Moscow, Russian Federation.
Leigh syndrome (LS) is one of the most frequent forms of mitochondrial
diseases in infancy and childhood. Typical presentation of LS is
in the first year of life with failure to thrive, psychomotor regression,
ataxia, signs of brainstem dysfunction, and peripheral neuropathy. LS
is characterized by symmetrical bilateral lesions in the brainstem and
basal ganglia. Etiologies of LS includes both mitochondrial and nuclear
DNA defects. Mutations in SURF1 have been shown to be the main
cause of LS with cytochrome c oxidase (COX) deficiency. The human
SURF1 gene encodes a protein localized in the inner mitochondrial
membrane and is thought to be involved in the assembly and biogenesis
of the cytochrome c oxidase complex. Most of known SURF1 mutations
in LS patients predict a truncated protein product. We describe
a new mutation in Surf1 gene found in one Russian patient with LS.
It is related to the group of complex rearrangements and represents a
114bp duplication with the 2bp deletion inside of the duplicated fragment.
The duplicated fragment starts with 45bp upstream exon 8 and
ends in exon 8 at nucleotide 816. This fragment except nucleotide AG
at the position 749 (749delAG) is inserted after nucleotide 816. The
duplication shifts the reading frame and predicts a preliminary stop-codon
at the 278 amino acid position and as a consequence skipping the
exon 9 of the gene. The phenotypic features of the patient are typical
for Leigh syndrome.
P0156. Atypical Leigh syndrome caused by T8993C mtDNA
mutation
P. G. Tsigankova, G. Rudenskaya;
Research Centre for Medical Genetics, Moscow, Russian Federation.
A case of early-onset Leigh syndrome with atypically mild course in
a 11-year-old girl is presented. Family history is negative apart from
ischemic stroke with complete recovery at the age of 52 years in maternal
grandmother. The child was born of uncomplicated pregnancy
and delivery. Since infancy she presented spasticity, generalized hyperkinesia,
and ataxia with motor and speech delay but normal mental
development. With age, her movement disorders and dysarthria diminished.
The girl walked independently, managed some everyday activities,
and was educated at home up to age. Her diagnosis was cerebral
palsy, there were no somatic disorders or ocular signs. MRI showed
moderate lesions of capsula externa and putamen. At the age of 9
years, epileptic seizures appeared but regressed soon with anticonvulsants.
In 10 years, with no provoking factors, she developed an acute
episode of somnolence, severe dysarthria, ataxia, hyperkinesias, and
inability to walk. Second MRI showed no deterioration. Moderate lactic
acidosis in plasma (2,33 mM) and homoplasmy for T8993C mtDNA
mutation in blood cells confirmed a supposed mitochondrial disorder.
With treatment, the girl’s status improved and returned to initial in
5_6 weeks. Nine months later, she remains stable and seizure-free.
T8993C mutation of ATP synthase 6 gene is known to be responsible
for diverse phenotypes of Leigh syndrome including juvenile forms.
However, a prolonged and relatively mild course with normal mental
development in a very early-onset case, like ours, is uncommon. The
observation contributes into phenotypic variability of Leigh syndrome.