2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
of Child Neurology, University Hospital Motol and 2nd Medical School, Charles
University, Prague, Czech Republic.
Sporadic neurofibromatosis type 1 (NF1) occurs in the absence of a
family history of the disease and usually results from a new mutation in
the germ cell of one of the parent. In most cases, the disease is caused
either by mutation in the NF1 gene, or by a particular or complete deletion
of the NF1 gene. The NF1 gene exhibits one of the highest mutation
rates of any human disorder. Here we report preliminary data of
the experimental NF1 gene study in patients from the Czech Republic.
We have screening germinal and somatic mutations spectrum of 30
unrelated sporadic NF1 patients, using denaturing high-performance
liquid chromatography (DHPLC) and multiplex ligation-dependent
probe amplification (MLPA) assay. DNAs of all patients were isolated
from peripheral blood and 10 cutaneous neurofibroma biopsies. By
direct sequencing of the pre-selected amplicons we identified 6 causal
germinal mutations, inclusive of 2 novel splice site mutations (c.2850+1
G >T, c.6641+1 G >A). All patiens were examined by MLPA metod and
one of them harboured entire gene deletion.
Supported by GAUK 200 072 and AV-CR-1ET 101210513
P02.133
two PtPN11 gene mutations (Y63c and R501J) detected in two
tunisian Noonan syndrome’s children
R. Louati1 , N. B. Abdelmoula1 , I. T. Sahnoun2 , S. Kammoun2 , T. Rebai1 ;
1 2 Medical University, Sfax, Tunisia, Department of Cardiology, CHU Hedi
Chaker, Sfax, Tunisia.
Congenital heart defects (CHD) remain the most common birth defect,
occurring in 1% of live births. Despite great advances in the CHD diagnosis
and treatment, there continues to be significant associated
mortality, morbidity and economic burden. The identification of genetic
causes of CHD is important; to improve understanding of the aetiology
of CHD and to promise the opportunity of a better prevention, diagnosis,
and care.
In Noonan syndrome (NS) characterized by CHD and dysmorphic
features, missense mutations of PTPN11 gene responsible of gain of
function in the protein tyrosine phosphatase Shp2 account for approximately
50% of cases. At the Medical University of Sfax; Department of
Histology; the pattern of PTPN11 mutations is defined in 15 NS Tunisian
patients (and 3 mothers) using Bi-directional direct sequencing of
PTPN11 exon 3 and its flanking intron boundaries. All patients harbour
congenital pulmonary vein stenosis (PVS) (with or without other CHD)
and NS facial dysmorphic features. Two mutations of the exon 3, Y63C
(known mutation) and R501J (new mutation) are identified. Y63C,
which is shown in a NS’s patient with PVS associated to an ASD, affects
the N-SH2 domain of SHP2. This mutation is not detected in the
mother who has NS clinical phenotype. We suggest that the patient is
a compound heterozygote with Y63C (de novo or paternal germline
inherited) mutation and an other mutation inherited from the mother.
R501J mutation that affect PTP domain of SHP2, was identified in a
patient with NS features and an isolated PVS.
P02.134
craniosynostosis in patients with Noonan syndrome caused by
germline KRAS mutations
M. Kriek1 , C. P. Kratz2 , G. Zampino3 , S. G. Kant1 , C. Leoni3 , F. Pantaleoni4 , A.
Oudesluys-Murphy1 , C. Di Rocco5 , S. P. Kloska6 , M. Tartaglia7 , M. Zenker8 ;
1 2 Leiden University Medical Center, Leiden, The Netherlands, Wellington
School of Medicine and Health Sciences, New Zealand, 3Università Cattolica
del Sacro Cuore, Italy, 4Istituto Superiore di Sanità, Italy, 5Università Cattolica
del Sacro Cuore, Leiden, Italy, 6University of Muenster, Leiden, Germany,
7 8 Istituto Superiore di Sanità, Leiden, Italy, University of Erlangen-Nuremberg,
Germany.
Craniosynostosis, the premature fusion of one or more cranial sutures,
is a developmental defect that disrupts the cranial morphogenetic program,
leading to variable craniofacial dysmorphism and associated
functional abnormalities. Craniosynostosis is frequently observed as
an associated feature in a number of clinically and genetically heterogeneous
syndromic conditions, including a group of disorders caused
by activating mutations of the fibroblast growth factor receptor family
members FGFR1, FGFR2 and FGFR3. In these disorders, dysregulation
of intracellular signaling promoted by the aberrant FGFR function
is mediated, at least in part, by the RAS-MAPK transduction pathway.
Mutations in RAS and other genes coding for proteins participating
in this signaling cascade have recently been identified as underlying
Noonan syndrome and related disorders.
We have identified an identical germline KRAS mutation in two unrelated
Noonan syndrome patients with a similar type of craniosynostosis.
Although craniosynostosis does not seem to be an invariant feature
of patients with this mutation, this finding highlights the significance
of aberrant signaling mediated by the RAS pathway in the origin of
craniosynostosis.
P02.135
two cases of LEOPARD syndrome with same missense mutation
in PTPN gene but different clinical manifestation
K. Muru 1,2 , I. Kalev 3 , R. Teek 1,4 , R. Žordania 5 , T. Reimand 1,2 , K. Õunap 1,2 ;
1 Department of Genetics, United Laboratories, Tartu University Hospital, Tartu,
Estonia, 2 Department of Pediatrics, University of Tartu, Tartu, Estonia, 3 Department
of Human Biology and Genetics, Institute of General and Molecular Pathology,
University of Tartu, Tartu, Estonia, 4 Department of Oto-Rhino-Laryngology,
University of Tartu, Tartu, Estonia, 5 Cildren`s Hospital, Tallinn, Estonia.
LEOPARD syndrome (LS, OMIM 151100) a rare multiple anomalies
condition belongs within of so called neuro-cardio-facial-cutaneous
syndromes group. Mutations in PTPN11 and RAF1 gene are the only
genes known to be associated with LS, mutation have been identified
in about 93% affected individuals.
Patient 1 was born from first pregnancy with normal birth parameters.
Parental main complaint was hyperactive behavior. First lentigines
were presented at birth, but intensive growth started at the age of 2
years. Heart ultrasound showed mitral insufficiency. Patient 2 is second
child in family born from the induced labor due to polyhydramnion.
Hypertrophic cardiomyopathy (HCM) was diagnosed at the age of 1
month and closely followed by since to find out the etiological factor.
She presented her first lentigines at birth, but rapid growth started only
at the age of 3 years.
Patients were referred to the genetic consultation due to rapid growth
of lentigines at the age of 4 years. They both had additionally slightly
short stature, characteristic facial features. Molecular analyses was
performed by bidirectional sequencing and revealed one of most frequently
described PTPN11 gene missense mutation in LS, 836A→G
(Tyr270Cys). Although patients have different health problems, rapid
growth of lentigines in infancy lead to correct diagnosis. In literature
mutation Tyr279Cys is more frequently associated with short stature,
deafness and also with HCM. An earlier diagnosis of LS is useful for
surveillance of the specific medical problems associated with LS and
for precise genetic counseling to the family.
P02.136
A boy with atypical phenotype of NF1 with a type 1 microdeletion
S. Kivirikko 1 , P. Alhopuro 1 , T. Lönnqvist 2 , P. Höglund 3 , L. Valanne 4 , L. Messiaen
5 , M. Pöyhönen 6,1 ;
1 Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki,
Finland, 2 Hospital for Children and Adolescent, Helsinki University Central Hospital,
Helsinki, Finland, 3 Rinnekoti Foundation, Espoo, Finland, 4 Department of
Radiology, Helsinki University Central Hospital, Helsinki, Finland, 5 Department
of Genetics, University of Alabama at Birmingham, Birmingham, AL, United
States, 6 Department of Medical Genetics, University of Helsinki, Helsinki, Finland.
Patient was born as a first child of healthy, non-consanguineous Caucasian
parents at week 38+5. During pregnancy hydronephrosis was
seen at 19 weeks of gestation. Birth weight was 3890 g, length 47
cm and head circumference 35 cm. As a newborn dysmorphic facial
features, anterior anus and an anocutaneal fistula was seen. The chromosomes
(400 bands) were normal.
He walked independently at the age of 2 years 4 months, but did not
speak. His height was 87.5 cm (slightly below his target height), body
mass index (BMI) 16.2 and head circumference 53 cm. His facial features
were distinct with high anterior hairline, thick eyebrows, epicanthal
folds and hypertelorism. The nasal tip was broad and he had anteverted
nostrils. The filtrum was long and the upper lip was thin. The
ears were thickened and the ear lobules were uplifted. He had one
classical cafe au lait spot.
In addition he has had severe feeding problems because of an intestinal
malrotation. His MRI revealed high signal intensity lesions of white
matter, hippocampal and cortical area. The spinal cord was thickened
at THVIII - LI.