2008 Barcelona - European Society of Human Genetics

Clinical genetics
matological anomalies . Almost 50% of patients with NS (sporadic or
familial) carry an missense mutation of PTPN11 gene (12q24), while
other genes ( KRAS and SOS1) play a minor role in the molecular
pathogenesis of the disease .
We present a familial case, mother and daughter, with NS diagnosed
by used a scoring system based by clinical signs .
The diagnosis was performed first in daughter, wich was identified at
birth . She presented polihidramnyos, nuchal oedema and premature
born . The patient was reevaluated of two months age . Clinical and
paraclinic evaluation revealed the major features of NS: feeding difficulties
with failure to thrive, short stature, typical facial dysmorphy (microcephaly,
broad and high forehead, down-slanting palpebral fisusures,
hypertelorism, epicanthic folds, micrognathia, low-set posteriorly
rotated ears), short neck with excess nucal skin, pectus excavatum,
Hypertrophic Obstructive Cardiomyopaty (HOMC) with asymmetrical
septum hypertrophy and neuromotor retardation . Other feature was
ombilical hernia . She had anemia, but no thrombocytopenia or other
coagulation defect . Clinical genetic examination of mother (N .C .M .),
31 years old, after delivery revealed the phenotype of NS (facial typical
dysmorphysm, pterygium colli, pectus carinatum superior and excavatum
inferior), pulmonar stenosis and mental retardation . The analysis
of pedigree showed the absence of other cases in family .In conclusion,
we emphasize, the importance of the clinical features for diagnosis,
leading further to an aprropiate management and for according genetic
counseling
P01.179
Noonan and cardio-facio-cutaneous syndromes: two clinically
and Genetically Overlapping Disorders
A. M. Nyström 1 , S. Ekvall 1 , E. Berglund 2 , M. Bjorkqvist 3 , G. Braathen 4 , K.
Duchen 5 , H. Enell 6 , E. Holmberg 4 , U. Holmlund 7 , M. Olsson-Engman 8 , G. Annerén
1 , M. L. Bondeson 1 ;
1 Uppsala University, Uppsala, Sweden, 2 Central Hospital, Skelleftea, Sweden,
3 University Hospial, Orebro, Sweden, 4 Sahlgrenska University Hospital, Gothenburg,
Sweden, 5 University Hospital, Linkoping, Sweden, 6 Regional Hospital
of Halmstad, Halmstad, Sweden, 7 Central Hospital, Vasteras, Sweden, 8 Regional
Hospital of Karlskrona, Karlskrona, Sweden.
Noonan and Cardio-facio-cutaneous (CFC) syndromes are related disorders
associated with dysregulated RAS-MAPK signalling . Noonan
syndrome (NS) is associated with mutations in the genes PTPN11,
SOS1, KRAS and RAF1 . The genetic aetiology of the clinically overlapping
CFC syndrome was recently assigned to four genes, BRAF,
KRAS, MEK1 and MEK2 . Here, we present a comprehensive mutation
analysis of BRAF, KRAS, MEK1, MEK2 and SOS1 in 31 unrelated NS/
CFC patients without mutations in PTPN11. Mutations were identified
in 8 patients, in whom we also present a detailed clinical investigation .
Seven of the mutations were identified in patients with CFC diagnoses
(2 in BRAF, 1 in KRAS, 1 in MEK1, 2 in MEK2 and 1 in SOS1) .
Two mutations were novel: MEK1 E203Q and MEK2 F57L . The SOS1
E433K mutation, identified in a patient diagnosed as CFC, has previously
been reported in patients with NS . In one NS patient, we also
identified a BRAF K499E mutation, previously reported in patients with
CFC . We thus suggest involvement also of BRAF in the pathogenesis
of NS .
Taken together, our results indicate that the molecular and clinical
overlap between CFC and NS is more complex than previously suggested
and that the syndromes might even present as allelic disorders .
Furthermore, we suggest that the diagnosis should be refined to, e.g.,
NS-PTPN11-associated or CFC- BRAF-associated after the genetic
defect has been established since this may have an impact on prognosis
and treatment of the patients .
P01.180
clinical and molecular studies in 95 polish patients with noonan
syndrome
E. Obersztyn, J. Klapecki, M. Łaniewski -Wołłk, A. Szpecht - Potocka, J. Bal,
T. Mazurczak;
Institute of Mother and Child, Warsaw, Poland.
Noonan syndrome (NS, OMIM 163950) is genetically heterogenous
disorder characterized by facial dysmorphism, short stature, variety
of heart defects (particularly pulmonary stenosis), chest deformations,
pterygium colli, lymphatic dysplasia, cryptorchidism and psychomotor
retardation . Heterogeneous mutations in PTPN11 gene are respon-
sible for 29-60% of NS cases . The aim of our study was to estimate
the frequency of PTPN11 gene mutations in Polish patients with NS .
Results of clinical and molecular studies the group of 95 probands are
reported . Detailed clinical evaluation, including family pedigree, dysmorphic
features, pre- and postnatal development and congenital malformations
is presented . Direct sequencing analysis of the 15 exons of
PTPN11 gene was performed and mutation was found in 32 (35%) of
the probands. The most frequent among 15 identified missense mutations
were: 1510A>G and 922A>G . In 9(28%) patients mutation was
familiar and in 77% of cases was maternal in origin .
All patients with PTPN11 mutation demonstrated typical NS phenotype .
Pulmonary valve stenosis, atrial septum defect, coagulation abnormalities,
mild mental retardation, short triangular face with pointed chin
were statistically the most frequent in patients with PTPN11 mutation .
Statistically significant correlation of pulmonary stenosis with 922A>G
and 1510A>G mutation was found . Heart defect was present in all probands
with PTPN11 mutation, but only in 66% of their parents .
We concluded that probably another mutations within SOS1, KRAS
and BRAF genes involved in the RAS-MAPK pathway may be responsible
for NS in subset of presented patients without PTPN11 mutation .
Further investigations are planned to explain NS phenotype in these
patients .
P01.181
sOs1 mutation as a cause for Noonan syndrome type 4: A report
of two patients
G. Yesil 1 , B. Tuysuz 1 , M. Zenker 2 ;
1 Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey, 2 Universitatsklinikum
Erlangen, Humangenetisches Insitut, Erlangen, Germany.
Noonan syndrome (NS) is an autosomal dominantly inherited disease
characterized by mental retardation (25%), short stature, pterygium
colli, congenital heart defect and hypogonadism . Approximately 50%
of cases are caused by mutations in the PTPN11 gene on chromosome
12q24 .1 . Recently, Roberts and Tartaglia (2007) found mutation
in the SOS1 gene on chromosome 2p22 to be responsible from %20
of NS who had ectodermal abnormalities but normal development .
This subtype called NS4 which share many clinical features with a
group of developmental disorders including Costello and CFC (Cardiofaciocutenous)
syndrome. Our first patient was a 7 month old male
and the second was 45 days old girl who had coarse face, sparse hair
and eyebrows and skin loss . Valvular pulmonary stenosis was shown
in echocardiography at the first patient and atrioventricular channel
defect and pulmonary hypertension at the second . One of our patients
had signs of hyperkeratotic skin too . SOS 1 mutation were detected on
exon 6; c .797C-> A heterozygous, p .T266K and on exon16 c .2536G>A
heterozygous p .E846K in patient 1 and patient 2 respectively . Pulmonary
stenosis was found more frequently in patients with SOS1 mutations
than PTPN1 mutations and atrial septal defect was relatively rare
in affected individuals with SOS1 mutations . Thus clinical examination
can be indeterminative . It is important to remember to identify SOS1
gene on patients who are free of BRAF, KRAS, MEK 1, 2 mutations
that are responsible from the etiology of CFC syndrome .
P01.182
Prenatal images and evolution to cutis verticis gyrata in a
newborn with Noonan syndrome
A. Moresco 1 , J. van der Velde 2 , M. Ingilde 2 , G. Chernovetzky 2 , S. Naddeo 2 , S.
Spinelli 2 , M. Rittler 2 ;
1 Centro Nacional de Genética Médica, Buenos Aires, Argentina, 2 Grupo de
Diagnóstico Prenatal. Hospital Materno Infantil Ramón Sardá, Buenos Aires,
Argentina.
Cutis verticis gyrata (CVG) is a rare defect, characterized by skin ridges
and
furrows forming cerebriform folds . Its primary form is associated with
neuropsychiatric disorders or genetic syndromes, such as Turner and,
more rarely, Noonan . Secondarily, CVG may be due to a local process
or a systemic illness .
Objective: To show the prenatal images of CVG in a fetus, and its
evolution until birth, when Noonan syndrome was diagnosed .
case report: The propositus was the third child of a young and healthy
couple . Pregnancy was uneventful until 18 gestational weeks, when an
ultrasound (US) scan revealed a cystic hygroma, hydrothorax and a
fluid collection at the cephalic pole, which first suggested an underlying