2008 Barcelona - European Society of Human Genetics

Clinical genetics
Mangiagalli e Regina Elena, Milano, Italy, 2 Oculistic Unit, Fondazione IRCCS,
Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy, 3 Dermatologic
Unit, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli
e Regina Elena, Milano, Italy, 4 Neurology Unit, Fondazione IRCCS, Ospedale
Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy, 5 Neurosurgery
Unit, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina
Elena, Milano, Italy, 6 Reconstructive Surgery Unit, Fondazione IRCCS, Ospedale
Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy, 7 Obstetrics
and Gynecology Clinic I, Fondazione IRCCS, Ospedale Maggiore Policlinico,
Mangiagalli e Regina Elena, Milano, Italy, 8 Neuroradiology Unit, Fondazione
IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano,
Italy, 9 Neuro-oncology Unit, Istituto Neurologico C. Besta, Milano, Italy, 10 Biology
and Genetics for Medical Sciences Department, University of Milan, Milano,
Italy, 11 Medical School Department - Polo Osp. San Paolo, University of Milan,
Milano, Italy.
Neurofibromatosis type 1 (NF1), a genetic disease, with an estimate
incidence of 1/3000 . It is a neurocutaneous disorder characterized by
multisystemic involvement . NF1 has a wide clinical variability even
between family members, with the possibility of mild forms and age
specific complications.
Although childhood clinical spectrum and possible complications are
well known, few data are available on adult patients, concerning the
evolution of the disease, the applicability of a follow up program, the
indications for genetic testing, the social and health needs typical of
this age .
We describe a clinical cohort of 80 adult NF1 patients, referred to
Clinical Genetics Unit at Ospedale Maggiore Policlinico Mangiagalli e
Regina Elena . The cohort is composed by 46 females and 34 males
patients, age range: 19-69 years . NF1 was inherited from an affected
parent in 24 cases (30%) . The diagnosis was segmental NF1 in 5 cases,
while the other 75 patients have a classical form of the disease .
Clinical features and detected complications of this cohort are compared
with the available literature data. Specific attention will be given
to the typical and specific needs of adulthood, related to the reproductive
life: demand for genetic counselling, recurrence risk, procreative
option discussion, prenatal diagnosis request, pregnancy follow up in
affected women .
P01.192
Prenatal diagnosis of neurofibromatosis type 1: Importance of
genetic counseling
Y. Terzi 1 , S. Oguzkan Balci 2 , B. Anlar 3 , S. Aysun 3 , S. Ayter 1 ;
1 Hacettepe University, Department of Medical Biology, Ankara, Turkey, 2 University
of Gaziantep, Department of Medical Biology, Gaziantep, Turkey, 3 Hacettepe
University, Department of Pediatric Neurology, Ankara, Turkey.
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder
with an incidence of about 1 in 3500 live births . Because of the large
size and complexity of the NF1 gene, the variety of mutations and the
need to identify the specific mutation in each family, indirect diagnosis
using linked markers has an important part in genetic counseling .
In this study, thirty-seven families have been characterized and two
prenatal diagnoses have been performed by using indirect analyses .
Two family were informative for NF1 markers . One of fetuses was under
NF1 risk . Now, she is 15 month old, has NF1 features .
The variability of the phenotypic expression of the NF1 gene makes
reproductive decisions in NF1 families very difficult. Even mutation detection
can not help for decision because molecular diagnosis can not
predict the severity of the disease . Therefore good genetic counseling
is very important for the couples with the NF1 risk .
P01.193
Detection of a de novo germline deletion and somatic NF
mutation in a 2 year-old boy with JmmL and multiple café au lait
spots
Y. J. Sznajer 1,2 , A. Klein 3 , P. Heimann 4 , M. Hortala 5 , K. Claes 6 ;
1 Hopital Universitaire des Enfants Reine Fabiola, Brussels, Belgium, 2 Center for
Human Genetics, U.L.B, Brussels, Belgium, 3 Haematology-Oncology, Hopital
Universitaire des Enfants Reine Fabiola, Brussels, Belgium, 4 Genetic Oncology,
Center for Genetics, ULB Hopital Erasme, Brussels, Belgium, 5 Dermatology,
Hopital Universitaire des Enfants Reine Fabiola, Brussels, Belgium, 6 Center for
Medical Genetics, Ghent University Hospital, Ghent, Belgium.
We describe the history of a child from healthy unrelated parents diagnosed
having juvenile myelomonocytic leukemia (JMML) at the age
of 10 months . Since 10% to 14% of patients with JMML have NF1; the
present patient had multiple café-au-lait spots allowing to consider for
Neurofibromatosis Type I (1,2). The standard karyotype on lymphocytes
was 46,XY normal male . Bone marrow karyotype showed monosomy
7 . By cDNA sequencing a frameshift mutation in NF1 gene was
characterized, c .2033dupC . With MLPA, total NF1 gene deletion was
observed. These mutations were confirmed on a second independent
sample. On fibroblasts, we confirmed the total gene deletion providing
evidence for a germline mutation while the c .2033dupC was absent
(most likely representing a second hit mutation) . Investigation on bone
marrow is planned. This is the first report on a NF1 microdeletion patient
with JMML. The finding of a second hit point mutation in a patient
with NF1 microdeletion represents another example of that the type
of germline mutation influences the type of second hit in the tumors
(3) . Loss of heterozygosity (LOH) in the NF1 region is not an usual
mechanism for somatic NF1 inactivation from tumors in patients with a
microdeletion . It is postulated that LOH of NF1 microdeletion region in
these patients would de facto lead to a nullizygous state of the genes
and might be lethal .
References
(1) L. Side et al. Blood 1998;92:267-272
(2) L. Side et al. New Engl J Med 1997;336:1713-1720
(3) De Raedt et al, Genes Chromosomes Cancer . 2006;45(10):893-
904
P01.194
Germline and somatic NF mutations and copy number
alterations of chromosome 17 in sporadic and NF1-associated
malignant peripheral nerve sheath tumors
I. Bottillo 1 , I. Torrente 1 , T. Ahlquist 2 , H. Brekke 2 , S. A. Danielsen 2 , E. van den
Berg 3 , F. Mertens 4 , R. A. Lothe 2 , B. Dallapiccola 1,5 ;
1 CSS-Mendel Institute, Rome, Italy, 2 Department of Cancer Prevention, Institute
for Cancer Research, Rikshospitalet Medical Centre, Oslo, Norway, 3 Department
of Genetics, University Medical Center Groningen, University of Groningen,
Groningen, The Netherlands, 4 Department of Clinical Genetics, Lund
University Hospital, Lund SE-221 85, Sweden, 5 Department of Experimental
Medicine, Sapienza University, Rome, Italy.
Malignant peripheral nerve sheath tumor (MPNST) is a rare malignancy
occurring with increased frequency in patients with neurofibromatosis
type 1 (NF1) . In contrast to the well known spectrum of germline
NF1 mutations, the information on somatic mutations in MPNSTs are
limited . In this study we evaluated the presence of NF1 mutations in 47
MPNSTs from patients with (n=25) or without (n=22) NF1; from 7 of the
NF1-patients neurofibromas were also analyzed. The mutation status
was assessed for two other genes, KRAS and BRAF. Mutation profiles
were compared with copy number changes for chromosome 17 and
TP53 mutation status . Germline NF1 mutations were detected in 17
NF1-patients: 6 frameshift, 5 truncating, 3 missense mutations, 2 large
deletions, and 1 chromosome 17 imbalance . Somatic NF1 mutations
were found in 17/25 NF1-associated MPNSTs, in 3/7 neurofibromas
and in 9/22 sporadic MPNSTs . Large chromosomal imbalances accounted
for 13/17 and 7/9 somatic mutations in NF1-associated and
sporadic MPNSTs, respectively . In the present cohort, 20 NF1-associated
and 11 sporadic tumors harbored distal 17q gain . Two NF1-associated
and 13 sporadic MPNSTs did not show any NF1 mutation,
arguing for a contribution of other genes . However, a major role of the
KRAS or BRAF gene was excluded . Loss of the 17p13 region including
the TP53 gene appeared to be implicated both in NF1-associated
and sporadic MPNSTs . The present results suggest that somatic and
germline NF1 mutations involved in MPNST development develop by
two distinct mechanisms, the former being the same in sporadic and
NF1-associated cases .
P01.195
Early-onset breast cancer in Neurofibromatosis type I
C. D. Delozier 1,2 , W. J. Podalsky 3 , C. J. Curry 1,2 ;
1 Genetic Medicine Central California, Fresno, CA, United States, 2 UCSF-
Fresno, Fresno, CA, United States, 3 Radiation Oncology, Saint Agnes Medical
Center, Fresno, CA, United States.
Neurofibromatosis type 1 (NF1), with an incidence of approximately
1/3500, is one of the most common hereditary disorders . Breast cancer,
usually due to somatic rather than inherited gene mutations, is one
of the most common malignancies; the lifetime risk for breast cancer in