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Study of the Neurofibromatosis 1 Expression: Identification of the Modifying Genes

18 Years
Open (Enrolling)
Neurofibromatosis 1

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Trial Information

Study of the Neurofibromatosis 1 Expression: Identification of the Modifying Genes

Neurofibromatosis 1 is a rare autosomal dominant disorder with an incidence of one birth out
of 3000. NF1 gene is located in 17q11.2. The penetrance is near 100% by the age of 8 and the
de novo mutations represent half the cases. The product of NF1 gene is neurofibromin, a
protein controlling cellular differentiation and proliferation. Phenotypic expression is
variable even in the same family. Neurofibromatosis 1 is characterized by café au lait
spots, freckling of the folds, Lisch'nodules (hamartomas of iris) and multiple
neurofibromas. Manifestations of neurofibromatosis 1 are pleiotropic, potentially severe and
unpredictable. Morbidity and mortality associated to neurofibromatosis 1 are linked with
complications, optic pathway gliomas, neurofibromas of the spine or of peripheral nerves,
learning disabilities, scoliosis and bone abnormalities and vasculopathy. The investigators
already demonstrated the existence of modifiers, genes modifying the phenotypic expression
of neurofibromatosis 1 (Hum Mol Genet. 2009;18(15):2768-78). Indeed, a quantitative analysis
of inter and intrafamilial variability performed with the data of the investigators
phenotype/genotype database showed a strong genetic component for most studied clinical
traits with an estimated heritability from 44 and 45% for subcutaneous and plexiform
neurofibromas, to 66% for small café au lait spots. The investigators also showed that the
NF1 gene had minor effect in the phenotypic variability. The investigators results suggested
the implication of genes non linked to NF1 gene. The identification of these variants called
modifiers of the phenotype is possible thanks to the investigators vast collection of
patients and its statistical power. The aim of the present study is to identify in the human
genome genetic variants in the evolving pattern of the most frequent manifestation of
neurofibromatosis 1, neurofibromas. The genetic association studies are the most adapted in
that purpose. The investigators bank includes at the present time 1099 patients of 575
families with genotypes, phenotypes and DNA samples.

The investigators will include 450 index cases more to have around 1000 independent patients
with neurofibromatosis 1 to get a 90% statistical power to detect variants of 30% frequency
in the general population and having an effect of odds ratio of 2 for studied trait. The
investigators will use Affymetrix® Genechips 6.0 covering well the whole genome.

Identification of the variants will provide new comprehension of pathophysiology and new
targets for treatment.

Inclusion Criteria:

- Aged of 18 or more

- Patient with neurofibromatosis 1 according the NIH criteria :

- Six or more café au lait macules over 15 mm in greatest diameter in postpubertal

- Two or more neurofibromas of any type or one plexiform neurofibroma

- Freckling in the axillary or inguinal regions (Crowe´s sign)

- Optic glioma

- Two or more Lisch nodules (iris hamartomas)

- A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone
cortex with or without pseudoarthrosis

- A first-degree relative (parent, sibling, or offspring) with NF1 by the above

- The criteria are met in an individual if two or more of the features listed are

Exclusion Criteria:

- Children (< 18 year-old)

- One member of the family already included in the study

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Outcome Measure:

Identification of the genetic variants involved in variability of clinical expression of neurofibromatosis 1.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Pierre Wolkenstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Ministry of Health

Study ID:

AOM 10 005



Start Date:

May 2012

Completion Date:

October 2015

Related Keywords:

  • Neurofibromatosis 1
  • Neurofibromatosis 1
  • Phenotype
  • Modifiers
  • Neurofibromatoses
  • Neurofibromatosis 1
  • Osteitis Fibrosa Cystica