Pathophysiology of Neurofibromatosis Type 1

Clinical Principles

Neurofibromatosis type 1 (NF1) was formerly known as von Recklinghausen disease.

It has autosomal dominant inheritance with complete penetrance, variable expression, and a high rate of new mutation.

It affects approximately 1 in 3500 individuals worldwide.

Diagnostic clinical signs include neurofibromas, café-au-lait macules, skinfold freckling, skeletal dysplasia, Lisch nodules, and optic gliomas.

Persons with NF1 are at increased risk for malignant conditions, especially malignant peripheral nerve sheath tumor (MPNST), leukemia, and rhabdomyosarcoma.

Other complications include cognitive problems and vascular dysplasias.

Molecular genetic testing is available.

Clinical trials of potential therapies for plexiform neurofibromas are under way.

Pathophysiologic Principles

Neurofibromatosis type 1 is a classic single-gene disorder with a high rate of new mutations.

The NF1 gene is located on chromosome 17.

The protein product, neurofibromin, consists of 2818 amino acids.

Protein includes a domain with guanosine triphosphatase (GTPase)–activating protein (GAP) function.

Neurofibromin GAP regulates conversion of Ras–guanosine triphosphate (GTP) to Ras–guanosine diphosphate (GDP).

NF1 gene mutations are highly diverse and are found throughout the gene.

Most mutations lead to lack of expression of the gene product.

Few genotype–phenotype correlations are known, although complete gene deletions lead to severe disease.

Loss of function of both NF1 alleles in Schwann cells of neurofibromas indicates that NF1 functions as a tumor suppressor gene.

Neurofibromas consist of Schwann cells with both NF1 alleles mutated, along with heterozygous fibroblasts, perineurial cells, and mast cells.

Malignant tumors require loss of NF1 function, as well as additional genetic changes.

Pathophysiology of …