Description

• Neurofibromatosis types 1 (NF1) and 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name, they are unrelated.
  • NF1, the most common of the phakomatoses, is a multisystem disorder that may affect any organ: the defining feature of NF1 is the neurofibroma, a nerve sheath tumor that forms in intimate association with spinal, peripheral or cranial nerves (1). It is also characterized by café au lait macules (CALM), axillary and inguinal freckling, Lisch nodules, choroidal freckling.
  • NF2 is a rare condition that causes bilateral vestibular schwannomas.
• System(s) affected: musculoskeletal; nervous; skin/exocrine; cardiovascular; neuro-ophthalmologic
• Synonym(s): von Recklinghausen disease, formerly peripheral NF

Epidemiology

Incidence

• Predominant sex for NF1: male = female
• Birth incidence NF1: 1:2,500 to 3,000

Prevalence
1:3,000 to 1:4,000

Etiology and Pathophysiology

• Neurofibromin is a GTPase–activating protein that acts as a tumor suppressor by down regulating p21-ras, a cellular proto-oncogene that enhances cell growth and proliferation.
• Some clinical manifestations of NF1, such as CALMs, require biallelic inactivation of NF1. Others, such as malignant peripheral nerve sheath tumors (MPNSTs), result from haploinsufficiency in combination with mutations in other genes, such as TP53.
• Neurofibromas are benign tumors composed of Schwann cells, fibroblasts, mast cells, and vascular components that develop along nerves.

Genetics

• Caused by a mutation in the NF1 gene on chromosome 17q11.2; autosomal dominant inheritance; protein product is called neurofibromin.
• 50% of cases are due to de novo mutations, mostly paternal; likelihood increases with paternal age.
• Prenatal diagnosis is possible if mutation is known.
• Gene is large (~60 exons), with >3,000 different germline mutations causing NF1. Molecular technology can detect 95% of clinically important NF1 mutations, but clinical diagnosis frequently can be made in childhood.
• Although expressivity is extremely variable, even within a family, the p.Arg1038Gly missense substitution correlates with a mild phenotype without neurofibromas or other complications.

Risk Factors

• Having an affected first-degree relative is a diagnostic criterion for NF1, although relatives may be unaware that they have NF1.
• Affected individuals with a positive family history (or a new mutation) have a 50% risk of transmitting NF1 to each offspring; 1 in 12 will be severely affected.

Commonly Associated Conditions

• Congenital heart disease, pulmonary stenosis, hypertension, renal artery stenosis
• Learning disabilities (50–75%)