Summary

Neurofibromatosis type 1 (NF1) is an inherited, multi-system, neurocutaneous disorder that predisposes to the development of benign and malignant tumors. Prevalence is estimated at 1 in 4000-5000. There is marked clinical heterogeneity between individuals with NF1, even within families. Two of the following criteria are required to diagnose NF1: six or more café au lait patches (95% of the cases, usually appear by the age of three), neurofibromas, i.e. peripheral nerve sheath tumors manifesting as cutaneous, sub-cutaneous or plexiform lesions (occur infrequently before puberty, clinically visible in 30% of the cases), skin-fold freckling, two or more iris Lisch nodules, an optic pathway glioma, a specific bony dysplasia (thinning of the long bone cortex, sphenoid wing dysplasia), an affected first-degree relative. Cognitive impairment is the most common complication (an IQ in the low average range, specific learning problems and behavioral difficulties). There is a 7-12% lifetime risk of developing malignant peripheral nerve sheath tumor (MPNST). Mosaic forms of NF1 can present as mild generalized or localized disease. Transmission is autosomal dominant. The NF1 gene (located on 17q11.2) codes for neurofibromin, a tumor suppressor. The diagnosis is based on clinical examination and can be confirmed by mutation analysis. The differential diagnosis includes other forms of neurofibromatosis (neurofibromatosis type 2, schwannomatosis, Watson syndrome, NF6 or autosomal dominant multiple café au lait patches alone), Noonan syndrome, some conditions with pigment changes (McCune-Albright syndrome, LEOPARD syndrome), overgrowth syndromes (Klippel Trenaunay Weber syndrome, Proteus syndrome), conditions causing tumors (multiple lipomas, Bannayan-Riley-Ruvalcuba syndrome, fibromatosis, MEN 2B), and homozygosity for one of the genes causing hereditary nonpolyposis cancer of the colon (see these terms). An affected individual has a 50% chance of passing on NF1 to a child,but the complications cannot be predicted. There is a 1 in 12 chance of having a severely affected child. Prenatal testing can be performed; however, it is not possible to predict the disease severity. Pre-implantation diagnosis is available in some centers. Children with NF1 should be reviewed annually to check skin, spine, vision, blood pressure and progress at school. Adult with complicated NF1 require regular follow-up by an expert multidisciplinary team. Treatment is symptomatic and can include surgery for symptomatic neurofibromas, progressive scoliosis and pseudoarthrosis. Children with learning problems require early intervention with learning support. A patient with severe plexiform neurofibromas affecting the face underwent a partial face transplantation in France in 2007. Malignant peripheral nerve sheath tumors and vascular disease are major causes of mortality in NF1.

Expert reviewer(s)

• Dr Rosalie FERNER