Neurofibromatosis Type I
Neurofibromatosis type I (NFI), also known as von Recklinghausen disease, is one of the most common inherited diseases in humans. Its incidence is one per 3,500–4,000 live births and it affects both sexes equally. NFI is an autosomal-dominant disorder and is the result of a mutation of a gene mapped to chromosome 17, which is the NFI gene.1,2 The product of the gene is a protein called neurofibromin, a GTPase-activating protein (GAP) that helps to maintain the protooncogene Ras in an inactive form. NFI is characterised by 100% penetrance but varying expressivity.
The diagnostic criteria for NFI have been formulated by the National Institutes of Health (NIH) Consensus Development Conference on NF,3 and include six or more café-au-lait macules (CALM), two or more neurofibromas of any type or one or more pleximorm neurofibroma, two or more Lisch nodules, distinct osseous lesions and a first-degree relative with NFI. If two or more of these signs are present, the diagnosis is NFI. Although direct sequencing could be used to detect the causative mutation for individuals who meet these diagnostic criteria for NFI, molecular testing is generally not necessary.
Patients with NFI manifest clinically with cutaneous, ophthalmological, musculoskeletal and/or neurological symptoms.4,5 The cutaneous and ocular manifestations are the most common and typically are CALM, axillary freckling and Lisch nodules. CALM are apparent in 99% of patients and are usually present at birth. Musculoskeletal abnormalities include bone abnormalities, such as skeletal dysplasia (particularly sphenoid wing dysplasia), scoliosis and tibial pseudarthrosis. The neurological manifestations of NFI are variable and may be due to brain, spine or peripheral nerve tumours, epilepsy, macrocephaly, hydrocephalus, meningoceles and/or peripheral neuropathy.
Neurofibromas in NFI manifest as cutaneous neurofibromas, subcutaneous neurofibromas, nodular plexiform neurofibromas and diffuse plexiform neurofibromas.6 In contrast with cutaneous neurofibromas, plexiform neurofibromas may undergo malignant transformation. Both NFI and NFII patients are at increased risk of developing intra-cranial tumours; however, the tumour types are quite different. Brain tumours that have a higher incidence in NFI patients than in the general population are gliomas, ependymosmas, meningiomas and primitive neuroectodermal tumours (PNETs). Gliomas are typically low-grade and involve the optic pathways, hypothalamus, cerebellum, brainstem and spinal cord.