This relatively common disorder affects about 1 in 3000 people and is inherited as an autosomal dominant trait. There are two main types: von Recklinghausen’s neurofibromatosis (NF1; which accounts for 85% of all cases) and bilateral acoustic neurofibromatosis (NF2); these are phenotypically and genetically distinct.
The NF1 gene has been localized to chromosome 17q11.1. It is unusually large (300 kb) and many dif-ferent mutations within it have now been identified. The NF1 gene is a tumour suppressor gene, the product of which, neurofibromin, interacts with the product of the RAS proto-oncogene. This may explain the sus-ceptibility of NF1 patients to a variety of tumours. The inheritance of NF1 is as an autosomal dominant trait but about one-half of index cases have no preced-ing family history.
The inheritance of NF2 is also autosomal domin-ant. Mapping to chromosome 22q12.2 followed the observation of changes in chromosome 22 in menin-giomas as these tumours may be seen in NF2. This gene also normally functions as a tumour-suppressor gene, the product of which is known as schwannomin.
The physical signs include the following
• Six or more café au lait patches (light brown oval macules; Fig. 21.1), usually developing in the first year of life.
• Axillary freckling (Fig. 21.2) in two-thirds of affected individuals.
• Variable numbers of skin neurofibromas, some small and superficial, others larger and deeper, ranging from flesh-coloured to pink, purple or brown (Fig. 21.1). Most are dome-like nodules, but others are irregular raised plaques. Some are firm, some soft and com-pressible through a deficient dermis (‘button-hole’ sign); others feel ‘knotty’ or ‘wormy’. Neurofibromas may not appear until puberty and become larger and more numerous with age.
• Small circular pigmented hamartomas of the iris (Lisch nodules; Fig. 21.3), appear in early childhood.
Nearly all NF1 patients meet the criteria for dia-gnosis by the age of 8 years, and all do so by 20 years. The usual order of appearance of the clinical features is café au lait macules, axillary freckling, Lisch nodules and neurofibromas.
• Bilateral acoustic neuromas.
• Few, if any, cutaneous manifestations.
• No Lisch nodules.
The café au lait marks, axillary freckling and Lisch nodules should be looked for, as they appear before the skin neurofibromas. A segmental form of NF1 is caused by a postzygotic mutation. Isolated neurofi-bromas are not uncommon in individuals without neurofibromatosis and are of little consequence unless they are painful.
A neurofibroma will occasionally change into a neuro-fibrosarcoma. Other associated features may include kyphoscoliosis, mental deficiency, epilepsy, renal artery stenosis and an association with phaeochromocy-toma. Forme fruste variants occur, e.g. segmental neurofibromatosis.
Other tumours of the central nervous system may occur, especially meningiomas and gliomas.
Ugly or painful lesions, and any suspected of undergo-ing malignant change, should be removed. The chance of a child of an affected adult developing the disorder is 1 in 2aparents should be advised about this.