Neurofibromatosis

Neurofibromatosis

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.

Cause

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.

Clinical features

The physical signs include the following

Von Recklinghausen’s neurofibromatosis (NF1)

•   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 neurofibromatosis (NF2)

•   Bilateral acoustic neuromas.

•   Few, if any, cutaneous manifestations.

•   No Lisch nodules.

Diagnosis

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.

Complications

Von Recklinghausen’s neurofibromatosis

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.

Bilateral acoustic neurofibromatosis

Other tumours of the central nervous system may occur, especially meningiomas and gliomas.

Management

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.