Neurofibromatosis

Pathophysiology

The development of tumors in neurofibromatosis is related to high levels of nerve growth stimulating activity. NF-1 occurs in 1 in 3,000 individuals worldwide, regardless of race and sex. The NF-1 gene is found on chromosome 17 and encodes the protein neurofibromin, which acts as a tumor suppressor. Mutations in this protein cause abnormal regulation of the cell cycle and tumor formation. Approximately 40 percent of NF-1 cases are caused by spontaneous mutations, and 60 percent are inherited. NF-1 symptoms are unpredictable even within families; they range from mild cutaneous manifestations to severe debilitating tumors affecting several tissues. Although NF-2 is less common, arising in one in 40,000 people, the pathogenesis is similar. The NF-2 gene on chromosome 22 also encodes a tumor suppressor protein Merlin, which, when mutated, results in vestibular schwannomas, meningiomas, and other tumors. NF2 symptoms are more predictable, as family members present similarly.

Symptoms and Diagnosis

Various manifestations are associated with NF-1; however, the diagnostic criteria are broad. Characteristic findings include café-au-lait macules, neurofibromas, and Lisch nodules. The skin macules arise in the first three years of life as irregular brown spots. In prepubertal individuals, six or more macules of diameter greater than 5 mm (15 mm in postpubertal [Page 1226]individuals) may suggest NF-1. Neurofibromas are benign heterogeneous tumors containing a mixture of nerve-supporting schwann cells and other structural cells. These tumors arise in late adolescence and can be found cutaneously or on deeper nerve plexuses. Lisch nodules are benign dome-shaped tumors found superficially in the iris of the eyes of younger patients.

Skeletal abnormalities in NF-1 patients include scoliosis, bowing of the tibia in the lower leg, fractures, and facial bony overgrowth known as sphenoid dysplasia. These patients may also present with freckling in the groin or armpit areas during puberty. Neurological symptoms, such as deafness, blindness from optic gliomas, and pain, may result from impingement of nerves by tumors. Patients may also have endocrine abnormalities, such as growth hormone deficiency, causing short stature. Of children with NF-1, 25 to 40 percent have learning disabilities and visuospatial deficits, whereas 5 to 10 percent have mental retardation.

NF-2 commonly presents around age 20 with tinnitus, poor balance, or hearing loss caused by bilateral vestibular schwannomas of the auditory nerve. Meningiomas in the brain and other tumors also affect NF-2 patients. Patients with schwannomatosis have excruciating pain caused by nerve impingement by multiple schwannomas throughout the body, everywhere except the auditory nerve.

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