Neurofibromatoses are disorders that affect the skin, nervous system, and bone in children and young adults. The three most common forms are neurofibromatosis type-1 (NF-1), neurofibromatosis type-2 (NF-2), and schwannomatosis. NF-1, also known as von Recklinghausen disease, commonly manifests with skin lesions known as “café-au-lait” spots, benign tumors known as neurofibromas that grow around peripheral nerves, scoliosis, and other soft tissue tumors. NF-2 usually presents with bilateral slow-growing tumors known as vestibular schwannomas, which may cause hearing loss or tinnitus (ringing in ears). The third variant, schwannomatosis, results in multiple painful schwannomas throughout the body. NF-1 and NF-2 are genetic disorders resulting from mutations in tumor suppressor genes, and they are inherited in an autosomal dominant fashion. The severity of symptoms varies widely among individuals. Tumors are treated by surgical excision, with chemotherapy, and radiation reserved for rare malignancies.
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.
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 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.
Proper diagnosis is best accomplished with magnetic resonance imaging (MRI) of the brain, orbits, and cervical spine for NF-1, as well as the internal auditory canals for NF-2. Slit-lamp examination of the eyes can reveal Lisch nodules, and chest computed tomography (CT) is used for detecting thoracic tumors.
The life expectancy for a patient with neurofibromatosis is slightly lower than that of an unaffected individual, mainly because neurofibromas occasionally become malignant (3 to 15 percent additional risk). Other complications, such as hydrocephalus and heart defects, are rare. The prognosis of neurofibromatosis varies, but most patients have mild symptoms and enjoy productive lives.
The approach to treating neurofibromatosis is primarily surgical; however, multiple disciplines are involved in caring for the patient. If neurofibromas enlarge or begin to cause pain, the surgeon should suspect malignant transformation and perform surgical excision. Oncologists should follow up with radiation and chemotherapy. Plastic surgeons can correct facial and skin deformities, just as orthopedic surgeons can treat tibial bowing and scoliosis. Patients should be monitored annually with visual, audiologic, and speech testing for learning disabilities. In addition, families should be offered genetic counseling, prenatal testing, and support group information to address patient psychological issues.
National Institute of Neurological Disorders and Stroke (NINDS); Neurologic Diseases (General); Scoliosis; Tinnitus.
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