Presented by: Christine Shaver, MD and Herbert Allen, MD
Drexel University College of Medicine
May 16, 2016
Neurofibromatosis type 1 (NF-1), also known as von Recklinghausen’s disease, is an autosomal dominant inherited neurocutaneous disorder. The clinical manifestations of NF-1 result from a mutation in the NF1 gene located on chromosome 17q11.2, and encodes the 327 kDa protein neurofibromin, a tumor suppressor protein. The incidence of NF1 is estimated at 1 in 3000 and about 30-50% of cases are the result of a new genetic mutation rather than inherited from a relative, which means a large proportion of cases are de novo with no preceding family history.
The signs and symptoms of NF1 can vary widely, although a set of criteria does exist for diagnosis. In general, two or more of the following seven criteria are required for diagnosis: 1) six or more café au lait macules, > 5mm in prepubertal, and > 15mm in postpubertal persons; 2) two or more neurofibromas or one plexiform neurofibroma; 3) axillary or inguinal freckling; 4) optic glioma; 5) two or more Lisch nodules; 6) a distinctive bony lesion such as sphenoid dysplasia, or thinning of long bone cortex with or without pseudoarthrosis; 7) first degree relative with NF-1 by the above criteria.
Cutaneous neurofibromas are benign tumors that grow in and along the nerves and are the most common peripheral tumor in NF-1. They often first appear during puberty, increase in number with age, and vary greatly in size and location. The second most common peripheral tumor observed is the plexiform neurofibroma, which can penetrate into muscle, bone and viscera, leading to soft tissue overgrowth and disfigurement. They can undergo degeneration into malignant peripheral nerve sheath tumors, which can be very aggressive and are a major cause of mortality in NF-1 patients. The overall lifetime risk of a malignant peripheral nerve sheath tumor in patients with NF-1 is 8-13%.
Management of these patients emphasizes annual skin assessment to look for new neurofibromas and evaluate changing, growing or painful lesions. Surgery should be employed in patients who experience pain or discomfort from lesions or those with tumors that may be encroaching on vital structures. Management should also include regular eye exams with an ophthalmologist, developmental monitoring including growth curves and learning assessments, and evaluation of skeletal changes for any abnormalities. Complications may include vision loss from gliomas, spinal cord tumors, and long-bone abnormalities.
Morbidity and mortality is related primarily to the increased risk for tumors in these patients. Patients with NF-1 have an increased risk of astrocytoma, meningioma, rhabdomyosarcoma, pheochromocytoma, Wilms’ tumor, and visceral neurofibromas. There is a 20-to-30-fold increased risk of developing juvenile myelomonocytic leukemia in patients with NF1 and multiple juvenile xanthogranulomas. Systemic involvement varies greatly and can include mental retardation, developmental delay, seizure disorder, GI bleeding, bowel obstruction, hypertension, and endocrine abnormalities. Fatal vasculopathy causing GI ulcers and bowel, liver, and spleen infarction has been reported.
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