Vol. 16: Summer, 1998

Management of Common Genetic Disorders

Neurofibromatosis 1 (von Recklinghausen disease)

Introduction
Neurofibromatosis 1 (NF1) is a progressive multisystem disorder which affects approximately 1 in 3,000 individuals. NF1 is an autosomal dominant disorder with a high degree of penetrance, widely variable clinical expression, and a high frequency of new mutations, with only half of patients having an affected parent. Affected individuals have a 50% risk of transmitting the disorder to their children. However, parents of a child with a new mutation are not at an increased risk to have another affected child.
The gene for NF1 is located on the long arm of chromosome 17 at band q11.2. It codes for a protein, called neurofibromin, which is thought to be a tumor suppresser. A number of point mutations and gene deletions have been identified in affected individuals. Commercial DNA testing for NF1 is offered as a protein truncation test, which does not detect all mutations. Due to controversy regarding the application of this test, the current standard of diagnosis remains clinical. In familial cases, prenatal diagnosis using DNA linkage analysis may be available.
Clinical Features
The diagnosis of NF1 requires the presence of 2 or more of the National Institutes of Health criteria including:
1. 6 or more cafe-au-lait spots of at least 5 mm. in diameter before puberty and 15 mm. in diameter after puberty;
2. 2 or more neurofibromata or one plexiform neurofibroma;
3. axillary or inguinal freckling;
4. optic glioma;
5. 2 or more Lisch nodules;
6. sphenoid dysplasia or cortical thinning of the long bones; or
7. a first-degree relative with NF1.
Some of these features, such as size and number of cafe-au-lait spots, neurofibromata, freckling, and Lisch nodules, are age-dependent. Therefore, repeated examinations may be necessary to make the diagnosis in non familial cases.
Common Medical Complications
The incidence of complications in NF1 varies among studies and is generally overestimated. There is extreme variability in this disorder even within families. Approximately 1/3 have serious complications and 1/2 are only mildly affected.
The most serious complication of NF1 is an increased risk of malignancy. Fibrosarcomas are the most common tumors but other malignancies, such as central nervous system tumors and leukemia, also occur with increased frequency in NF1. The exact incidence of malignancy in NF1 is not known but is estimated to be approximately 5%. Therefore, each medical encounter should include evaluation for proptosis, increasing head size, focal neurological signs, pain or rapid growth of neurofibromata, and other signs and symptoms which could be indicative of malignancy. Treatment of malignancy in NF1 is no different than for the general population.
Various neurologic complications occur with increased frequency in NF1 including mental retardation, learning disabilities, speech delay, ADHD, seizures, and subtle neurologic abnormalities. Psychological and audiological assessments may be indicated prior to entering school. Early interventions should be initiated if abnormalities are present. Patients with seizures need to be evaluated for tumors of the central nervous system.
Optic gliomas occur with increased frequency in NF1 and may lead to blindness. Some authors advocate cranial imaging at the time of diagnosis to look for presymptomatic optic gliomas. However, the NIH Consensus Development Conference recommends cranial imaging only when clinically indicated. Patients with NF1 should have an annual ophthalmologic and neurologic evaluation to look for early signs of optic glioma or other CNS tumors.
Hypertension is common in NF1 and may be associated with renal artery stenosis, aortic stenosis, pheochromocytomas, adrenal tumors, or a variety of vascular hypertrophic lesions. Therefore, blood pressure should be monitored at every visit beginning in infancy.
A variety of skeletal changes may occur in NF1 including kyphosis, scoliosis, localized hypertrophy due to a plexiform neurofibroma, pseudoarthrosis, sphenoid dysplasia, and cortical thinning of the long bones. Each examination should include evaluation of asymmetry, deformity, and joint limitation and, if found, appropriate referrals should be made.
Gastrointestinal bleeding may occur due to a gastrointestinal neurofibroma. Referral to a gastroenterologist may be indicated.
Other Medical Considerations
Disfigurement may occur from the neurofibromata, especially if they are present on the face. In general, surgical removal of cutaneous neurofibromata is reserved for lesions which are very disfiguring or compromise function. Recurrence after removal is common.
Both precocious and delayed puberty are seen with increased frequency in NF1. In cases of precocious puberty, optic glioma or hypothalamic tumor should be ruled out. Puberty and pregnancy may cause cafe-au-lait spots and neurofibromata to increase in size and number.
Conclusion
In view of the complex nature of the disorder, all patients with NF1 should pursue surveillance of their health status every six to 12 months. A multidisciplinary team approach is recommended with the patient's primary care physician coordinating the care. Treatment of NF1 is primarily aimed at complications which are easier to manage when identified early. Each medical encounter should include evaluations of the skin, nervous system, skeletal system, and monitoring of blood pressure. If any abnormalities are detected, referral to the appropriate specialist should occur. Referral to local and national support groups may also be beneficial to the family.
References:
Gutmann DH, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278(1):51-57, 1997
Health Supervision for Children with Neurofibromatosis. Committee on Genetics. Pediatrics 96 (2): 368-372, 1995
Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 305(27):1617-1627, 1981

Contributed by Peggy Pearson, MD (AZ)

The Genetic Drift Newsletter is not copyrighted. Readers are free to duplicate all or parts of its contents. The Genetic Drift Newsletter is published semiannually by the Mountain States Genetics Network for associates & those interested in Human Genetics. In accordance with accepted publication standards, we request acknowledgement in print of any article reproduced in another publication. The views expressed in the newsletter do not necessarily reflect local, state, or federal policy. For additional information, contact Carol Clericuzio, M.D., Editor, Department of Pediatrics, The University of New Mexico, Albuquerque, NM, 87131

Table of Contents:
Management of Common Genetic Disorders

Introduction
Achondropasia
Down Syndrome / Trisomy 21
Fragile X Syndrome
Marfan Syndrome
Neurofibromatosis
Turner Syndrome
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