A C A D E M Y GUIDELINES This report reflects the best data available at the time the report was prepared, but caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report.
Guidelines of care for neurofibromatosis type 1 Task Force: Lawrence F. Eichenfield, MD, Chairman, Moise L. Levy, MD, Amy S. Paller, MD, Vincent M. Riccardi, MD, and the Guidelines/Outcomes Committee*
I. Introduction The American Academy of Dermatology's Guidelines/Outcomes Committee is developing guidelines of care for our profession. The development of guidelines will promote the continued delivery of quality care and assist those outside our profession in understanding the complexities and scope of care provided by dermatologists. For the benefit of members of the American Academy of Dermatology who practice outside the jurisdiction of the United States, the listed treatments may include agents that are not currently approved by the U.S. Food and Drug Administration. II. Definition Neurofibromatosis type 1 (NF-1) is a genetic disorder that primarily affects cell growth of neural tissues. This disorder can cause tumors to grow, most commonly on periphera! nerves, at any location and at any time. Some manifestations are progressive and may result in significant morbidity or mortality. Other forms of "neurofibromatosis" have been described. This document relates to the most common type, NF-1 (previously known as von Recklinghausen's neurofibromatosis, classic neurofibromatosis, or peripheral neurofibromatosis). NF-1 is a dis*Guidelines~Outcomes Committee: Evan R. Farmer, MD, Tsu-Yi
Chuang, MD, Scott M. Dinehart, MD, Gloria E Graham, MD, Maria K. Hordinsky, MD, Marianne N. O'Donoghue, MD, David M. Pariser, MD, Stephen B. Webster, MD, Duane C. Whitaker, MD, and Barbara J. Lowery, MPH. Reprint requests: American Academy of Dermatology, P.O. Box 4014, Schaumburg, IL 60168-4014. J Am Aead Dermatol 1997;37:625-30. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/82985
tinct disorder and does not evolve into other forms of "neurofibromatosis." NF-1 is a progressive genetic disorder with diverse cutaneous, neurologic, skeletal, and neoplastic manifestations. The genetic defect, which lies on chromosome 17, changes cellular development and function. The disorder is characterized by caf6-au-lait macules, intertriginous freckles, neurofibromas, Lisch nodules, optic gliomas, bony dysplasias, and learning disabilities. Neurofibromas are tumors of nerve and fibrous tissue that grow in and along nerves and nerve sheath. The number, location, and size of tumors vary greatly from individual to individual. Noncutaneous tumors of nerve structures may develop and may interfere with function. Dermal neurofibromas may occasionally become malignant. There is an increased risk of other tumors and malignancies associated with NF-1, including gliomas, neurofibrosarcomas, leukemia, and pheochromocytomas. III. Rationale A. Scope NF-1 is an autosomal dominant disorder affecting approximately 1 in 3500 to 4000 persons. Approximately 50% of cases represent spontaneous mutations. There appears to be no racial, gender, or ethnic predilection. Multiple hyperpigmented areas (caf6-au-lait macules) and neurofibromas are characteristic. B. Issue There is considerable variation of manifestations in persons with NF-1, even within a family, confounding classifica625
626 Eichenfield et al. tion in some patients. This variability may affect management because it is often not possible to predict the course in an individual patient. In childhood, physical signs and symptoms may be limited, requiring careful consideration of the diagnosis, evaluation, and follow-up. Care may require involvement of multiple medical disciplines because of the multisystem nature of the disease. The NF-1 gene has been localized to chromosome 17ql 1.2, and a large number of mutations within the large neurofibromin gene may be responsible for the NF-1 phenotype. Advances in genetic testing may influence diagnosis, classification, patient care, counseling of families, and research. IV. Diagnostic criteria A. Established criteria National Institutes of Health (NIH) Consensus Development Conference on Neurofibromatosis Guidelines for Diagnosis are met in a person if two or more of the following are found. 1. Six or more caft-au-lait macules larger than 5 m m in greatest diameter in prepubertal persons and larger than 15 m m in greatest diameter in postpubertal persons 2. Two or more neurofibromas of any type or one plexiform neurofibroma 3. Freckling in the axillary or inguinal region 4. Optic glioma 5. Two or more Lisch nodules (iris hamartomas) 6. A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis 7. A first-degree relative (parent, sibling, or offspring) with NF-1 by the above criteria B. Clinical Diagnosis is usually made on a clinical basis, but may require other specialty examination or diagnostic tests. Diagnosis should be considered in persons having any one of the six signs of the disorder as listed in the NIH criteria
Journal of the American Academy of Dermatology October 1997 for diagnosis and in persons with a firstdegree relative with known or suspected NF-1. 1. History a) General medical history as indicated b) Onset of disease and symptoms 1) Caft-au-lait spots (common at birth, may increase in size and number the first decade of life) 2) Axillary/inguinal freckling (similar age at onset as caftau-lait spots) 3) Neurofibromas (onset usually in late childhood/adolescence onward) 4) Plexiform neurofibromas (can be present at birth) 5) Pain 6) Vision problems 7) Cognitive or psychomotor problems, including learning disabilities (may be evident in childhood) 8) Progressive neurologic defect 9) Constipation 10) Growth problems (e.g., precocious puberty or hypogonadism [may be evident in childhood]) ll)Orthopedic problems (e.g., pseudoarthrosis, scoliosis) 12) Hypertension c) Family history Include grandparents, great aunts and uncles, and their descendants. An effort should be made to locate medical records of affected firstand second-degree relatives. 2. Physical examination may include a) Cutaneous 1) Caft-au-lait spots 2) Axillary/inguinal freckles 3) Neurofibromas (cutaneous, subcutaneous, plexiform) 4) Neurofibrosarcomas (symptom complex of unexplained pain, enlargement of neurofibroma, focal neurologic deficit) 5) Other pigmentary anomalies
Journal of the AmericanAcademyof Dermatology Volume37, Number4
(a) Hyperpigmentation overlying plexiform neurofibromas (b) Midline hyperpigmentation or hypertrichosis may indicate underlying midline neuraxis involvement 6) Juvenile xanthogranulomas (may be associated with increased risk of juvenile myelogenous leukemia) b) Noncutaneous 1) Ophthalmic (a) Lisch nodules (highly specific finding seen in the majority of patients by third decade and ophthalmic examination with slit lamp is indicated) (b ) Proptosis (c) Ptosis (d) Optic gliomas (e) Optic atrophy secondary to gliomas (f) Congenital glaucoma 2) Skeletal anomalies (a) Scoliosis/kyphosis (b ) Macrocephaly (c) Sphenoid dysplasia ( d ) Pseudoarthrosis (e) Scalloping/erosion of vertebrae (f) Rib anomaly (g) Pectus excavatum (h) Short stature 3) Assessment of blood pressure (a ) Hypertension (b) Renovascular disease (c) Pheochromocytomas 4) Neurologic (a)Intracranial tumors, including glial or meningeal tumors (b) Spinal tumors (c) Seizures (d) Cognitive or psychomotor defects (learning impairment, mental retardation) 5) Assessment of pubertal status (hypogonadism, precocious puberty) 6) Other neoplasia (a) Pheochromocytomas (b ) Rhabdomyosarcomas
Eichenfield et al. 627 (c) Gastrointestinal tumors C. Diagnostic tests Diagnosis is usually made on a clinical basis, but may be aided by slit lamp ophthalmic examination. None of the tests below are routinely performed on all patients. Their use is dictated by findings on clinical evaluation. Routine laboratory testing in asymptomatic patients is of uncertain value, but may be helpful for diagnosis and as an adjunct to assess for potential complications. Testing may include the following: 1. Roentgenography (bony lesions, chest in neonates for mediastinal plexiform neurofibromas) 2. Computed tomography or magnetic resonance imaging (MRI) may detect optic gliomas, unidentified bright signals, focal central nervous system tumors, and plexiform neurofibromas. MRI with or without gadolinium contrast may be the imaging method of choice. 3. Electroencephalography and visual evoked response 4. Biopsy and histologic examination of cutaneous lesions (giant melanosomes seen by electron microscopy of caf6au-lait spots are most common in NF1, but are not pathognomonic) 5. Developmental and neuropsychiatric testing 6. Genetic testing based on polymerase chain reaction technology is commercially available, although restricted in its sensitivity and utility. (See section G below.) D. Differential diagnosis Other disorders of pigmentation may resemble NF-1. These include but are not limited to the following: 1. McCune-Albright syndrome 2. Watson syndrome (may be an allelic variant) 3. Bannayan-Riley-Rulvalcaba syndrome 4. Epidermal nevus syndrome 5. Proteus syndrome 6. Multiple lentigines syndromes
628 Eichenfield et al. 7. Segmental NF (NF type 5) may be a mosaic form of NF-1 8. Multiple caf6-au-lait lesions E. Inappropriate diagnostic tests Not applicable E Exceptions Not applicable G. Evolving diagnostic tests Genetic testing for NF-1 gene mutations may prove helpful in confirming the diagnosis of NF-1, as well as in prenatal diagnosis of NF-1. Linkage analysis, direct mutation analysis of DNA, protein truncation assay, and fluorescent in situ hybridization are among the genetic techniques being used. V. Recommendations A. Management Annual visits (more often if indicated) should be scheduled with a clinician familiar with NF-1. When symptoms suggest major manifestations of NF-1, the patient may be referred to the appropriate specialist for evaluation and diagnostic testing. Surgical intervention and radiation therapy should be used sparingly and only when it is clear that they will contribute to the patient's well-being. Patients are followed up for development of common complications, including the following: 1. Optic glioma (serial eye examinations are recommended; highest risk of rapidly progressive tumors in first 6 years of life) 2. Neural tumors (includes surveillance for focal neurologic deficits, and facial, shoulder, paraspinal plexiform tumors) 3. Developmental disabilities (developmental milestone delays, learning disabilities, speech impediments, school performance problems, retardation) 4. Vascular problems Routine blood pressure checks are indicated at all ages. Hypertension in patients with NF-1 is fully evaluated with particular emphasis on identifying treatable causes such as pheochromocytoma and renal vas-
Journal of the AmericanAcademyof Dermatology October 1997 cular stenosis. Other vascular disorders are handled on an individual basis in the same manner as they would be in the general population. 5. Orthopedic Surveillance for scoliosis/kyphosis, evolving pseudoarthrosis 6. Malignancy (increased incidence of sarcomas and leukemias, especially in childhood) When malignancies are detected, patients with NF-1 are evaluated and treated the same as other patients. Because patients with NF-1 also have an increased incidence of second malignancies, close long-term followup is indicated. 7. Disfigurements Disfigurements that may benefit from intervention are common, although the need for major surgery is less frequent. Removal of neurofibromas may contribute to maintenance of function and psychologic well-being. Sphenoid dysplasia occurs in a few patients. The resulting facial asymmetry and exophthalmos may be improved by reconstructive surgery. Deformities secondary to large soft-tissue masses are difficult to repair and have a tendency to recur. B. Treatment (cutaneous) 1. Medical Ketotifen (may be useful for pruritus associated with neurofibromas) 2. Surgical a) Neuroflbromas 1) Surgical excision 2) Carbon dioxide laser excision b) Caf6-au-lait spots Q-switched ruby, Q-switched Nd:YAG laser, and pigmented lesion dye lasers may be useful for lesions of cosmetic significance. 3. Inappropriate treatment The use of radiotherapy for treatment of neurofibromas is not advised. C. Patient education and counseling Counseling for patients and their families may be accomplished by a skilled clinician or by referral to other medical pro-
Journal of the American Academy of Dermatology Volume 37, Number 4
fessionals with expertise in NF-1 and genetic counseling. Information may include the following: 1. Prognosis The natural history of the disorder is progressive and variable, but includes serious complications in some persons. There is a risk of progression during puberty or pregnancy. 2. Genetics The probability of having an affected child, given one parent with NF-1, is 50% with each pregnancy. Siblings of a person with NF, who do not themselves have NF, will not transmit NF to their children. Fifty percent of cases represent spontaneous mutations. Manifestations of this disorder vary among persons within affected families. 3. Psychologic and social adjustment Issues to be addressed include anxieties regarding the uncertainties of the disorder's course and fear of possible disfigurement and of developing other severe complications. 4. Family members Family members, particularly firstdegree relatives, should be evaluated to determine whether they have NF-1. Appropriate counseling accompanies such assessments. Involvement of family members is a major aspect of care for patients with NF-1. 5. Follow-up Annual visits (more often if indicated) should be scheduled with a clinician familiar with the disorder. Annual ophthalmology examinations are indicated. 6. Resources for patients with NF-1 Patients may be offered the addresses and telephone numbers of specialized clinics that provide a broad array of relevant clinical expertise and of appropriate lay organizations that can give additional information and facilitate access to patient support groups. D. Miscellaneous Some patients, particularly children, have insufficient findings to meet NF-1
Eichenfield et al. 629 criteria. These patients require annual evaluations. Evolving molecular genetic techniques (see section IV, G) may allow earlier confirmation of diagnosis of NF1. Patients who do not fit into the NF-1 category by clinical or genetic criteria may, in the future, constitute the basis for establishing additional types of NF. These patients may require referral for more precise diagnosis or treatment of specific complications. VI. Supporting evidence See Bibliography (Appendix) VII. Disclaimer Adherence to these guidelines will not ensure successful treatment in every situation. Further, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of all of the circumstances presented by the individual patient. For the benefit of members of the American Academy of Dermatology who practice in countries outside the jurisdiction of the United States, the listed treatments may include agents that are not approved by the U.S. Food and Drug Administration. Appendix. Bibliography Ackerman CD, Cohen BA. Juvenile xanthogranuloma and neurofibromatosis. Pediatr Dermatol 1991;8:339-40. Arnsmeier SL, Riccardi VM, Paller AS. Familial multiple cafe au lait spots. Arch Dermatol 1994;130:1425-6. Becket DW Jr. Use of the carbon dioxide laser in treating multiple cutaneous neurofibromas. Ann Plast Surg 1991;26:582-6. Brodeur GM. The NF1 gene in myelopoiesis and childhood myelodysplastic syndromes. N Engl J Med 1994;330:6379. Crowe FW, Schull WJ. Diagnostic importance of cafe-an-lait spot in neurofibromatosis. Arch Dermatol 1953;91:758-66. Korf BR. Diagnostic outcome in children with multiple cafe au lait spots. Pediatrics 1992;90:924-7. Listernick R, Charrow J. Neurofibromatosis type 1 in childhood. J Pediatr 1990;116:845-53. Listernick R, Charrow J, Greenwald MJ, et al. Optic gliomas in children with neurofibromatosis type 1. J Pediatr 1989;114:788-92. Lubs ML, Bauer MS, Formas ME, et al. Lisch nodules in neurofibromatosis type 1. N Engl J Med 1991;324:1264-6. Mulvihill JJ, Parry DM, Sherman JL, et al. NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis): an update. Ann Intern Med 1990;113:39-52.
Journal of the American Academy of Dermatology October 1997
630 Eichenfield et al. National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis 1988;1:172-8. Obringer AC, Meadows AT, Zackai EH. The diagnosis of neurofibromatosis-1 in the child under the age of 6 years. Am J Dis Child 1989;143:717-9. Riccardi VM. Neurofibromatosis: past, present and future. N Engl J Med 1991;324:1283-5. Riccardi VM. Neurofibromatosis: phenotype, natural history, and pathogenesis. 2nd ed. Baltimore: Johns Hopkins University Press; 1992. Riccardi VM. Type 1 neurofibromatosis and the pediatric patient. Cult Probl Pediatr 1992;22:66-107.
Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med 1981:305:1617-27. Sorensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of yon Recklinghausen neurofibromatosis: survival and malignant neoplasms. N Engl J Med 1986;314:1010-5. Truhan AP, Filipek PA. Magnetic resonance imaging: its role in the neuroradiologic evaluation of neurofibromatosis, tuberous sclerosis, and Sturge-Weber syndrome. Arch Dermatol 1993;129:219-26. Wallace MR, Marchuk DA, Andersen LB, et al. Type-1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990;249:181-6.
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