SEMINARS IN NEUROLOGY-VOLUME
12, NO. 4 U E C L M B E R 1992
Diagnosis of Neurofibromatosis by Cutaneous Examination
Neurofibromatosis (NF) is among the most curs through autosonla1 dominant inheritance or, common of autosomal dominantly inherited dis- as in half of all cases, through spontaneous mutaorclers. The potentially dramatic disfigurement tion. T h e incidence of NF is 1 in 3000 persons, that afflicts some patients was exemplified, albeit with NF1 (von Recklinghausen type) accounting through incorrect diagnosis, by the "Elephant for 85 to 95% of all cases." Man."' John Mcrrick, in fact, did not have neuroThe initial diagnosis of NF1 is generally made fibromatosis, but had the proteus syndrome,'," a by finding the characteristic lesions: cafe au lait distinct disease entity with physical findings similar spots (Fig. l ) , axillary or skinfold freckling (Fig. 2), to NF type 1 (NF1). T h e image of this man's sco- or neurofibromas (Fig. 3). Affected patient.^ may liotic spine, numerous skin tumors, and, perhaps also have skeletal abnormalities such as scoliosis worst of all, social isolation, is a haunting reminder and tibia1 bowing, endocrinologic disturbances, imof the ravaging effects of extreme neurocutarleous paired mental function, seizures, and learning disorders." NF2 designates a disease characterized by disease. Although NF1 may be expressed with severe acoustic neuromas, usually bilateral, tumors of the disfigurement, the degree of cutaneous involve- central nervous system (CNS) such as optic gliomas ment is extremely variable. One patient may have or rneningiomas, and much less frequent cafe au almost imperceptible cafe au lait macules and lait spots and neurofibromas than in NF1. T h e axrllary freckling, and another may develop most common presenting symptom is hearing loss. hundreds of rieurofibromas and facial distortion. Table 2 outlines diagnostic criteria for NF1 and Orily one specific marker (hamartomatous nodules NF2. of the iris, known as Lisch nodules) occurs in 100% Segmental NF (NF5) is a localized form of of NFl adult patients. In persons younger than 20 NF1 and is the only type among the eight classified forms that is not inherited.6 years, the nodules may be a b ~ e n t . ~ It is the developmental nature of NF that creIn this article, we explore the cutaneous feaates uncertainty for individuals at risk, as well as tures of NF and their diagnostic implications for their families. A healthy child, for example, may the neurologist. have no Lisch nodules but four cafe au lait macules, a suspect though nondiagnostic number. This patient requires a yearly follow-up for new eviHISTORY dence of NF1 such as neurofibromas, which develop in late childhood, or Lisch nodules, which Virchow5 in 1847 first reported multiple neubegin to appear after age 6 years. NF enconipasses a broad spectrum. Ri~cardi.~romas occurring in more than one family member. has classified the disease into the categories listed Von Recklinghausen, also a German physician, is in Table 1. It is neuroectodermal in origin and oc- credited with describing the clinical and pathologic
Department o f Dermatology, Harvard Medical School, Massachusetts General Ilospital, Boston, Massachusetts Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Bonnie 7: Macknol, M.D., M.S.P.H., ard Thomas B. Fitzpat~ck,M.D., Ph.D., D.Sc. (Hon.)
DIAGNOSIS O F NEUROFIBKOMATOSIS-MACKOOL.FITZPATRICK
Table 1. Riccardi6Classification of Neurofibromatosis Category Von Recklinghausen Acoustic Mixed Variant Segmental Cafe au lait spots Late onset Not otherwise specified
See Table 2 See Table 2 Multiple brain and spinal cord tumors, with cafe au lait spots and neurofibromas Cafe au lait spots and neurofibromas diffuse, unable to categorize further Cafe au lait spots or neurofibromas, or both, limited to localized area Multiple cafe au lait spots without neurofibromas Onset of neurofibromatosis after 20 years of age Definite neurofibromatosis but not characteristic of any other category
features of NF in 1882.8 Pigmentary changes were not added to the disease description until 1896," Lisch called attention to hamartomatous nodules of the eye in 1937;"' and Crowe reported axillary freckling in 1964." T h e high prevalence of Lisch nodules in NF patients was not recognized until 1981," and only recently was it established that they appear in 100% of NF1 patients older than 20 years." Through scientific investigation, the genetics of NF has been further elucidated. It is now known that the genetic defects of NF 1 and 2 reside on different chromosomes, chromosomes 17 and 22, respectively.".lVhe NF1 gene has been shown to encode a protein with suppressor properties homologous to the catalytic region of the RAS
Figure 1. Cafe au lait macules scattered over the back of a young man with neurofibromatosis.
GTPase-activating protein.14 As we discuss later, genetic information may, in certain cases, be applied to diagnose the disease and to assess risk for children born to NF-affected families.
CLINICAL PRESENTATION Two or more of the criteria listed in Table 2 support the diagnosis of N F 1.I3 T h e first three criteria include the chief cutaneous manifestations of NFl, which are cafe au lait macules, neurofibromas, and skin fold freckling. Hyperpigmented macules, blue-red and pseudoatrophic macules, Lisch nodules, and nevoxanthornas are additional features of the disease.
Figure 2. Axillary freckling (Crowe's sign).
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NF-1 NF-2 NF-3
Features
V O L U M E 12, NUMBER 4 DECEMBER I992
Figure 3. Neurofibromas scattered over the chest with typical pendulous neurofibromas of the nipples. (Courtesy of Jeffrey S. Dover, M.D.)
CUE AU LAIT SPOTS
Cafe au lait spots are light to medium brown, uniformly colored macules of melanic origin varying in size from 0.5 to 50 cm; the vast majority are under 10 cm. They may occur anywhere on the body. Cafe au lait macules in young children are often pale and tend to darken with age. Wood's light examination, a shortwave, blue, portable light, facilitates examination of patients with fair skin.15 Table 2.
Diagnostic Criteria for the Neurofibromatoses*
Neurofibromatosis 1. Two or more of the following 1. Six or more cafe au lait spots over 5 mm in greatest diameter in prepubertal children and over 15 mm in postpubertal children and in adults 2. Two or more neurofibromas of any type or one plexiform neurofibroma 3. Freckling in the axillary or inguinal regions 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 pseudarthrosis 7. Afirst-degree relative (parent, sibling, or offspring) with neurofibromatosis type 1 by the above criteria Neurofibromatosis 2. Either of the following 1. Bilateral eighth nerve masses seen with appropriate imaging techniques (for example, computerized tomographic or magnetic resonance imaging) 2. A first-degree relative with NF2 and either unilateral eighth nerve mass or two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity 'Adapted from Mulvihill, Parry, Sherman, et aI.l3
Cafe au lait macules are very common in the unaffected population. Whitehousel%howed that children frequently have one or two cafk au lait spots; more than three is unusual and should raise suspicion of NF. The criterion for a diagnosis of NF based on cafe au lait spots in children is a minimum of six lesions each measuring 5 mm or greater. The criterion for NF1 adults with cafe au lait is the same number as children, six or more, but larger than 1.5 cm. T h e minimum number is based on the study by Crowe1' that found 75% of affected adults to have a minimum of six cafk au lait spots larger than 1.5 cm. One large European study found multiple cafe au lait spots present in greater than 90% of patients.17 Cafk au lait spots are the first manifestation of the disease in children. In Huson's study of NF in Wales, the age-related onset of specific cutaneous features was examined. Cafe au lait spots were rarely present at birth. Children with cafe au lait at an early age rarely had other signs of NF;I8 80% of children in the study with NF reportedly had one cafe au lait by 1 year of age, 100% of children by age 4 years. 'The cafe au lait spots of NF cannot be distinguished clinically or histopathologically from those in patients with McCune-Albright syndrome.15 NEVUS SPZLUS
Nevus spilus lesions are hyperpigmented macules of melanic origin quite similar to cafe au lait spots. They differ from cafe au lait in their speck-
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SEMINARS I N NEUROLOGY
DIAGNOSIS OF NEUKOI'IRROMATOSIS-MACKOOL. FI.I.ZPA.FRICK
NE UROFZBROMAS
Disfigurement in NF occurs chiefly from bony defects, macrocephaly, arid subcutaneous or cutaneous neurofibro~nas.T h e latter are flesh-colored or pink, soft., dome-shaped, or sonletimes pedunculated lesions that may occur anywhere on the t)ody; they have a predilection for the areola in women. They tend to enlarge with age. N F patients may have none, a few, or hundreds of these lesions. T h e "buttonholing" sign describes the herniation into the dermis that results from palpation of the raised portion of' the lesion. Neurofibromas are frequently pruritic, especially in pregnancy and puberty, which are periods of increased lesional growth as well. Any patient with NF is at risk for developing deeper neurofibromas that encase the length of a nerve and are called plexiform neurofibromas o r neuromas. 'l'hose developing in trigeminal or upper cervical nerves cause tremendous disfigurement. Elephantiasis neurofibromatosus describes the disproportional, gigantesque appearance of an area occupied by a diffuse neurofibroma of nerve trunks with soft tissue overgrowth and coarsened hairs. Hyperpigmented macules will sometimes overlie and demarcate the borders of a plexiforrn neuroma and be confused with a giant pigmented hairy nevus."O For this reason, any midline hyperpigmented rilacule in a child born to an affected parent should be evaluated for an underlying plexiform neuronla involving the CNS. With the exception of plexiform neuromas, rieurofibromas are not congerlital. Neurofibromas rarely develop in children younger than 6 years, and often not until puberty,'"t which time they may increase rapidly in size and number. Later adult life, ages 50 through the 70s, is another period of active growth arid appearance of neurofibromas. ~ a r k e dgrowth of one specific portion of the tumor or the oriset of' pruritus or pain should raise suspicion of possible change to a neurofibrosarcoma. This occurs predominantly in plexiform iieurofibrorrias and is rare. Biopsy is the only means of diagnosis. Neurofibromas may involve the lungs, kidney, and gastrointestinal tract and, when they involve the tongue, may lead to an initial presentation of rnacroglossia. The presence of one plexiforrn neurofibroma or two or more neurofibromas fulfills the second criterion iri Table 1. Neurofibromas occur in unaffected individuals as well, but usually as a solitary lesion.
-
HYPERPZGMENTED MACULES
Hyperpigmented macules are generally darker than caf6 au lait spots and their borders, as mentioned earlier, may correspond to those of an underlying plexiform neurofibroma. AXZLLARY FRECKLING
Freckling in sun-protected areas such as the axilla, inguinal fold, and perineum is another diagnostic feature of NF. Lesions are small pigmented macules occurring most commonly in the axilla of affected patients. In one large study 67% of NF patients had axillary freckling; the youngest patient found to have this feature was 3 years old.I8 lntertriginous freckling can also occur in the leopard syndrome. l 5 Downloaded by: Universite de Sherbrooke. Copyrighted material.
led appearance, relative rarity, and recently reported ability to undergo maligriant change.'"
BLUE-RED MACULES AND PSEUDOATROPHZC MACULES
Blue-red macules and pseudoatrophic macules were described early in the 20th century as characteristic features of NF, but in later literature are seldom r ~ ~ e n t i o n e d .Blue-red ~ ' . ~ ~ macules are primarily truncal, average 3 cm in diameter, and disappear when compressed, indicating their vascular nature. Pseudoatrophic nlacules are also primarily truncal, slightly depressed, oval lesions. 'I'hey average 5 to 10 cm in diameter.'" LZSCH NODULES
Lisch nodules are transparent, dome-shaped, pigmented hamartomas of the iris recently found to occur in 100% of NF patients older than 20 years. They begin to appear at age 5 years, and can be found in 95% of patients aged 6 or older in NFI. They must be distinguished from iris freckling by slit lamp examination. NEVOXANTHOMAS
Nevoxanthomas are benign, yellow-orange nodules that are usually self-limited and occur most frequently in young children. Numerous case reports have suggested an association with NF,23 but their prevalence in the disease is not kriown.
HISTOPATHOLOGY Solitary ncurofibromas and those of N F have identical histopathologic features. S-shaped spindle cells are the predominant cell among wavy, hintly eosinophilic collagen fibers coursing in var36 1
GENETICS IN DIAGNOSIS AND ASSESSMENT Children of an NF parent have a 50% chance of having the disease, unless a parerit is affected through spontaneous mutation, in which case offspring carry the same risk as the general population. It follows that children of parents with NF5, the noninherited type, are at no greater risk than the general population. Two case reports, however, contradict this conclusion. Rubenstein et a130 reported apparent transmission of segmental NF from father to daughter. Similarly, the case of a father with segmental NF whose son developed generalized NF has been r e p ~ r t e d . ~ The ' risk of a patient with segmental NF passing on the disease to offspring is difficult to define, in part because of
our limited ability to distinguish segmental from generalized NF. Our current definition of NF5 limits involvement to a circumscribed body segrricnt but with no size limitations. Moreover, the number of' reported cases available to permit pooling of experience is small (fewer than 50); and, most importantly, the pathogenesis of NF is still unclear. Some studies suggest advanced paternal age as a risk f'actor for new mutations of NF in offspring.32 NF5 has been the model for studying spontaricous mutation in NF, whereas NF1 remains the model of familial inheritance. DNA marker studies now allow prenatal and presyrnptomatic diagnosis of familial NF1 in situations in which two affected family rriernbers have been identified and are available for testing. NF1 in affected individuals has 100% penetrance and variable expressivity. This means that family members carrying the gene defect will manifest some sign of NF (penetrance) but vary individually in disease severity (expressivity)."Vhe recent finding of 1,isch nodules in 100% of NFl patients older than 20 years allows for age-adjusted risk assessment for asymptomatic persons based on the absence of Lisch nodules.'
TREATMENT No satisfactory treatment of NF exists. Cutaneous neurofibrornas may be simply excised. Repeated excision with recoristruction is generally required in treating lesions of the orbit, eyelids, cheeks, ears, lips, nose, and mouth." Neurofibromas of the areola may be excised and larger lesions reportedly have been successfully treated with reduction rnarnmopla~ty.~Wermabrasion for disfiguring facial neurofibromas has been d e ~ c r i b e d . ~ ~ Ketotifen, a mast cell stabilizer, has been associated with a decrease in pruritus or tenderness of neurofibromas. A study of 10 patients with severe NF reports subjective decreases in the rate of neurofibroma growth.37 It is interesting that patients undergoing surgery while taking ketotifen did not have the excessive bleeding that is expected with intraoperative mariipulation of neurofibromas. H I and H, blockers have not been shown to be of use in symptomatic treatment of NF.37
CONCLUSION Our knowledge of NF has advanced since its original descriptiori by von Recklinghausen over 100 years ago. Within the last decade, genes for
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ious directions. T h e tumor is usually well circumscribed but not encapsulated. Mast cells comprise approxirriately 5% of all nuclei.'Weurofibromas contain all three cell types found in peripheral nerves: Schwann cells, perineurial cells, and endoneurial fibroblasts. Plexiform neurofibromas have a similar histologic appearance but involve large, deep nerves. Controversy persists as to whether the neurofibroma is a schwannoma or fibroblastonia; studies continue to explore this issue. Some results suggest that Schwann cell mitogen released during nerve cell degeneration coritributes to neurofibromas.'Wther mechanisms invoke nerve growth factor, mast cell biology, oncogenes, and embryonic neural crest in the pathogericsis. Neurofibrosarcomas may uncommonly arise in neurofibrornas. In one series, 2 1 of 678 patients with NF developed a neurofibrosarcoma; these occurred rriost often in association with a plexiform or subcutaneous neurorna. Only 2 of the 21 patients developed a neurofibrosarcorna in a cutaneous neurofibroma."' Lever and SchaurnburgLever27make the distinction between neurolibrosarcoma of low malignancy, often with only a mild to moderate increase in cellularity and the presence of mitoses, from those of high malignancy with enlarged nuclei varying in size and shape, dense cellularity, and lack of any wavy pattern. Cafe au lait macules display an increase in mt:lanin in melanocytes and keratinocytes compared with normal skin. Giant melanin particles called melanin macroglobules, u p to 5 mp. in dianieter, may be present in rrielanocytes and basal cells; they are nonspecific for NF, since they occur in the cafe au lait spots of other pigmentary conditions, such as nevus spilus; multiple lentiginosis syndrome; and, rarely, in Albright's ~yndrorne.'~-'"
familial NFI and NF2 have been cloned, and flanking DNA markers permit prenatal and presymptomatic diagnosis of the familial type of N F l . NF5 continues to be a hypothetical model of spontaneous mutation. Familiarity with the varied cutaneous manifestatiorls of' the disease is perhaps among the most useful of tools for early detection. Prompt diagnosis may lead to corrective therapy of neurologic disorders such as learning- disabilities and skeletal and endocrinologic disturbances and to genetic counseling. 'l'he extent of cutaneous and systemic involvement in the disease is highly variable, the threat or , reality of devastating developmental deformities is emotionally burdensome. Treatment remains severely limited and will depend on further illurnination of genetic, biochemical, and pathologic mechanisms of the disease.
16. 17. 18. 19. 20. 21.
22. 23. 24.
REFERENCES 1. Webcr FP. Cutaneous pigmentation as a n incomplete form of Recklinghausen's disease. Br J Dermatol 1909; 21:49 2. Coheri MM Jr. Further diagnostic thought about the Elephant Man. Am J Med Genet 1988;29:777-82 3 . Tibbles JAR, Cohen hfM Jr. 'l'he proteus syndrome. B r Med J 1986;293:683-5 4. Lubs M E . I h c h nodules in neurofibromatosis type 1. N Er~glJ Med 1993;24:451-3 5. Kiccardi VM. Neurofibromatosis: clinical heterogeneity. C u r r Probl Cancer 1982;7: 1-34 6. Crowe FW, Srhull WJ, Neel JV. A clinical pathological and genetic study of multiple neurofibromatoses. Springfield, IL: Charles C Thomas, 1956 7. Virct~ow R. Ueber die Keform d e r patologischen und therapcutischen Anschauungen durch die mikroskopischen Untersuchungen. Virchow's Arrh Pathol Anat Physiol Klin Med 1847;1:207-55 (cited by tioldberg arid Collir~s.'~) 8. Recklinghausen FD von. Ueber die rnultiplen Fibronie d e r Maut und ihre Beziehung zu den multiplen Neuromen. Berlin: A. Hirschwald, 1882 (cited by Lisch"') 9. Marie P, Bernard A. Neurofibromatose generalisee. Soc Med H o p Paris 1896; 13:200-9 10. Lisch K. Ueber Beteiligung d e r Augen, ins Besor~dere das Vorkommen van Irisknotchen bei d e r Neurofibrornatose (Recklinghausen). Z Augenheilkd 1937;YY: 137-43 (cited by Mulvihill et all3) 11. Crowe FW. Axillary freckling as a diagnostic aid in neurofibromatosis. Ann Intern Med 1964;61: 1142-3 12. Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis: incidence of iris hamartomata. Ophthalmology 198 1;88:348-54 13. Mulvihill JJ, Parry DM, Sherman JL, et al. Neurofibronlatosis I (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). Ann Iriterri Med 1990; 113:39-52 14. Goldberg NS, Collins FS. T h e hunt for the neurofibromatosis gene. Arch Derrnatol 1991; 127: 1705-7 15. Tong AKF, Fitzpatrick TB. T h c skin in neurofibromatosis. In: Rubenstein AE, Korff BR, eds: Neurofibroma-
25.
26.
27. 28. 29.
30. 3 1. 32. 33.
34. 35. 36. 37.
tosis: a handbook for patients, families and health care professionals. New York: Thieme, National NF Foundation, 1990;88-98 Whitehousc D. Diagnostic value of the cafe au lait spot in children. Arch Dis Child 1966;41:316-9 Ortonne JP, Brocard E, F l o r e ~D, Perrot H , Thivolet 1 . Valeur diagnostique des taches cafe au lait (T.C.L.). Ann Derniatol Venereol 1980; 107:3 13 Hrison SM, Harper PS, Con~pstorlDAS. Von Kecklinghausen neurofibromatosis: a clinical and population study in South-east Wales. Brain 1988; 11 1: 1355-81 Khodes AK, Mihm M. Origin of cutaneous melariorria in a congenital dysplas~icrle'itus spilus. Arch Dermatol 1990; 126:500-5 Rook .4, Wilkinsori DS, Ebling FJG. Textbook of dermatology, 5th ed. Oxford: Rlackwell Scientific, 1991: 322-27 Carol WLL, Van Heusdcn JC. Reitrag zur Kenntr~isdes Morbus Rourneville-Pririgle und d e r Recklinghausenclien Neurofibromatosis. Arch Dermatol Syphil 1936; 175: 1-37 W'esterhof W, Klaus K. Blue-red marules and pseudoatrophic macules-additional cutaneous signs in ncurnfibromatosis. Arch Dermatol 1982; 118:577-81 Jensen NE, Sabharwal S, Walker AE. Naevoxanthoendothelionla and neurofibromatosis. Br J Der~natol 1971 ;85:326-30 Jurecka W, Lassmann H , Gebhart W, et al. Classification of peripheral nerve sheath tumors. (Abstr.) Arch Dermatol Kes 1977;258: 100 Ratner N , IIong DM, Lieberman MA, et al. T h e neuronal cell-surface molecule mitogenic for Schwann cells is a heparin-binding protein. Proc Natl Acad Sci USA 1988;85:6992-6 D'Agostino AN, Soule EH, Miller RH. Sarcomas of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (von Recklinghausen's disease). Cancer 1963; 16: 10 15-27 Lever WF, Schaumburg-Lever G. Histopathology of the skin, 7th ed. Philadelphia: J B Lippincott, 1990:739-43 Eady RAT, Cowen T C . Naevus spilus. Br J Dermatol 1975;93(1 l):16 Jimbow K, Szabo G, Fitzpatrick T B . Ultrastructure of giant pigment granules (macromelanosomes) in the cutaneous pigmented ~naculesof neurofibromatosis, .J Invest Dermat 1973;61:300-9 Rubenstein AE, BaderJI,, Aron AA, et al. Familial transmission of segrnerital rieurofibron~atosis.Neurology 1983;33(Suppl 2):76 Sloan JB, Fretzirl DF, Bovenmyer DA. Genetic counseling in segmental neurofihromatosis. J Am Acad Derrnatol 1990;22:461-7 Jadayel D, Fain P, Upadhyaya M, et al. Paternal origin of new mutations in Von Recklinghausen neurofibromaLosis. Nature 1990;343:558-9 Riccardi VM, Lewis RA. Penetrance of vorr Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. An1 J H u m Genet 1988;42: 284-9 Bromley GS, Sherman J E , Goulian D Jr. Neurofibromatosis-distribution of lesions and surgical treatment. Ann Plast Surg 1982;8:272-6 Sherman ,JE, Smith JW. Neurofibromatosis of the breast arid nipple areolar area. Ann Plast Surg 198 1;7:302-7 Hanke CW, Conner AC, Reed JC. Treatment of multiple facial neurofibromas with derrnabrasion. J Dermatol Surg Oncol 1987;13:6 Riccardi VM. Mast-cell stabilization to decrease neurofibroma growth, preliminary experience with ketotifen. Arch Dermatol 1987; 123: 101 1-6
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DIAGNOSIS O F NEUROFIBROMATOSIS-MACKOOL,FITZPATRICK
12, NO. 4 U E C L M B E R 1992
Diagnosis of Neurofibromatosis by Cutaneous Examination
Neurofibromatosis (NF) is among the most curs through autosonla1 dominant inheritance or, common of autosomal dominantly inherited dis- as in half of all cases, through spontaneous mutaorclers. The potentially dramatic disfigurement tion. T h e incidence of NF is 1 in 3000 persons, that afflicts some patients was exemplified, albeit with NF1 (von Recklinghausen type) accounting through incorrect diagnosis, by the "Elephant for 85 to 95% of all cases." Man."' John Mcrrick, in fact, did not have neuroThe initial diagnosis of NF1 is generally made fibromatosis, but had the proteus syndrome,'," a by finding the characteristic lesions: cafe au lait distinct disease entity with physical findings similar spots (Fig. l ) , axillary or skinfold freckling (Fig. 2), to NF type 1 (NF1). T h e image of this man's sco- or neurofibromas (Fig. 3). Affected patient.^ may liotic spine, numerous skin tumors, and, perhaps also have skeletal abnormalities such as scoliosis worst of all, social isolation, is a haunting reminder and tibia1 bowing, endocrinologic disturbances, imof the ravaging effects of extreme neurocutarleous paired mental function, seizures, and learning disorders." NF2 designates a disease characterized by disease. Although NF1 may be expressed with severe acoustic neuromas, usually bilateral, tumors of the disfigurement, the degree of cutaneous involve- central nervous system (CNS) such as optic gliomas ment is extremely variable. One patient may have or rneningiomas, and much less frequent cafe au almost imperceptible cafe au lait macules and lait spots and neurofibromas than in NF1. T h e axrllary freckling, and another may develop most common presenting symptom is hearing loss. hundreds of rieurofibromas and facial distortion. Table 2 outlines diagnostic criteria for NF1 and Orily one specific marker (hamartomatous nodules NF2. of the iris, known as Lisch nodules) occurs in 100% Segmental NF (NF5) is a localized form of of NFl adult patients. In persons younger than 20 NF1 and is the only type among the eight classified forms that is not inherited.6 years, the nodules may be a b ~ e n t . ~ It is the developmental nature of NF that creIn this article, we explore the cutaneous feaates uncertainty for individuals at risk, as well as tures of NF and their diagnostic implications for their families. A healthy child, for example, may the neurologist. have no Lisch nodules but four cafe au lait macules, a suspect though nondiagnostic number. This patient requires a yearly follow-up for new eviHISTORY dence of NF1 such as neurofibromas, which develop in late childhood, or Lisch nodules, which Virchow5 in 1847 first reported multiple neubegin to appear after age 6 years. NF enconipasses a broad spectrum. Ri~cardi.~romas occurring in more than one family member. has classified the disease into the categories listed Von Recklinghausen, also a German physician, is in Table 1. It is neuroectodermal in origin and oc- credited with describing the clinical and pathologic
Department o f Dermatology, Harvard Medical School, Massachusetts General Ilospital, Boston, Massachusetts Copyright O 1992 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
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Bonnie 7: Macknol, M.D., M.S.P.H., ard Thomas B. Fitzpat~ck,M.D., Ph.D., D.Sc. (Hon.)
DIAGNOSIS O F NEUROFIBKOMATOSIS-MACKOOL.FITZPATRICK
Table 1. Riccardi6Classification of Neurofibromatosis Category Von Recklinghausen Acoustic Mixed Variant Segmental Cafe au lait spots Late onset Not otherwise specified
See Table 2 See Table 2 Multiple brain and spinal cord tumors, with cafe au lait spots and neurofibromas Cafe au lait spots and neurofibromas diffuse, unable to categorize further Cafe au lait spots or neurofibromas, or both, limited to localized area Multiple cafe au lait spots without neurofibromas Onset of neurofibromatosis after 20 years of age Definite neurofibromatosis but not characteristic of any other category
features of NF in 1882.8 Pigmentary changes were not added to the disease description until 1896," Lisch called attention to hamartomatous nodules of the eye in 1937;"' and Crowe reported axillary freckling in 1964." T h e high prevalence of Lisch nodules in NF patients was not recognized until 1981," and only recently was it established that they appear in 100% of NF1 patients older than 20 years." Through scientific investigation, the genetics of NF has been further elucidated. It is now known that the genetic defects of NF 1 and 2 reside on different chromosomes, chromosomes 17 and 22, respectively.".lVhe NF1 gene has been shown to encode a protein with suppressor properties homologous to the catalytic region of the RAS
Figure 1. Cafe au lait macules scattered over the back of a young man with neurofibromatosis.
GTPase-activating protein.14 As we discuss later, genetic information may, in certain cases, be applied to diagnose the disease and to assess risk for children born to NF-affected families.
CLINICAL PRESENTATION Two or more of the criteria listed in Table 2 support the diagnosis of N F 1.I3 T h e first three criteria include the chief cutaneous manifestations of NFl, which are cafe au lait macules, neurofibromas, and skin fold freckling. Hyperpigmented macules, blue-red and pseudoatrophic macules, Lisch nodules, and nevoxanthornas are additional features of the disease.
Figure 2. Axillary freckling (Crowe's sign).
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NF-1 NF-2 NF-3
Features
V O L U M E 12, NUMBER 4 DECEMBER I992
Figure 3. Neurofibromas scattered over the chest with typical pendulous neurofibromas of the nipples. (Courtesy of Jeffrey S. Dover, M.D.)
CUE AU LAIT SPOTS
Cafe au lait spots are light to medium brown, uniformly colored macules of melanic origin varying in size from 0.5 to 50 cm; the vast majority are under 10 cm. They may occur anywhere on the body. Cafe au lait macules in young children are often pale and tend to darken with age. Wood's light examination, a shortwave, blue, portable light, facilitates examination of patients with fair skin.15 Table 2.
Diagnostic Criteria for the Neurofibromatoses*
Neurofibromatosis 1. Two or more of the following 1. Six or more cafe au lait spots over 5 mm in greatest diameter in prepubertal children and over 15 mm in postpubertal children and in adults 2. Two or more neurofibromas of any type or one plexiform neurofibroma 3. Freckling in the axillary or inguinal regions 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 pseudarthrosis 7. Afirst-degree relative (parent, sibling, or offspring) with neurofibromatosis type 1 by the above criteria Neurofibromatosis 2. Either of the following 1. Bilateral eighth nerve masses seen with appropriate imaging techniques (for example, computerized tomographic or magnetic resonance imaging) 2. A first-degree relative with NF2 and either unilateral eighth nerve mass or two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity 'Adapted from Mulvihill, Parry, Sherman, et aI.l3
Cafe au lait macules are very common in the unaffected population. Whitehousel%howed that children frequently have one or two cafk au lait spots; more than three is unusual and should raise suspicion of NF. The criterion for a diagnosis of NF based on cafe au lait spots in children is a minimum of six lesions each measuring 5 mm or greater. The criterion for NF1 adults with cafe au lait is the same number as children, six or more, but larger than 1.5 cm. T h e minimum number is based on the study by Crowe1' that found 75% of affected adults to have a minimum of six cafk au lait spots larger than 1.5 cm. One large European study found multiple cafe au lait spots present in greater than 90% of patients.17 Cafk au lait spots are the first manifestation of the disease in children. In Huson's study of NF in Wales, the age-related onset of specific cutaneous features was examined. Cafe au lait spots were rarely present at birth. Children with cafe au lait at an early age rarely had other signs of NF;I8 80% of children in the study with NF reportedly had one cafe au lait by 1 year of age, 100% of children by age 4 years. 'The cafe au lait spots of NF cannot be distinguished clinically or histopathologically from those in patients with McCune-Albright syndrome.15 NEVUS SPZLUS
Nevus spilus lesions are hyperpigmented macules of melanic origin quite similar to cafe au lait spots. They differ from cafe au lait in their speck-
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SEMINARS I N NEUROLOGY
DIAGNOSIS OF NEUKOI'IRROMATOSIS-MACKOOL. FI.I.ZPA.FRICK
NE UROFZBROMAS
Disfigurement in NF occurs chiefly from bony defects, macrocephaly, arid subcutaneous or cutaneous neurofibro~nas.T h e latter are flesh-colored or pink, soft., dome-shaped, or sonletimes pedunculated lesions that may occur anywhere on the t)ody; they have a predilection for the areola in women. They tend to enlarge with age. N F patients may have none, a few, or hundreds of these lesions. T h e "buttonholing" sign describes the herniation into the dermis that results from palpation of the raised portion of' the lesion. Neurofibromas are frequently pruritic, especially in pregnancy and puberty, which are periods of increased lesional growth as well. Any patient with NF is at risk for developing deeper neurofibromas that encase the length of a nerve and are called plexiform neurofibromas o r neuromas. 'l'hose developing in trigeminal or upper cervical nerves cause tremendous disfigurement. Elephantiasis neurofibromatosus describes the disproportional, gigantesque appearance of an area occupied by a diffuse neurofibroma of nerve trunks with soft tissue overgrowth and coarsened hairs. Hyperpigmented macules will sometimes overlie and demarcate the borders of a plexiforrn neuroma and be confused with a giant pigmented hairy nevus."O For this reason, any midline hyperpigmented rilacule in a child born to an affected parent should be evaluated for an underlying plexiform neuronla involving the CNS. With the exception of plexiform neuromas, rieurofibromas are not congerlital. Neurofibromas rarely develop in children younger than 6 years, and often not until puberty,'"t which time they may increase rapidly in size and number. Later adult life, ages 50 through the 70s, is another period of active growth arid appearance of neurofibromas. ~ a r k e dgrowth of one specific portion of the tumor or the oriset of' pruritus or pain should raise suspicion of possible change to a neurofibrosarcoma. This occurs predominantly in plexiform iieurofibrorrias and is rare. Biopsy is the only means of diagnosis. Neurofibromas may involve the lungs, kidney, and gastrointestinal tract and, when they involve the tongue, may lead to an initial presentation of rnacroglossia. The presence of one plexiforrn neurofibroma or two or more neurofibromas fulfills the second criterion iri Table 1. Neurofibromas occur in unaffected individuals as well, but usually as a solitary lesion.
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HYPERPZGMENTED MACULES
Hyperpigmented macules are generally darker than caf6 au lait spots and their borders, as mentioned earlier, may correspond to those of an underlying plexiform neurofibroma. AXZLLARY FRECKLING
Freckling in sun-protected areas such as the axilla, inguinal fold, and perineum is another diagnostic feature of NF. Lesions are small pigmented macules occurring most commonly in the axilla of affected patients. In one large study 67% of NF patients had axillary freckling; the youngest patient found to have this feature was 3 years old.I8 lntertriginous freckling can also occur in the leopard syndrome. l 5 Downloaded by: Universite de Sherbrooke. Copyrighted material.
led appearance, relative rarity, and recently reported ability to undergo maligriant change.'"
BLUE-RED MACULES AND PSEUDOATROPHZC MACULES
Blue-red macules and pseudoatrophic macules were described early in the 20th century as characteristic features of NF, but in later literature are seldom r ~ ~ e n t i o n e d .Blue-red ~ ' . ~ ~ macules are primarily truncal, average 3 cm in diameter, and disappear when compressed, indicating their vascular nature. Pseudoatrophic nlacules are also primarily truncal, slightly depressed, oval lesions. 'I'hey average 5 to 10 cm in diameter.'" LZSCH NODULES
Lisch nodules are transparent, dome-shaped, pigmented hamartomas of the iris recently found to occur in 100% of NF patients older than 20 years. They begin to appear at age 5 years, and can be found in 95% of patients aged 6 or older in NFI. They must be distinguished from iris freckling by slit lamp examination. NEVOXANTHOMAS
Nevoxanthomas are benign, yellow-orange nodules that are usually self-limited and occur most frequently in young children. Numerous case reports have suggested an association with NF,23 but their prevalence in the disease is not kriown.
HISTOPATHOLOGY Solitary ncurofibromas and those of N F have identical histopathologic features. S-shaped spindle cells are the predominant cell among wavy, hintly eosinophilic collagen fibers coursing in var36 1
GENETICS IN DIAGNOSIS AND ASSESSMENT Children of an NF parent have a 50% chance of having the disease, unless a parerit is affected through spontaneous mutation, in which case offspring carry the same risk as the general population. It follows that children of parents with NF5, the noninherited type, are at no greater risk than the general population. Two case reports, however, contradict this conclusion. Rubenstein et a130 reported apparent transmission of segmental NF from father to daughter. Similarly, the case of a father with segmental NF whose son developed generalized NF has been r e p ~ r t e d . ~ The ' risk of a patient with segmental NF passing on the disease to offspring is difficult to define, in part because of
our limited ability to distinguish segmental from generalized NF. Our current definition of NF5 limits involvement to a circumscribed body segrricnt but with no size limitations. Moreover, the number of' reported cases available to permit pooling of experience is small (fewer than 50); and, most importantly, the pathogenesis of NF is still unclear. Some studies suggest advanced paternal age as a risk f'actor for new mutations of NF in offspring.32 NF5 has been the model for studying spontaricous mutation in NF, whereas NF1 remains the model of familial inheritance. DNA marker studies now allow prenatal and presyrnptomatic diagnosis of familial NF1 in situations in which two affected family rriernbers have been identified and are available for testing. NF1 in affected individuals has 100% penetrance and variable expressivity. This means that family members carrying the gene defect will manifest some sign of NF (penetrance) but vary individually in disease severity (expressivity)."Vhe recent finding of 1,isch nodules in 100% of NFl patients older than 20 years allows for age-adjusted risk assessment for asymptomatic persons based on the absence of Lisch nodules.'
TREATMENT No satisfactory treatment of NF exists. Cutaneous neurofibrornas may be simply excised. Repeated excision with recoristruction is generally required in treating lesions of the orbit, eyelids, cheeks, ears, lips, nose, and mouth." Neurofibromas of the areola may be excised and larger lesions reportedly have been successfully treated with reduction rnarnmopla~ty.~Wermabrasion for disfiguring facial neurofibromas has been d e ~ c r i b e d . ~ ~ Ketotifen, a mast cell stabilizer, has been associated with a decrease in pruritus or tenderness of neurofibromas. A study of 10 patients with severe NF reports subjective decreases in the rate of neurofibroma growth.37 It is interesting that patients undergoing surgery while taking ketotifen did not have the excessive bleeding that is expected with intraoperative mariipulation of neurofibromas. H I and H, blockers have not been shown to be of use in symptomatic treatment of NF.37
CONCLUSION Our knowledge of NF has advanced since its original descriptiori by von Recklinghausen over 100 years ago. Within the last decade, genes for
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ious directions. T h e tumor is usually well circumscribed but not encapsulated. Mast cells comprise approxirriately 5% of all nuclei.'Weurofibromas contain all three cell types found in peripheral nerves: Schwann cells, perineurial cells, and endoneurial fibroblasts. Plexiform neurofibromas have a similar histologic appearance but involve large, deep nerves. Controversy persists as to whether the neurofibroma is a schwannoma or fibroblastonia; studies continue to explore this issue. Some results suggest that Schwann cell mitogen released during nerve cell degeneration coritributes to neurofibromas.'Wther mechanisms invoke nerve growth factor, mast cell biology, oncogenes, and embryonic neural crest in the pathogericsis. Neurofibrosarcomas may uncommonly arise in neurofibrornas. In one series, 2 1 of 678 patients with NF developed a neurofibrosarcoma; these occurred rriost often in association with a plexiform or subcutaneous neurorna. Only 2 of the 21 patients developed a neurofibrosarcorna in a cutaneous neurofibroma."' Lever and SchaurnburgLever27make the distinction between neurolibrosarcoma of low malignancy, often with only a mild to moderate increase in cellularity and the presence of mitoses, from those of high malignancy with enlarged nuclei varying in size and shape, dense cellularity, and lack of any wavy pattern. Cafe au lait macules display an increase in mt:lanin in melanocytes and keratinocytes compared with normal skin. Giant melanin particles called melanin macroglobules, u p to 5 mp. in dianieter, may be present in rrielanocytes and basal cells; they are nonspecific for NF, since they occur in the cafe au lait spots of other pigmentary conditions, such as nevus spilus; multiple lentiginosis syndrome; and, rarely, in Albright's ~yndrorne.'~-'"
familial NFI and NF2 have been cloned, and flanking DNA markers permit prenatal and presymptomatic diagnosis of the familial type of N F l . NF5 continues to be a hypothetical model of spontaneous mutation. Familiarity with the varied cutaneous manifestatiorls of' the disease is perhaps among the most useful of tools for early detection. Prompt diagnosis may lead to corrective therapy of neurologic disorders such as learning- disabilities and skeletal and endocrinologic disturbances and to genetic counseling. 'l'he extent of cutaneous and systemic involvement in the disease is highly variable, the threat or , reality of devastating developmental deformities is emotionally burdensome. Treatment remains severely limited and will depend on further illurnination of genetic, biochemical, and pathologic mechanisms of the disease.
16. 17. 18. 19. 20. 21.
22. 23. 24.
REFERENCES 1. Webcr FP. Cutaneous pigmentation as a n incomplete form of Recklinghausen's disease. Br J Dermatol 1909; 21:49 2. Coheri MM Jr. Further diagnostic thought about the Elephant Man. Am J Med Genet 1988;29:777-82 3 . Tibbles JAR, Cohen hfM Jr. 'l'he proteus syndrome. B r Med J 1986;293:683-5 4. Lubs M E . I h c h nodules in neurofibromatosis type 1. N Er~glJ Med 1993;24:451-3 5. Kiccardi VM. Neurofibromatosis: clinical heterogeneity. C u r r Probl Cancer 1982;7: 1-34 6. Crowe FW, Srhull WJ, Neel JV. A clinical pathological and genetic study of multiple neurofibromatoses. Springfield, IL: Charles C Thomas, 1956 7. Virct~ow R. Ueber die Keform d e r patologischen und therapcutischen Anschauungen durch die mikroskopischen Untersuchungen. Virchow's Arrh Pathol Anat Physiol Klin Med 1847;1:207-55 (cited by tioldberg arid Collir~s.'~) 8. Recklinghausen FD von. Ueber die rnultiplen Fibronie d e r Maut und ihre Beziehung zu den multiplen Neuromen. Berlin: A. Hirschwald, 1882 (cited by Lisch"') 9. Marie P, Bernard A. Neurofibromatose generalisee. Soc Med H o p Paris 1896; 13:200-9 10. Lisch K. Ueber Beteiligung d e r Augen, ins Besor~dere das Vorkommen van Irisknotchen bei d e r Neurofibrornatose (Recklinghausen). Z Augenheilkd 1937;YY: 137-43 (cited by Mulvihill et all3) 11. Crowe FW. Axillary freckling as a diagnostic aid in neurofibromatosis. Ann Intern Med 1964;61: 1142-3 12. Lewis RA, Riccardi VM. Von Recklinghausen neurofibromatosis: incidence of iris hamartomata. Ophthalmology 198 1;88:348-54 13. Mulvihill JJ, Parry DM, Sherman JL, et al. Neurofibronlatosis I (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). Ann Iriterri Med 1990; 113:39-52 14. Goldberg NS, Collins FS. T h e hunt for the neurofibromatosis gene. Arch Derrnatol 1991; 127: 1705-7 15. Tong AKF, Fitzpatrick TB. T h c skin in neurofibromatosis. In: Rubenstein AE, Korff BR, eds: Neurofibroma-
25.
26.
27. 28. 29.
30. 3 1. 32. 33.
34. 35. 36. 37.
tosis: a handbook for patients, families and health care professionals. New York: Thieme, National NF Foundation, 1990;88-98 Whitehousc D. Diagnostic value of the cafe au lait spot in children. Arch Dis Child 1966;41:316-9 Ortonne JP, Brocard E, F l o r e ~D, Perrot H , Thivolet 1 . Valeur diagnostique des taches cafe au lait (T.C.L.). Ann Derniatol Venereol 1980; 107:3 13 Hrison SM, Harper PS, Con~pstorlDAS. Von Kecklinghausen neurofibromatosis: a clinical and population study in South-east Wales. Brain 1988; 11 1: 1355-81 Khodes AK, Mihm M. Origin of cutaneous melariorria in a congenital dysplas~icrle'itus spilus. Arch Dermatol 1990; 126:500-5 Rook .4, Wilkinsori DS, Ebling FJG. Textbook of dermatology, 5th ed. Oxford: Rlackwell Scientific, 1991: 322-27 Carol WLL, Van Heusdcn JC. Reitrag zur Kenntr~isdes Morbus Rourneville-Pririgle und d e r Recklinghausenclien Neurofibromatosis. Arch Dermatol Syphil 1936; 175: 1-37 W'esterhof W, Klaus K. Blue-red marules and pseudoatrophic macules-additional cutaneous signs in ncurnfibromatosis. Arch Dermatol 1982; 118:577-81 Jensen NE, Sabharwal S, Walker AE. Naevoxanthoendothelionla and neurofibromatosis. Br J Der~natol 1971 ;85:326-30 Jurecka W, Lassmann H , Gebhart W, et al. Classification of peripheral nerve sheath tumors. (Abstr.) Arch Dermatol Kes 1977;258: 100 Ratner N , IIong DM, Lieberman MA, et al. T h e neuronal cell-surface molecule mitogenic for Schwann cells is a heparin-binding protein. Proc Natl Acad Sci USA 1988;85:6992-6 D'Agostino AN, Soule EH, Miller RH. Sarcomas of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (von Recklinghausen's disease). Cancer 1963; 16: 10 15-27 Lever WF, Schaumburg-Lever G. Histopathology of the skin, 7th ed. Philadelphia: J B Lippincott, 1990:739-43 Eady RAT, Cowen T C . Naevus spilus. Br J Dermatol 1975;93(1 l):16 Jimbow K, Szabo G, Fitzpatrick T B . Ultrastructure of giant pigment granules (macromelanosomes) in the cutaneous pigmented ~naculesof neurofibromatosis, .J Invest Dermat 1973;61:300-9 Rubenstein AE, BaderJI,, Aron AA, et al. Familial transmission of segrnerital rieurofibron~atosis.Neurology 1983;33(Suppl 2):76 Sloan JB, Fretzirl DF, Bovenmyer DA. Genetic counseling in segmental neurofihromatosis. J Am Acad Derrnatol 1990;22:461-7 Jadayel D, Fain P, Upadhyaya M, et al. Paternal origin of new mutations in Von Recklinghausen neurofibromaLosis. Nature 1990;343:558-9 Riccardi VM, Lewis RA. Penetrance of vorr Recklinghausen neurofibromatosis: a distinction between predecessors and descendants. An1 J H u m Genet 1988;42: 284-9 Bromley GS, Sherman J E , Goulian D Jr. Neurofibromatosis-distribution of lesions and surgical treatment. Ann Plast Surg 1982;8:272-6 Sherman ,JE, Smith JW. Neurofibromatosis of the breast arid nipple areolar area. Ann Plast Surg 198 1;7:302-7 Hanke CW, Conner AC, Reed JC. Treatment of multiple facial neurofibromas with derrnabrasion. J Dermatol Surg Oncol 1987;13:6 Riccardi VM. Mast-cell stabilization to decrease neurofibroma growth, preliminary experience with ketotifen. Arch Dermatol 1987; 123: 101 1-6
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DIAGNOSIS O F NEUROFIBROMATOSIS-MACKOOL,FITZPATRICK
