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Neurofibromatosis: review and report of case
JAD)A C L I N I C A L
R E P O R T S
Neurofibromatosis: review and report of case
R ich ard L. R ey n o ld s, D D S , M S C lara A. P in ed a , D D S
N e u ro fib ro m a to s is, or v o n R e c k lin g hausen’s disease, is the result o f a genetic m u ta tio n a ffe c tin g m o re th a n 80,000 persons in the United States. A lso known as th e “ E le p h a n t M a n ” disease, it is m arked by m u ltip le p ed u n cu la ted soft tum ors distributed over the entire body associated w ith areas o f pigm en tation . T h is a rtic le discu sses v a r io u s asp ects o f the disease, an d presents a report of classical neurofibromatosis.
on R ecklinghau sen’s disease, or neurofibrom atosis, was first iden tified as a disease of neu ral nature in 1882.1 It is a g e n e tic d iso rd e r th a t occurs once in every 3,000 live b irth s,2 m ak in g it as com m on as cystic fibrosis a n d D o w n ’s s y n d ro m e , a n d tw ice as com m on as m u sc u la r d y stro p h y .1 It is inherited as an autosom al d o m in a n t trait w ith w o rld w id e d is t r ib u t io n , a n d n o racial or ethnic restrictions. M ore than 80,000 p atien ts w ith n eu ro fib ro m ato sis are fo u n d in the U n ite d S ta te s.2 (T h e life of J o h n M e rric k , a p a tie n t w ith n eu ro fib rom atosis, was depicted in the play an d m ovie T h e E lephant M an.) T h e d ise ase is ca u se d by a g e n e tic m u ta tio n an d , th u s, can o cc u r in off s p rin g of p a re n ts w ith o u t the disease. M en, a t ag e 31-32 o r age 40, seem to have a greater tendency to father offspring w ith neurofibrom atosis than m en of other ages.2 O f the children of affected patients, 50% w ill have n e u ro fib ro m a to s is w ith
100% penetrance (frequency of heritable tra it) b u t v a ria b le e x p re ssiv ity o f th e d is e a s e .2 F irs t-d e g re e re la tiv e s o f th e p a tie n t (parents, siblings, o r offspring) w h o do n o t h av e sig n s of th e disease and are postpubertal may be considered free of risk for developing it, an d at the same risk as the general p o p u la tio n for p aren tin g affected offspring.2 T h e re are fo u r m a in fo rm s o f n e u r o fib ro m a to s is . T h e y in c lu d e : c lassic n e u ro fib ro m a to sis—the p rin c ip a l topic
V
Fig 1 ■ Patient at age 11 with no evidence of neurofibromatosis; cafe-au-lait spots, if present, were not identified.
of th is p ap e r; a c o u s tic n e u r o f ib r o m a to s is —c h a ra c te riz e d by few er n e u r o f i brom as an d cafe-au-lait spots, b u t always e x h ib itin g b ila te ra l aco u stic n eurom as; seg m en ted n e u ro fib ro m a to s is — lim ite d to a circum scribed body segm ent (usually the u p p e r r ig h t o r left q u a d r a n t w ith the head an d neck spared); an d a fourth, nonspecific fo rm — featu rin g cafe-au-lait spots as the sole sign (possibly an o th er disease entity).2 Defining features
In classic n e u ro fib ro m a to sis, th ere are three d efin in g features. At least o ne of these defining features is found in every n e u r o f ib r o m a to s is p a tie n t. A p p r o x i m ately 20 o th e r c h a ra c te ristic featu res are seen in v arying incidence b u t n one m ore th a n 50% of th e tim e. T h e three d e fin in g features are cafe-au -lait spots, m u ltip le n e u r o f ib r o m a s , a n d L isc h nodules.2 C afe-au-lait sp o ts are seen in 99% of cases. T hey are lig h tly colored, p igm ented lesions w ith sh arp borders an d are usually p re se n t a t b irth b u t m ay also d ev elo p w ith in the first year. T hey vary in size from 1-2 m m to 15 cm .2 T h e presence of six o r m ore cafe-au -lait spots larg er th an 1.5 cm is considered diagnostic of n e u r o f ib r o m a to s is by so m e, b u t n o t p a th o g n o m o n ic by o th e rs .3 T h ey have a random d istrib u tio n b u t few are found on the face. D arker spots are seen w hen the borders of the lesio n o v erlap w ith p le x ifo rm n e u ro fib ro m a s. F reckles u p to 2-3 m m are also seen, especially in JADA, Vol. 117, November 1988 ■ 735
CLINICAL
REPORTS
the axilla, groin, an d other intertriginous areas. T h e u n d e rly in g n a tu re of these hy p erp ig m entations is n o t k now n.2 T h e s e c o n d d e f in in g f e a tu re is th e n eurofibrom a. Most infants an d children are free o f n e u r o f ib r o m a s . In m o st p atients, they begin to develop at puberty. A ste ad ily p ro g re ssiv e d ev e lo p m e n t of sessile and pedunculated lesions follows, whereby they increase in size an d num ber, u n til by the mid-40s, hundreds of lesions cover the entire body, som etim es in clu d in g th e p a lm s of th e h a n d s a n d soles of the feet.2 T h e th ird d efining feature is the Lisch n o d u le , w h ic h is a p ig m e n te d iris ham arto m a. Of patients aged 6 or older, 94% have L isch n o d u le s.2 T h e nodules c o n tin u e to in c re a se in n u m b e r w ith age, b u t are asym ptom atic an d have no c o rrela tio n w ith o th e r m anifestations or w ith the severity of the disease. Lisch nodules aid in establishing the diagnosis, b u t a re n o t d e fin itiv e by th e m se lv es.2 A re c e n t r e p o r t of 13 p a tie n ts w ith acoustic neurofibrom atosis indicated that six had various types of cataracts.4
Fig 2 ■ At age 21, no facial lesions were evident,Fig 3 ■ At age 36, facial lesions were evident b ut n eu ro fib ro m as of th e chest were p resen t (grade I or II disease). (grade I disease).
Characteristic features
M acroencephaly is com m on. T h e large size o f th e h e a d m ay be a b s o lu te o r relevant to the p a tie n t’s height, as short stature is an o th e r com m on characteristic. In stu d ies of affected p atien ts, m edian head size has been in the 75th percentile a n d m edian stature in the 25th percentile.2 Jo h n M errick reportedly died in his late 20s w h en h e fell asleep a n d h is la rg e h ead fell back, c a u sin g a b roken neck or asp h y xiation, or b o th .1 T u m o rs in the central nervous system o c c u r in 5% to 10% of p a tie n ts w ith neurofibrom atosis; visceral tum ors occur in less th a n 1%.2 M a lig n a n t tr a n s f o r m a tio n of tu m o rs m ay o c c u r la te r in life w ith neurofibrosarcom a and m alig n a n t sch w an n o m a developing the m ost o fte n .5 O f the p a tie n ts, 2% to 5% have m e n ta l h a n d ic a p p in g c o n d itio n s, an d 40% have “ intellectual h a rd sh ip ” (school p e rfo rm a n c e p ro b le m s, h y p e ra c tiv ity , learn in g disability).5 Speech im pedim ents o c c u r in 30% to 40%. H e a d a c h e s are com m on an d can indicate brain tum ors o r p h e o c h ro m o c y to m a s. H y p e rte n sio n of u n k n o w n origin is often seen. It may be re la te d to ren a l v ascu la r lesions or p h eo c h ro m o cy to m as. Seizures are seen in a sm all percentage of cases. Psycho logical disorders are com m on as a result of social in teractio n an d negative reac tio n s r e s u ltin g fro m th e p h y sic a l d is 736 ■ JADA, Vol. 117, November 1988
Fig 4 ■ At age 56 (grade III disease).
figurem ent caused by the disease.2 Skeletal involvem ent occurs in ab o u t 50% of cases, w ith k y p h osco lio sis the m ost com m on fin d in g .5 A recent rep o rt of 13 p atien ts w ith acoustic neurofibrom atosis indicated that six had various types of cataracts.4 Diagnosis
L aboratory diagnosis is n ot helpful for c o n firm a tio n of disease o r e v a lu a tio n of severity. T w enty-four h o u r m o n ito rin g
Fig 5 ■ At age 69 (grade IV disease).
of levels of ep in ep h rin e an d n o rep in ep h rine may indicate a pheochrom ocytom a, if elevated. A biopsied specim en of the n e u ro fib ro m a show s v ario u s c o m b in a tio n s of neurons, Schw ann cells, fib ro blasts, vascular elements, m ast cells, and o cc asio n ally , p ig m e n t cells. H ow ever, n one of the histological or ultrastructure f in d in g s o f th e n e u ro fib ro m a s o r th e c a fe -a u -la it sp o ts is u n iq u e to n e u r o fibrom atosis. In addition, prenatal diag nosis is n ot possible.2
CLINICAL
Pathogeaesis
T h e p athogenesis of neurofibrom atosis re m a in s u n c le a r. T h e n e u r a l c re st, a tra n sie n t em bry o n ic stru c tu re , m ay be th e key. O th e r in v e s tig a tio n s 2 have centered o n nerve grow th factors (NGF) an d the m ast cell. It has been speculated th a t N G F m ay in d u c e a p r o life ra tio n an d tran sform ation of sheath cells into b e n ig n tu m o r cells. C lin ic a l evidence of disease occurs as c o n tin u in g elevations of N G F stim ulate these transform ed cells to p ro d u ce tu m o rs.6 T h e m ast cell has b een in d ic a te d b ec au se it is fo u n d in n erv e tissu e a n d n e u r o f ib r o m a s , its secretio n s can a lte r c e ll f u n c tio n a n d p ro life ra tio n , a n d it ca n cause d is tu r bances in melanocytes an d bone m arrow (leukem ia in neurofibrom atosis).2 Other factors
T h e sev erity of n e u r o f ib r o m a to s is is u n a ffe c te d by w h e th e r th e m o th e r or father does or does n o t have the disease. O nce the disease is seen a t puberty, there is a u n idirectional progression, in small, steady increments, b u t w ith sudden m ajor ju m p s possible. Cases can be graded from I (m in im a lly affected) to IV (severely affected). A ty p ic a l g r o u p o f p a tie n ts w o u ld co n sist of 25% to 30% in grade I II a n d IV. S tu d ies o f th e a m o u n t of tim e a p atient spends in each grade, and the final grade th a t patients reach before d ea th are in te re s tin g b u t have p ro v ed nonprecedental as no firm pattern exists in predicting how lo n g particu lar grades w ill last or to w hat final grade patients w ill reach.2 Medical m anagem ent of patients w ith neurofibrom atosis includes genetic co u n seling, surgery, and psychological coun se lin g . S u rg ic a l re m o v a l of le sio n s is lim ite d to se rio u s o r lif e -th r e a te n in g neurofibrom as th a t interfere w ith func tio n o r are u n u su a lly disfig u rin g . T h e n u m b e r a n d size of c u ta n e o u s lesio n s m ake m ore am bitious surgical m anage m e n t no n feasible. M any p a tie n ts have serious psychological problem s, as m ight be expected.2 N o d ru g th erapy is in d ic ated except a n tic o n v u ls a n t th e ra p y for sy m p to m s re la te d to e p ile p s y . S p e c ia l d ie ts or n u tr itio n a l s u p p le m e n ts d o n o t seem help fu l. A baseline ev a lu a tio n of d iag n o se d p a tie n ts is re c o m m e n d e d , a n d includes taking an IQ m easurem ent, an e le c tro e n c e p h a lo g ra m , a n a u d io g ra m , an ocular exam ination, a psychological test, a radiological skeletal exam ination
(esp ecially sk u ll, o p tic fo ra m in a , an d spine), a cranial C T scan, an d 24-hour u r in e levels of e p in e p h r in e a n d n o r e p in e p h rin e .2 C o n tin u in g m an ag em en t includes evaluation of blood pressure, a le rtn e s s to th e d e v e lo p m e n t o f new ch aracteristics, a n d e v a lu a tio n of n e u rofibrom as for m a lig n a n t transform ation. O ral m anifestations of n eurofibrom a to sis in c lu d e m a c ro g lo s s ia , e n la rg e d lin g u a l p a p illa e , o ra l n e u ro fib ro m a s, m axillary an d m a n d ib u la r bone a b n o r m a lities re s u ltin g in facial asym m etry (7% in c id en c e), a n d r a d io lu c e n t areas in the jaw s.3 O ral lesions are m ucosalcolored replicas of the skin lesions and account for 5% of neurofibrom as.1 These lesions are com m only seen on the tongue, fo llo w e d by b u c c a l m u c o sa , a lv e o la r rid g e , g in g iv a , to n s ils , p a la te , a n d p te r y g o m a x illa r y s p a c e .1 C h a n g e s in appearance can indicate m a lig n a n t trans fo rm a tio n . T u m o r g ro w th m ay cause o ste o c la stic re s o rp tio n c a u s in g ra d io lu cen t areas u su a lly in d icativ e of n eu rofibrom as found d u rin g biopsy.3 D en ta l m a n a g e m e n t in c lu d e s o b se r vation for oral lesions th a t may interfere w ith m a s tic a tio n o r sh o w m a lig n a n t tran sfo rm atio n . A sym m etry m ay affect o c c lu sio n a n d re s to ra tiv e p ro ce d u re s. O rthognathic surgery can be indicated.3 Sensitivity w hen caring for the p a tie n t’s general o ral needs is im p o rta n t to the p atien t’s psychological well-being. Report of case
A 69-year-old w hite female was exam ined an d requested: “Give me some teeth that I can chew w ith .” T h e p a tie n t’s ap p ear ance m ade the diagnosis of neurofibro m a to sis o b v io u s. She w as e d e n tu lo u s w ith poor-fitting com plete dentures, and was assigned to a third-year dental student at the College of D entistry for prosthetic treatment. T h e p a tie n t w as th e se v en th o f ten children, and the only one w ith evidence of n e u ro fib ro m a to s is . S he s a id her deceased f a th e r m ay h av e h a d a few nod u les o n h is back. T h e p a tie n t had six p re g n a n c ie s w ith tw o liv e b irth s . O ne offspring died at age 2 an d on e at age 17. T h e 1 7 -y ear-o ld d ie d w h ile u n d e rg o in g surgery for th e th ird tim e for a b rain tum or. T h e p atient was diagnosed w ith neu rofibrom atosis at age 19. As the disease p ro g re sse d , sh e su ffe re d m a n y so c ial indignities; people th o u g h t her condition was contagious, or th at she sh o u ld stay inside an d n o t be seen. She was m arried
REPORTS
at age 19 a n d w idow ed at age 58. She appeared psychologically stable. T h e p a tie n t h a d h u n d red s of lesions of various sizes scattered over the entire body surface in c lu d in g the palm s of the han d s an d soles of the feet. T h ey were sessile, p ed u n cu lated , sm ooth, an d p ig m ented. She also h a d in te rn a l lesio n s ev id en c ed by a h is to ry of 16 su rg ic a l procedures for rem oval of in tern al lesions. O th e r h isto ry in c lu d e d : five su rg erie s for rem oval of cataracts; she h ad a 30% hearing loss; cu rren t m edication of arlid in (6 m g p e r day) a n d m e clizin e (25 m g p er day) for in n e r ear distu rb an ce; she w as also ta k in g o gen (25 m g p er day) as estrogen replacem ent, an d asp irin (15 g rains per day) for pain. O rally, the p a tie n t h ad m acroglossia a n d e n la rg e d lin g u a l p a p illa e . T h e re were no neurofibrom as, bony radiolucent areas, nor facial asymmetry. T h e p a tie n t w as 5 ft 0 in ta ll, w ith a noticeably large head (Fig 1-5). Summary
N eurofibrom atosis is a genetic disorder inherited as an autosom al d o m in an t trait. T h e c la ssic a l le s io n seen w ith th is disorder is the n eu ro fib ro m a, w h ich is disfiguring externally an d may interfere w ith f u n c tio n in te r n a lly . T h e m o u th can have lesions in te rfe rin g w ith fu n c tio n , u n d e rg o in g m a lig n a n t tr a n s f o r m ation, or involving bone. M acroglossia and facial asymmetry may occur. A case rep o rt describes m any characteristics of classical neurofibrom atosis. -------------------------- JA D )A --------------------------Dr. Reynolds is professor em eritus and form er chair, departm ent of oral diagnosis and radiology, University of Oklahoma, College of Dentistry, PO Box 26901, Oklahom a City, OK 73190. Dr. Pineda is dental resident, Oklahom a Children’s Memorial H o s p ita l, O k lah o m a C ity. Address req u ests for reprints to Dr. Reynolds. 1. W hite, A.K., and others. H ead an d neck manifestations of neurofibromatosis. Laryngoscope 96:732-737, 1986. 2. R iccardi, V.M. Von R ecklinhausen n eu ro fi bromatosis. N Engl J Med 305:1617-1627, 1981. 3. Rose, L .F., an d Kaye, D. In tern al m edicine for dentistry. St. Louis, C. V. Mosby Co, 1983, pp 878-880. 4. Pearson-Webb, M.A.; Kaiser-Kupfer, M.I.; and E ldridge, R. Eye fin d in g s in b ila te ra l acoustic (central) neurofibromatosis: association with presen ile lens o p acities and cataracts b u t absence of Lisch nodules (letter). N Engl J Med 315:1553-1554, 1986. 5. Stoke, R.W. Neurofibromatosis: review of the literature. J Am Osteopath Assoc 86:49-52, 1986. 6. W yngaarden, J.B ., an d S m ith , L .H . Cecil textbook of m edicine, ed 16. P hiladelphia, W. B. Saunders, 1982, pp 2043-2044.
R eynolds-P ineda : N E U R O FIB R O M A T O S IS ■ 737
R E P O R T S
Neurofibromatosis: review and report of case
R ich ard L. R ey n o ld s, D D S , M S C lara A. P in ed a , D D S
N e u ro fib ro m a to s is, or v o n R e c k lin g hausen’s disease, is the result o f a genetic m u ta tio n a ffe c tin g m o re th a n 80,000 persons in the United States. A lso known as th e “ E le p h a n t M a n ” disease, it is m arked by m u ltip le p ed u n cu la ted soft tum ors distributed over the entire body associated w ith areas o f pigm en tation . T h is a rtic le discu sses v a r io u s asp ects o f the disease, an d presents a report of classical neurofibromatosis.
on R ecklinghau sen’s disease, or neurofibrom atosis, was first iden tified as a disease of neu ral nature in 1882.1 It is a g e n e tic d iso rd e r th a t occurs once in every 3,000 live b irth s,2 m ak in g it as com m on as cystic fibrosis a n d D o w n ’s s y n d ro m e , a n d tw ice as com m on as m u sc u la r d y stro p h y .1 It is inherited as an autosom al d o m in a n t trait w ith w o rld w id e d is t r ib u t io n , a n d n o racial or ethnic restrictions. M ore than 80,000 p atien ts w ith n eu ro fib ro m ato sis are fo u n d in the U n ite d S ta te s.2 (T h e life of J o h n M e rric k , a p a tie n t w ith n eu ro fib rom atosis, was depicted in the play an d m ovie T h e E lephant M an.) T h e d ise ase is ca u se d by a g e n e tic m u ta tio n an d , th u s, can o cc u r in off s p rin g of p a re n ts w ith o u t the disease. M en, a t ag e 31-32 o r age 40, seem to have a greater tendency to father offspring w ith neurofibrom atosis than m en of other ages.2 O f the children of affected patients, 50% w ill have n e u ro fib ro m a to s is w ith
100% penetrance (frequency of heritable tra it) b u t v a ria b le e x p re ssiv ity o f th e d is e a s e .2 F irs t-d e g re e re la tiv e s o f th e p a tie n t (parents, siblings, o r offspring) w h o do n o t h av e sig n s of th e disease and are postpubertal may be considered free of risk for developing it, an d at the same risk as the general p o p u la tio n for p aren tin g affected offspring.2 T h e re are fo u r m a in fo rm s o f n e u r o fib ro m a to s is . T h e y in c lu d e : c lassic n e u ro fib ro m a to sis—the p rin c ip a l topic
V
Fig 1 ■ Patient at age 11 with no evidence of neurofibromatosis; cafe-au-lait spots, if present, were not identified.
of th is p ap e r; a c o u s tic n e u r o f ib r o m a to s is —c h a ra c te riz e d by few er n e u r o f i brom as an d cafe-au-lait spots, b u t always e x h ib itin g b ila te ra l aco u stic n eurom as; seg m en ted n e u ro fib ro m a to s is — lim ite d to a circum scribed body segm ent (usually the u p p e r r ig h t o r left q u a d r a n t w ith the head an d neck spared); an d a fourth, nonspecific fo rm — featu rin g cafe-au-lait spots as the sole sign (possibly an o th er disease entity).2 Defining features
In classic n e u ro fib ro m a to sis, th ere are three d efin in g features. At least o ne of these defining features is found in every n e u r o f ib r o m a to s is p a tie n t. A p p r o x i m ately 20 o th e r c h a ra c te ristic featu res are seen in v arying incidence b u t n one m ore th a n 50% of th e tim e. T h e three d e fin in g features are cafe-au -lait spots, m u ltip le n e u r o f ib r o m a s , a n d L isc h nodules.2 C afe-au-lait sp o ts are seen in 99% of cases. T hey are lig h tly colored, p igm ented lesions w ith sh arp borders an d are usually p re se n t a t b irth b u t m ay also d ev elo p w ith in the first year. T hey vary in size from 1-2 m m to 15 cm .2 T h e presence of six o r m ore cafe-au -lait spots larg er th an 1.5 cm is considered diagnostic of n e u r o f ib r o m a to s is by so m e, b u t n o t p a th o g n o m o n ic by o th e rs .3 T h ey have a random d istrib u tio n b u t few are found on the face. D arker spots are seen w hen the borders of the lesio n o v erlap w ith p le x ifo rm n e u ro fib ro m a s. F reckles u p to 2-3 m m are also seen, especially in JADA, Vol. 117, November 1988 ■ 735
CLINICAL
REPORTS
the axilla, groin, an d other intertriginous areas. T h e u n d e rly in g n a tu re of these hy p erp ig m entations is n o t k now n.2 T h e s e c o n d d e f in in g f e a tu re is th e n eurofibrom a. Most infants an d children are free o f n e u r o f ib r o m a s . In m o st p atients, they begin to develop at puberty. A ste ad ily p ro g re ssiv e d ev e lo p m e n t of sessile and pedunculated lesions follows, whereby they increase in size an d num ber, u n til by the mid-40s, hundreds of lesions cover the entire body, som etim es in clu d in g th e p a lm s of th e h a n d s a n d soles of the feet.2 T h e th ird d efining feature is the Lisch n o d u le , w h ic h is a p ig m e n te d iris ham arto m a. Of patients aged 6 or older, 94% have L isch n o d u le s.2 T h e nodules c o n tin u e to in c re a se in n u m b e r w ith age, b u t are asym ptom atic an d have no c o rrela tio n w ith o th e r m anifestations or w ith the severity of the disease. Lisch nodules aid in establishing the diagnosis, b u t a re n o t d e fin itiv e by th e m se lv es.2 A re c e n t r e p o r t of 13 p a tie n ts w ith acoustic neurofibrom atosis indicated that six had various types of cataracts.4
Fig 2 ■ At age 21, no facial lesions were evident,Fig 3 ■ At age 36, facial lesions were evident b ut n eu ro fib ro m as of th e chest were p resen t (grade I or II disease). (grade I disease).
Characteristic features
M acroencephaly is com m on. T h e large size o f th e h e a d m ay be a b s o lu te o r relevant to the p a tie n t’s height, as short stature is an o th e r com m on characteristic. In stu d ies of affected p atien ts, m edian head size has been in the 75th percentile a n d m edian stature in the 25th percentile.2 Jo h n M errick reportedly died in his late 20s w h en h e fell asleep a n d h is la rg e h ead fell back, c a u sin g a b roken neck or asp h y xiation, or b o th .1 T u m o rs in the central nervous system o c c u r in 5% to 10% of p a tie n ts w ith neurofibrom atosis; visceral tum ors occur in less th a n 1%.2 M a lig n a n t tr a n s f o r m a tio n of tu m o rs m ay o c c u r la te r in life w ith neurofibrosarcom a and m alig n a n t sch w an n o m a developing the m ost o fte n .5 O f the p a tie n ts, 2% to 5% have m e n ta l h a n d ic a p p in g c o n d itio n s, an d 40% have “ intellectual h a rd sh ip ” (school p e rfo rm a n c e p ro b le m s, h y p e ra c tiv ity , learn in g disability).5 Speech im pedim ents o c c u r in 30% to 40%. H e a d a c h e s are com m on an d can indicate brain tum ors o r p h e o c h ro m o c y to m a s. H y p e rte n sio n of u n k n o w n origin is often seen. It may be re la te d to ren a l v ascu la r lesions or p h eo c h ro m o cy to m as. Seizures are seen in a sm all percentage of cases. Psycho logical disorders are com m on as a result of social in teractio n an d negative reac tio n s r e s u ltin g fro m th e p h y sic a l d is 736 ■ JADA, Vol. 117, November 1988
Fig 4 ■ At age 56 (grade III disease).
figurem ent caused by the disease.2 Skeletal involvem ent occurs in ab o u t 50% of cases, w ith k y p h osco lio sis the m ost com m on fin d in g .5 A recent rep o rt of 13 p atien ts w ith acoustic neurofibrom atosis indicated that six had various types of cataracts.4 Diagnosis
L aboratory diagnosis is n ot helpful for c o n firm a tio n of disease o r e v a lu a tio n of severity. T w enty-four h o u r m o n ito rin g
Fig 5 ■ At age 69 (grade IV disease).
of levels of ep in ep h rin e an d n o rep in ep h rine may indicate a pheochrom ocytom a, if elevated. A biopsied specim en of the n e u ro fib ro m a show s v ario u s c o m b in a tio n s of neurons, Schw ann cells, fib ro blasts, vascular elements, m ast cells, and o cc asio n ally , p ig m e n t cells. H ow ever, n one of the histological or ultrastructure f in d in g s o f th e n e u ro fib ro m a s o r th e c a fe -a u -la it sp o ts is u n iq u e to n e u r o fibrom atosis. In addition, prenatal diag nosis is n ot possible.2
CLINICAL
Pathogeaesis
T h e p athogenesis of neurofibrom atosis re m a in s u n c le a r. T h e n e u r a l c re st, a tra n sie n t em bry o n ic stru c tu re , m ay be th e key. O th e r in v e s tig a tio n s 2 have centered o n nerve grow th factors (NGF) an d the m ast cell. It has been speculated th a t N G F m ay in d u c e a p r o life ra tio n an d tran sform ation of sheath cells into b e n ig n tu m o r cells. C lin ic a l evidence of disease occurs as c o n tin u in g elevations of N G F stim ulate these transform ed cells to p ro d u ce tu m o rs.6 T h e m ast cell has b een in d ic a te d b ec au se it is fo u n d in n erv e tissu e a n d n e u r o f ib r o m a s , its secretio n s can a lte r c e ll f u n c tio n a n d p ro life ra tio n , a n d it ca n cause d is tu r bances in melanocytes an d bone m arrow (leukem ia in neurofibrom atosis).2 Other factors
T h e sev erity of n e u r o f ib r o m a to s is is u n a ffe c te d by w h e th e r th e m o th e r or father does or does n o t have the disease. O nce the disease is seen a t puberty, there is a u n idirectional progression, in small, steady increments, b u t w ith sudden m ajor ju m p s possible. Cases can be graded from I (m in im a lly affected) to IV (severely affected). A ty p ic a l g r o u p o f p a tie n ts w o u ld co n sist of 25% to 30% in grade I II a n d IV. S tu d ies o f th e a m o u n t of tim e a p atient spends in each grade, and the final grade th a t patients reach before d ea th are in te re s tin g b u t have p ro v ed nonprecedental as no firm pattern exists in predicting how lo n g particu lar grades w ill last or to w hat final grade patients w ill reach.2 Medical m anagem ent of patients w ith neurofibrom atosis includes genetic co u n seling, surgery, and psychological coun se lin g . S u rg ic a l re m o v a l of le sio n s is lim ite d to se rio u s o r lif e -th r e a te n in g neurofibrom as th a t interfere w ith func tio n o r are u n u su a lly disfig u rin g . T h e n u m b e r a n d size of c u ta n e o u s lesio n s m ake m ore am bitious surgical m anage m e n t no n feasible. M any p a tie n ts have serious psychological problem s, as m ight be expected.2 N o d ru g th erapy is in d ic ated except a n tic o n v u ls a n t th e ra p y for sy m p to m s re la te d to e p ile p s y . S p e c ia l d ie ts or n u tr itio n a l s u p p le m e n ts d o n o t seem help fu l. A baseline ev a lu a tio n of d iag n o se d p a tie n ts is re c o m m e n d e d , a n d includes taking an IQ m easurem ent, an e le c tro e n c e p h a lo g ra m , a n a u d io g ra m , an ocular exam ination, a psychological test, a radiological skeletal exam ination
(esp ecially sk u ll, o p tic fo ra m in a , an d spine), a cranial C T scan, an d 24-hour u r in e levels of e p in e p h r in e a n d n o r e p in e p h rin e .2 C o n tin u in g m an ag em en t includes evaluation of blood pressure, a le rtn e s s to th e d e v e lo p m e n t o f new ch aracteristics, a n d e v a lu a tio n of n e u rofibrom as for m a lig n a n t transform ation. O ral m anifestations of n eurofibrom a to sis in c lu d e m a c ro g lo s s ia , e n la rg e d lin g u a l p a p illa e , o ra l n e u ro fib ro m a s, m axillary an d m a n d ib u la r bone a b n o r m a lities re s u ltin g in facial asym m etry (7% in c id en c e), a n d r a d io lu c e n t areas in the jaw s.3 O ral lesions are m ucosalcolored replicas of the skin lesions and account for 5% of neurofibrom as.1 These lesions are com m only seen on the tongue, fo llo w e d by b u c c a l m u c o sa , a lv e o la r rid g e , g in g iv a , to n s ils , p a la te , a n d p te r y g o m a x illa r y s p a c e .1 C h a n g e s in appearance can indicate m a lig n a n t trans fo rm a tio n . T u m o r g ro w th m ay cause o ste o c la stic re s o rp tio n c a u s in g ra d io lu cen t areas u su a lly in d icativ e of n eu rofibrom as found d u rin g biopsy.3 D en ta l m a n a g e m e n t in c lu d e s o b se r vation for oral lesions th a t may interfere w ith m a s tic a tio n o r sh o w m a lig n a n t tran sfo rm atio n . A sym m etry m ay affect o c c lu sio n a n d re s to ra tiv e p ro ce d u re s. O rthognathic surgery can be indicated.3 Sensitivity w hen caring for the p a tie n t’s general o ral needs is im p o rta n t to the p atien t’s psychological well-being. Report of case
A 69-year-old w hite female was exam ined an d requested: “Give me some teeth that I can chew w ith .” T h e p a tie n t’s ap p ear ance m ade the diagnosis of neurofibro m a to sis o b v io u s. She w as e d e n tu lo u s w ith poor-fitting com plete dentures, and was assigned to a third-year dental student at the College of D entistry for prosthetic treatment. T h e p a tie n t w as th e se v en th o f ten children, and the only one w ith evidence of n e u ro fib ro m a to s is . S he s a id her deceased f a th e r m ay h av e h a d a few nod u les o n h is back. T h e p a tie n t had six p re g n a n c ie s w ith tw o liv e b irth s . O ne offspring died at age 2 an d on e at age 17. T h e 1 7 -y ear-o ld d ie d w h ile u n d e rg o in g surgery for th e th ird tim e for a b rain tum or. T h e p atient was diagnosed w ith neu rofibrom atosis at age 19. As the disease p ro g re sse d , sh e su ffe re d m a n y so c ial indignities; people th o u g h t her condition was contagious, or th at she sh o u ld stay inside an d n o t be seen. She was m arried
REPORTS
at age 19 a n d w idow ed at age 58. She appeared psychologically stable. T h e p a tie n t h a d h u n d red s of lesions of various sizes scattered over the entire body surface in c lu d in g the palm s of the han d s an d soles of the feet. T h ey were sessile, p ed u n cu lated , sm ooth, an d p ig m ented. She also h a d in te rn a l lesio n s ev id en c ed by a h is to ry of 16 su rg ic a l procedures for rem oval of in tern al lesions. O th e r h isto ry in c lu d e d : five su rg erie s for rem oval of cataracts; she h ad a 30% hearing loss; cu rren t m edication of arlid in (6 m g p e r day) a n d m e clizin e (25 m g p er day) for in n e r ear distu rb an ce; she w as also ta k in g o gen (25 m g p er day) as estrogen replacem ent, an d asp irin (15 g rains per day) for pain. O rally, the p a tie n t h ad m acroglossia a n d e n la rg e d lin g u a l p a p illa e . T h e re were no neurofibrom as, bony radiolucent areas, nor facial asymmetry. T h e p a tie n t w as 5 ft 0 in ta ll, w ith a noticeably large head (Fig 1-5). Summary
N eurofibrom atosis is a genetic disorder inherited as an autosom al d o m in an t trait. T h e c la ssic a l le s io n seen w ith th is disorder is the n eu ro fib ro m a, w h ich is disfiguring externally an d may interfere w ith f u n c tio n in te r n a lly . T h e m o u th can have lesions in te rfe rin g w ith fu n c tio n , u n d e rg o in g m a lig n a n t tr a n s f o r m ation, or involving bone. M acroglossia and facial asymmetry may occur. A case rep o rt describes m any characteristics of classical neurofibrom atosis. -------------------------- JA D )A --------------------------Dr. Reynolds is professor em eritus and form er chair, departm ent of oral diagnosis and radiology, University of Oklahoma, College of Dentistry, PO Box 26901, Oklahom a City, OK 73190. Dr. Pineda is dental resident, Oklahom a Children’s Memorial H o s p ita l, O k lah o m a C ity. Address req u ests for reprints to Dr. Reynolds. 1. W hite, A.K., and others. H ead an d neck manifestations of neurofibromatosis. Laryngoscope 96:732-737, 1986. 2. R iccardi, V.M. Von R ecklinhausen n eu ro fi bromatosis. N Engl J Med 305:1617-1627, 1981. 3. Rose, L .F., an d Kaye, D. In tern al m edicine for dentistry. St. Louis, C. V. Mosby Co, 1983, pp 878-880. 4. Pearson-Webb, M.A.; Kaiser-Kupfer, M.I.; and E ldridge, R. Eye fin d in g s in b ila te ra l acoustic (central) neurofibromatosis: association with presen ile lens o p acities and cataracts b u t absence of Lisch nodules (letter). N Engl J Med 315:1553-1554, 1986. 5. Stoke, R.W. Neurofibromatosis: review of the literature. J Am Osteopath Assoc 86:49-52, 1986. 6. W yngaarden, J.B ., an d S m ith , L .H . Cecil textbook of m edicine, ed 16. P hiladelphia, W. B. Saunders, 1982, pp 2043-2044.
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