N e v o id B a sa l-C e ll S y n d ro m e : lite ra tu re re v ie w
a n d c a se re p o rt in a fa m ily
H e a d a n d N e c k S u r g i c a l S e r v i c e s a n d a t t h e P l a s t i c S u r g e r y D i s c i p l i n e .
M e d i c a l S c h o o l o f U N / C A M P - C a m p i n a s , S p ' B r a z i l
The N evoid B asal-C ell C arcinom a S yndrom e (N B C C ), or as it is also referred to, basal-cell nevus syndrom e or G orlin-G oltz syn-drom e, is characterized by m ultiple early-appearing basal cell carcinom as, keratocytosis of the m andible, and anom alies of the ocular, skeletal reproductive system . W e describe four patients in the sam e fam ily, all of them possessing a large num ber of skin tum ors associated w ith other typical clinical and X -R ay anom alies of N B C C . The definitive treatm ent of N B C C has yet to be estab-lished, how ever, early diagnosis is very im portant as w ell as the periodical follow -up exam ination of ten patients, m ainly due to the transform ations in the skin lesions that m ay occur.
U N ITE R M S : B asal-cell carcinom a. S kin tum ors. G orlin-G oltz S yndrom e.
IN TR O D U C TIO N
T
h e f ir s t h is to r ic a lg o e s b a c k to th e e v id e n c e1 1 th E g y p tia nr e g a r d in gd y n a s ty .th e s y n d r o m eT h e f ir s t c a s e o f s k in m a n if e s ta tio n o f th e n e v o id b a s a l- c e llc a r c in o m a s y n d r o m e o r th e G o r lin - G o ltz s y n d r o m e w a s
d e s c r ib e d b y J a r is c h a n d W h ite in 1 8 9 4 ( 1 0 ,1 9 ) . A lth o u g h
o n ly in th e m id d le o f th is c e n tu r y th e c lin ic a l f in d in g s o f
th e s y n d r o m e w e r e s y s te m a tiz e d b y G o r lin a n d G o ltz ( 4 ) .
T h e s y n d r o m e p r e s e n ts a d o m in a n t a u to s o m a l
tr a n s m is s io n ( 2 ,1 2 ) a n d o n e th ir d o f th e p a tie n ts d o n o t
h a v e p r e v io u s f a m ily h is to r y th u s s u g g e s tin g m u ta tio n o r
in c o m p le te p e n e tr a tio n o f th e g e n e ( 5 ) .
A d re s s fo r c o rre s p o n d e n c e : A lfio J o s e T in c a n i
R u a L u v e rc i P e re ira d e S o u z a 1 7 6 5
C a m p in a s - S P - B ra s il - C E P 1 3 0 8 4 -0 3 1
H o w e ll a n d A n d e r s o n ( 7 ) e s tim a te d a p e n e tr a tio n o f
th e g e n e in a p p r o x im a te ly 9 7 % o f th e c a s e s a n d c lo s e to
7 5 % o f th e in d iv id u a ls w ith N B C C r e p r e s e n te d p r e m a tu r e
e m e r g e n c e o f m u ltip le b a s a l- c e ll c a r c in o m a s .
T h e c h a r a c te r iz a tio n o f th e g e n e w h ic h c a u s e s th e
s y n d r o m e m a y h e lp w ith th e u n d e r s ta n d in g o f p a th o g e n e s is
o f o th e r b a s a l- c e ll c a r c in o m a s . I n a d d itio n th e a n a ly s is o f
th e g e n e tic h e r ita g e d e m o n s tr a te d th a t th e g e n e is lo c a te d
in c h r o m o s o m e 9 q 2 2 .3 - q 3 1 . T h e lo c a tio n o f th e g e n e o f f e r s
th e p o s s ib ility th a t th e D N A m a r k e r s s h o u ld b e u s e d in
th e e v a lu a tio n o f th e s u r v iv a l o f th e s e p a tie n ts a s w e ll a s
a llo w in g th e d ia g n o s is p a tie n ts th a t h a v e b e e n d ia g n o s e d
w ith e a r ly s y m p to m s .
T h e m in im u m p r e v a le n c e is o n e 'in e v e r y 5 7 ,0 0 0
a lth o u g h 1 in e v e r y 2 0 0 p a tie n ts w ith b a s a l- c e ll c a r c in o m a
p r e s e n t N B C C a n d th e p r o p o r tio n is m u c h la r g e r w ith
p a tie n ts th a t d e v e lo p b a s a l- c e llu la r c a r c in o m a b e f o r e th e
a g e o f 1 9 ( 1 5 ,1 ) . A n e n z y m e d e f e c t m a y b e r e s p o n s ib le
f o r th e d e v e lo p m e n t o f N B C C b e c a u s e th e s e a b n o r m a litie s
a r e m u lti- s y s te m ic .
TIN C A N I, A .J., A N D R A D E , R .G ., FR A N C O JR , E .F.M ., C A M A R G O , M A B . & M A R TIN S , A .S . -N evoid B asal-C ell S yndrom e: literature review and case report in a fam ily
i= ig u r ~ 1 : C h a r a c te r is tic le s io n s o f N B C C in th e d o r s a l c e n te r lin e , m o s t o f th e m b e in g p ig m e n te d b a s a l- c e ll c a r c in o m a s .
T h e g e n e tic s tu d ie s s u g g e s t th a t th e c o n tro l o f c e llu la r
g ro \y ~ h is th e m a in fu n c tio n o f th e g e n e in v o lv e d w ith
N B C C .
A ls o th e re is th e p o s s ib ility o f th e tra n s fo rm a
-tio n o f b a s o -c e llu la r tu m o rs in to e p id e rm o id c a rc
i-n o m a s a n d m e la n o m a .
T h e m a jo r c lin ic a l m a n ife s ta tio n s in v o lv e th e
a p p e a ra n c e o f m u ltip le b a s a l-c e ll c a rc in o m a s , k e ra
-to c y s ts o f th e ja w a n d s k e le ta l a b n o rm a litie s e s p e
-c ia lly in th e rib s a n d v e rte b ra e .
T h e c lin ic a l fin d in g s in v o lv e m u ltip le s y s te m s .
T y p ic a l fa c ia l c h a ra c te ris tic s a re fo u n d in u p to 7 0 % o f
th e c a s e s c o n s is tin g o f a n in c re a s e in th e o c c ip ito fro n ta l
c irc u m fe re n c e , m o d e ra te -h y p e rte lo riu m , m e rg in g o f th e
b ro w s , a n d a n e x c e s s iv e d e v e lo p m e n t o f th e s u p e rio r
o rb ita l rin g . O th e r th a n th e c ite d tu m o rs , a t th e s k in le v e l
o n e fin d s k e ra to s is o n th e s o le s a n d p a lm s 6 5 % o f th e
c a s e s c h a ra c te riz e d b y p u n c tifo rm a n d a s y m e tric a l.
M ilia ria , s e b a c e o u s c y s ts a n d e p id e rm ic c y s ts h a v e a ls o
b e e n d e s c rib e d .
T h e b o n e a b n o rm a litie s o f th e rib s , s u c h a s its fu s io n ,
s p in a b ifid a , c e rv ic a l rib , s a c ra liz a tio n o f th e lu m b a r
v e rte b ra e s p in a l, d e v ia tio n s s u c h , th e p re s e n c e o f p e c tu s
e x c a v a tu m , o r c a rin a tu m a n d h a m a rto m a a re a m o n g th e
m o s t fre q u e n t fin d in g s .
C a lc ifie d c y s ts , fib ro m a a n d
fib ro s a rc o n a o f th e o v a rie s a re a ls o
d e s c rib e d . C a lc ific a tio n s o f th e
fa lx e s c e re b ri a n d th e te n to riu m
c e re b e lli h ip e rp n e u m a tiz a tio n o f
th e p a ra n a s a l s in u s e s a n d
s tra b is m u s in h ig h e r n u m b e rs o f
c a s e s (5 ) (ta b le 1 ).
C A S E R E P O R T
T a b le 1 d e s c rib e s th e m a in
fin d in g s o n o f th e fo u r p a tie n ts ,
a ll b e lo n g in g to th e s a m e a m ily .
W e w a n t to c a ll a tte n tio n to th e
la rg e n u m b e r o f b a s a l-c e ll
c a rc in o m a s fo u n d in e v e ry
m e m b e r a n d , o th e rs th a t ..a ro s e
d u rin g fo llo w u p .
T a b le I
M a jo r d ia g n o s tic fin d in g s in a d u lts w ith N e v o id
B a s a l- C e ll S y n d r o m e
( N a ld i e t a I., A r c h D e r m a to l, 1 9 9 1 ) ( 1 6 ) .
T y p ic a l fa c ia l c h a r a c te r is tic s
M a r fa n - lik e a s p e c t
M u ltip le b a s a l- c e ll c a r c in o m a s
P la n ta r a n d p a lm a r k e r a to s is
M ilia r ia a n d e p id e r m a l c y s ts
O d o n to g e n ic c y s ts o f th e m a n d ib le
C a lc ific a tio n o f s o ft tis s u e s
( e s p e c ia lly fa lx c e r e b r is ) fa lx c e r e b r is
B o n e a b n o r m a litie s
R ib o r b ifid e fu s io n
V e r te b r a e - k ifo s c o lio s is o r to s p in a b ifid e
P e c tu s c a r in a tu m o r e x c a v a tu m
S n o r t fo u r th m e ta c a r p
P o ly d a c tily o r s in d a c tily
M e s e n te r ic c y s ts
O c u la r a b n o m a litie s
C o n g e n ita l c a ta r a c t, g la u c o m a , ir is c o lo b o m a
T u m o r s
M e d u llo b la s to m a , m e n in g e o m a , fe ta l
r a b d o m y o m a , c a r d ia c fib r o m a , o v a r ia n
fib r o s a r c o m a
s a o P a u lo M e d ic a l J o u r n a V R P M 1 1 3 ( 3 ) : 9 1 7 - 9 2 1 ,1 9 9 5
n I C f " " I I C C I f " 1 \ 1
T able II
N am e G ender A ge years N um ber of Lesion P athologic A ssociated
lesions evolution* anatom y and m anifestations
num ber of
lesions
E A V (fig.1) F 55 32 B .C .C .** T ypical facial
characteristics E piderm oide cysts O varian fibrom e C alcification of the falx
M andibular cyst S acralization of L5
K iphoscoliosis
JD V (fig.2) M 32 9 10 B .C .C . - 15 T ypical facial
S olid epitheliom a characteristics
-2 Lum bar scoliosis
N evocellular H yperteleorbitism
nevus - 1 S acralization of
L5
M andibular cyst
A M V F 29 6 B .C .C - 5 T ypical facial
M elanocytic characteristics
nevus - 5 E rosion of the
sella tursica
A LV (fig.3) M 20 7 2 B .C .C -7 T ypical facial
N evocellular characteristics
nevus - 1 M andibular cyst
M icroinvasive 8.C .C . - 1
Lesion E volution - N um ber of lesions that appeared during patient's follow -up S .C .C . - B asal-C ell C arcinom a
A m ong the single basal-cell tum ors, the percentage
of solid tum ors is high (88.9% ). A ccording to the results
of M cK night et al. (15); M addox (13); and a study by
Jackson and G ardere (9), the frequency of the different
subtypes of basal-cell tum ors found in patients w ith N B C C
(is solid type 72% , cystic 19% , scleroderm iform 17% ,
adenoid 27% , and superficial 6% ). A pproxim ately one
third of the patients show tw o or m ore types of tum ors.
M ason discovered in 1965 (14) that out of the 370 tum ors
exam ined, 11 presented osteoids or associated bone tissue.
T his study show ed that it is not possible to diagnose N B C C
based on histologic exam ination solely.
N B C C is a good study m odel for oncogenesis,
particularly the interaction betw een environm ental and
genetic factors.
M any findings suggest that the prim ary function of
the gene is the control of cellular grow th. T he pattern of
m ultisystem ic m alform ations presented suggest that its
activity influences the three germ inative tissues of the
em bryo (2).
T IN C A N I, A .J., A N D R A D E , R .G ., F R A N C O JR , E .F .M ., C A M A R G O , M A B . & M A R T IN S , A .S . -N evoid B asal-C ell S yndrom e: literature review and case report in a fam ily
Figure 2: The arrow shows calcification areas in the falx cerebri
B iochem ical studies try to characterize the
association of the excessive prostaglandin level w ith the
aggressive grow th of the basal-cell carcinom as, as w ell
as w ith its effect on the bone reabsorption present at the
form ation of odontogenic cysts of the jaw (6,18).
. T he differential diagnosis of N B C C m ust be m ade
w ith the B azex S yndrom e, R om bo S yndrom e, and the
R asm ussen S yndrom e (5). T he present of a large cranial
circum ference and vertebral or rib abnorm alities in
children w ithout a fam ily history should be an indication
for further investigations.
T he variety of clinical signs constitute a diagnostic
problem . S om e of these signs are seen in less than 10%
of the described cases, and there are a num ber of possible
associations (m edulloblastom a, m eningiom a, m etacarpus
brevis, palate and labium fissure, congenital cataract,
glaucom a, colobom a, fibrom a, etc.) (5).
Figure 3: Cysts in the mandibular arch (arrows)
In view of the frequent pathologic skin
m odifications, the follow -up of patients every 3 to 6
m onths is required particularly betw een puberty and the
age of 35, m ainly because of the possible appearance
of epiderm oid carcinom a and cutaneous m elanom a at
the lesions. S pecial attention m ust be given to lesions
located near the natural orifices (ears, eyes, nose) due
to their potential destruction by the invasion of the
tum ors.
T he treatm ent in m ost cases is the surgical
rem oval of the lesion because of its w ell know n
aggress.ive evolution. In som e cases of sm all lesions
treatm ent can be cryosurgery and
elec-trocauterization, as w ell as curettage (16). T he real
value of topical im m unotherapy and the use of
5-fluoracil are under study. T he use of 13-cis-retinoic
acid taken orally and in high dosages seem s to be
effective in the prevention of tum or appearances, as
w ell as in the reduction of the grow th rate of old
lesions (16).
T he com plete rem oval of the m andibular cysts
is necessary due to the high rate of relapse (4).
T he association w ith radiotherapy in the
treatm ent m ay not be advisable, due to the fact that
the exposure to radiation stim ulates the appearance
of new lesions and that it requires large areas to be
m edulloblastom a has been firm ly established by the
appearance of the tum or in 20% of patients w ith
N BCC. Patients w ith N BCC and m edulloblastom a and
treated w ith radiotherapy have show n a higher rate of
sarcom atous transform ation of ovarian fibrom as as
w ell as the appearance of a large num ber of skin
tum ors at the site w here the radiotherapy w as applied
(1 ).
In literature there are descriptions of N BCC cases
in fam ilies of m any different ethnic backgrounds
(3 ,1 1 ,1 7 ).
C O N C L U S IO N S
N BCC is a rare entity and little is know n regarding
its physiopathology. A precise and early diagnosis is of
utm ost im portance in order to im prove the approach to
skin lesions, thus avoiding their consequences.
Solar protection is im portant for all patients and a
periodic follow -up in addition to genetic counseling is
necessary.
RESUMO
In tro d u ~ a o : A S fn d ro m e d o N e v o B a s o c e lu la r (S N B C ), ta m b e m c h a m a d a d e S fn d ro m e d o C a rc in o m a N e v 6 id e B a s o c e lu la r o u S fn d ro m e d e G o rlin -G o ltz , c a ra c te riz a -s e p o r m u ltip lo s c a rc in o m a s b a s o c e lu la re s d e a p a re c im e n to p re c o c e , c is to s e m m a n d fb u la , a le m d e o u tra s a n o m a lia s c o m o a s 6 s s e a s , p ro b le m a s o c u la re s e n o a p a re lh o re p ro d u tiv o . C o n c lu s a o : 0 tra ta m e n to d e fin itiv o d a S N B C a in d a n a o fo i b e m e s ta b e le c id o , p o re m re s s a lta -s e a im p o rt€ m c ia d o d ia g n 6 s tic o p re c o c e , a le m d o s e g u im e n to p e ri6 d ic o d o s p a c ie n te s , p rin c ip a lm e n te d e v id o a s tra n s fo rm a 9 0 e s d a s le s o e s d a p e le q u e p o d e m o c o rre r.
R E F E R E N C IA S
B IB L IO G R A F IC A S
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J.M . Birch. The incidence of G odin syndrom e in 173 consecutive
cases of m edulloblastom a. Br
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Cancer 64: 959-961,1991.2. Farndon P.A .; D el M astro RG .; Evans D .G .R; K ilpatrick M .W .
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Studies on the genetics of basal cell nevus syndrom e in one
fam ily. Chin M ed
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98: 538-542, 1985.4. G orlin R.J. and G oltz R.W . M ultiple novoid basal-cell
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908-912, 1960.
5. G odin RJ. N evoid basal-cell carcinom a syndrom e. M edicine
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6. H auenstein H . and Schettler D . U ntersuchungen U ber
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syndrom e. In A ndrade R at all editors. Cancer of the skin.
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Canad M ed A ssoc
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105: 850-862, 1971.10. J arisch W oo Zur lehre von den H autgeschw tilsten. A rch
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basal-cell syndrom e. A rch Path 79:401-408, 1965.
15. M cK night e.K . and M agnusson Boo Tum ors in Iceland.
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M icrob Scand Sect A 87:37-44, 1974.
16. N aldi L.; M archesi L.; Locati F.; Cainelli T.; M ultiple papular
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18. V anderveen EE; G rekin Re.; Sw anson N .A .; K ragballe K ..
A rachidonic acid m etabolites in cutaneous carcinom a: evidence
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T IN C A N I, A .J ., A N D R A D E , R .G ., F R A N C O J R , E .F .M ., C A M A R G O , M A B . & M A R T IN S , A .S . -N e v o id B a s a l-C e ll S y n d ro m e : lite ra tu re re v ie w a n d c a s e re p o rt in a fa m ily
