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8/10/2019 Etiology of Fibrous Dysplasia
1/6
Int . J. Oral Maxi llofac. Surg. 1999; 28:3 66-3 71
Printed in Denmark. Al l r ights reserved
Copyr igh t 9 Munksga ard 1999
[ntemadonalJournal of
Oral
MaxillofacialSurgery
IS SN 0901-502 7
E t io lo g y o f f i b r o u s d y s p la s ia
a n d M c C u n e A l b r i g h t
syn rome
a t h o l o g y
M . M i c h a e l C o h e n , J r . 1 ,
R o b i n E . H o w e l l 2
Depar tments of
1 2Ora l Maxillofacial
Sciences; 1Pediatr ics ; 1Community Health
Epidem iology; 1He alth Serv ices
Adm inis trat ion; 1Soc io logy Soc ia l
Anthropology, Dalhous ie U nivers i ty , Hal i fax ,
N ova Scot ia, C anada
M . M . C o h en J r . R . E . H o w e l l : E t io l o g y o f i b r o u s d y sp l a si a a n d M c C u n e -
A l b r i g h t s y n d r o me . I n t . J. O r a l M a x i l l o f a c . S u r g . 1 9 9 9; 2 8 : 3 6 6 - 3 7 1 .
9 M u n k s g a a r d , 1 9 9 9
A b s t r a c t . I n t h is p a p e r , t h e e t i o l o g y o f m o n o s t o t i c f ib r o u s d y p l a s ia a n d M c C u n e -
A l b r i g h t s y n d r o m e is ex p l a in e d . B o t h m o n o s t o t i c f ib r o u s d y s p l a si a a n d M c C n n e -
A l b r i g h t s y n d r o m e a r e s p o r a d i c a l l y o c c u r r i n g d i so r d e r s i n w h i c h a m u t a t i o n i n
t he G N A S1 ge ne oc c u r s po s t z ygo t i c a l l y in a s om a t i c c ei l. A l l ce ll s de s c e nde d
f r o m t h e m u t a t e d c el l c a n m a n i f e s t f e a tu r e s o f M c C u n e - A l b r i g h t s y n d r o m e o r
f i b r ous dys p l a s i a . C e l l s de s c e nde d f r om non- m ut a t e d c e l l s de ve l op i n t o no r m a l
t is sue s. Thu s , t he - c l in i c a l pa t t e r n i s va r i a b l e i n d i s t ri bu t i on a nd a ppe a r a nc e .
Mor e ge ne r a l i z e d vs m or e l oc a l i z e d e xp r e s s i on de pe nd on ( a ) how s m a l l o r how
l a r ge t he c e l l m a s s i s du r i ng e m br yoge ne s i s w he n t he m u t a t i on oc c u r s a nd ( b )
w he r e i n t he c e l l m a s s t he m u t a t i on oc c u r s . Top i c s d i s c us s e d i nc l ude G p r o t e i n s
a nd t he i r r e c e p t o r s , c yc l ing o f s t i m u l a t o r y G p r o t e i n be t w e e n a c t i ve a nd i na c t i ve
f o r m s , a nd s pe c !f ic m u t a t i ons i n G N A SI . W e a ls o d i s c uss f ou r pos s i b i li ti e s : ( a )
A r e t he r e m a s ke d m u t a t i ons ? ( b ) A r e t he r e e f fe c t s o f i m pr i n t i ng? ( c ) A r e t he r e
non- c l a s s i c a l m u t a t i ons ? a nd ( d ) I s f i b r ous dys p l a s i a a ne op l a s m ?
K e y
words: f ibrous
dysplasia; pituitary
adenoma; McCune-AIbright
syndrome;
GNAS1 gene; G prote in; somat ic mosaic ism;
neoplas ia.
A cce p te d
f o r p u b l i c t i o n
4 Apr i l 1999
Monos t o t i c f i b r ous dys p l a s i a i s a w e l l -
k n o w n b o n e d i s o r d e r o f g r e a t i n te r e st
t o s u r ge ons a nd pa t ho l og i s t s . The e t i o l -
o g y is n o w k n o w n . A c t i v a t i n g m u t a -
t i ons i n t he ge ne t ha t e nc od e s t he ce s ub -
un i t o f s t i m u l a t o r y G p r o t e i n ( G ~a )
c a us e m onos t o t i c f i b r ous dys p l a s i a ,
po l yos t o t i c f i b r ous dys p l a s i a , p i t u i t a r y
a d e n o m a , a n d M c C u n e - A l b r i g h t s y n -
d r om e . To unde r s t a nd t he e t i o l ogy , G
pr o t e i n s , G p r o t e i n - c oup l e d r e c e p t o r s ,
c y c l in g o f s t i m u l a t o r y G p r o t e i n ( G s a )
be t w e e n i t s a c t i ve a nd i na c t i ve f o r m s ,
a n d t h e c o n c e p t o f s o m a t i c m o s a i c is m
n e e d t o b e e x p l ai n e d . T e r m i n o l o g y u s e d
i n t h i s pa pe r i s s um m a r i z e d i n Ta b l e 1 .
G p r o t e i n s , p a r t i c u l a r l y G s a
G pr o t e i n s ( gua n i ne nuc l e o t i de p r o -
t e in s ) a r e a f a m i l y o f m o l e c f il e s c om -
po sed of three su bun i t s d es ign ated c~, f l,
a nd 7 . The f unc t i on a nd s pe c i f i c i t y o f
e a c h G p r o t e i n i s de t e r m i ne d by t he a
s ubun i t , w h i c h i s un i que f o r e a c h t ype .
T h e f l a n d 7 s u b u n i t s t e n d t o b e m o r e
hom oge ne ous . I n t h i s pa pe r , w e s ha l l be
c o n c e r n e d w i t h s t i m u l a t o r y G p r o t e i n
( G s c 0 w h i c h a c t i va t e s a de ny l y l c yc l a s e
w h i c h , i n t u r n , c a t a l y z es t h e f o r m a t i o n
o f c A M P ( 3 ', 5 '- c y c li c a d e n o s in e m o n o -
p h o s p h a t e ) f r o m A T P ( a d e n o s i n e t r i -
phos p ha t e ) . Th e ge ne f o r G ~c~ i s
G N A S 1 ( g u a n i n e n u c l e o t i d e - b i n d i n g
prote in , c~-st imula ting a c t iv i ty po lyp ep -
t i de 1 ) ; i t s c h r om os om e m a p l oc a t i on i s
20q13.215.
L i ke a l l G p r o t e i n s , t he i na c t i ve f o r m
o f G sc ~ c o n t ai n s b o u n d G D P ( g u a n o -
s in e d i p h o s p h a t e ) . A G P C R ( G p r o t e in -
c oup l e d r e c e p t o r ) f a c i l i t a t e s t he e x -
c h a n g e o f b o u n d G T P ( g u a n o s i n e tr i-
p h o s p h a t e) f o r G D P p r o d u c i n g t h e ac -
t ive fo rm 3~
G p r o t e i n - c o u p l e d r e c e p t o r s
G pr o t e i n - c oup l e d r e c e p t o r s l i nk t he
b i nd i ng o f a n e x t r a c e l lu l a r l i ga nd , s uc h
a s a g r o w t h f a c t o r o r h o r m o n e , t o t h e
a c t i va t i on o f the a s s oc i a t e d G p r o t e i n
a nd i n t r a c e l l u l a r s i gna l ge ne r a t i on . The
G P C R f a m i ly h a s s ev e n h y d r o p h o b i c
m e m b r a n e - s p a n n i n g d o m a i n s , a n e x t r a -
c e l l u l a r a m i n o - t e r m i n a l r e g i o n , a n d a n
i n t r a c e l l u l a r c a r boxy- t e r m i na l r e g i on .
The i n t r a c e l l u l a r l oop be t w e e n t he f i f t h
a n d s i x t h m e m b r a n e - s p a n n i n g d o m a i n s
t oge t he r w i t h t he i n t r a c e l l u l a r c a r boxy-
t e r m i n a l s e g m e n t a r e i m p o r t a n t f o r G
pr o t e i n i n t e r a c t i ons 3~
C y c l i n g s t im u l a t o r y G p r o t e i n G s a )
b e t w e e n i ts a c ti v e a n d i n a c t i v e f o r m s
C y c l i n g o f s t i m u l a t o r y G p r o t e i n ( G s a )
be t w e e n i t s a c t i ve a nd i na c t i ve f o r m s i s
8/10/2019 Etiology of Fibrous Dysplasia
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E t i o l o g y o f i b r o u s d y s p la s ia M c C u n e - A l b r i g h t s y n d r o m e 3 6 7
Table 1.
Terminology
Abbreviations Definitions
ATP
cAMP
CS
DAG
Gay
GDP
GNAS 1
GPCR
Gsg
GTP
GTPase
tP
MAS
MFD
PA
PFD
PIP2
PKC
PKA
PLC
RS
STK
Adenosine triphosphate
3 ,5 -cyclic adenosine monophosphate
Catalytic subunit of PKA
Diacylglycerol
/]7 subunit of G protein
Guanosine diphosphate
Guanine nucleotide-binding protein, a-stimulating activity polypeptide 1
G protein-coupled receptor
a subunit of G protein
Guanosine triphosphate
Guanosine triphosphatase
Inositol trisphosphate
McCune-Albright syndrome
Monostotic fibrous dysplasia
Pituitary adenoma
Polyostotic fibrous dysplasia
Phosphatidylinositol bisphosphate
Protein kinase C
Protein kinase A or cAMP-dependent protein kinase
Phospholipase C
Regulatory subunits of PKA
Serine/threonine kinase
Table 2. Mutations in the GNASI Gene
Nucleotide
Disorder Exon change Amino acid substitution
McCune-Albright syndrome
Polyostotic fibrous dysplasia
Monostotic fibrous dysplasia
Panostotic fibrous dysplasia
Isolated pituitary adenoma
8 C--+T Arg201Cys
8 G--+A Arg201His
8 C---~T Arg201 Cys
8 C--+T Arg201Cys
8 G-+A Arg201His
8 C--+A Arg201Ser
8 C--+T Arg201Cys
8 G--+A Arg201His
8 C--+A Arg201Ser
9 A--+G Gln227Arg
9 G---~T Gln227His
Based on ~EINSTEINet al., 199134, SCHWINDINGER t al. , 199225, S~NI~R et al ., 199329, 199428,
199527, CANDELIEREet al., 19954, LANDISet al ., 198914, MALCI-IOFF t al., 199416, WILLIAMSON
et al., 199535, CANDELIE~et al., 19973.
shown in Fig. 1. The inactive G~c~ is
shown in (A) and (D). Ligand-binding
(B) produces a confo rmati onal change
in the receptor and GDP is replaced by
GTP, which results in dissociation of
the cc subunit. Binding of the active
form of the c~ subun it to adenylyl cyc-
lase (C) activates this enzyme, resulting
in the formation of cAMP from ATR
Hydrolysis of GTP to GDP is catalyzed
within seconds by the intrinsic GTPase
(guanosine triphosphatase) activity of
Gsa cau sing dissociation of the a sub-
unit from adenylyl cyclase and binding
to the/] and ? subunits, resulting in the
inactive form (D). Liga nd-bi nding will
cause repe titi on o f the cycle 31.
M u t a t i o n s i n G N A S
Mutations in GNAS1 have been associ-
ated with different disorders. Gain-of-
function mutations have been found in
McCune-Albright syndrome (MAS),
polyostotic fibrous dysplasia (PFD),
monostotic fibrous dysplasia (MFD),
and pituitary adenoma (PA). Loss-of-
function mutations have been found in
endocrine disorders characterized by
hormone resistance, such as type la
pseudohypoparathyroidism, hereditary
glucocorticoid deficiency, and nephro-
genic diabetes insipidus3~
Bone marrow contains hematopoietic
tissue and skeletal progenitor cells of
Adeny ly l
G P r o t e i n / Y c la s e
Extracellular
A) ~ Cel lMembrane
Intraceflular
G D p ~
l i v t
adeny ly l
c )
A T P c A M P
p i~ r l + P P i
Fig. l . Activation of adenylyl cyclase follow-
ing ligand binding to G protein-coupled re-
ceptor. (A) G protein composed of a, fl, and
), subunits. This is the inactive form. L -
Ligand. R=Receptor. GDP=Guanos ine di-
phosphate. (B) Ligand (L) binding produces
conformational change in receptor (R) and
guanosine diphosphate (GDP) is replaced by
guanosine triphosphate (GTP), resulting in
dissociation of the a subunit. (C) Binding of
a subunit to adenylyl cyclase activates 3 ,5 -
cyclic adenosine monophosphate (cAMP)
from adenosine tripbosphate (ATP). (D) Hy-
drolysis of GTP to GDP by GTPase, causing
dissociation of the a subunit from adenylyl
cyclase and binding to the/~ and ), subunits,
the inactive form. Ligand binding causes rep-
etition of the cycle.
the mar row spaces 19. GNAS1 muta-
tions in MAS cause hyperfunction of
(1) skeletal progenitor cells from the
marrow spaces producing abnormal os-
teoblasts2,~9, (2) melanocytes25, and (3)
endoc rine cells 9. The same abn orma l
osteoblasts are also found in PFD and
MFD. To date, no mutations have been
reported in Jaffe-Lichtenstein syndrom e
characterized by polyostotic fibrous
dysplasia and caf~-au-lait spots without
endocrine disturbances. Since this syn-
drome is part of the same clinical spec-
trum, it can be assumed that a GNAS1
mutation is causative.
How activating GNAS1 mutations
affect the cycling o f G~c~ between its ac-
tive and inactive forms is shown in Fig.
2. One of two specific mutations can be
demonstrated in these disorders (Table
2): C--+T, resulting in Arg201Cys, or
G-+A, resulting in Arg201His.
8/10/2019 Etiology of Fibrous Dysplasia
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368 C o h e n a n d H o w e l l
Activated
~ r ~ adenyly l
_._.~/cyclase
A )
P PPi
/ P
Acfivatingmutations
n
G ~
||-, |
/ IP [- ,~rg2OlCys-[m___~ +
L Arg201His~ PKA PKA
Mobilizationof / ~ 1 ~=~ ATP
intracellularCa2+ J ~ ~ ~ ', -~k ~, ~
Pi ~ ~ - ~
B ) )
I Dp |
Fig. 2. Activating m utations (Arg201Cys or Arg201His) in the gene encoding the a subunit
of stimu lator y G pr otein (Gsa). (A) Ligand-independent persistent activation o f Gsa. There
is inapprop riate s timulation of adenylyl cyclase. The m utations are located adjace nt to the y-
phospha te of GTP, thus interfering with hydrolysis of G TP by GT Pase to GDP. (B) Therefore,
the a subu/ait (Gsa) cannot dissociate from adenylyl cyclase and bind to the 87 subunit (G&).
Two downstream pathways are shown in A. The PKC pathway (protein kinase C pathway) is
shown on the left. The PKA pathway (protein kinase A or cAMP-dependent protein kinase
pathway) is shown on the right. B oth pathways are present with norm al functioning as well
as with mutations. How ever, to keep F igures 1 and 2 as simple as possible, these pathways
are omitted except in 2A. The PK C and P KA pathways are specifically shown in 2A because
the mu tations interfere w ith hydrolysis of GT P to G DP , resulting in continued s timulation of
the a subunit (Gsa) and continued dissociation of the fly subunit (G y). The dissociated 137
subunit overactivates the PK C pathway. PL C (phospholipase C) cleaves PIP2 (phosphatidyli-
nosi tol bisphosphate) int o two intr acell nlar messengers: DA G (diacylglycerol) and IP3 (inositol
trisphosphate). The lat ter triggers the release of sequestered calcium ions (C a2+) which to-
gether with DA G activate PKC. Because the a subunit (G ~a) cann ot dissociate from adenylyl
cyclase, cAM P is overproduced which, in turn, overactivates the PK A pathway. PK A is com-
posed of two regulato ry subunits (RS) that have binding s ites for cAM P, and two ca talytic
subunits (C S) that, when dissociated, phosp hor ylate serine/threonine kinases (STK).
A c t i v a t i o n i s m a i n t a i n e d i n a i i g a n d -
i n d e p e n d e n t m a n n e r ( F i g . 2 A ) , p r o d u c -
i n g i n a p p r o p r i a t e s t i m u l a t i o n o f
a d e n y l y l c y c la s e . M u t a t i o n s a r e l o c a t e d
n e a r t h e s i te w h i c h i n t e r a c t s w i t h t h e 7 -
p h o s p h a t e o f G T P , t h u s i n t e r f e r i n g w i t h
h y d r ol y s is o f G T P t o G D R B e c a us e G s a
c a n n o t d i s s o c i a t e f r o m a d e n y l y l c y cl a s e
a n d b i n d t o G p r , a d e n y l y l c y cl a s e r e -
m a i n s a c t i v e , p r o d u c i n g i n c r e a s e d
c A M P a c t i v i t y w h i c h r e s u l t s in t h e p a t h -
o l o g y o f M A S , P F D , M F D , a n d P A .
T w o d o w n s t r e a m p a t h w a y s : p r o t e in
k i n a s e A a n d p r o t e i n k i n a s e C
A c t i v a t i o n o f G s a l i n k e d r e c e p t o r s o p e n s
m u l t i p l e d o w n s t r e a m p a t h w a y s . T w o i m -
p o r t a n t p a t h w a y s a r e t h e p r o t e i n k i n a s e
A o r c A M P - d e p e n d e n t p r o t e i n k i n a s e
p a t h w a y ( P K A p a t h w a y ) a n d t h e p r o t e in
k i n a se C p a t h w a y ( P K C p a t h w a y ) ( F i g .
2 A ) . T h e s e p a t h w a y s w e r e n o t c o n -
s i d e r e d e a r l ie r t o k e e p t h e m o l e c u l a r b i -
o l o g y f r o m b e i n g o v e r l y c o m p l i c a t e d .
F o r t h e s a m e r e a s o n , t h e s e p a t h w a y s
w e r e o m i t t e d i n F i g u r e 1 . T h e y m u s t b e
c o n s i d e r e d w i t h a c t i v a t i n g G N A S 1
m u t a t i o n s , h o w e v e r , b e c a u s e c o n t i n u e d
a c t i v a t i o n o f t h e a s u b u n i t ( G s a ) r e s u lt s
i n ( 1) i n c r e a se d c A M P w h i c h o v e r a c t i v -
a t es t h e P K A p a t h w a y a n d ( 2) c o n ti n u e d
d i s s o c i a t i o n o f t h e t 7 s u b u n i t (G p e )
w h i c h m a y s y n e r g i s t i c a l l y s t i m u l a t e a d -
e n y l y l c y c l a se a n d s t i m u l a t e s s o m e i s o -
f o r m s o f P L C s ( F i g. 2A ) . P K A c a n p r o -
d u c e m a n y e f f e c t s d e p e n d i n g o n t h e c e ll
t y p e a n d t h e p a r t i c u l a r p r o t e i n s P K A
p h o s p h o r y l a t e s . I n t h e P K C p a t h w a y ,
o n c e P K C i s a c t i v a t e d , i t a c t i v a t e s t h e
M A P k i n a s e p a t h w a y . T h e s e p a t h w a y s
p r o d u c e v a r i o u s t y p e s o f c e l l u l a r r e -
s p o n s e a n d p l a y a f u n d a m e n t a l r o l e i n
c o n t r o l l i n g c e l l g r o w t h .
B e c a u s e t h e a s u b u n i t ( G s a ) c a n n o t
d i s s o c i a t e f r o m a d e n y l y l c yc l a s e, c A M P
i s o v e r p r o d u c e d w h i c h , i n t u r n , o v e r -
a c t i v a t e s t h e P K A p a t h w a y ( F i g . 2 A ) .
P K A i s c o m p o s e d o f tw o r e g u l a t o r y s u b -
u n i t s ( R S ) t h a t h a v e b i n d i n g s i t e s f o r
c A M P , a n d t w o c a t a l y t i c s u b u n i t s ( C S )
t h a t , w h e n d i s so c i a t e d , p h o s p h o r y l a t e
s e r i n e / t h r e o n i n e k i n a s e s ( S T K ) .
T h e d i s s o c ia t e d ,6 7 s u b u n i t (G y )
o v e r a c t i v at e s t h e P K C p a t h w a y s . P h o s -
p h o l i p a s e C ( P L C ) c l e a v es p h o s p h a -
t i d y l i n o s i t o l b i s p h o s p h a t e ( P I P2 ) i n t o
t w o i n t r a c e l l u l a r m e s s e n g er s : d i a c y l g l y -
c e ro l ( D A G ) a n d i n o s i to l t r i s p h o s p h a t e
( IP 3 ) . T h e l a t t e r t r i g g e r s th e r e l e a s e o f
s e q u e s t e re d c a l c iu m io n s (C a 2 +) w h ic h ,
t o g e t h e r w i t h D A G , a c t i v a t e P K C .
M c C u n e - A l b r i g h t s y n d r o m e , f i b r o u s
d y s p l a s i a , a n d s o m a t i c m o s a i c i s m
M c C u n e - A l b r i g h t s y n d r o m e ( M A S ) i s
c h a r a c t e r i z e d b y p o l y o s t o t i c f i b r o u s
d y s p l a s i a , c a f 6 - a u - l a i t s p o t s , a n d
m u l t i p l e e n d o c r i n o p a t h i e s , i n c l u d i n g
s e x u a l p r e c o c i t y , p i t u i t a r y a d e n o m a ,
a n d h y p e r t h y r o i d is m . M a n y o t h e r a b -
n o r m a l i t i e s a r e k n o w n t o o c c u r a n d
th e s e h a v e b e e n r e v ie w e d a n d d i s c u s s e d
by S t iN Ke R e t a129 . In 1986, HAPPLE1~
n o t i n g t h a t M A S o c c u r r e d s p o r a d i c a l l y ,
s e t f o r t h t h e i n t r i g u i n g h y p o t h e s i s t h a t
t h e d i s o r d e r w a s c a u s e d b y s o m a t i c m o -
s a i c i s m , l e th a l i n th e n o n -m o s a ic s t a t e .
S p o r a d i c o c c u r r e n c e a n d v a r i a b i l i t y o f
e x p r es s io n i n M A S a r e c o m p a t i b l e w i t h
H a p p l e ' s h y p o t h e s i s .
W i t h s o m a t i c m o s ai c i sm , a m u t a t i o n
o c c u r s p o s t z y g o t i c a l l y in a s o m a t i c c e ll
r a t h e r t h a n i n a g e r m c e l l. A l l c el l s d e -
s c e n d e d f r o m t h e m u t a t e d c e l l c a n m a n i -
f e s t M A S f e a t u r e s . C e l l s d e s c e n d e d f r o m
n o n - m u t a t e d c e l l s d e v e l o p i n t o n o r m a l
t i ss u e s. T h u s , t h e c l i n i c a l p a t t e r n i s m o -
s a i c i n d i s t r i b u t i o n a n d v a r i a b l e i n a p -
p e a r a n c e . S e v er e v er s u s m i l d m a n i f e s -
t a t i o n s a n d m o r e g e n e r a l i z e d v e r s u s
m o r e l o c a l i z e d e x p r e s s i o n d e p e n d o n ( a )
h o w s m a l l o r h o w l a r g e t h e c e ll m a s s i s
d u r i n g e m b r y o g e n e s i s w h e n t h e m u t a -
t i o n o c c u r s a n d ( b ) w h e r e i n t h e c e l l m a s s
t h e m u t a t i o n o c c u r s .
T h e s a m e t w o G N A S 1 m u t a t i o n s
f o u n d i n M A S a l so o c c u r i n p o l y o st o t i c
f i b ro u s d y s p l a s i a ( P F D ) , m o n o s t o t i c
f i b ro u s d y s p l a si a ( M F D ) , a n d i s o la t e d
p i t u i t a r y a d e n o m a ( P A ) o f t h e g r o w t h
h o r m o n e s e c r e t i n g t y p e a , l e s s c o m -
m o n l y o f t h e A C T H s e c re t in g
a If the epiphyses are closed, patients can de-
velop acromegaly.
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Et io lo g y o f i b ro u s d y sp las ia Mc C u n e -A lb r ig h t sy n dro m e 369
McCu n e
A ib r i gh t
s y n d r ome
Po lyos to t i c
f i b rous
dysp l a s i a
Monos t o t i c
f i b rous
dysp l a s i a
t
m
I I
O Normal
9 Som atic mutation of GN AS 1 gene
l
Fig. 3.
How muta tions cause McC une-A lbright syndrome, polyosto tic fibrous dysplasia , and
mo nostotic fibrous dysplasia depend on w hen during emb ryonic development or during post-
natal life the mutation occurs . Somatic mutation in a small cell mass is likely to result in
Mc Cune- Albrigh t syndrome. M utation in a larger ceil mass may result in polyostotic fibrous
dyspIasia . A mu tation in postn atal life , during infancy, chiIdhood, or aduIt life may resuIt in
monostotic fibrous dysplasia.
ty p e 1'3'9,11'14'16,27-29'34,35 T a b le 2 ) . H o w
t h e s e m u t a t i o n s c a u s e t h e s e d i s o r d e r s
s e p a r a t e l y d e p e n d s o n w h e n d u r i n g e m -
b r y o n i c d e v e l o p m e n t o r d u r i n g p o s t -
n a t a l l i fe th e m u t a t i o n o c c u r s ( F i g . 3 ) .
S o m a t i c m u t a t i o n i n a s m a l l c e ll m a s s
i s l i k e ly t o r e s u l t i n M A S . M u t a t i o n i n
a l a r g e r c e ll m a s s m a y r e s u l t i n P F D . A
m u t a t i o n i n p o s t n a t a l l i f e , d u r i n g i n -
f a n c y, c h i l d h o o d , o r a d u l t l i f e m a y r e -
s u l t i n M F D ( F i g . 3) o r i n P A , d e p e n d -
i n g o n t h e a n a t o m i c l o c a t i o n o f t h e
m u t a t i o n . A l l o f t h e s e d i s o r d e r s a r e
c o m p o n e n t s o f M A S .
F i b r o u s d y s p l a s i a : o t h e r p o s s i b i l i t i e s
A r e t h e r e m a s k e d m u t a t i o n s ?
O n e p o s s i b il i t y m a y b e t h a t s o m a t i c
m u t a t i o n s m a y n o t b e c o m e m a n i f e s t
ab
initio, b u t s u r v i v e i n m a s k e d f o r m t o b e -
c o me a c t iv e a t a l a t e r t ime . F o r e x -
a m p l e , a m u t a t i o n f o r m o n o s t o t i c f i -
b r o u s d y s p l a s i a m a y o c c u r d u r i n g f e t a l
l i f e , b u t n o t b e c o m e m a n i f e s t u n t i l 2 5
y e a r s o f a g e .
T h a t s u c h a p o s s i b i l i t y i s w o r t h c o n -
s i d e r i n g i s b o r n e o u t b y t h e s t u d y o f
Drosophila m u t a t i o n s b y R U T H E R -
FORD
~ LIND QUIST 3.
T h e y s u g g e s t e d
t h a t t h e Drosophila g e n o m e c o n t a i n s
m a s k e d m u t a t i o n s p r o t e c te d b y h e a t
s h o c k p r o t e i n s t h a t s t a b il i z e t h e m u -
t a n t p r o t e i n s a n d k e e p t h e m f u n c -
t i o n i n g p r o p e r l y . W h e n t h e o r g a n i s m i s
s t r e ss e d , h e a t s h o c k p r o t e i n s n o
l o n g e r p r o t e c t t h e m u t a n t p r o t e i n s
w h i c h t h e n b e c o m e u n m a s k e d , a l t e r i n g
p h y s i c a l t r a i t s i n h a r m f u l w a y s .
A r e th e r e e f fec ts o f i mp r in t in g ?
I n g e n o m i c i m p r i n t i n g , m o d i f i c a t i o n s i n
t h e g e n e t i c m a t e r i a l o c c u r d e p e n d i n g o n
w h e t h e r g e n et i c i n f o r m a t i o n i s m a t e r n -
a l l y o r p a t e r n a l l y d e r i v e d . I f t h e p a -
t e rn a l a l l e l e i s imp r in t e d ( in a c t iv e ) , t h e
m a t e r n a l a l l e le is a c t iv e . I n c o n t r a s t , i f
t h e m a t e r n a l a l l e le i s i m p r i n t e d ( i n a c -
t iv e ) , t h e p a te rn a l a l l e l e i s a c t iv e . Im-
p r i n t e d g e n es c a n b e o n a u t o s o m e s , a n d
th e e f f e c t s c a n b e t i s s u e - s p e c i f i c o r m o re
g e n e ra l i z e d . F o r e x a mp le , g e n e s a t
1 1 p 1 5 .5 , s u c h a s IG F 2 a n d p 5 7 K IP 2,
a m o n g o t h e r g e n e s , h a v e d i f f e r e n t i a l
m a t e r n a l a n d p a t e r n a l e f f ec ts7.
P s e u d o h y p o p a r a t h y r o i d i s m i s a l s o
c a u s ed b y m u t a t i o n s i n G N A S 1 , b u t i n -
a c t i v a t i n g o n e s t h a t r e d u c e t h e e x p r e s s-
i o n a n d f u n c t i o n o f G s a . S o m e p a t i e n t s
w i t h p s e u d o h y p o p a r a t h y r o i d i s m h a v e
r e s i s t a n c e t o m u l t i p l e h o r m o n e s , w h i l e
o t h e r s h a v e r e s i s t a n c e t o o n l y s o m e h o r -
m o n e s . T h e 1a t y p e o f p s e u d o h y p o p a r a -
t h r o i d i s m i s a l m o s t a l w a y s i n h e r i t e d m a -
t e r n a l l y , s u g g e s t i n g t h a t G N A S 1 i s a n
im pr in t ed gene . HAYWARD e t a l . 12 were
a b l e t o d e m o n s t r a t e d i f f e r e n t i a l
m e t h y l a t i o n b e tw e e n m a t e r n a l a n d p a -
t e rn a l a l l e l e s. Y u e t a l . 38 g e n e r a t e d m ic e
w i t h a n u l l a l l e le i n G n a s ( t h e m o u s e
h o m o l o g u e o f h u m a n G N A S 1 ) . M a t -
e r n a l ( G n a s r e - /p + ) a n d p a t e r n a l
( G n a s m + / p - ) h e t e r o z y g o t e s f o r t h e n u l l
a l l e le w e r e s h o w n t o h a v e d i s t i n c t p h e n o -
t y p e s . R e s i s t a n c e t o p a r a t h y r o i d h o r -
m o n e w a s p r e s e n t in G n a s m / p+ b u t n o t
i n G n a s m + / p m i c e . T hu s , v a r i a b l e h o r -
m o n e r e s i s t a n c e a p p e a r s t o b e e x p l a i n e d
b y G n a s i m p r i n t i n g i n m i ce . S i m i l a r i m -
p r i n t i n g i n h u m a n G N A S 1 m a y e x p la i n
d i f f e r en c e s i n h o r m o n e r e s i st a n c e a n d
t h e v a r i a b l e p h e n o t y p e s o b s e r v e d i n
p s e u d o h y p o p a r a t h y r o i d i s m .
JuPP~ ~R
e t
a l . 1~ s h o w e d th a t t h e g e n e d e fe c t i n ty p e
l b p s e u d o h y p o p a r a t h y r o i d i s m w a s p a -
t e r n a l l y i m p r i n t e d a n d w a s t h e r e f o r e
m a t e r n a l l y i n h e r i t ed i n t h e s a m e m a n n e r
a s t h e t y p e 1a f o r m .
G N A S 1 i s o n a n a u to s o m e
(2 0 q 1 3 . 2 ) I s a n d , s in c e imp r in t in g t a k e s
p l a c e e a r l y i n d e v e l o p m e n t , t h e g e n e
m a y b e i m p r i n t e d b e f o r e a s o m a t i c
m u t a t i o n t a k e s p l a ce . P o s s i b le im -
p r i n t i n g e f f e c t s o f a n a c t i v a t i n g m u t a -
t i o n i n G N A S 1 f o r m o n o s t o t i c fi b r o us
d y s p l a s i a , p o l y o s t o t i c f i b r o u s d y s p l a s i a ,
p i t u i t a r y a d e n o m a , a n d M c C u n e - A 1 -
b r i g h t s y n d r o m e r e m a i n u n k n o w n . W e
s u g g e s t t h a t m u t a t e d c e ll s i n t h e s e d i s -
o r d e r s b e s t u d i e d t o d e t e r m i n e i f a n y
d i f f e r e n c e s e x i s t b e t w e e n m a t e r n a l l y
a n d p a t e r n a l l y e x p r e s s e d c e ll s.
A r e t h e r e n o n c l a s s i c a l m u t a t i o n s ?
A m i n o r i t y o f c a s e s m a y b e c a u s e d b y
n o n - c l a s s i c a l m u t a t i o n s ( T a b le 2 ). F o r
e x a m p l e , G l n 2 2 7 A r g a n d G l n 2 2 7 H i s
m a y b e f o u n d i n s o m e i n s t a n c e s o f i s o -
l a t e d p i tu i t a r y a d e n o m a . A n A r g 2 0 1 S e r
m u t a t i o n h a s b e e n r e p o r t e d i n a c a s e o f
p a n o s t o t i c f i b r o u s d y s p l a s i a . W h e t h e r
t h e s e m u t a t i o n s o r p o s s i b l y s o m e d o w n -
s t r e am m u t a t i o n s a r e f o u n d i n a m i n o r -
i t y o f c a s e s o r i n r a r e c a s e s o f t h e s p e c -
t r u m o f d i s o r d e r s l i s t e d i n T a b l e 2 r e-
m a i n s t o b e d e t e r m i n e d . S t u d i e s o f
o t h e r g e n e t i c d i s o r d e r s h a v e s o m e t i m e s
s h o w n t h a t a s m a l l p e r c e n t a g e o f p a -
t i e n t s h a v e m u t a t i o n s o t h e r t h a n t h e
c l a s s i ca l o n e s k n o w n t o c a u s e t h e d i s -
o r d e r s . F o r e x a m p l e , m u t a t i o n s i n t h e
g e n e p a t c h e d a r e f o u n d c o m m o n l y i n
b a s a l c e l l c a r c i n o m a a n d i n m e d u l l o -
b l a s t o m a . H o w e v e r , m u t a t i o n s d o w n -
s t r e a m o f p a t c h e d h a v e b e e n r e c o r d e d
in a few ins ta nce s 6 .
I s f i b r o u s d ysp l as i a a n eo p l asm?
T r a d i t i o n a l l y , f i b r o u s d y s p l a s i a h a s b e e n
c o n s i d e r e d a b o n e d i s o r d e r . H o w e v e r , i t
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3 7 Cohen and Howell
is well-known that, in a few instances,
lesions in fibrous dysplasia behave more
aggressively than in most cases. The
same activating mutation that causes
fibrous dysplasia also causes pituitary
adenoma which is a neoplasm. The
mutatio n may be found in isolated pitu-
itary adenoma and in McCune-A1-
bright syndrome which is often associ-
ated with pituitary adenoma.
CANDELmRE et al. 4 fou nd high levels
of c-fos proto-oncogene expression in
cells populating the bone marrow
spaces in eight patients with fibrous
dysplasia. In contra st, very low levels of
c-fos expression were detected in other
bone disorders such as vitamin D-resis-
tant rickets and osteogenesis imper-
fecta, suggesting that increased expres-
sion of c-fos may be specific for fibrous
dysplasia. If so, activating mutations in
GNA S 1, which cause fibrous dysplasia,
may increase c-fos expression by in-
creased adenylyl cyclase activity.
CANDELIEP~ et al. 4 n oted that the
cells pogulating the bone marrow
spaces were fibrob last s. RIMrNUCCI et
al. 19 and BIANCO et al ? fou nd tha t the
GNAS1 mutated cells occupying the
marrow spaces were skeletal progenitor
cells that produced abnormal osteo-
blasts. The fibroblas ts o f CANDELmP,E et
al. 4 may, in fact, be skeletal pro geni tor
cells, but not so named because the re-
search on this topic was not published
at the time of the CA~ELm~ et aI.
study. The high levels of c-fos expres-
sion and the mutated GNASl-induced
increase in adenylyl cyclase may thus be
occurring in the same cell.
In studies of transgenic mice, overex-
pression of c-fos results in bone lesions
that closely resemble fibrous dysplasia21
and osteosarcomas develop in some
cases22. In studies of human osteo-
sarcomas, c-fos expression is in-
creased 36. Osteosarcomas are know n to
develop in about 4~ of patients with
McCune-Albright syndrome and in
abou t 0.5% of patients with fibrous dys-
plasia37.
Osteosarcoma has been shown to be
caused by ionizing radiation in some
cases 8. Post-ir radiati on osteosarcoma
has also been observed in a nu mber of
24 32
cases of fibrous dysplasia , . The com-
bination of a GNAS1 mutation, in-
creased c-fos expression, and radiation
exposure in a few cases suggests multi-
step carcinogenesis of osteosarcoma,
which could account for the low fre-
quency of tumors in cases-of fibrous
dysplasia.
In summary, fibrous dysplasia mani-
fests as single or multiple bone tumors
that progressively enlarge. Lesions are
composed of islands of immature woven
bone within a mass of fibroblast-like
cells. They essentially consist of unen-
capsulated clonal proliferations of
fibroblast-like osteoprogenitor cells
with an activating mutat ion of GNAS1,
which demonstrate constitutively high
expression of the proto-on cogene c-fos.
The osteoprogenitor cells, or derived
cell lines, have an increased rate of pro-
liferation and display markers of early
osteoblastic differentiation but undergo
abnormal maturation and fail to ex-
press normal levels of late osteoblastic
markers 17,19. These findings describe a
lesion best categorized as a benign un-
encapsulated neoplasm.
A r e t h e r e d i f fe r e n t t y p e s o f f i b ro u s
d ysp l as i a?
RIMINUCCI et al. 2~ have suggested site-
specific patterns of histopathology in
fibrous dysplasia. They identified three
patterns: Chinese writing type, associ-
ated with the axial and apendicular
skeleton; sclerotic/Pagetoid type, associ-
ated with the cranial bones; and sclero-
tic/hypercellular type, associated with
the maxilla and the mandible. Fifteen
specimens from the axial and apendicu-
lar skeleton were studied, bu t on ly three
specimens each were studied from the
cranial bone s an d the jaws 2~ Thus, the
sample size for these latter anatomic
sites is small.
Our own experience is different. We
have seen numerous examples of jaw
lesions with C-shaped or Chinese
character-shaped bony trabeculae, The
distribution of discontinous bony tra-
beculae in a remark ably ordered, often
parallel, patte rn suggested by RIMIN-
UCO et al. 2~ has only been observed b y
us occasionally. Our experience is also
borne out by authorities in oral and
maxillofacia l patholo gy 1s,26.
Various radiographic appearances
are found with fibrous dysplasia of the
jaws. Radiolucent lesions may be uni-
locular or multilocular. A mottled
radiolucent/radiopaque pattern may
also be observed in some cases which
can be described as Pagetoid is'z6. WAL-
DRON
G I A N S A N T 1 3 3
in a study of 65
cases of fibrous dysplasia of the jaws,
noted that jaw lesions mature with time
and may show lamellar bone. Thus, the
mature form of fibrous dysplasia has a
Pagetoid radiographic appearance simi-
lar to what RIMINUCCI et al. 2~ have de-
scribed. However, it is important to
note that many cases of fibrous dys-
plasia of the jaws do not have either the
histologic or radiographic appearance
described by RIMINUCCIet al. 2~
To the extent that there may be histo-
pathologic diversity of bone lesions in
fibrous dysplasia, they may be ex-
plained by the different structural fea-
tures of various bones, as suggested by
RIMINUCCI et al. 2~ For example, the
sclerotic component of the craniofacial
lesions may reflect a higher ratio of
compact to cancellous bone than that
found in the long bones and vertebral
column.
R e f e r e n c e s
I. ALMAN BA, GRUELDA, et al. Activating
mutations of Gs protein in monostotic
fibrous lesions of bone. J Orthop Res
1996:14 (2): 311-5.
2 . B I A N CO P K U Z N E TS O V S A RI MI N U CCI M .
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3. CANDELrEl~ GA, ROUGHLEY PJ, GLOR-
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a l p h a c h a i n o f G ( s ) a n d s t i m u l a t e a d e n -
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s u b u n i t o f t h e s t i m u l a t o r y G p r o t e i n o f
a de nyly l c yc la se (GNAS1) to 20q13.2-
q 1 3 .3 i n h u m a n b y
in situ
hybr id iz a t ion .
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16. MALCHOFF CD REARDON G MA CGIL-
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t a t i o n o f M c C u n e - A l b r i g h t s y n d r o m e
c o n f i r m e d b y a n a c t i v a t i n g m u t a t i o n o f
t h e G ( s ) a l p h a - s u b u n i t f ro m a b o n e
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803-6 .
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Addre s s :
M. Michae l Cohen , J r . , DMD, PhD
Dalhousie University
Hal i fax
Nova Sco t ia
C a na d a B 3 H 3 J 5
Tel. +1 902 494 6412
Fax: +1 902 494 6411
E-maiL remaclea@is.daL ca
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