Etiology of Fibrous Dysplasia

8/10/2019 Etiology of Fibrous Dysplasia

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Int . J. Oral Maxi llofac. Surg. 1999; 28:3 66-3 71

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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


2/6

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.


3/6

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.


4/6

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


5/6

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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p r i n t e d a n d m a p s i n f o u r u n r e l a t e d k i n -

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G T P a s e i n h i b i t i n g m u t a t i o n s a c t i v at e t h e

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 -

y l y l cy c l as e i n h u m a n p i t u i t a r y t u m o u r s .

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M a p p i n g o f t h e g e n e e n c od i n g t h e a l p h a

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-

LIVRARY DC e t a l . A n u n u s u a l p r e s e n -

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

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17. M ~ m PJ, t~E POLLAK C, CHANSON P e t

a l . Inc re a se d pro l i f e ra t ion of os te obla s t i c

c e l l s e xpre s s ing the a c t iva t ing Gs a lpha

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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 [email protected] ca

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Etiology of Fibrous Dysplasia