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M e d i c a l PR o g r e s s Short

Stature

Physiology and

Pathology

D A V I D L . R I M O I N , M D , P h D , L o s A n g e l e s ; Z V I B O R O C H O W I T Z , M D , T o r r a n c e , C a l i f o r n i a , and WILLIAM A. HORTON, M D, H o u s t o n

S t a t u r e , t h e q u a n t i t a t i v e m e a s u r e o f h e i g h t , v a r i e s w i d e l y w i t h i n e a c h e t h n i c group w i t h a f a i r l y n o r m a l d i s t r i b u t i o n . O f t h e numerous p a t i e n t s w h o m p h y s i c i a n s e n c o u n t e r b e c a u s e o f s h o r t s t a t u r e , relatively few are pathologically small

in t h ec of family a o n t e x t ethnic b n d a c k g r o u n d

Physici ans

end d o f t h e n o r m a l curve b e f o r e must b e a b l e t o d i f f e r e n t i a t e p a t h o l o g i c s h o r t s t a t u r e f r o m t h e l o w e r en e m b a r k i n g o n a c o m p l e x d i a g n o s t i c e v a l u a t i o n . T h e r e ar e l i t e r a l l y h u n d r e d s o f d i f f e r e n t c a u s e s o f s h o r ts t a t u r e

requires a wide variety of clinical

t h eclinical e a n d v a l u a t i o n

radiograp aphic, hic, pathologic

a n d b i o c h e m i c a l t o o l s . A l t h o u g h s p e c i f i c t r e a t m e n t t o p r o m o t e g r o w t h i s a v a i l a b l e o n l y i n persons w i t h t h e e n d o c r i n o p a t h i e s a n d t h e a c q u i r e d n u t r i t i o n a l , e m o t i o n a l and c h r o n i c d i s e a s e s t a t e s , d i a g n o s i s o f t h e s p e c i f i c f o r m o f s ho rt s t a t u r e c an h a v e g r e a t i m p o r t a n c e i n b e i n g a b l e t o p r e v e n t c o m p l i c a t i o n s a n d t o o f f e r a c c u r a t e p r o g n o s t i c i n f o r m a t i o n and g e n e t i c c o u n s e l i n g . B o r o c h o w i t z Z , H o r t o n W A : S h o r t s t a t u r e - P h y s i o l o g y a n d p a t h o l o g y [ M e d i c a l P rroo g 1986Jun; 144:710-721)

DL, r e s s ] . W e s t J M ed

(Rimoin

formal s t a t u r e v a r i e s w i d e l y a m o n g e t h n i c groups a n d v a r i e s w i t h i n e a c h e t h n i c group i n a f a i r l y n o r m a l d i s t r i b u t i o n .  S h o r t s t a t u r e i s t h e r e f o r e an i m p r e c i s e t e r m a n d c l e a r l y r e l a t i v e to a p e r s o n ' s e t h n i c , f a m i l i a l a n d n u t r i t i o n a l b a c k g r o u n d . R e l a t i v e l y f e w o f t h e many p a t i e n t s w h o comp l a i n o f s h o r t s t a t u r e ar e p a t h o l o g i c a l l y s m a l l . T h u s , i t i s i m p e r a t i v e t h a t before beginning a c o m p l e x d i a g n o s t i c evalua t i o n or c o n t e m p l a t i n g g r o w t h - p r o m o t i n g t h e r a p y , p h y s ic i a n s ar e a b l e t o d i f f e r e n t i a t e b e t w e e n p a t h o l o g i c s h o r t s t a t u r e a n d t h e l o w e r e n d o f t h e n o r m a l curve. T h i s w i l l b e c o m e e v e n

tion.2 There is quick d e c e l e r a t i o n of growth following birth, a period of r e l a t i v e l y s l o w but c o n s t a n t g r o w t h d u r i n g c h i l d hood, a r a p i d g r o w t h spurt a t puberty a n d total c e s s a t i o n of g r o w t h w i t h e p i p h y s e a l f u s i o n . Ap e r s o n ' s g r o w t h p o t e n t i a l i s f e l t to b e d e t e r m i n e d p r i m a r i l y b y g e n e t i c f a c t o r s through t h e c o m b i n e d e f f e c t s o f m a n y genes ( p o l y g e n i c i n h e r i t a n c e ) a n d i s thus s i m i l a r to t h a t o f the b i r t h p a re nts. 3 D i f f e r e n c e s i n h e i g h t b e t w e e n n o r m a l p ers o ns ar e d u e t o t h e i n t e r a c t i o n o f t h i s polygenic growth p o t e n t ia l with environmental factors, such a s n u t r i t i o n a l d e f i c i e n c y or c h r o n i c d i s e a s e .

o f human g r o w t h h o r b e c o m e a v a i l a b l e t h r os uu gp hp l irees c o m b i n a n t DN DNA A techn o l o g y . R e g a r d l e s s o f i t s cause, h o w e v e r , s h o r t s t a t u r e c a n r e s u l t i n p s y c h o s o c i a l p r o b l e m s t h a t a re f a i r l y i n d e p e n d e n t o f t h e r e l a t i v e d e g r e e o f g r o w t h r e t a r d a t i o n . A p h y s i c i a n must therefore take a p a t i e n t ' s com plaint s e r i o u s l y , c on f i r m w h e t h e r or n o t a p a t h o l o g i c f o r m o f s h o r t stature e x i s t s a n d d e c i d e on the ap p ro p riate therapy a n d c o u n s e l i n g .

S i ze a t b i r t h i s thought to be highly c o r r e l a t e d w i t h i n t r a e n v i r o n m e n t as w e l l as g e n e t i c f a c t o r s . T h e m a t e r n a l e n vi r o n me n t a n d g en ot y pe have long been considered f ar more i m p o r t a n t t h a n f e t a l g e n o t y p e i n d e t e r m i n i n g b i r t h s i z e . R e c e n t s t u d i e s , h o w ev er , h a v e suggested t h a t i nt ri nsi c fetal f a c t o r s may b e more i m p o r t a n t t h a n p r e v i o u s l y c o n s i d e r e d . N e v e r t h e l e s s , b e t w e e n b i r t h a n d 2 years o f age, i n f a n t s m a k e adjustmen t f o r those maternal f a c t o r s t h a t i n f l u e n c e b i r t h l e n g t h a n d i n c r e a s e or d e c r e a s e t h e i r g r o w t h v e l o c i t y i n r e l a t i o n s h i p to t h e norm to r e a c h t h e i r g e n e t i c p o t e n t i a l . 4 A p e r s o n ' s h e i g h t a t 2 years o f a g e i s h i g h l y c o r r e l a t e d w i t h f i n a l a d u l t h e i g h t . B e t w e e n b i r t h a n d 2 years o f age, t h e g r o w t h r a t e c o n t i n u e s to d e c r e a s e a n d l e v e l s o f f a t b e t w e e n 2 or 3 years u n t i l r a p i d g r o w t h o ccu r s a t p u b e r t y ( p u b e r t a l g r o w t h s p u r t ) . D u r i n g c h i l d h o o d , s i g n i f i c a n t a l t e r a t i o n s i n b o d y p ro -

m o r e i m p o r t a n t as u n l i m i t e d mone

N o r m a l Grow th T h e n o r m a l g r o w t h c u r v e h a s c h a r a c t e r i s t i c s t h a t a re s h a r e d b y d i f f e r e n t e t h n i c g r o u p s , t h e mean a n d rang e o f h e i g h t v a r y i n g among p o p ul ul a t i o n s ( F i g u r e 1 ) . I 2 I t i s c h a r a c t e r i z e d by r a p i d fetal growth, with t h e p e a k i n t r a u t e r i n e gr o w t h v e l o c i t y occurring at about t h e f o ur t h m o n t h of gesta-

uterine

Division s ,wDweiptah rCtm temdeanr ts -oSfi Pn ea di i aM terdi ic cs a, lH Ca ernbt oe rr,- LU oCsL AA n Mg ee dl ei sc .a l C e n t e r , T o r r a n c e , i cRailm Go einne ti si cno M e d i From c a l S c thhoeo l a t H o u s toofn M. eDd r

S u p p o r t e d i n p a r t b y US P u b l i c H e a l t h S e r v i c e P r o g r a m P r o j e c t G r a n t N o . HD - 1 1 9 6 6 - 0 8 . R e p r i n t r e q u e s t s t o D a v i d L. R i m o i n , MD , PhD , D i r e c t o r , D e p a r t m e n t of P e d i a t r i c s , a n d D i r e c t o r , B e v e r l y B l v d , Los A n g e l e s , CA 90048. 710

California, and the

Department of P e d ia t r ic s ,

Medical Genetics-Birth Defects

U n i v e r s i t y of Te x a s

C e n t e r , Cedars-Sinai M e d i c a l

Center, 8 7 0 0

T H E W E S T E R N J O U R NA L O F MEDICINE

 

S H O R T ST A T U R E

ABBREVIATIONS USED I N TEXT C T = c o m p u te t e d t o mmoo g ra ra p h y GHRF = g ro wth hormone-releasing f a c t o r h CS = h u m a n c h o r i o n i c s o m a t o m a m m o t r o p i n hGH = h u m a n growth hormone o r m o n e , n oorr m a l ( a c t i v e ) h G H - N = h u m a n g r ooww t h h or th h or m on e , v a r i a n t ( i n a c t i v e ) h G H - V = h u m a n g r o w th Ig = immnunoglobulin IG F = insulinlike growth factor IGHD = i s o l a t e d g ro wth h o r m o n e d e f i c i e n c y MR = m a g n e t i c r e s o n a n c e U/ L = u p p e r s e g m e n t l e n g t h v l ooww e r s e g m e n t l e n g t h

p o r t i o n s t a k e p l a c e w i t h r a p i d g r o w t h o f t h e l i m b s , so t h a t t h e m idp o int of t h e b o d y c h a n g e s f r o m c l o s e to t h e umbilicus a t b i r t h to t h e s y m ph y s i s p u b i s b e f o r e t h e time of p u b e r t y . Puberty i s a c co mp a ni e d by a r a p i d i n c r e a s e i n g r o w t h v e l o c i t y , k n o wn a s   t h e p u b e r t a l g r o w t h s p u r t . B e f o r e p ub e r t y , m a l e a n d f e m a l e c h i l d r e n ar e r e m a r k a b l y s i m i l a r i n t h e i r h e i g h t a n d growth v e l o c i t i e s . I n girls, t h e growth spurt occurs r e l a t i v e l y e a r l y i n t h e s e q u e n c e o f p u b e r t a l e v e n t s , w h e r e a s i n b o y s i t o ccu r s l a t e r . T h u s , a l t h o u g h t h e a vera ge bo y enters p u b e r t y only s i x to e i g h t m o n t h s l a t e r than t h e a vera ge g i r l , h i s g r o w t h s p u r t o c c urs a b o u t t wo years l a t e r a n d l a s t s l o n g e r . I n a d d i t i o n to t h e l a t e r a n d l o n g e r p u b e r t a l g r o w t h s p u r t i n b o y s , t h e mean p e a k v e l o c i t y i s a l s o g r e a t e r . T h e r e i s a l s o a g r e a t d e a l o f i n d i v i d u a l v a r i a t i o n i n t h e ag e o f t h e onset of p u b e r t y , w h i c h a l s o ha s a f a m i l i a l t e n d e n c y . P e r s o n s wh o u n d e r g o p u b e r t y e a r l y ar e f r e q u e n t l y t a l l e r t h a n t h e i r peers a t a g e 1 0 t o 1 2 y e a r s , b u t g r o w t h ceases s o o n a f t e r p u b e r t y a n d t h e i r r e l a t i v e l y s h o r t peers w i t h l a t e o n s e t o f p u b e r t y may surpass t h e m i n f i n a l a d u l t h e i g h t . I n g i r l s , m e n a r c h e serves a s a m a r k e r t h a t g r o w t h i s n e a r i n g a n e n d . A n a vera ge g i r l g a i n s a b o u t 6 cm ( 2 1 / 2 i n ) i n h e i g h t a f t e r mena r c h e , b u t t h e r e i s n o s u c h m a r k e r i n b o y s . Th e p e a k o f t h e g r o w t h v e l o c i t y i n a b o y may o c c u r a f t e r h e h a s b e c o m e r e l a t i v e l y s e x u a l l y m a t u r e a n d h e c an s t i h l g ro w f o r s e v e r a l y e a r s t h e r e a f t e r ( F i g u r e 1 ) . In a d d i t i o n to a b s o l u t e h e i g h t d u r i n g t h e g r o w t h p e r i o d , s k e l e t a l m a t u r i t y i s an i m p o r t a n t i n d e x of gr owt h. S k e l e t a l m a t u r i t y i s m e a s u r e d by the r e l a t i v e r a d i o g r a p h i c appearance o f t h e e p i p h y s e s a n d m e t a p h y s e s b u t r e f l e c t s t h e o v e r a l l b i o l o g i c m a t u r a t i o n o f e a c h pers o n a n d i s Girls generto ag e o f t h e o n s e t o f ra t i o n v a r i e s ar le ll ya t me ad t u r teh ef a rs et le ar t ti vh ea n b o y s , b u t t h e r a t e p ou fb emratty u. ra w i d e l y a n d a ppea rs t o b e g e n e t i c a l l y d e t e r m i n e d . Some c h i l d r e n may t a k e 1 4 y e a r s t o r e a c h f i n a l a d u l t h e i g h t , w h i l e o t h e r s may r e q u i r e 2 0 o r more y e a r s . T h u s , h e i g h t a t a p a r t i c u l a r ag e i s d e t e r m i n e d n o t o n l y b y o n e ' s g e n e t i c g r o w t h p o t e n tial ( w h i c h determ ines f i n a l adult h e i g h t ) but also by the d e g r e e o f s k e l e t a l m a t u r a t i o n ( w h i c h i s r e l a t e d to t he a g e one a c h i e v e s f i n a l a d u l t h e i g h t ) . F o r e x a m p l e ,   t a l l f or a g e c h i l d r e n may b e s o e i t h e r b e c a u s e t h e y h a v e a v e r a g e g r o w t h p o t e n t i a l b u t ar e more m a t u r e t h a n t h e i r p e e r s o r b e c a u s e t h e y h a v e t h e g e n e t i c p o t e n t i a l t o b e t a l l a n d ar e o f average m a t u r i t y . F a c t o r s t h a t d e l a y s k e l e t a l g r o w t h s u c h as c h r o n i c i l l n e s s , m a l n u t r i t i o n a n d so f o r t h u s u a l l y a l s o d e l a y s k e l e t a l m a t u r a t i o n . D e n t a l m a t u r a t i o n p a r a l l e l s osseous m a t u r a t i o n a n d , t h u s , e s t i m a t i o n o f t h e d e n t a l ag e b y t o o t h f o r m a t i o n a n d e r u p t i o n may b e a n o t h e r i n d e x o f s k e l e t a l m a t u r a t i o n . I n g e n e r a l , h o w e v e r , s k e l e t a l ag e i s b e t t e r e v a l u a t e d b y b o n e m a t u r a t i o n t h a n b y t o o t h f o r m a t i o n , as t h e c o r r e l a t i o n between t o o t h f o r m a t i o n a n d b o d y g r ooww t h i s n o t as w e l l e s t a b l i s h e d . JUNE 1 9 8 6

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E a c h n o r m a l p e r s o n t h u s f o l l o w s a g r o w t h curve t h a t i s a c c o m p a n i e d b y o r d e r l y a n d w e l l - c o r r e l a t e d c h a n g e s i n body p r o p o r t i o n s , d e n t a l e r u p t i o n a n d epiphy seal o s s i f i c a t i o n . Al l o f t h e s e d e p e n d p r i m a r i l y on t h e p e r s o n ' s g e n e t i c c o n s t i t u t i o n b u t may b e a l t e r e d , e i t h e r p e r m a n e n t l y or t r a n s i e n t l y , b y i n f l u e n c e s s u c h as n u t r i t i o n a n d d i s e a s e .

M e a s u r e s of G r o w t h T o j u d g e w h e t h e r a c h i l d h a s n o r m a l g r o w t h a n d maturat i o n , s t a n d a r d n o r m a l c u r v e s a re r e q u i r e d . S u c h cu r ve s h a v e b e e n d e v e l op op e d b o t h f o r a b s o l u t e a c c u m u l a t e d h e i g h t , t h e s o - c a l l e d d i s t a n c e curves, a n d f o r g r o w t h v e l o c i t y . 5 6 B e c a u s e t h e r e ar e g r e a t d i f f e r e n c e s i n g r o w t h r a t e s , a d u l t h e i g h t a n d a g e o f o n s e t o f p u b e r t y among d i f f e r e n t e t h n i c g r o u p s , i t w o u l d b e o f g r e a t a d v a n t a g e t o u s e s t a n d a r d s b a s e d on e t h n i c b a c k g r o u n d f o r e a c h person a s s e s s e d . U n f o r t u n a t e l y , s u c h c u r v e s ar e g e n e r a l l y n o t a v a i l a b l e . T h u s , i n u s i n g t h e s e g r o w t h cu r ve s f o r n o n w h i t e s , a d j u s t m e n t s s h o u l d b e made f o r

e t h n i c i t y , e s p e c i a l l y i n t h o s e g r o u p s s u c h as s o u t h e a s t A s i a n s w h o s e mean h e i g h t d i f f e r s s i g n i f i c a n t l y f r o m t h a t o f w h i t e s . 180 160 140 E

 

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Age, Years F i g u r e 1 . - I d e a l i z e d n o r m a l g r o w t h c u r v e : Th e t o p g r a p h s h o w s a c c u m n u l a t e d h e i g h t an d t h e b o t t o m s h o w s g r o w t h v e l o c i t y . 711

 

SHORT S T A T U R E

An a d j u st m e n t s h o u l d a l s o be m a d e f o r c h i l d r e n of l o we r socioeconomic backgrounds and disadvantaged c o u n t r i e s

w ho are more apt to have nutritional deficiencies and chroni c infectious diseases, which tend to limit the ability to reach

g e n e t i c h e i g h t potential. Moreover, growth c u r v e s a l l o w i n g f o r p a r e n t a l h e i g h t c o r r e l a t i o n s c a n a l s o be u s e d , e s p e c i a l l y i f t h e p ar e nt s ' h e i g h t s f a l l at e it h e r end o f t h e normal s p e c t r u m . ' The usua l growth c u r v e s are d i v i d e d into percentiles a r o uunn d a n a r i t h m e t i c m e a n . A l t h o u g h t h e 9 7 t h a n d 3 r d p e r cent i l es a re u su al l y t a k e n a s t h e u p p e r a n d lower l i m i t s o f

n o r m a l , i t m u s t be e m p h a s i z e d t h a t , by d e f i n i t i o n , 3 o f normal c h i l d r e n l i e beyond b o t h t h e 3 r d and 9 7 t h p e r c e n t i l e s . Because there is a correlation between a child's h e i g h t and parental stature, adjusting for parental height can add a c c ur a c y . F or e x a m p l e , a c h i l d w i t h s h o r t p a r e n t s w h o f a l l s at t h e 3 rd p e r c e n t i l e f o r h e i g h t m i g h t be c o n s i d e r e d a b n or ma l l y

c a n s . 1 F or e x a m p l e , a w h i t e i n f a n t h a s a U / L r a t i o of a b o u t 1 .7 ; it r e a c h e s 1 . 0 at 7 to 10 y e a r s a nd f a l l s t o a m e a n o f 0.95 i n a d u l t h o o d . Blacks have relatively l o n g l i m b s and r e a c h a U/ L ratio o f a b o u t 0.85 a s adults. Although s t a n d a r d c u r v e s a re n ot a va il ab l e f o r p e o p l e o f Asi an a nd A m e r i c a n I n d i a n background, t h e y appear t o have r e l a t i v e l y s h o r t e r limbs a nd t h e r e f o r e w o u l d be e x p e c t e d t o h a v e a s o m e w h a t h i g h e r m e a n U/ L ratio t h a n w h i t e s . Arm-span measurements ar e a n o t h e r i n d e x of body p r o p o r t i o n , a s t h e a r m span u s u a l l y f a l l s w i t h i n a f e w c e n t i m e t e r s o f t h e total h e i g h t . F or example, s ho r t-

t r u n k e d dwarfs w i l l ha ve a l ow U / L ra ti o a n d a n a r m span c on sidera bly greater t h a n their height. Sitting hei ght is a more a c c u r a t e measure of body p r o p o r t i o n b u t i s m o r e d iffic u lt t o u s e in a s t a nd a r d office practice. Physiology of Growth

short, b ut if m i d p a r e n t a l height is c on sidered, the child's c o r r e c t e d h e i g h t i s w el l w i t hi n normal limits. After the ag e of 2 years, there is a t e n d e n c y for each child to f o l l o w th e same percentile o f t he growth c u r v e . D e v i a t i o n ma y signal a pathologic process interfering with growth. A normal ch i l d m a y d e v i a t e from this percentile d u r i n g ad o l e s c e n c e , depending on t h e t i m i n g o f t h e p u b e r t a l growth spurt. G r o w t h - c u r v e d a t a c a n a l s o be u s e d t o c a l c u l a t e   h e i g h t a g e . T he h e i g h t age is d e f i n e d as t h e age at which a child's h e i g h t w o u l d f a l l at t h e 5 0 t h p e r c e n t i l e . Although this m easurem ent

Growth is a p r o d u c t o f c o n t i n u o u s interaction between the e n d o c r i n e and skeletal sy stems. N e a r l y all o f the b o d y ' s horm o n e s i n f l u e n c e g r o w t h . 1 1' 2 F or e x a m p l e , growth hormone, t h y r o x i n e , insulin and corticosteroids can al l affect growth rate, whereas p a r a t h o r m o n e , 1 , 2 5 - d i h y d r o x y v i t a m i n D and c a lc it o n in a l l modulate skeletal m i n e r a l i z a t i o n a nd d e v e l o p m e n t . I n a d d i t i o n , g o n a d a l a n d a d r e n a l s t er o i d s a r e o f p r i m a r y i m p o r t a n c e in skeletal m a t u r a t i o n and th e p u b e r t a l growth spurt. T he key f act or i n this growth r e g u l a t o r y scheme i s t h e

m a y b e slightly i n a c c u r a t e b e c a u s e  t assumes that all p e r s o n s grow at the 50th percentile, calculations of height age are useful in correlating the stature of a person w i t h the d e g r e e o f

h u m a n growth hormone (hGH). T h i s relatively s m a ll p e p t i d e h o r m o n e ( 1 9 1 a m i n o a c i d s ) i s m a d e by s p e c i f i c c e l l s ( s o m a t o t r o p e s ) i n t h e a n te r io r p i t u i t a r y g l a n d . hG H i s c o d e d f o r b y a g e n e t h a t h a s been m a p p e d t o t h e d i s t a l e n d of t h e l o n g a r m o f c h ro m o s o m e 1 7 ( 1 7 q ) . 1 3 D i f f e r e n t i a l messenger RNA s p l i c i n g r ese s u l t s i n t w o p o p u l a t i o n s o f h G H m o l e c u l e s ( 2 0 K and 22K). I n a d d i t i o n to t h e gene c o d i n g f or a c t i v e hGH (hGH-N), this gene cluster also c o n t a in s an a p p a r e n t l y inactive hGH-like gene (hGH-V), g e n e s c o d i n g for human chorion ic somatomammotropin ( h C S , also known as placental

skeletal maturation.

Gr o wth -v e l o c i ty curves are more accurate in following the progress o f an in dividu a l child's g r o w t h . G r o w t h - v e l o c i t y d e t e r m i n a t i o n s s h o u l d , h o w e v e r , b e m a d e o v e r r e l a t i v eell y l o n g i n t e r v a l s - t h a t is, six months or a year-because n o r m a l pers o n s f l u c t u a t e w i d e l y i n t h eie i r s h o r t - t e r m g r o w t h v e l o c i t i e s (Figure 1). A v a r i e t y o f s t a n d a r d s h a v e b ee n d e v e l o p e d t o a s s e s s m a t u r i t y . 8 9 Skeletal m a t u r i t y serves as a good i n d e x o f overall biologic maturation and correlates well wi th other variables, such a s d e n t a l m a t u r i t y a n d o n s e t o f p u b e r t y . S k e l e t a l m a t u r i t y i s b a s e d o n t h e s i z e a n d s ha ha p e o f t h e e p i p h y s e s o n x - r a y f i l m s . A l t h o u g h a n u m b e r o f a re a s o f t h e b o d y ha v e be en u s e d t o e va l u a t e this process, the hand and wrist p r o v i d e a large n u m b e r o f bones to ex am ine and a r e t h e most c o n v e n i e n t for g e n e r a l use. With the G r e u l i c h - P y l e m e t h o d , a hand x - r a y f i l m o f t h e c h i l d i n q u e s t i o n i s c o m p a r e d w i t h a set o f s t an d a rd hand f i l m s a t d i f f eren t a g e s ; that age s t a n d a r d that most c l o s e l y r e s e m b l e s t h e c hi l d' s f i l ms i s g i v e n a s t h e b o n e a g e . D i f f e r e n t s t a n d a r d s must b e used f or boys a nd girls b e c a u s e o f d iffe r e n c e s in t he rate o f ma t u r a t io n . More a c c u r a t e and tim e-consum ing m et h o ds f o r a s s e s s i n g bone a g e ha ve b e e n d e v e l o p e d , s u c h a s t h e TW2 s y s t e m , t h a t a r e b a s e d on t h e r a d i o g r a p h i c appearance of several e p i p h y s e a l s ites . 9 V a r i o u s s t a n d a r d s h a v e b e e n d e v e l op op e d f o r a n t h r o p o m e t r i c m e a s u r e m e n t s of b o d y p r o p o r t i o n s . T h e u p p e r / l o w e r s e gm e n t ( U/ L ) r a t i o i s a n e a s i l y o b t a i n e d a n d u s e f u l i n d e x o f body p r op o rt i o n ( F i gu r e 2) . T he lower s e g m e n t i s measured from t he symphysis p u b i s to th e floor at t h e i n si d e o f the heel. T he upper se g me n t f i g u r e i s o b t a i n e d by s u b t r a c t i n g tha t o f t h e l ow ow e r s e g m e n t f r o m t h e t o t a l h e i g h t . S t a n d a r d U / L r a t i o c u r v e s have been p u b l i s h e d f or b o t h w h i t e and b l a c k Ameri12

2 . - D i s p r o p o r t i o n a t e s h o r t stature: compar ed w i t h a normal 8-year-old child in t h e c h i l d on t h e l e f t ha s and s h o r t s t a t u r e w i t h atnh ee lc e vn ta et re ,d U / L r a t i o , w h e r e a s t h e c hs ih lodr to nl it mh be s r i g h t h a s a s h o r t t r u n k a n d s h o r t s t a t u r e w i t h a r e d u c e d U / L . U/ L = u p p e r s e g m e n t l e n g t h versus l o w e r s e g m e n t l e n g t h . Figure

T H E W E S T E R N JO UR NAL O F MEDICINE

 

S H O R T STATURE

l a c t o g e n ) t o g e t h e r w ith a n u m b e r of r e l a t e d g e n e s t h a t d o not code f or w e l l - k n o w n hormones. T o d a te , f iv e n o n a l l e l i c hGH o r h CS g e n e s i n t h i s c l u s t e r h a v e b e e n c l o n e d a n d s e quenced. 1 4 1 5

P i t u i t a r y h GH s e c r e t i o n i s p r i m a r i l y r e g u l a t e d by tw o hy pothalamic hormones: growth hormone-releasing fa c tor ( G H R F ) a n d s o m a t o s t a t i n . 1 6 G r ow t h h or mo n e s e c r e t i o n i s s t i m u l a t e d p r i m a r i l y by h yp ot h a l a mi c GH R F i n a p u l s a t i l e m a n n e r , t h e maximum p u l s e o c c u r r i n g a t t h e o n s e t o f s l o w w a v e sleep. G r o w t h hormone s e c r e t i o n i s r e g u l a t e d by m e a n s of a s e r i e s of n e g a t i v e f e e d b a c k l oop s i n v o l v i n g t h e som atom ed i n s a n d g ro w th h o r m o n e i t s e l f o p e r a t i n g v i a t h e r e g u l a t i o n of t h e r e l a t i v e r e l e a s e of t h e tw o hyp ot halamic hormones. T he s y n t h e s i s a n d r e l e a s e of hG H i n t h e somatotropes i s u n d e r t he c on t r ol of t h e adenosine 3 ' : 5 ' - c y c l i c m o n o p h o s p h a t e system. A f t e r growth h o r m o n e i s r e l e a s e d i n t o t h e c i r c u l a t i o n , i t s m a j o r grow th-stim ulating e f f e c t s a re m o d u l a t e d through t h e s t i m u l a t i o n of t h e production of t h e s o m a t o m e -

d i n s in t h e liver. 1 7

The somatomedins, whi c h a re more c o m m o n l y r e fe r r e d to no w a s t h e i n s u l i n l i k e g r o w t h f a c t o r s ( I G F ) , c o m p r i s e t w o m a j o r t y p es : i ns ul i nl i ke g r o w t h f a c t o r I ( I G F I ) , w h i c h is ide n t ic a l t o somatomedin-C, and in s u lin like growth fa c t o r I I ( I G F I I ) . 1 7 - 1 9 T h e s e growth f a c t o r s , w h i c h a re h om ologues of proinsulin, have biologic effects qualitatively similar to ins u l i n . T h e s e m olecules w e i g h about 7 , 5 0 0 d a l t o n s a n d s h a r e about 50 of t h e a m i n o a c i d s of t h e i n s u l i n mol e c u l e . Ra d i o i m m u n o a s s a y s f o r e a c h of t h e s e I G F s h a v e b e e n d e v e l o p e d a n d t h e g e n e s coding f o r t h e m h av e be e n m a p p e d t o ch ro m o s o m e s 1 1 a n d 1 2 . P r o d u c t i o n o f b oott h I G F I a n d I G F H a p p e a r s t o be under h G H c o n t r o l . Although t h e r e s u l t s of r e c e n t s t u d i e s suggest a d i r e c t e f f e c t on l o n g i t u d i n a l growth by hG H i t s e l f , t h e bulk of e v i d e n c e s u g g e s t s t h a t t h e major m e c h a n i s m t h r o u gh w h i c h h G H s t i m u l a t e s b on e g r ow t h i s v i a t h e p r o d u c t i o n o f IG F 1 . 2 0 2 1 S k e l e t a l m a t u r a t i o n a p p e a r s t o be u n d e r t h e p ri m a ry c on t r o l of h or m on e s f r o m t h e t h y r oi d , a d r e n a l a n d se x g l a n d s . A n excess of a n y o n e of t h e s e w i l l a c c e l e r a t e b o n e m a t u r a t i o n , w h e r e a s a d e f i c i e n c y w i l l cause d e l a y . A t p u b e r t y , both t h e se x h o r m o n e s a n d g r o w t h h o r m o n e p a r t i c i p a t e i n p r o d u c i n g

t h e p u b e r t a l growth s p u r t ; t h e c e a s i n g of growth t h a t f o l l o w s t h i s s p u r t i s d u e p r i m a r i l y t o t h e a c t i o n of t h e se x h o r m o n e s i n closing the epiphyses. T h e s k e l e t o n r e s p o n d s t o t h e s e s t i m u l i by t w o m ajor f or ms

of o s s i f i c a t i o n - e n d o c h o n d r a l a n d m e m b r a n o u s . In e n d o c h o n d r a l o s s ific a t io n , t h e precursor f o r bone i s f or me d as c a r t i l a g e . T h e d e v e l o p m e n t a n d s u b s e q u e n t growth of t h o s e bones r e s ult from t h e t r a n s f o r m a t i o n of t h is c a r t i l a g e i n t o t r u e b o n e . Endochondral o s s ific a t io n i s la r g e ly r e s p o n s i b l e f o r t h e e l o n g a t i o n of i n d i v i d u a l bones a n d i s t h u s t he m a j o r process c o n t r i b u t i n g t o t h e i n c r e a s e i n h e i g h t , or  growth. W i t h membranous ossification, t h e bone is directly formed from t h e m e m b r a n e t h a t surrounds t h e b o n e ( p e r i o s t e u m ) . T h e r e i s n o c a r t i l a g e i n t e r m e d i a r y . This process occurs p r i m a r i l y i n t h e c a l v a r i u m , t h e c l a v i c l e s a n d p a r t s of t h e j a w , s p i n e a n d p e l v i c b o n e s . I n a d d i t i o n , t h e widening of limb bones results from this p r o c e s s . Thus, a n increase i n t h e l e n g t h of a bone i s d ue t o endochondral whereas an increase in its width is d u e t o m e m b r a no sosui fsi co as ts i of in c, a t i o n . 1 2 E n d o c h o n d r a l o s s i f i c a t i o n commences a t s e v e n w e e k s o f fetal l i f e w h e n p r i m i t i v e me se n c hyma l tissue forms c a r t ila g e JUNE 1 9 8 6

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144

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6

i n a r e a s d e s t i n e d t o b e c o m e bone. W it h in t w o w eeks , blood v e s s e l s p e n e t r a t e i n t o t h e c e n t e r of t h e bone-to-be a n d t h e o s s i f i c a t i o n process ha s begun. T h e t r a n s f o r m a t i o n spreads r a p i d l y , so t h a t , by t h r e e mont h s, m o s t of t h e precursor ha s b een converted i n t o t r u e bone. C a r t i l a g e is r e t a i n e d only a t t h e e n d s of t h e b o n e s , w h e r e it c o n t i n u e s t o g r o w a n d be converted i n t o b o n e . This site, w h i c h i s s i m i l a r i n a l l long bones, i s termed t h e endochondral growth plate. M i c r o s c o p i c a l l y it ca n be seen a s a ve r y o r d e r l y r e g i o n c o m p o s e d of d i s t i n c t z o n e s of ri n g , d e g e n c a r t i l a g e c e l l s s y n c h r o n o u s l y p r o l i f e r a t i n g , m a ttuu ri a n d d y i n g i s f i n a l l y a s erating t h e cart i l age r e p l a c e d by bone. S e v e r a l of t h e h o r m o nes m e n t i o n e d p r e v i o u s l y , e s p e c i a l l y IG F I , t o w h i c h t h e c h o n d r o c y t e s p o s s e s s s p e c i f i c r e c e p t o r s , a r e thought t o r e g u l a t e t h i s p r o c e s s . 1 2 Af t er p u b e r t y , t h e growth plate d i s a p p e a r s , al l remaining cartilage is r e p l a c e d by bone a nd skeletal growth c e a s e s .

D i f f e r e n t i a l D i a g n o s i s of G r o w t h R e t a r d a t i o n T he fi r st step in e v a l u a t i n g f or short stature i s to determine if i t i s p a t h o l o g i c . This c a n be d on e by using s t a n d a r d g r o w t h curves with a d j u s t m e n t s f or e t h n i c and family background and by d e t e r m i n i n g t h e s k e l e t a l m a t u r i t y of p r e p u b e r t a l p e r s o n s . T h e m o s t common c a u s e s f o r c o m p l a i n t s o f s h o r t s t a t u r e t h a t p h y s i c i a n s e n c o u n t e r a r e n o t p a t h o l o g i c but f a l l wi t h i n t h e r a ng e o f n o r m a l h u m a n v a r i a b i l i t y - t h a t i s , f a m i l i a l s h o r t stature and constitutional delay.

Short Stature T he normal v a r i a t i o n i n s t at u r e i n each population i s t h o u g h t t o - b e p o l y g e n i c i n n a t u r e , d ue t o t h e i n t e r a c t i o n of Familial

many g e n e s a n d e n v i r o n m e n t a l f a c t o r s . T h e n o r m a l g r o w t h curv es ha ve be en d e r i v e d by measuring l a r g e n u m b e r s of normal c h i l d r e n at differen t ages a nd pl otti n g t h e m e a n a nd r a n g e of t h e i r h e i g h t s . D e p e n d i n g o n t h e p a r t i c u l a r c u r v e , e i t h e r t h e 5 t h or t h e 3 rd p e r c e n t i l e are f r e q u e n t l y taken as t h e  l o w e r l i m i t of normal, e v e n though it i s c l e a r l y r ecognized t h a t 5 or 3 , r e s p e c t i v e l y , of t h e n o r m a l p o p u l a t i o n f a l l b e l o w t h i s l e v e l . T h e s e p e o p l e a re f r e q u e n t l y c o n s i d e r e d t o be a b n o r n i a l l y short, a l t h o u g h  t is o n l y t h e m i n o r i t y of persons f a l l i n g b e l o w t h e 5 t h p e r c e d t i l e wh o a r e t r u l y p a t h o l o g i c a l l y s h o r t . M o s t p e r s o n s wh o f a l l a t t h e l o w e n d o f t h e n o r m a l sta ture because a re curve have familial p r o g r a m m e d t o b e ss hh oo rr tt - t h a t i s , t h e y a rt eh ec yh i l d r eg en n eo tf i cs ah lo lr yt p a r e n t s a n d are g r o w i n g a p p r o p r i a t e l y f or t he ir g e n e t i c end o w m e n t . T h e i r s k e l e t a l m a t u r a t i o n ( b o n e a g e ) i s commensur a t e w i t h c h r o n o l o g i c a g e a n d t h e y a re otherwise c o m p l e t e l y

healthy.2 12 I t i s t h u s i m p o r t a n t t h a t p a r e n t a l h e i g h t be c o n s i d e r e d w h e n e v a l u a t i n g s h o r t persons because this i s g e n e r a l l y t h e b e s t i n d i c a t o r of t h e i r p o l y g e n i c m a k e u p a n d c a n be use d t o p r e d i c t e x p e c t e d height. F or instance, c o n s i d e r a n o t h e r w i s e h e a l t h y a n d n oorr m a l l y p r o p o r t i o n e d c h i l d g r o w i n g a t t h e 3 r d p e r ce nt i l e with a bone age c o n s i s t e n t with t h e c h r o n o l o g i c age ( h e i g h t a g e i s s i g n i f i c a n t l y y o u n g e r than bone a g e ) . If t h e p a r e n t s a r e relatively t a l l , this c h i l d might be considered t o h a v e s i g n i f i c a n t g r o w t h d e l a y , but i f t h e m i d p a r e n t a l h e i g h t ( m e a n of t h e p a r e n t s ' h e i g h t ) i s a t t h e 3 rd p e r c e n t i l e , t h e is f or h is or he r g e n e t i c c o n s t i t u child's t i o n a n dg rt oh ew tdhi a g n ao ps pi rs o op fr if aa tm ei l i a l s h o r t s t a t u r e c a n b e m a d e . M e t h o d s a re a v a i l a b l e by w h i c h t h e m i d p a r e n t a l h e i g h t m e a s ur e me n t c a n b e u s e d t o a d j u s t a c h i l d ' s p o s i t i o n o n s t a n d a r d

713

 

SHORT S T A T U R E

growth c u r v e s and t h u s compensate f or short parental height. 7 T h i s m a y n ot b e n e c e s s a r y , however, as a s i m n p l e m e n t a l a d j u s t m e n t w i l l u s u a l l y s u f f i c e . O n c e a d i a g n o s i s of f a m i l i a l s h o r t stature i s m ade, one must a s s u r e t h e c h i l d and t h e p a r ents that th e growth pattern is c o m p l e t e l y normal f or his o r h e r familial and e t h n i c background and that n o t h i n g can presently b e done to safely s t imu la t e t h e child's g r o w t h .

Constitutional Delay P e r h a p s t he s e c o n d most c o m m o n c a u s e o f referral for ss hl oorwt ms at ta tu ur ra et ii os nk. n2 oSwunc ha s c ch oi nl sd triet nu tairoen anlo dremlaaly bo ur t c ao rn se t si tm ua tl ilo nf ao lr their age and have sexua l and skeletal m a t u r a t i o n that is comm e n s u r a t e l y delayed-that is, their h e i g h t and bone a g e s are e q u a l l y d e l a y e d . These p e r s o n s can b e e x p e c t e d to u n d e r g o p u b e r t y at a relatively late a ge, b u t t h e y have a normal p u be r tal growth s p u r t a nd r e a c h t h e normal a d u l t r a n g e f o r stature. Co n s t it u t io n a l growth d e l a y , therefore, represents th e l o w e r e n d o f t h e n o r m a l r a n g e o f t i m i n g of s k e l e t a l a n d p u bertal d e v e l o p m e n t . These c h i l dr e n ar e s i m p l y programmed to t a k e l o n g e r t h a n a v e r a g e to become s e x u a l l y mature adults. Slow m a t u r a t i o n is o b s e r v e d more frequently in b o y s , and a simila r history is o ft e n f o u n d in their parents. 1 In most cases, t r e a t m e n t s h o u l d be l i m i t e d t o r e a s s u r a n c e t h a t t h e c h i l d w i l l

develop normally. Providing a predicted adult height is quite u s e f u l , s t r e s s i n g t h a t t h e c h i l d m a y e v e n t u a l l y be t a lle r t h a n of

pm earns yo n s i hn i sw he aor ml i e pr s ym ca ht ou lr oi gn ig c, a lt a lp l re or b flrei me sn d se x. i' s8t , I ns tt ihmouslea t fi en wg g r o w t h w i t h t h e u s e of t e s t o s t e r o n e or o x a n d r o l o n e m a y be indicated, wi th the proviso that eventual adult height will p r o b a b l y n o t be g r e a t e r a n d m a y e v e n b e less t h a n i f n a t u r e w e r e a l l o w e d t o t a k e it s c o u r s e . C l i n i c a l t r i a l s w i t h recombin a n t DNA-derived growth hormone a r e p r e s e n t l y under w a y in s u c h patients. Pathologic Short Stature W h e n a p h y s i c i a n establishes that a p e r s o n is truly short

f o r h i s o r h e r g e n e t i c b a c k g r o u n d a n d d o e s n ot s i m p l y h a v e c o n s t i t u t i o n a l d e l a y , t h e e x a c t cause of t h e p a t h o l o g i c s h o r t s t a t u r e m u st st b e d e l i n e a t e d . I t i s e s s e n t i a l t h a t a s p e c i f i c d i a g nosis b e made, if possible, b e c a u s e there are literally hund r e d s of c a u s e s of s h o r t s t a t u r e t h a t h a v e d i f f e r e n t p r o g n o s e s ,

F i g u r e 3.-Children of a p p r o x i m a t e l y ' t h e same a g e ( 5 t o 7 y e a r s ) w i t h s e v e r a l forms o f s h o r t s t a t u r e ( s c a l e in centimet e r s ) : A , B l o o m ' s s y n d r o m e . A u t o s o m a l -L recessive, a ssoc i a t ed with intrauterine growth retardation, proportionate short stature, photosensitive ra sh and predis- 2. position  to l e u k e m i a . B, P s y c h o s o c i a l d w a r f i s m . Note t h e p r o p o r t i o n a t e s h o r t stature, young appearance and prot r u d i n ghoarbmdoonmee n . C , M u l t i t r o p i c p i t u tary

youthful

deficiency.

appearance and

Note

the

 

complications and p o t e n t i a l for

treatment ( F i g u r e 3 ) . T he f i r s t i n t h e c l i n i c a l e v a l u a t i o n of s h o r t s t a t u r e i s t o d e t e r m i n e step w h e t h e r t h e b o d y h a b i t u s i s p r o p o r t i o n a t e or d i s p r o p o r t i o n a t e (Figure 3) . I n general, children w i t h disproportionate short s t a t u r e have a skeletal dysplasia, whereas t h o s e w i t h p r o p o r tionate short stature usually have a m o re g e n e r a l i ze d d i sord er s u c h as intrauterine g r o w t h retardation, malnutrition, c h r o n i c

d i s e a s e , p s y c h o s o c i a l d w a r f i s m , chromosomal a n o m a l i e s or an e n d o c r i n e d i s o r d e r . E x c e p t i o n s t o t h i s r u l e d o o c c u r , h o w ev er, s u c h as disproportionate dwarfism in cases o f severe c r e t i n i s m or t h e proportionate s h o r t e n i n g that m a y occur in persons w i t h osteogenesis imperfecta. A mildly dispropor-

t i o n a t e b o d y h a b i t u s m a y n ot be a p p a r e n t o n c a s u a l e x a m i n a t i o n a n d , t h u s , a n t h r o p o m e t r i c measurements, s u c h a s s i t t i n g h e ig h t or u p p e r / l o w e r segment ratio and a r m span must b e m ade bef ore a skeletal dysplasia, s u c h as hypochondroplasia, c a n be e x c l u d e d . B e c a u s e of t h e d i f f e r e n t i a l g r o w t h of t h e t r u n k and l i m b s t h r o u g h chi l d hood , normal b o d y proportion s v a r y w i t h a g e a n d a n t h r o p o m e t r i c m e a su r e m e n t s m u s t be c o m p a r e d with a p p r o p r i a t e s t a n d a r d s f or a g e . O n c e t h e s t a t u r e o f a s h o r t p e r s o n i s f o u n d t o be p r o p o r t i o n a t e , i t i s h e lp fu l t o d e t e r m i n e whether t h e growth w a s r e t a r d e d p r e n a t a l l y or p o s t n a t a l l y . A p r e n a t a l onset of growth r e t a r d a t i o n u s u a l l y i m p l i c a t e s a fetal e n v i r o n m e n t a l i n s u l t or a g e n e r a l i z e d c e l l u l a r g e n e t i c d e f e c t . A p o s t n a t a l onset of p r o p o r tionate g r o w t h retardation, on the other hand, usually impli-

p o s t n a t a l e n v i r o n m e n t a l i n s u l t , such as infection, c h r o n i c d i s e a s e or m a l n u t r i t i o n or a n e n d o c r i n e , p s y c h o l o g ical or m a l a b s o r p t i o n disorder.

c ate s a

Proportionate

Short Stature o f P r e n a t a l O n s e t Intrauterine Growth Retardation When t h e o n s e t o f s h o r t s t a t u r e i s p r e n a t a l , o n e m u s t d i f -

fe r e ntiate b et ween t h e v a r i o u s forms o f in tra uterin e g r o w t h r e t a r d a t i o n . T h i s i s a v e r y h e t e r o g e n e o u s g r o u p of d i s o r d e r s w i t h multiple causes r a n g i n g from placental insufficiency to t e r a t o g e n i c e x p o s u r e t o s p e c i f i c g e n e t i c or c h r o m o s o m h a l s y n d r o m e s . A l t h o u g h in most cases t h e cause i s o b s c u r e , o f t e n a r e c o g n i z a b l e s y n d r o m e a n d a s p e c i f i c d i a g n o s i s c a n be m a d e . ' 2 ' 2 2 F or e x a m p l e , B l o o t n ' s s y n d r o m e , S e c k e l ' s s y n -

d r o m e , Donahue's s y n d r o m e a n d D u b o w i t z ' s syndrome are a l l a u t o s o m a l r e c e s s i v e d i s o r d e r s . On t h e o t h e r h a n d , t h e

 ;

3*.0

_3

'

proportionate

short stature similar to patient B. D , A c h o n d r o p l a s i a . N o t e t h e s h o r t l i m b s w i t h t h e arms e x t e n d i n g o n l y t o t h e h i p l e v e l a n d t h e p e c u l i a r f a c i e s w i t h s c o o p e d - o u t b r i d g e o f t h e E , S p o n d y l o e p i p h y s e a l d y s p l a s i a w i t h a s h o r t t r u n k . Note t h e n o r r m a l h ea d a n d s h o r t n e c k ( fr o m Rimoin a n d H o r t o n 2 ) . 14

nose.

T H E WESTERN J O U R N A L O F M E D I C I N E

 

S H O R T STATURE H a l l e n a n - S t r e i f f s y n d r o m e , R u s s e l l - S i l v e r ' s s y nd ro me , d e Lange's syndrome and Williams' syndrome* u s u a l l y occur s p o r a d i c a l l y a n d ma y r e p r e s e n t n e w d o m i n a n t m u t a t i o n s . E a c h o f t h e s e s y n d r o m e s h a s i t s o wn c l i n i c a l a n d r a d i o g r a p h i c f e a t u r e s t h a t p er m it a d i a g n o s i s t o b e m a d e o r a t l ea st s u s p e c t e d . E s t a b l i s h i n g a d i a g n o s i s m a k e s it p o s s i b l e f o r on e t o provide a n a c c u r a t e prognosis a nd g e n e t i c c o u n s e l i n g .

r i p h e r a l u n r e s p o n s i v e n e s s t o t h e a c t io n s - of I G F. Th e s e c h i l dren u su al l y have a bone age commensurately o r even more severely retarded t h a n their h e i g h t a g e , depending on th e state of t h e i r g o n a d a l a n d t h y r o i d s y s t e m s . An a c c u r a t e d i a g n o s i s i s e s p e c i a l l y important f o r persons with t h is group of d i s o r d e r s because m a n y of t h e m w i l l respond t o s p e c i f i c t h e r a p e u t i c neasures.

C h r o m o s o m a l Disorders

Psychosocial Dwarfism

M o s t chr omosomal d i s o r d e r s , wit h t h e e x c e p t i o n of t h e m u l t i p l e X a nd Y syndromes, result i n i n tra uteri n e growth retardation. In a d d i t i o n to t h e p re na ta l growth retardation, t h o s e syndromes c o m p a t i b l e with su rv i v al beyond i n f a n c y , such a s t r i s o m y 2 1 , t h e X d e l e t i o n s y n d r o m e s ( T b r n e r ' s s y n d r o m e ) a n d a v a r i e t y of a u t o s o i n a l p a r t ia l d e l e t i o n a n d d u p l i c a t i o n s y ndro m es , a re c h a r a c t e r i z e d by continued po o r growth t h r o u g h o u t c h i l d h o o d and a b l u n t e d p u b e r t a l growth s p u r t a s w e l l . As t h e n u m b e r of r e c o g n i z e d c h r o m o s o m a l d i s o r d e r s ha s i n c r e a s e d d u e t o i m p r o v e d b a n d i n g t e c h n i q u e s , their precise clinical diagnosis h a s become increasingly difficult. T h e r e f o r e , a pat i ent with intrauterine growth retardati on a n d d y s m o r p h i c f e a t u r e s wh o d o e s n o t f i t i n t o a r e c o g n i z a b l e syndrome s h o u l d have k a r y o t y p i n g done to e x c l u d e a chromos o m a l a n om om a l y . I t s h o u l d a l s o b e r e m e m b e r e d t h a t s o m e g i r l s with t h e Tmrner syndrome, e s p e c i a l l y t h o s e with mosai c i s m - t h a t i s , 4 5 X , 4 6 X X -may e x p r e s s f e w p h e n o t y p i c f e a t u r e s of t h i s s y n d r o m e p r e p u b e r t a l l y , except f o r s h o r t s t a t u r e . Thus, c h r o m o s o m a l s t u d i e s s h o u l d be d ohe o n a l l s h o r t g i r l s w it h r e l a t i v e l y n o r m a l b od y p r o p o r t i o n s f o r whom a n o t h e r d i a g n o s i s h a s n ot b ee n m a de .

Intrauterine Infections I n t ra u t er i ne i n f ec t i on s with r u b e l l a , s y p h i l i s , t o x o p l a s m os is a n d c y t o m e g a l i c i n c l u s i o n d i s e a s e c a n p r o d u c e p r e n a t a l growth retardation that results in postnatal p r o p o r t i o n a t e short stature. A f f e c t e d n e oonn a ttee s a r e u s u a l l y s e v e r e l y i l l w i t h s y s t e m i c m a n i f e s t a t i o n s , i n c l u d i n g m i c r o c e p h a l y , hepatosplenomegaly, petechiae and seizures. The diagnosis is ultimately m a d e by d e t e r m i n i n g e l e v a t e d s er u m Torchs t i t e r s .

Teratogenesis

ethanol, nicotine, h y d ant o i ns w a r f a r i n ma y r e s u l t i n p r e n a t a l g r o w t h r e t a r d a t i o n . 2 2 M a ternal smoking m a y result i n o t h e r w i s e n o r m a l , sm al l - f ord a t e s b a b i e s , w h e r e a s t h e use of e t h a n o l , h y d a n t o i n s a n d w a r f a r i n produces w e l l - c h a r a c t e r i z e d t e r a t o g e n i c syndromes.

and

Maternal consumption of

o f Postnatal On s e t p o s t n a t a l onset of p r o p o r t i o n a t e s h o r t

Proportionate Short Stature

Persons with a stature usually have a prenatal e n v i r o n m e n t a l i nsul t , a c h r o n i c d i s e a s e o r a n e n d o c r i n e d i s o r d e r , a l l o f w h i c h ma y b e a s s o c i a t e d with t h e i n s u f f i c i e n t g e n e r a t i o n of I G F or p e r i p h e r a l u n r e s p o n s i v e n e s s t o i t s a c t i o n . The r e m a y be d i r e c t s u p p r e s s i o n o f h e p a t i c IG F s y n t h e s i s , d e f i c i e n t h G H s e c r e t i o n w i t h s e c o n d a r i l y r e d u c e d IG F p r o d u c t i o n , i n a b i l i t y t o r e s p o n d t o

h G H s t i m u l a t i o n o f I G F , c i r c u l a t i n g IG F i n h i b i t o r s a n d p e

* A l t h o u g h e p o n y m s a re n o t w r i t t e n a s p o s s e s s i v e s i n t h e f i e l d o f g e n e t i c s , W J A f s sty le f o l l o w s Dorland  s Medical D i c t i o n a r y ( 2 6 t h edit ion) and t h e AMA s M a n u a l f o r Authors a n d E d i t o r s . JUNE 1 9 8 6

*

144

*

6

Emotional d i s t u r b a n c e s m a y result i n pronounced growth r e t a r d a t i o n i n c e rt a in c h i l d r e n . 2 3 Th e s e c h i l d r e n u s u al l y c o m e from homes where marital discord, separation, p r o mis c u it y, a l c o h o l i s m a n d t h e l i k e a r e f o u n d , but t h e y c a n a l s o be s een i n su perf i ci al l y w e l l - t o - d o a n d w e l l - a d j u s t e d f a m i l i e s . Ah i s t o r y o f e m o t i o n a l d e p r i v a t i o n ma y b e r e a d i l y a p p a r e n t b u t i n s o m e c h i l d r e n m a y be d i f f i c u l t t o o b t a i n . T h e y u s u a l l y h a v e n o r mal-growing sibs. There i s u s u a l l y a poor plasma hGH response t o t h e u s u a l s t i m u l i a n d l e v e l s of c i r c u l a t i n g I G F a r e l o w . Other p i t u i t a r y h o r m o n e d e f i c i e n c i e s c a n a l s o be f o u n d . B o n e - a g e m a t u r a t i o n i s u s u a l l y g r e a t l y d e l a y e d . When r e m o v e d from their adverse e n v i r o n m e n t , t h es e c h i l d r en show a s t r i k i n g c a t c h - u p i n t h e i r b o n e a g e a n d t h e i r h G H a n d IG F l ev el s r e tu r n t o normal. P s y c h o s o c i a l d w a r f i s m i s thought t o r e p r e s e n t f u n c t i o n a l h y p o p i t u i t a r i s m i n w h i c h psychic f a c t o r s h a v e p r oodd u c e d p i t u i t a r y i n s u f f i c i e n c y t h r o u g h h y p o t h a l a m i c s u p p r e s s i o n . T h i s c o n d i t i o n a p p e a r s t o b e r e l a t i v e l y common b u t it u s u a l l y occurs i n o n l y on e person i n a f a m i l y .

Malnutrition Chronic m a l n u t r i t i o n r e t a r d s growth a n d i s a s s o c i a t e d with reduced s y n t h e s i s of IGF. 8 I n d ee d , c h i ld r en with p r o t e i n - c a l o r i e n i a l n u t r i t i o n ( k w a s h i o r k o r ) h a v e l o w s e r u m IG F d e s p i t e high l e v e l s of h G H . W h i l e c a l o r i c i n t a k e appears t o r e g u l a t e I G F g e n e r a t i o n , d i e ta r y p r o te i n s e e m s t o be important i n both m a i n t a i n i n g I G F a c t i v i t y a n d i n f l u e n c i n g t h e IG F a c t i o n a t t h e t i s s u e l e v e l . T h e a b s e n c e of a n a d eq ua te s u b s t r a t e f o r g r o w t h m a y co nt r ib u t e to growth failure in m a l n u t r i t i o n as well. Maln u t r i t i o n r e s u l t i n g f r o m m a l a b s o r p t i o n ma y a l s o r e s u l t i n g r o w t h r e t a r d a t i o n . T h e r e h a v e no w b e e n s e v e r a l r e p o r t s o f c a s e s of o t h e r w i s e a s y m p t o m a t i c c el i ac d i s e as e r e s u l t i n g i n p e r s o n s with p r o p o r t i o n a t e growth retardation.I1 Small bowel have been r e c o m m e n d e d i n t h e w o rk up f o r such c h i l bd iroepns ii en s w h o m o t h e r c a u s e s o f g r o w t h r e t a r d a t i o n h a v e b e e n excluded. Chronic Disease od a r e a s s o c i a t e d w i t h Ma n y c h r o n i c d i s e a s e s o f c h i l d hhoo od

growth f a i l u r e . 112'24'25 Chronic liv e r d i s e as e , chronic r e n a l

d i sea se, c h r o n i c c e l i a c d i s e as e , r e g i o n a l enteritis, chronic i nf ecti ous disease, d i a b e t e s nmllitus, t h e hemoglobinopathies, a s t h m a , congeni tal h e a r t d i s e a s e and m a n y ot hers fit i n t o this categoiry. Often t h e reduced growth m a y be t h e domin a n t c l in i ca l f e at u re . A l th o ug h t h e m e c h a n i s m f o r g ro w th s u p p r e s s i o n i s v a r i e d , a l o w IG F l e v e l i s u s u a l l y f o u n d . I n a d d i t i o n , m a n y p a t i e n t s w i t h chronic d i s e a s e a re i n a s t a t e of n e ga t i v e n i t r o ge n b a l a n c e . Poor a b s o r p t i o n of n u t r i e n t s m a y be found i n p a t i e n t s with g a s t r o i n t e s t i n a l d i s o r d e r s such as re o r c o n t r o l o f t h e d i s e a s e , t h e r e i s i l e i t i s . A f t e r c u re ur se ug ai ol nl ya l s i g n i f i c a n t c a t c h - u p g r o w t h , t h e f i n a l a d u l t s t a t u r e d e p e n d i n g on t h e d u r a t i o n a n d s e v e r i t y of t h e d i s e a s e a n d t h e a g e of o n s e t of t h e d i s o r d e r a n d i t s t h e r a p y . 715

 

S H O R T STATURE

Drug Administration

I n a d d i t i o n to t h e v a r i o u s intrinsic c a u s e s o f r e d u c e d hu ma n growth hormone secretion, certain m e d i c a t i o n s u s e d in treating hyperactivity, s u c h as m e t h y l p h e n i d a t e (Ritalin) h y d r o c h l o r i d e and d e x t r o a m p h e t a m i n e , m a y alter t h e normal r e g u l a t i o n of hGH s e c r e t i o n . 2 6 2 7 C h i l d r e n o f t e n s h o w a lowe r - t h a n - e x p e c t e d growth rate d u r i n g t h e f irs t few y e a r s after t r e a t me n t is b e g u n , b u t t o le r a n c e to t h e growth s u p p r e s s i o n seems to d e v e l o p in m a n y after several years. Similarly, glucocorticoids u s e d in treating certain diseases s u c h as a s t h m a , t h e n ephrot i c syndrome, j u v en i l e r h e u m a t o i d arthritis and l eukem i a ma y significantly retard grow t h. The g r o w t h - s u p p r e s s i n g e f f e c t s o f s t e r o i d s m a y be s e e n w i t h r e l a t i v e l y s m a l l d o s e s t h a t a r e o f t e n t h o u g h t t o be h a r m l e s s - t h a t i s , t h e p r o l o n g e d u s e o f t o p ic a l o i n t m e n t s , n a s a l s p r a y o r eye drops cont ai ni ng these c o m p o u n d s . 2 5 The lo ng - t e r m effects o f these and o t h e r d r u g s on growth and f i n a l a d u l t h e i g h t have n ot been established. Endocrine Disorders M a n y d i s t u r b a n c e s i n t h e e n d o c r i n e system c a n i m p a i r g r o w t h . 1 2 . 2 4 . 2 8 , 2 9 T h y r o i d h o r m o n e d e f i c i e n c y c a n r eess u l t i n either proport i on a t e o r d i s p r o p o r t i o nat e short stature, d e p e n d i n g on t h e d e g r e e of s e c o n d a r y e p i p h y s e a l d y s p l a s i a . Cu s h in g 's disease can lead to proportionate short stature si m i l a r to that s e e n w i t h t h e exogenous a d m i n i st ra t i on o f steroids.

E x c e s s g o n a d a l s t e r o i d s e c r e t i o n or t h e a d r e n o g e n i t a l s y n -

d r o m e c a n l e a d t o a c c e l e r a t i n g growth w i t h a d v a n c e d bone age in early c h i l d h o o d , b u t significant a dult short stature results due to premature c l o s u r e o f t h e e p i p h y s e s . T h e p r o t o t y p e of e n d o c r i n e s h o r t stature, o f c o u r s e , i s hGH deficiency. Growth h o r m o n e - r e l a t e d c a u s e s o f short stature can result from m a n y interruptions in the h y p o t h a l a m i c or pituitary peripheral tissue axis. The v a ri ous t y p e s o f p i t u i t a r y d w a r f i s m c a n be c l a s s i f i e d o n t h e b a s i s of t h e l e v e l o f t h e d e f e c t ; w h e t h e r i t i s g e n e t i c or a c q u i r e d a n d , i f g e n e t i c , t h e m o d e o f i n h e r i t a n c e ; w h e t h e r or n o t t h e r e i s a n o b v i o u s

l a r g e s e l l a t u r c i c a , l a t e r a l x - r a y f i l m s of t h e s k u l l m a y be s u f f i c i e n t t o d e t e c t an i n t r a c r a n i a l a n o m a l y . I n o t h e r d i s o r d e r s , h o w e v e r , such a s t h e h o l o p r o s e n c e p h a l y s y n d r o m e s a n d s e p t o o p t i c d y s p l a s i a , c o m p u t e d t o m o g r a p h y ( C T ) or magn e t i c resonance ( M R ) i m a g i n g o f t h e b r a i n a n d h y p o t h a l a m u s m a y be n e c e s s a r y t o d e t e c t t h e m a l f o r m a t i o n . T h u s , a n y

hGH-deficient child with malformations

of t h e f a c e or e y e s s h o u l d h a v e C T o r MR i m a g i n g o f t h e b r a i n a n d s e l l a t u r c i c a t o r u l e out a m a l f o r m a t i o n of t h e h y p o t h a l a m u s or p i t u i t a r y

gland.

Genetic Syndromes Associated

With

Pituitary Insufficiency

There a re a n u m b e r of g e n e t i c s y n d r o m e s , u n a s s o c i a t e d w i t h k n o w n d e v e l o p m e n t a l m a l f o r m a t i o n s of t h e h y p o t h a l amus o r p i t u i t a r y , t h a t h a v e p i t u i t a r y i n s u f f i c i e n c y a s a common c o m p o n e n t ( T a b l e 2 ) . 2 9 I n c e r t a i n o f t h e s e d i s o r d e r s , such a s h i s t i o c y t o s i s X a n d h e m o c h r o m a t o s i s , t h e h o r m o n a l d e f i c i e n c i e s have been f o u n d t o be d ue t o d e g e n e r a t i v e d i s e a s e of t h e h y p o t h a l a m u s a n d p i t u i t a r y . I n m o s t of t h e s e s y n d r o m e s , h o w e v e r , t h e p a t h o g e n e s i s of t h e p i t u i t a r y insufficiency is unknown. Both sickle cell anemia and t h a l a s s e m i a are a s s o c i a t e d w i t h d e l a y e d g r o w t h a nd s e x u a l d e v e l o p m e n t w i t h resultant adult short stature. In the thalassemias, this is apparently due to posttransfusion t h e r ap y resulting i n hemosiderosis a f f e c t i n g the p i t u i t a r y , whereas in person s w i t h s i c k l e c e l l a n e m i a t h e e x a c t c a u s e of t h e s h o r t s t a t u r e i s un known.

Idiopathic Hypopituitarism

g r o w t h hormone deficiency i s th e   i d i o p a t h i c t y p e - t h a t is, one in which no orga n ic lesion c an b e f o u n d . T h i s i s a h e t e r o g e n e o u s g r o u p o f d i s o r d e r s , h o w e v e r , t h a t c a n be c l a s s i f i e d o n t h e b a s i s of w h e t h e r o n l y g r o w t h h o r m o n e i s d e f i c i e n t or w h et h er t h e r e a r e m u l t i t r o p i c T h e commonest f o r m o f

d e v e l o p m e n t a l o r d e g e n e r a t i v e d i s e a s e of t h e h y p o t h a l a m u s or p i t u i t a r y ; w h e t h e r t h e p i t u i t a r y d e f i c i e n c y i s m o n o t r o p i c ( i s o l a t e d g r o w t h h o r m o n e d e f i c i e n c y ) or m u l t i t r o p i c , a n d , i n t h o s e c a s e s d ue t o a d e f e c t i n growth hormone a c t i o n , w h e t h e r s o m a t o m e d i n g e n e r a t i o n i s n o r m a l or d e f e c t i v e . Pituitary Insufficiency T h e m ost c o m m o n c a u s e s of a c q u i r e d p r e p u b e r t a l p i t u itary insufficiency a r e birth t r a u m a , cranial irradiation for n eopl a si a , c r a n i o p h a r y n g i o m a in which t h e e x p a n d i n g tumor m a s s c o m p r o m i s e s p i t u it it ar y f u n c t i o n a n d h e m o s i d e r o s i s f o l l o w i n g chronic transfusion therapy. In addition, trauma, surgical damage, infection and sarcoidosis can also lead to pituitary i n s u f f i c i e n c y . 2 Acquired

D e v e l o p m e n t a l A n o m a l i e s A s s o c i a t e d With P i t u i t a r y Insufficiency A n u m b e r o f d e v e l o p m e n t a l a n o m a l i e s of t h e h y p o t h a l a m u s a n d p i t u i t a r y r e s u l t i n h G H d e f i c i e n c y w i t h or w i t h o u t o t h e r tropic hormone deficiencies ( Tab l e 1 ) . 2 9 M a n y o f these s y n d r o m e s a r e a s s o c i a t e d w i t h f a c i a l or o pt ic a n o ma l i e s . I n ce emrpt ta iy n ds ei ls lo ar d se ry sn ,d rs ou mc eh , a s t cr oa nn gs es np ih te an lo ia dbasl e n ecnec eo pf ht ah le o pc iet lu ei t aar ny d, t w o r a r e s y n d r o m e s a s s o c i a t e d w i t h a n u n u s u a l l y s h a p e d or 16

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b r e e c h o r f o r c e p s d e l i v e r i e s , e a r l y v a g i n a l b l e e d i n g , p ro l o n g e d or u n u s u a l l y s h o r t l a b o r s f r e q u e n t l y o c c u r i n p e r s o n s w i t h h y p o p i t u i t a r i s m , as d o s i g n s o f i n t r a p a r t u m f e t a l d i s t r e s s or a n o x i a . I t h a s b e e n s u g g e s t e d t h a t t h e s e p e r i n a t a l i n s u l t s l e a d to t h e h y p o p i t u i t a r i s m . as

Multitropic Pituitary Hormone Deficiency Mu lt it r o p ic pituitary hormone d e ficie ncy (p a n h y p o p it u it a r y d w a r f i s m ) i s a s s o c i a t e d w i t h d e f i c i e n c y o f h G H a n d one or m o r e o f t h e o t h e r p i t u i t a r y t r o p i c h o r m o n e s . A l t h o u g h a g r e a t m a j o r i t y o f t h e c a s es ar e s p o r a d i c a n d t h o u g h t t o b e r e l a t e d t o p e r i n a t a l a n o x i a , a t l e a s t t wo g e n e t i c f o r m s o f t h e d i s e a s e have been described-autosomal r e c e s s i v e and X l i n k e d r e c e s s i v e . 2 9 T h e r e i s both i n t e r f a m i l i a l a n d i n t r a familial v a ri a t i on in t he a s s o c i a t e d hormonal deficiencies. In c e r t a i n f a m i l i e s , o n e p ers o n m i g h t l a c k a l l o f t h e t r o p i c h o r m o n e s , w h e r e a s a n o t h e r may l a c k o n l y h G H a n d g o n a d o t r o p i n s . A t l e a s t h G H a n d g o n a d o t r o p i n d e f i c i e n c y occur i n a l l a f f e c t e d m e m b e r s , h o w e v e r . T h e r e h a v e b e e n no f a m i l i a l crossovers b e t w e e n m u l t i t r o p i c p i t u i t a r y h o r m o n e d e f i c i e n c y a n d i s o l a t e d g r o w t h h o r m o n e d e f i c i e n c y y e t r e p o r t e d . No c l i n i c a l o r e n d o c r i n e d i f f e r e n c e s e x i s t b e t w e e n t h e t wo g e n e t i c f o rms of m u l t i t r o p i c p i t u i t a r y h o r m o n e d e f i c i e n c y a n d t h e m o r e common a c q u i r e d d i s e a s e , m a k i n g g e n e t i c c o u n s e l i n g d i f f i c u l t i n s p o r a d i c c a s e s . T h e c l i n i c a l f e a t u r e s o f t h i s synd r o m e d e p e n d on w h i c h of t h e t r o p i c h o r m o nes i s d e f i c i e n t . T h e b a s i c d e f e c t a p p ea rs t o l i e a t t h e h y p o t h a l a m i c , r a t h e r t h a n t h e p i t u i t a r y , l e v e l i n a b o u t t wo t h i r d s o f t h e c a s e s . Isolated Growth Hormone Deficiencies I sol a t ed growth hormone d e f i ci e nci e s ( I GHD ) w i t h otherwise normal pi t u i t ary f u n c t i o n result in p r o p o r t i o n a t e d w a r f i s m w i t h n o r m a l s e x u a l d e v e l o p m e n t . A l t h o u g h most persons w i t h h G H d e f i c i e n c y h a v e a f a i r l y t y p i c a l p h y s i c a l ap p earanc e w i t h c h a r a c t e r i s t i c m e t a b o l i c a b n o r m a l i t i e s , i t i s now a p p a r e n t t h a t o n t h e b a s i s o f c l i n i c a l , g e n e t i c , m o l e c u l a r a n d m e t a b o l i c v a r i a b i l i t y , IGHD i s a h e t e r o g e n e o u s group of disorders.

t y p e L . T h e most common f o r m o f

IGHD,

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(also referred I - B ) , i s i n h e r i t e d as a n a u t o s o m a l rec essi v e t r a i t and is a s s o c i a t e d with p r o p o r t i o n a t e dwarfism, i n c r e a s e d subcutaneous f a t , t y p i c a l pinched f a c e with h i g h t o as t y p e

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h o r m o n e d e f i c i e n c i e s , w h e t h e r i t i s g e n e t i c or a c q u i r e d , a n d , i f g e n e t i c , t h e m o d e o f i n h e r i t a n c e or w h e t h e r t h e g r o w t h h o r m o n e m o l e c u l e i s n o r m a l or a b n o r m a l . I n a d d i t i o n , t h e s e d i s o r d e r s must b e d i s t i n g u i s h e d f r o m t h e v a r i o u s f o r m s o f I G F or g r o w t h h o r m o n e r e s i s t a n c e . P e r i n a t a l p r o b l e m s s u c h

IGHD

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: ,;

f o r e h e a d , wr i n kl e d s k i n a n d h i g h - p i t c h e d v o i c e . 2 9 Persons w i t h t h i s d i s o r d e r may h a v e s p o n t a n e o u s h y p o g l y c e m i c e p i s o d e s i n i n f a n c y , b u t t h i s i s not a probl e m a f t e r e a r l y c h i l d hood, although they m ai ntai n hypersensitivity to exogenous insulin into a d u l t h o o d . As adults, abnormal g l u c o s e t o l e r a n c e a s s o c i a t e d w i t h i n s u l i n o p e n i a i s ch ar act e r is t ic. P u b e r t y occurs s p o n t a n e o u s l y b u t i s f r e q u e n t l y d e l a y e d t o t h e l a t e t e e n s or e a r l y t w e n t i e s . P u b e r t y f r e q u e n t l y a p p e a r s a b r u p t l y d u r i n g t h e f i r s t m o n t h s of h GH t h e r a p y , how e ve r . G r o w t h h o r m o n e r e l e a s e ha s b e e n d o c u m e n t e d f o l l o w i n g a d m i n i s t r a t i o n of growth h o r m o n e - r e l e a s i n g factor, and i m m u n o u l t r a s t r u c t u r a l studies have shown normal hGH-staining g r a n u l e s i n th e i t a r y g l a n d o f an a f f e c t e d p e r s o n , s u g g e s t i n g t h a t t h e bpaist iu cdefect in this disorder is at the h y p o t h a l a m i c , rather t h a n the pituitary, level.30 F u r t h e r m o r e , l i n k a g e studies u s i n g restrict i o n f r a g m e n t l e n g t h p o l y m o r p h i s m s of t h e g r o w t h h o r m o n e gene h a v e s h o w n a l a c k o f l i n k a g e b e t w e e n t h e h G H g e n e a n d type I

IGHD.3

type I- A. In 1971 I l l i g and co-workers d e s c r i b e d a o f g r o w t h h o r m o n e d e f i c i e n c y t h a t wa s f e l t t o b e d i s t i n c t type f r o m t y p e I on t h e b a s i s of a t o t a l l a c k of i m m u n o a c t i v e hG H a n d t h e appearance o f h i g h c o n c e n t r a t i o n s o f h G H a n t i b o d i e s

IGHD

f o l l o w i n g hGH t h e r a p y , r e n d e r i n g th e subjects resistant to h G H t h e r a p y . 3 2 T h i s s y n d r o m e w a s d e s c r i b e d i n an i n b r e d S w i s s k i n d r e d a n d w a s f e l t t o b e i n h e r i t e d a s an a u t o s o m a l r e c e s s i v e t r a i t . I t wa s s a i d to r e s u l t i n s h o r t n e s s a t b i r t h a n d even m o r e s e v e r e d w a r f i s m a n d e x a g g e r a t e d l y p i n c h e d f a c e s t h a n i n t h e m o r e common f o r m s o f h G H d e f i c i e n c y . D u r i n g h G H t h e r a p y , h o w e v e r , h G H a n t i b o d i e s d e v e l o p i n h i g h co n c e n t r a t i o n s , w h i c h suppress i t s growth-promoting effects. U si n g r e s t r i c t i o n e n d o n u c l e a s e a n a l y si s , P h i l l ip s a n d a s s o c i a t e s r e c e n t l y s t u d i e d n u c l e a r DNA f r o m f o u r cases o r i g i n a l l y r e p o r t e d by this Swiss group.'5 T h e y found t h a t t h e p a t i e n t s were h o m o z y g o u s f o r a d e l e t i o n o f a t l e a s t 7 . 5 k i l o b a s e s o f D N A . T h i s d e l e t i o n i n c l u d e d t h e g ene t h a t c o d e s f o r n o r m a l h G H ( h G H - N g e n e ) b u t n ot t h e v a r i a n t h G H ( h G H - V ) g e n e . T h e y h a v e r e c e n t l y r e p o r t e d t h e cases o f t h r e e s i b l i n g s f r o m a n A r g e n t i n e f a m i l y w i t h an a p p a r e n t l y i d e n t i c a l h G H - N d e l e t i o n wh o h a d s o m e m i n o r p h e n o t y p i c d i f f e r e n c e s f r o m t h e Swiss families.33 These d i f f e r e n c e s included t h e f act that o n l y one o f t h e p a t i e n t s h a d i n t r a u t e r i n e g r o w t h r e t a r d a t i o n w h e r e a s t h e o t h e r s h a d n o r m a l b i r t h w e i gh t a n d l e n g t h . F u r t h e r m o r e , a l t h o u g h hGH a n t i b o d i e s developed in all patients, g r o w t h p e r s i s t e d w i t h h G H t h e r a p y i n t wo o f t h e m . P h i l l i p s h a s r e c e n t l y found a n u m b e r of o t h e r p a t i e n t s of J a p a n e s e , I t a l i a n , A u s t r i a n a n d Spanish b a c k g r o u n d s w i t h t y p e I- A IG HD. 3 4 These last p at ie nt s ha d f u n c t i o n a l l y ide n tic a l d e l e 717

 

SHORT ST A T U R E

t i o n s of t h e hGH-N g e n e b u t , i n c o n t r a s t t o t h e S w i s s a n d Argentine p a t i e n t s , t h e d e l et i o ns w e r e e a c h p h y s i c a l l y s o m e w h a t d i f f e r e n t f r o m t h e o t h e r . Thus, ty pe I- A IGHD appears t o be a r e s u l t of a d e l e t i o n i n t h e h G H gene, w ith a r e s u l t a n t c o n g e n i t a l absence of normal hG H a n d a l a c k of immunotolera n c e t o h o m o l o g o u s hGH. T h i s w o u l d e x p l a i n t h e t o t a l a bs e n c e o f i m m u n o r e a c t i v e h G H a n d t h e p a t i e n t s ' h i g h a n t i bboo d y titers f o l l o w i n g hGH a d m i n i s t r a t i o n . I t i s of interest t h at a n u m b e r o f p a t i e n t s h a v e now b e e n d e s c r i b e d w i t h v a r i o u s m u t a t i o n s or o t h e r d e l e t i o n s i n t h e h G H g e n e c l u s t e r t h a t spare t h e hGH-N gene. T h e s e p a t i e n t s h a v e b e e n of n o r m a l h e i g h t a n d a r e otherwise c l i n i c a l l y n o r m a l but h a d c o m p l e t e a n t e n a t a l d e f i c i e n c y o f hCS p r o d u c t i o n . T h e s p a r i n g o f t h e hGH-V g e n e i n type I- A IGHD a n d i t s i n c l u s i o n i n t h e d e l e t i o n i n t h e s e f a m i l i e s i n d i c a t e s t h a t t h e hGH-V g e n e e x p r e s s i o n i s n o t necessary f o r e i t he r p r e na t a l or p o s t n a t a l growth. IGHD t y p e I I . IGHD type I I w a s f i r s t d e f i n e d a s a d i s t i n c t f o r m of h G H d e f i c i e n c y t h a t w a s a s s o c i a t e d w i t h i n c r e a s e d r a t h e r than decreased i n s u l i n response t o glucose a n d a r g i n i n e , a p p a r e n t l y i n h e r i t e d a s a n a u t o ssoo m a l d o m i n a n t t r a i t . 2 9 Th e s e persons d o n o t s e e m t o h a v e t h e w r i n k l e d s k i n or c h a r a c t e r i s t i c v o i c e s e e n i n o t h e r p i t u i t a r y d w a r f s . I t i s no w c l e a r t h a t t h e r e i s m o r e h e t e r o g e n e i t y i n t h e IGHD syn d r ome s than a s i m p l e d i v i s i o n in t o type I a nd type I I because t h e r e have been f am i l i es r e p o r t e d with apparent dominant inheritance h e roe cc el is ns ii cv ae l lfyo rr em s oe fm bt lh ee dwh i s eoa shea. v eO nt h et h me e ot ta hbeorl ihca nf de ,a t pu re er ss oonfs t wh t h o s e with type I IGHD ha v e been r e p o r t e d with f a m i l i a l a g g r e g a t i o n , s u g g e s t i n g autosomal d o m i n a n t i n h e r i t a n c e . Re s u l t s of p r e l i m i n a r y l i n k a g e s t u d i e s with r e s t r i c t i o n f r agment l e n g t h p o l y m o r p h i s m s of t h e h G H g e n e h a v e s u g g e s t e d t ha t i n cases of type I I I G H D , it i s t h e h G H g e n e it self t h a t i s i n v o l v e d . P h i l l i p s ha s p o s t u l a t e d t h a t a d o m i n a n t d i s o r d e r could be t h e r e s u lt of a mutation i n t h e s i g n a l p e p t i d e of t h e h G H g e n e a f f e c t i n g t h e i n t r a c e l l u l a r t r a n s f e r of t h e hormones.34

P i t u i t a r y D w a r f i s m With B i o l o g i c a l l y I n a c t i v e hG H In 1 9 7 8 s e v e r a l c a s e s w e r e d e s c r i b e d of p a t i e n t s w i t h t h e c l i n i c a l f e a t u r e s o f I G H D wh o a c h i e v e d n o r m a l p l a s m a i m m u n o r e a c t i v e h G H l e v e l s f o l l o w i n g s t i m u l a t i o n b u t wh o h a d l o w l e v e l s of I G F . 3 s Following h G H a d m i n i s t r a t i o n , h o w e v e r , t h e iy n g e n e r a t e d n o r rmaat le s I. 3G6 F l e v e l s a nf du nhc at di o an swa i g sn i fo it ch ae nr tt h e ir growth increase Pituitary wise normal. I t w a s p o s t u l a t e d that t h e s e persons s e c r e t e d a n a b n o r m a l g r o w t h h o r m o n e m o l e c u l e t h a t wa s b i o l o g i c a l l y i n a c t i v e but i m m u n o l o g i c a l l y c r o s s - r e a c t iv e . Valenta and c o ll e a g u e s h a v e r e c e n t l y r e p o r t e d t h e c a s e o f a p a t i e n t wh o h a d n or ma l l e v e l s of i mmu n or e a c t i v e h o r m o n e w it h d e c r e a s e d

r a d i o r e c e p t o r - a s s a y a b l e a nd b i o a s s a y a b l e a c t i v i t y . 3 7 This pat i e n t d i f f e r e d f r o m t h e o r i gi n a l p a ti e n ts noted a b o v e i n t ha t he

h a d a n o r m a l p l a s m a s o m a t o m e d i n l e v e l . W h en t r e a t e d w i t h a n e x o g e n o u s h G H , h o w e v e r , h i s r e s p o n s e wa s e x c e l l e n t . B i o c h e m i c a l a n a l y s i s of t h e p a t i e n t ' s s e r u m s h o w e d a s t r u c t u r a l a b n o r m a l i t y of t h e c i r c u l a t i n g growth hormone, with m o s t of t h e i m m u n o a c t i v e growth h o r m o n e m i g r a t i n g a s l a r g e m o l e c u l e s . T h e a u t h o r s c o n c l u d e d t h a t a b n o r m a l g r o w t h hormone s t r u c t u r e s h o u l d b e s u s p e c t e d i n c h i l d r e n w i t h s h o r t

hormone concenwh o h a v e a n o r m a l s e r u m ts rt aa tt iu orne, n o r m a l g r o w t h h o r m o n e r e sgproon ws te h t o t h e u s u a l s t i m u l i a n d n o r m a l p i t u i t a r y f u n c t i o n a n d wh o r e s p o n d r e a d i l y w i t h linear growth t o h u m a n growth hormone therapy . This raises 18

t h e q u e st i o n a s t o w h i c h s h o r t c h i l d r e n should h a v e trials with h G H . T h e b i o l o g i c a c t i v i t y of t h e c i r c u l a t i n g h o r m o n e i n t h e s e p a t i e n t s i s low, w h i c h c a n be e s t a b l i s h e d by determining t h e r a t i o of r a d i o r e c e p t o r - a s s a y a b l e t o r a d i oi mmu n oa ssa ya b l e ho r s p o i n t o u t t h a t a l o w IG F h o r m o n e o r b y b i o a s s a y . T h e a u t ho c o n c e n t r a t i o n i s n o t a d i a g n o s t i c p r e r e q u i s i t e of t h i s type of p i t u i t a r y d w a r f i s m , a s t h e i r p a t i e n t h a d n or ma l s e r u m l e v e l s of IG F. I t is l i k e l y t h a t various o t h e r forms of p i t u i t a r y dwarfism are associated with structural abnormalities in the growth h o r m o n e molecule. Ph illip s , however, could f i n d n o t r a c e o f a d e f e c t i n t h e h G H - N g e n e f o l l o w i n g c a r e f u l DNA a n a l y s i s i n s u c h a p a t i e n t . 3 4 He p o s t u l a t e s t h a t t h e h G H r e c e p t o r i n t h e l i v e r ma y b e i n v o l v e d , r a t h e r t h a n t h e h G H g e n e . S o m e of t h e s e p a t i e n t s h a v e h a d a d e l e t i o n o n c h r o m o s o m e 13 r a t h e r than on c h r o m o s o m e 17 on w h i c h t h e h G H g e n e i s l o c a t e d . F u r t h e r s t u d i e s w i l l be n e ed e d t o d o c u m e n t t h e d e f e ct in this disorder. X-Linked I sol at ed Growth H o nno ne D e f i c i e n c y a n d Hypogamnaglobulinemia-IGHD Type IX A kindr ed has been d e s c r i b e d i n w h i c h t w o b r o t h e r s a n d their tw o ma tern a l u n c l e s had a syndrome consi stent with hypogammaglobulinemia and isolated hGH deficiency.38 T h e y ha d p r o p o r t i o n a t e s h o r t stature, r e t a r d e d bone a ge i n c h i l d h o o d , d e l a y e d o n s e t of p u b e r t y , l a c k of p l a s m a h G H or et sh pe or nw si es ,e ln oo wr nbailo a psi st au yi at ab rl ye fa unn dc t ii mo nm .u n Roeacsusraryeanbt l ep u Il mG oFn aa rn yd infections were a problem in tw o patients, which w ere a b a t e d b y g a m m a g l o b u l i n t h e r a p y . T h r e e o f t h e p a t i e n t s h a d p a n hhyy p o g a m m a g l o b u l i n e m i a a nd a n a b s e n c e of c i r c u l a t i n g B c e l l s , whereas t h e o t h e r pa ti en ts ha d normal serum immunoglobulin ( I g ) A a n d Ig M l e v e l s a n d d e c r e a s e d l e v e l s o f c i r c u l a t i n g B cells. T - c e l l f u n c t i o n a nd n u m b e r w e r e normal. These pat i e n t s a p p e a r t o h a v e a d i s t i n c t X - linked r e c e s s i v e f o r m of isolated hGH d e f i ci e ncy a s s o c i a t e d with hypogammaglobulinemia.

Partial Growth Hormone Deficiency S e v e r a l a u t h o r s h a v e d e s c r i b e d cases of s h o r t c h i l d r e n with growth h o r m o ne responses a b ov e t h e u s u a l c u t o f f p o i n t f o r g r o w t h h o r m o n e d e f i c i e n c y ( 7 n g p e r m l ) , wh o h a v e e i t h e r m o d e s t r e s p o n s e s ( l e s s t h a n 1h0o rn gm opneer cmol n) c, e nltor wa t IG i o nFs loe vv ee rl s ,a d e c r e a s e d integrated growth 24-hour p e r i o d , a decr eas ed n u m b e r of h o r m o n e p e a k s or d e c r e a s e d responses f o l l o w i n g s l e e p . T h e common f a c t o r i n t h e s e c h i l d r e n w a s t h a t t h e y d i d not h a v e growth h o r m o n e d e ficie ncy but seemed to r e s p o n d t o growth hormone thera p y . 3 9 F u r t h e r m o r e , s om e of t h e s e c h i l d r e n r e v e r t e d to n o r m a l hGH responses t o p h a r m a c o l o g i c agents f o l l o w i n g e i t h e r pub e r t y or t h e a d m i n i s t r a t i o n of g o n a d a l s t e r o i d s . I t i s l i k e l y t h a t t h e r e i s a l a r g e n u m b e r of p a t i e n t s w i t h d i f f e r e n t f o r m s of p a r t i a l o r t r a n s i e n t g r o w t h h o r m o n e d e f i c i e n c y wh o m a y b e n efit from hG H t h e r a p y . An accurate d e s c r i p t i o n of t h e s e cases w i l l be of g r e a t importance o n c e u n l i m i t e d s u p p l i e s of g r o w t h hormone b eco m e available.

IG F D e f i c i e n c y o r R e s i s t a n c e

a t e dT hw ie t vh a dr ii om ui sn i fsohre md so ro fa bt sr ue en t p is teucirt ea tr iy o nd woafr gf ri os wm t ah r he oa rs ms oocni e-

a n d a s e c o n d a r y d e f i c i e n c y of I G F . Various s y n d r o m e s h a v e b e e n described in w h i c h g ro w th h o r m o n e s e c r e t i o n i s n o r m al EDD I CI C I NE NE THE WESTERN JOURNAL OF ME

 

S H O R T STATURE

t h e r e i s p e r i p h e r a l i n s e n s i t i v i t y t o t h e effects of g r o w t h h o r m o n e a d m i n i s t r a t i o n ; p l a s m a IG F l e v e l s a r e l o w a n d r e s p o n s i v e t o g r o w t h h o r m o n e a d m i n i s t r a t i o n or e l e v a t e d . Thus, t h e s e persons resemble p i t u i t ar y dwarfs clinic a l l y but a r e r e s i s t a n t t o t h e a c t i o n s of g r o w t h h o r m o n e because t h e y d o n o t g e n e r a t e or r e sp on d t o I G F . or h igh a n d

Laron

Dwarfism

Laron dwarfs c lin ic a lly resemble p a t ie n t s with is o la t e d

hhoGrHm odne ef i cc io en nc ec ny t reaxtci eo pn ts . 4f 0o 'r 4 ti h eT ihri sn oaruntaols oomra le l er ev ca et se sd i vg er oswytnhd r o m e w a s f i r s t d e s c r i b e d i n Asi a n J e w s b u t ha s s i n c e b e e n found i n nu m er o u s o t h e r e t h n i c groups. These p a t i e n t s h a ve t h e c l i n i c a l a p p e a r a n c e of p a t i e n t s w i t h IGHD t o a n exaggera t e d e xt e nt , with severe growth ret ard at i on, s e v e r e l y pinched faces, high-pitc hed vo ice s and , w hen m a l e , small genitalia. E a r l y d e v e l o p m e n t i s g e n e r a l l y s l o w , f o nt an el l e c l o su r e i s d e l a y e d a n d many h a v e s y m p t o m s o f h y p o g l y c e m i a . H a n d s a n d f e e t a re s m a l l a n d , l i k e p i t u i t a r y d w a r f s , t h e y a re ob ese a n d t h e b o d y p r o p o r t i o n s a r e c h i l d l i k e . T h e i r t e e t h ma y b e discolored, defective and crowded. V i s u a l and motor coordi n a t i o n a r e p o o r a n d t h e i r I Q s c o r e s a re t o w a r d s t h e l ow e r e n d o f t h e n o r m a l r a n g e . L a r o n h a s f o u n d t h a t t h e i r U/ L r a t i o s a r e more t h a n 2 s t a n d a r d d e v i a t i o n s above t h e mean, indicating

that their limbs

a re

relatively short. A f t e r puberty, their skin

Simiof l a r l y , s k ep lre et ma la taugree la yn da gt ei dm ,i nl gi koe ft ph ua bt e r t py i ta ur iet da er yl ad yw ea dr .f sG.l u c o s e i n t o l e r a n c e i s p r e s e n t i n a s s o c i a t i o n w it h s y m p t o m s of hyp oglycemia and h y p o i n s u l i n e m i a , as in pituitary d w a r f s . Plasma g r o w t h h o r m o n e l e v e l s , h o w e v e r , a re e l e v a t e d b u t suppress n o r m a l l y with g l u c o s e . P l a s m a I G F- I c o n c e n t r a t i o n s are l ow a n d d o n ot i n c r e a s e f o l l o w i n g g r o w t h h o r m o n e a d m i n i s t r a t i o n . T h e s e p a t i e n t s are r e s i s t a n t t o t h e g r o w t h - p r o m o t i n g e f f e c t s of h G H a d m i n i s t r a t i o n . appears

P l a s m a g r o w t h h o r m o n e a p p e a r s to be q u a l i t a t i v e l y n or ma l o n t h e b a s i s of s e r ia l i m m un o a s s a y d i l u t i o n s , e l e c t r o f o c u s i n g a n d m o l e c u l a r s i z e d i s t ri b u t i on . F u r t h e r m o r e , s u b s t ant i al q u a n t i t i e s of r e c e p t o r - a c t i v e h G H h a v e b e e n found by r a d i o r e c e p t o r a s s a y . Using a n e r y t h r o i d p r o g e n i t o r t e c h n i q u e , G o l d e a n d c o - w o r k e rrss f o u n d t h a t t h e r e wa s a s p e c i f i c cellular resistance to hGH in Laron d w a r f s . 4 2 F u r t h e r m o r e , it

h a d b e e n f o u n d t h a t l i v e r c eell l m i c r o s o m e s f r o m t h e s e p a t i e n t s d o not b i n d h GH n o r m a l l y , a l t h o u g h i n s u l i n do es bind normally . T h u s , t h e p at h o g e ne t ic mechanism in Laron dwarfism appears to i n v o l v e a defect in IG F generation, which is p r o b a b l y d ue t o a u ni v er sa l d ef e ct i n g r o w t h h o r m o n e receptors. 40,42 The

Afiican

Pygmies

T h e A f r i c a n p y g m i e s , wh o i n h a b i t t h e r a i n f o r e s t s o f A f -

r i ca, resemble pi t u i t ary dw ar f s i n s i z e a nd s ke le t a l proport i o n s b u t d o n ot h a v e t h e t r u n c a l o b e s i t y , p e c u l i a r f a c i e s a n d wr inkled s k i n of p i t u i t a r y d w a r f s . 2 8 ' 2 9 F o l l o w i n g i n s u l i n - i n d u c e d h y p o g l y c e m i a a n d a r g i n i n e i n f u s i o n , h G H I l e v e l s a re n o r m a l , but l i k e p a t i e n t s w i t h t y p e I I G H D , A f r i c a n p y g m i e s h a v e decreased i n s u l i n l e v e l s a n d are h y p e r s e n s i t i v e to t h e e f f e c t s of e x o g e n o u s i n s u l i n . T h e y a re c o m p l e t e l y unresponand sive to the lipolytic, n i n Fg p r o p e r t i e s o f h G H , a n di n si nu l ii nn i-ttira ol p is ct u d i e s , nbiit or ao sg se an y- ar eb tl ae i IG l e v e l s w e r e a p p a r e n t l y normal. T h e s e r e s u l t s l e a d to t h e s u g g e s t i o n t h a t t h e s h o r t stature of t h e p y g m i e s i s d u e to a p e r i p h JUNE 19 8 6

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144

*

6

e r a l unresponsiveness t o IGF. R e e x a m i n a t i o n of t h e s e blood samples with t h e n e w IG F immunoassays, however, in dic a te t h a t t h e p y g m i e s h a v e a p r i m a r y d e f i c i e n c y o f IG F I w i t h n o r m a l IG F I I . F u r t h e r m o r e , I G F l e v e l s d o n o t i n c r e a s e following growth h o r m o ne a d m i n i s t r a t i o n . Thus, s h o r t s t a t u r e o f t h e p y g m i e s ma y w e l l b e d u e t o a p r i m a r y d e f i c i e n c y o f IG F I . T h i s i s i n c o n t r a s t t o L a r o n d w a r f s wh o a r e u n a b l e t o g e n e r a t e e i t h e r IG F I o r I G F I I . A n u m b e r o f w h i t e p a t i e n t s w i t h s i m i l a r p r i m a r y d e f i c i e n c i e s o f IG F I h a v e b e e n i n i oc a l hl ya vae n dn om re mt aa ldb oe ls ic cr ai lb ley d , r es su eg mg be sl et i np gi t tu hi at ta rpy e rdswoanrsf ws hbou tc l wh l e v e l s o f i m m u n o a s s a y a b l e h G H s h o u l d h a v e t h e i r IG F l e v e l s and responsiveness to growth hormone carefully evaluated. IGF-Resistant Dwarfism

S e ve r al patients with p r o p o r t i o n a t e dwarfism have rec e n t l y b e e n d e s c r i b e d wh o h a v e e l e v a t e d I G F - I c o n c e n t r a t i o n s a n d n o r m a l o r e l e v a t e d l e v e l s o f c i r c u l a t i n g h G H . 4 4 IG F l e v e l s w e r e e l e v a t e d r e g a r d l e s s of w h e t h e r they w e r e assayed b y b i o a s s a y , r a d i o r e c e p t o r a ssss a y o r r a d i o i m m u n o a s s a y . I n a case d e s c r i b e d by Bierich a n d a s s o c i a t e s , bone a ge a nd d e n t a l e r u p t i o n we r e delayed a nd h yp o g l yc e m i a occurred during t h e p a t i e n t ' s f i r s t y e ar of l i f e , s i m i l a r t o t h e c a s e i n p i t u i t a r y d w a r f s . 4 5 Cultured skin f i b r o b l a s t s f r o m t h i s p a t i e n t s h o w e d a 5 0 d e c r e a s e i n IG F b i n d i n g , s u g g e s t i n g d e f e c t i v e I G F - I cause of Thus, tr oe cIeGp Ft o Ir as papse at rh es t o b e a b a ts hi ec Id eGf Fe c rte si in stt ha en sc ee .p a t i e n t s . r eW shi es tt ahnec re or n o t t h e r e i s a d i f f e r e n c e b e t w e e n those p a t i e n t s w i t h n o r m a l p l a s m a h G H l e v e l s a n d those w i t h e l e v a t e d p l a s m a g r o w t h hormone l e v e l s remains t o be answered.

Disproportionate Short Stature If a d i s p r o p o r t i o n a t e body h a b i t u s i s found on physical

e x a m i n a t i o n , then t h e p a t i e n t m o s t l i k e l y ha s a f o r m of s k e l e t al d y s p l a s i a . This i s a h e t e r o g e n e o u s gr o u p of i n h e r i t e d d i s o r d e r s of c o n n e c t i v e t i s su e i n w h i c h t h e c l i n i c a l f e a t u r e s a re u s u a l l y d o m i n a t e d by d w a r f i sm .4 6 W e l l o v e r 1 0 0 d i s t i n c t d i s o r d e r s h a v e now b e e n r e c o g n i z e d a n d i t i s i m p o r t a n t t o m a k e a s p e c i f i c d i a g n o s i s so t h a t a n accurate prognosis c a n be g iv en a n d proper g e n e t i c c o un s el i n g p r ov i d e d . Furthermore, e a c h of t h e s e d i s o r d e r s i s a s s o c i a t e d w i t h a v a r i e t y of s k e l e t a l n o n s k e l e t a l c o m p l i c a t i o n s , or b o t h , t h a t a n accurate d i a g n o s i s w i l l allow one t o anticipate, treat p r o m p t l y or p r e v e n t . T h e differen tia l d i a g n o s i s of d i s p r o p o r t i o n a t e d wa rfi sm r e q u i r e s t h a t v a r i o u s c l i n i c a l o b s e r v a t i o n s b e m a d e . Was t h e s h o r t e n i n g e v i d e n t a t b i r t h or d i d it b e g i n a t a l a t e r d a t e ? ( I n s o m e d i s o r d e r s , gr owt h m a y be no rm al f o r s e ve r al y e a r s . F or i n s t a n c e , i n t h e X - linked f o r m of s p o n d y l o e p i p h y s e a l d y s p l a s i a t a r d a , growth r e t a r d a t i o n i s not apparent u n t i l b e t w e e n 5 a n d 1 0 y e a r s o f a g e . ) A r e t h e l i m b s r e l a t i v e l y s h o r t compared with t h e t r u n k ( s h o r t - l i m b e d d w a r f i s m ) or i s t h e trunk p r i m a r i l y a f f e c t e d ( s h o r t - t r u n k d w a r f i s m ) ? M o s t of t h e s e d i s o r d e r s c a n be c l e a r l y c l a s s i f i e d i n t o o n e or t h e o t h e r f or ms of d i s p r o p o r t i o n . H o w e v e r , r e l a t i v e b o d y p r o p o r t i o n s ma y change with a ge i n s o m e d i s o r d e r s such as m e t a t r o p i c d y s p l a s i a i n w h i c h t h e lim bs are r e l a t i v e l y s h o r t a t b i r t h ; b ecau se of p r o g r e s s i v e k y p h o s c o l i o s i s , such p a t i e n t s b e c o m e s h o r t or

childhood. I f a c h i l d has short-limbed a r e a dl lu roifn tg h e s e g m e n t s o f t h e l i m b e q u a l l y s h o r t -

trunked d w a r f s

dwarfism,

e n e d or does t h e s h o r t e n i n g p r i m a r i l y a f f e c t t h e proximal ( r h i z o m e l i c ) , middle (mesomelic) or distal ( a c r o m e l i c ) seg719

 

S H O R T STATURE me n t s? I s t h e d i s o r d e r l i m i t e d t o t h e s k e l e t o n , or a re t h e r e e x t r a s k e l e t a l a b n o r m a l i t i e s such a s l i g a m e n t o u s laxity, j o i nt c o n t r a c t u r e s , m y o p i a , c l e f t p a l a t e , c l u b f o o t or h e a r i n g l o s s ? T h e p r e s e n c e or absence of t h e s e e x t r a s k e l e t a l c o m p l i c a t i o n s m a y be h e l p f u l i n m a k i n g a d i a g n o s i s . T h e f a m i l y h i s t o r y ma y a l s o b e h e l p f u l i n a r r i v i n g a t a d i a g n o s i s . F or e x a m p l e , i f t w o d w a r f e d s i b l i n g s a re born t o normal p a r e n t s , t h e n a c h o n d r o p l a s i a , w h i c h i s a n autosomal d o m i n a n t t r a i t , i s u n l i k e l y , a n d o n e should s u s p e c t a n auto-

Conclusions T h e w o r k u p of a s h o r t p a t i e n t i s a ve r y o r d e r l y a n d l o g i c a l e x e r c i s e . A f l o w c h a r t c a n be c o n s t r u c t e d t h a t e n a b l e s on e t o approach e v a l u a t i n g f or short stature in a s t e p w i s e manner, u l t i m at e l y e s t ab l i s hi n g a d i a g n o s i s ( F i g u r e 4 ) . F ir s t , t h e t w o common n o n p a t h o l o g i c f o r m s o f s h o r t s t a t u r e , f a m i l i a l s h o r t s t a t u r e a n d c o n s t i t u t i o n a l d e l a y , must be excluded by t a k i n g i n t o account t h e f a m i l y h i s t o r y both w i t h r e g a r d t o a b s o l u t e

gs eonmeat li c r eq cu ee ss st ii vo en s d im sao yr d eb re . s uTfhf ie c iae nn st wteor ms a tko e t ah ne s ae c cc ul ir na itcea ld iaa ng dn o s i s or t o l i m i t t h e d i a g n o s i s t o a r e l a t i v e l y s m a l l n u m b e r of d i s o r d e r s . F or e x a m p l e , a large head with b u l g i n g f o r e h e a d , m i d f a c e h y p o p l a s i a , lum bar g i b b u s , r h i z o m n e l i c s h o r t e n i n g of t h e e x t r e m i t i e s a nd t r i d e n t c o n f i g u r a t i o n of t h e fin g e r s s t r o n g l y s u g g e s t t h e d i a g n o s i s of a c h o n d r o p l a s i a . S i m i l a r l y , s h o r t l i mb s , p o l y d a c t y l y , c on ge n i t a l h e ar t d i s e a s e a n d o r a l frenula indicate a diagnosis of chondroectodermal dysplasia. I n m o s t c a s e s , h o w e v e r , f u r t h e r s t u d i e s a re r e q u i r e d t o m a k e a diagnosis. T h e next s t e p i s t o o b t a i n s k e l e t a l r a d i o g r a p h s . A s e r i e s of f i l m s i n c l ud i n g a n t e ro p o s te r i o r a n d l a t e r a l v i e w s of t h e s k u l l a n d s p i n e a n d a n t e r o p o s t e r i o r v i e w s of t h e p e l v i s a n d e x t r e m i ties s h o u l d be t a k e n . A t t e n t i o n should be p a i d t o t h e s p e c i f i c p a r t s of t h e s k e l e t o n t h a t a re i n v o l v e d ( s p i n e , l i m b s , p e l v i s ,

should be d e l a y e d t o about t h e s a m e e x t en t a s t h e h e i g h t a g e i n c o n s t i t u t i o n a l d e l a y , w h e r e a s it s h o u l d be n o r m a l f o r a g e i n f a m i l i a l s h o r t s t a t u r e . I n both c a s e s , t h e c h i l d r e n should h a v e n o evidence of o t h er d i s e as e a n d I G F l e v e l s should be normal. If pat hol ogi c short stature is established, proportionality must be d e t e r m i n e d . If t h e s h o r t e n i n g i s p r o p o r t i o n a t e a n d a p r en a ta l o n s e t i s f o u n d , t h e n t h o s e d i s o r d e r s w i t h i n t h e c a t e gory of i n t r a u t e r i n e g ro w th r e t a r d a t i o n , such a s t h e d ysmor p h i c syndromes, chromosomal ab norm al i t i es, intrauterine st b e c o n i n f e c t i o n a n d m a t e r n a l e x p o s u r e t o t e r a t o g e n s , m u st s i d e r e d . C h r o m o s o m e s t u d i e s a r e i n d i c a t e d i f t h e c h i l d ha s d y s m o r p h i c f e a t u r e s o r i s a g i r l w i t h a n u n d i a g n ooss e d f o r m o f p r o p o r t i o n a t e s h o r t s t at u r e . I f t h e o n s e t of t h e p r o p o r t i o n a t e dwarfism i s postn a ta l , t h e n e n d oc r i n e, m e t ab o l i c , p s y c h i a t r i c a n d n u t r i t i o n a l causes or c h r o n i c d i s e a s e s m u s t be c o n s i d e r e d . M e a s u r i n g I G F a n d t h y r o i d h o r m o n e l e v e l s ma y p r o v i d e a q u i c k sc reen in g t e s t , b u t p r o v o c a t i v e tests f or plasma hGH a n d s t u d y of t h e I G F a n d g r owt h r e s p o n s e t o e xog e n ou s h G H ma y b e r e q u i r e d t o m a k e a d i a g n o s i s . I f , o n t h e o t h e r h a n d , t h e i n i t i a l examination shows d i s p r o p o r t i o nat e dwarfism, th e c h i l d p r o b a b l y h a s on e of t h e s k e l e t a l d y s p l a s i a s a n d t h e

s( ke up li lp) h y as ni ds ,, mw ei tt ah pi hn y se ia sc ,h , d iwahp eh ry es i st h oe r aa bl ln ot rh mr ea el )i .t yB e ics a ul os ce a tt eh de s k e l e t a l r a d i o g r a p h i c f e a t u r e s i n m a n y of t h es e d i so rd e rs c h a n g e w i t h age, r e v i e w i n g ra diogra ph s ta ken at different ages w h e n possible is helpful. M o r e o v e r , the e p i p h y s e a l clos u r e , w h i c h occurs after p u b e r t y , f r e q u e n t l y o blit e r a t e s t h e specific a b n o r m a l i t i e s that would have permit t ed a specific d i a g n o s i s t o be m a d e h a d t h e f i l m s b e e n t a k e n b e f o r e p u b e r t y . N e v e r t h e l e s s , s k e l e t a l f i l m s a re o f t e n s u f f i c i e n t t o m a k e t h e d i a g n o s i s . I n d e e d , t h e c l a s s i f i c a t i o n of t h e s e d i s o r d e r s h a s been based p r i m a r i l y on t h e ir r a d i o g r a p h i c features. I n m a n y i n s t a n c e s , h o w e v e r , o n l y t h e g e n e r a l t y p e of d y s p l a s i a , such a s a s p o n d y l o e p i p h y s e a l d y s p l a s i a , c a n be r e c o g n i z e d , b u t t h e s p e c i f i c e n t i t y canno t be i d e n t i f i e d on r a di o gr a ph i c g r o u n d s alone. T h e m i c r o s c o p i c e v a l u a t i o n of g r o w t h - p l a t e c a r t i l a g e a n d of bone i s becoming a n p o r t i o n a t e s h o r t s t a t u rien. t4 e7 g rS ap le c pi af ri tc h i set vo ap lautahtoilnogg ifco r o rd i us lptrr oa -s t ru c t ur a l a l t e ra t i o ns h a v e b e e n r e c o g n i z e d i n p a t i e n t s w i t h c e r t a i n t y p e s of s k e l e t a l d y s p l a s i a , b y a u t o p s y s t u d i e s or by t h e e x a m i n a t i oonn o f b i o p s y s p e c i m e n s o b t a i n e d f r o m t h e i l i a c c r e s t , c o s t o c h o n d r a l j u n c t i o n or t i b i a l e p i p h y s i s . In c e r t a i n of t h e s e d is o r d e r s , such as t h a n a t o p h o r i c d y s p l a s i a , t h e p a t h o l o g i c a b n o r m a l i t y i s d i a g n o s t i c ; i n o t h e r s , it i s o nl y s u gg es tive. I n s t i l l o t h e r d y s p l a s i a s , n o obvious h i s t o l o g i c a b n o r m a l i t y c a n be f o u n d . B e c a u s e of t h e l a c k of e x p e r i e n c e of most m o r p h o l o g i s t s with such g r o w t h - p l a t e secti ons, t h e i r p r o c e s s i n g a n d e v a l u a t i o n should be d o n e i n one of t h e c e nt e rs dev o t ed t o t h e s t u d y of t h e s e d i s e a s e s . B i o c h e m i c a l s t u d i e s a r e of d i a g n o s t i c v a l u e i n o n l y a f e w of t h e s k e l e t a l d y s p l a s i a s , such as h y p o p h o s p h a t a s i a , t h e r a c h it ic d i s o r d e r s and t h e m uc o p o l y s a c c h a r i d o s e s . Various alterations i n t y p e I c o l l a g e n

ah na dv e i tn ios wl ibkeeel ny dt eh sa tc r si ib meidl ai rn cm aosleesc uo fl ao rs td ee of ge ec nt es s ii ns it my pp ee r fI eI c ct oal,l a g e n a n d t h e p r o t e o g l y c a n s w i l l be discovered i n o t h e r t y p e s of sk eleta l d y s p l a s i a i n t h e near f u t u r e . 4 8 20

h e i g h t and th e t i m e t a k e n to r e a c h that hei ght. Bone age

Short Stature

N o r ma l Variants

Pathologic

Familial short stature Constitutional delay

Proportionate

Disproportionate

Postnatal

Prenatal

IUGR syndromes

Psychosocial dwarfism hG H d e f i c i e n c y s y n d r o m e s

Chromosorne

disorders Intrauterine infections

hG H

or

Skeletal Dysplasias

IGF resistance

syndromes

Teratogens

Other endocrine disorders Malnutrition Chronic disease

Drugs

Figure 4.-Differential diagnosis

growt h h o r m o n e , IG F growth retardation

=

o f s h o r t s t a t u r e . hGH = h u m a n insulinlike g r o w t h factor, I U G R = intrauterine THE WESTERN J O U R N A L OF M E D I C I N E

 

SHORT S T A T U R E

w o r k u p w i l l be c o n s i d e r a b l y d i f f e r e n t . C a r e f u l a t t e n t i o n m us t be p a i d t o t h e c l i n i c a l a n d g e n e t i c f e a t u r e s , b u t t h e se d i s e as e s h a v e g e n e r a l l y b e e n d e f i n e d o n t h e b a s i s of t h e r a d i o g r a p h i c ch anges a n d , m o r e r e c e n t l y , h i s t o l o g i c f e a t u r e s . A full s e t of s k e l e t a l x - r a y f i lm s w il l be r e q u i r e d a n d , i n s o m e c a s e s a l s o , a n iliac c r e s t biopsy t o e s t a b l i s h t h e d i a g n o s i s . O n c e d i a g n o s i s i s m a d e , t h e f a m i l y m us t be g i v e n a c c u r a t e o r m a t i on on r e g ar d i n g t h e g e n e t i c c o u n s e l i n g , p r o g n o s t i c i n f or c o m p l i c a t i o n s of t h e d i s o r d e r a n d t h e i r t r e a t m e n t o r preven-

tt ii oo nn , ta hn ed ,p o s fs ii nb ai ll li yt,y oprs yl ca hc ok loofg ip co as ls i b ialni dt y os of c gi ar lo w tc oh u sntsiemlu il na gr e g a r d i n g t h e u p br br i n g i n g o f a d w a r f e d c h i l d a n d h o w t o a d j u s t b e s t t o t h e situation. These last problems a r e f r e q u e n t l y b e s t a p p ro ro a c h e d b y r e f e r r a l t o a l a y g r o u p , s u c h a s t h e L i t t l e P eo p le of A m e r i c a .

REFERENCES 1 . T an n er J M : P h y s i c a l growth a n d development, In Forfar JO, A m i l G C ( E d s ) :

Te xt book of P e d i a t r i c s . E d i n b u r g h , C h u r c h i l l L i v i n g s t o n e, 1 9 7 3 , p p 2 2 4 - 2 2 9

2 . Sm i th DW: G r o w t h a n d I t s D i s o r d e r s - M a j o r P r o bl e m s i n C l i n i c a l P e d i a t r i c s ,

15th

Ed .

P h i l a d e l p h i a , WB S a u n d e r s ,

1977

3 . C a r t e r C O , M a r s h a l l WA : T h e g e n e t i c s o f a d u l t s t a t u r e , I n F a l k n e r F , T a n n e r JM ( E d s ) : Human G r o w t h : P r i n c i p l e s a n d P r e n a t a l G r o w t h . N ew Y o r k , P l e n u m P r e s s ,

1 9 7 9 , pp 299-305

4 . S m i t h D W, T r u o g W, R o g e r s J E , e t a l : S h i f t i n g l i n e a r g r o w t h d u r i n g i n f a n c y : I l l u s t r a t i o n of g e n e t i c f a c t o r s i n g row th f rom fetal l i f e t h r o u g h i n f a n c y . J P e d i a t r 1976; 89:225-230

5 . National Center f o r Health S t a t i s t i c s : NCHS g ro w th c h a r t s , v o l 2 5 ( S u p p l t h a n d Human S e r v i c e s , 1 9 7 6 H A R ) : 7 6 . US D e p t H e a lt 6 . T a n n e r J M , W h i t e h o u s e R H , T a k a i s h i M: S t a n d a r d s f r o m b i r t h t o m a t u r i t y f o r h e i g h t , w e i g h t , h e i g h t v e l o c i t y a n d w e i g hhtt v e l oocc i t y : B r i tit i s h c h i l d r eenn , 1 9 6 5 - P a r t s I a n d I I . A r c h Di s Child 1 9 6 6 ; 4 1 : 4 5 4 - 4 7 1 , 6 1 3 - 6 3 5 7 . T a n n e r J M : Charts f or t he d i a g n o s i s of s h o r t s t a t u r e a n d l ow g r o w t h v e l o c i t y , allowance f o r

12:1-13

h e i g h t of p a r e n t s a n d p r e d i c t i o n of a d u l t h e i g h t . B i r t h D e f e c t s 1 9 7 6 ;

8. Bayley N, Pinneau SR: T a b l e s f or p r e d i c t i n g a d u l t h e i g h t from skeletal age r e v i s e d f o r u se w i t h t h e G r e u l i c h - P y l e h a n d s t a n d a r d . J P e d i a t r 1 9 5 2 ; 4 0 : 4 2 3 - 4 4 1 9 . T a n n e r J M , W h i t e h o u s e RH , M a r s h a l l W, e t a l : A s s e s s m e n t o f S k e l e t a l M a t u r i t y and P r e d i c t i o n ofAdult Height (T W 2). London, A c a d e m i c P r e s s , 1975 1 0. M c K u s i c k VA: H e r i t a b l e D i s o r d e r s ofConnective T i s s u e . St L o u i s , CV Mosb y , 1972

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2 5 . Z a c h m a n n M: D i a g n o s i s of t r e a t a b l e t y p e s of s h o r t a n d t a l l s t a t u r e . Postgrad M e dJ 1 9 7 8 ; 5 4 ( S u p p l 1 : 1 2 1 1 2 9 r s k og og D , F e v a n g F O , K l o v e H , e t a l : T h e e f f e c t o f t h e s t i m u l a n t d r u g s , 2 6 . A a rs t h y lp l p he h e n i d a te te o n s e c r e t i o n o f g r o w t h h o r m o n e i n h y p e r a c d e x t r o a m p h e t a m i n e a n d m e th tive children. J Ped i a tr 19 7 7 ; 90:136-139 2 7 . R o c h e A F , L i p m a n RS , O v e r a l l JE, e t al : T h e e f f e c t s of s t i m u l a n t m e d i c a t i o ns on t h e g row th of h y p e r k i n e t i c c h i l d r e n . P e d i a t r i c s 1979; 6 3 : 8 4 7 - 8 5 0 2 8 . R i m o i n D L , S c h i m k e RN : G e n e t i c D i so s o rrdd e r s o f t h e E n d o c r i n e G l a n d s . S t

L o u i s , CVMosby, 1 9 7 1 2 9 . R i m o i n D L : G e n e t i c d i s o r d e r s o f t h e p i t u i t a r y g l a n d , I n E m e r y AEH, R i m o i n D L ( E d ss)) : P r i n c i p l e s a n d P r a c t i c e o f M e d i c a l G e n e t i c s . E d i n b u r g h , C h u r c h i l l L i v i n g stone, 1 9 8 3 , pp 1 1 34-1151 3 0 . S c h e c h t e r J , K o v ac s K , R i m o i n D : I s o l a t e d g r o w t h h o r m o n e d e f i c i e n c y : I m m u n o c y t o c h e m i s t r y . J C l i n Endocrinol 1 9 8 4 ; 5 9 : 7 9 8 - 8 0 0 3 1 . P h i l l i p s JA I I I , P a r k s J S , H j e l l e B L , e t a l : G e n e t i c a n a l y s i s o f f a m i l i a l i s o l a t e d growth hormone d e f i c i e n c y type I. J C l i n I n v e s t 1982; 70:489-495 3 2 . I l l i g A , P r a d e r A , F e rr r r a nd nd e z M , e t a l : H e r e d i t a r y p r e n a t a l g r o w t h h o r m n o n e d e f i c i e n c y w i t h i n c r e a s e d t e n d e n c y t o g ro w th h o r m o n e a n t i b o d y f o r m a t i o n , A -t yp e of isolated growth hormone d e f i c i e n c y . Acta P e d i a t r Scand 1 9 7 1 ; 60:607 3 3 . R i v a r o l a M A , P h i l l i p s JA I I I , M i g e o n C J , e t a l : P h e n o t y p i c h e t e r o g e n e i t y i n f a m i l i a l i s o l a t e d growth hormnone d e f i c i e n c y type I - A . J Clin Endocrinol M e t a b 1 9 8 4 ; 59:34-40

3 4 . P h i l l i p s JA I I I : G e n e t i c d i a g n o s i s : D i f f e r e n t i a t i n g g r o w t h d i s o r d e r s . H o s p P r a c t 1 9 8 5 ; 20:85-114 35 . Kowarski AA, Schneider E , Ben - G alim V , et al : G ro w th failu r e with normal s e r u m RIA -G H a n d l o w s o m a t o m e d i n a c t i v i t y : S o m a t o m e d i n r e s t r i c t i o n a n d g r o w t h a c c e l e r a t i o n a f t e r e x o g e n o u s G H. J C l i n E n d o c r i n o l 1 9 7 8 ; 4 7 : 4 6 1 - 4 6 4 t e r Q L , K o w a r s k i A A : Human g r o w t h h o r m o n e t r e a t m e n t 3 6 . P l o t n i c k L P , V a n M e te o f c h i l d r e n w i t h g r o w t h f a i l u r e a n d n oorr ma ma l g r o w t h h o r m o n e l e v e l s b y i m m u n o a s s a y : L a c k of c o r r e l a t i o n with s o m a t o m e d i n g e n e r a t i o n . P e d i a t r i c s 1 9 8 3 ; 7 1 : 3 2 4 - 3 2 7 3 7 . V a l e n t a L I , S i g e l M B, L i s n i a k M A , e t a l : P i t u i t a r y d w a r f i s m i n a p a t i e n t w i t h c i r c u l a t i n g a b n o r m a l g r o w t h h o r m o n e p o l y m e r s . N E n g l J M ed 1 9 8 5 ; 3 1 2 : 2 1 4 - 2 1 7 3 8 . F l e i s h e r T A , W h i t e RM , B r o d e r S , e t a l : X - l i n k e d h y p o g a m n m a g l o b u l i n e m i a a n d i s o l a t e d g r o w t h h o r m o n e d e f i c i e n c y . N E n g l J M ed 1 9 8 0 ; 3 0 2 : 1 4 2 9 - 1 4 3 3 3 9 . R u d m a n D, K u t ne r M H, Blackston R D , e t a l : C h ildren wi t h nor m a l - va r i a nt a t m e nt n t w i t h h u m a n g r o w t h h o r m o n e f o r s i x m o n t h s . N E n g l J M ed s h o r t s t a t u r e : T r e at 1 9 8 1 ; 305:123-131 4 0 . L a r o n Z: A d v a n c e s i n I n t e m a l M e d ic i n e a n d P e d i a t r i c s . H e i d e l b e r g , S p r i n g e r V e r l a g , 1 9 8 4 , p 1 18 4 1 . L a r o n Z , K o w a d l o - S i l b e r g e l d A , E s h e t R, e t a l : G r o w t h h o r m o n e r e s i s t a n c e . An n C l i n R e s 1 9 8 0 ; 1 2 : 2 6 9 - 2 7 7 4 2 . G o l d e D W, B e r s c h N , K a p l a n S A , e t a l : P e r i p h e r a l u n r e s p o n s i v e n e s s to h u m a n g r o w t h h o r m o n e i n L a r o n d w a r f iiss m . N E n g l J M ed 1 9 8 0 ; 3 0 3 : 1 1 5 6 - 1 1 5 9 4 3 . M e r i m e e T i , Z a p f J, Froesch E R: I n s ul i n -l i ke growth f a c tors ( I G F ' s ) in p y g m i e s a n d s u b j e c t s w i t h t h e pygmy t r a i t : C h a r a c t e r i z a t i o n o f t h e m e t a b o l i c a c t i o n s o f IG F I and I G F II . J C l i n Endocrinol M e t a b 1 9 8 2 ; 55:1081- 1088 4 4 . L a n e s R, P l o t n i c k L P, P , S p en e n c e r EM , e t a l : D w a r f i s m a s s o c i a t e d w i t h n o r m a l and immunoass a y a b l e s o m a t o m e d i n . J C l i n iEn nc dr oe ca rs ie nd o bli oM aests aa by a b1 l9 e8 ,0 ;r e5 c0 e:p4t 8o 5r -a s4 s8a8y a b l e , 4 5 . B i e r i c h J R , M o e l l e r H , R a n k e M B, e t a l : P s e u d o p i t u i t a r y d w a r f i s m d u e to r e s i s t a n c e t o s o m a t o m e d i n : A ne w s y n d r o m e . E u r J P e d i a t r 1 9 8 4 ; 1 4 2 : 1 8 6 - 1 8 8 4 6 . R i m oi n DL, L a c h m a n RS: T he c h o n d r o d y s p l a s i a s , I n E me ry A E H , R i m oi n D L ( E d s ) : P r i n c i p l e s and P r a c t i c e of Medical G e n e t i c s . E d i n b u r g h , C h u r c h i l l L i v i n g s t o n e . 1983, pp 703-735 4 7 . S i l l e n c e D O , H o r t o n WA , R i m o i n D L : M o r p h o l o g i c s t u d i e s i n t h e s k e l ete t a l d y s p l a s i a s . AmJ P a t h o l 1 9 7 9 ; 9 6 : 8 1 1 - 8 7 0 48. Prockop D: Mutations i n t h e c o l l a g e n g e n e s- C on se q u e n c e s f o r rare a n d common d i s e a s e s . J C l i n I n v e s t 1 9 8 5 ; 7 5 : 7 8 3 - 7 8 7 serum growth hormone and

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