American Journal of Medical Genetics 23:221-226 (1986)

CEREBRAL GIGANTISM (SOTOS SYNDROME) I N TWO PATIENTS W I T H FRA(X) CHROMOSOMES

F r i t s A . Beemer, Henk Veenema and Johanna M . de P a t e r C l i n i c a l G e n e t i c s Cen te r U t r e c h t (FAB,JMdP) and C l i n i c a l G e n e t i c s C e n t e r Leiden ( H V ) , The Ne the r l ands

ABSTRACT

Two boys were s t u d i e d who had a l a r g e s ize a t b i r t h and /o r overgrowth, unusua l l e n g t h , l a r g e head c i r cumfe rence and minor anomal i e s , ma in ly fac ia l . T h e i r men ta l development appea red m i l d l y r e t a r d e d . A c l i n i c a l d i a g n o s i s of c e r e b r a l g igan t i sm ( S o t o s syndrome) was made. However, subsequen t chromosome s t u d i e s (medium 199, w i t h 5% f e t a l c a l f serum) showed f r a (X) (q27) i n 4 and 6% o f ce l l s , r e s p e c t i v e l y . These o b s e r v a t i o n s g i v e ev idence f o r g e n e t i c h e t e r o g e n e i t y i n c e r e b r a l g igan t i sm. Fra(X) s t u d i e s are recommended i n a l l cases o f c e r e b r a l g i g a n t i s m ( S o t o s syndrome).

INTRODUCTION

The main c h a r a c t e r i s t i c s of c e r e b r a l g i g a n t i s m ( S o t o s syndrome") have been w e l l d e f i n e d s i n c e i t s f i r s t

d e s c r i p t i o n ( S o t o s e t a1 ,1964) . Recen t ly a r ev iew on 22 cases was p u b l i s h e d ( W i t e t a1 ,1985) . C e r e b r a l g i g a n t i s m ( S o t o s "syndrome") is c h a r a c t e r i s e d by l a r g e s i z e a t b i r t h

' 1

Keywords: c e r e b r a l g i g a n t i s m , S o t o s syndrome, f r a ( X ) ( q 2 7 ) syndrome, X-linked men ta l r e t a r d a t i o n

Address r e p r i n t r e q u e s t s t o F r i t s A.Beemer, C l i n i c a l G e n e t i c s C e n t e r U t r e c h t , P.O.Box 18009, 3501 CA U t r e c h t , The Ne the r l ands .

0 1986 Alan R. Liss, Inc.

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and overgrowth, e s p e c i a l l y i n t h e f i r s t y e a r s o f l i f e , advanced growth i n l e n g t h , we igh t , s k u l l (OFC) c i r cumfe rence and bone age.There are minor anomal i e s i n c l u d i n g h i g h f o r e h e a d , f r o n t a l b o s s i n g , h y p e r t e l o r i s m , an t imong lo id s l a n t o f p a l p e b r a l f i s s u r e s , l a r g e ears, prominent jaw and high-arched p a l a t e . Many, bu t n o t a l l p a t i e n t s are m e n t a l l y r e t a r d e d . The d i a g n o s i s " c e r e b r a l g igan t i sm" ( S o t o s 11 syndrome") is ma in ly based on p h y s i c a l c h a r a c t e r i s t i c s . Up t o now n e i t h e r c o n s i s t e n t chromosomal n o r biochemical a b n o r m a l i t i e s have been r e p o r t e d . Only r e c e n t l y B u t l e r e t a1 (1985) and D i j k s t r a (1985) s u g g e s t e d t h a t metacarpophalangeal p a t t e r n p r o f i l e (MCPP) a n a l y s i s w i l l p r o v i d e more c o n c l u s i v e ev idence . Here w e r e p o r t on 2 cases w i t h a c l i n i c a l d i a g n o s i s of c e r e b r a l g i g a n t i s m ( S o t o s syndrome) i n whom chromosomal i n v e s t i g a t i o n s showed a f r a ( X ) chromosome.

Beemer, Veenema, and de Pater

CLINICAL REPORTS

P a t i e n t 1

WS w a s born a t term on Oct 18, 1984 as t h e first c h i l d o f h e a l t h y p a r e n t s who were second c o u s i n s . G e s t a t i o n and d e l i v e r y were normal. B i r t h weight was 4470 g , l e n g t h 57 c m ( b o t h above 9 7 t h c e n t i l e ) , OFC unknown. The p a r e n t s were slow l e a r n e r s i n pr imary s c h o o l . From b i r t h on p a t i e n t 1 vomited o f t e n and c r i e d a l o t . A t t h e a g e of 4 months he was admi t t ed because of a n a p n e i c s p e l l a f t e r vomit ing; EEG showed no s p e c i f i c a b n o r m a l i t i e s . The c h i l d was h y p e r a c t i v e ; h e had a l e n g t h of 67 c m , weight of 7250 g and OFC of 42 c m ( a l l above 9 7 t h c e n t i l e ) . He w a s d o l i c h o c e p h a l i c and had a h igh f o r e h e a d ( F i g . l ) , f r o n t a l b o s s i n g , a p p a r e n t h y p e r t e l o r i s m , l e f t ant imongoloid p a l p e b r a l f i s s u r e s l a n t , dep res sed b r i d g e of nose , a p p a r e n t l y l a r g e ears, prognathism, a high-arched p a l a t e , and a p p a r e n t l y l a r g e hands and feet . T e s t i c u l a r s i z e appeared normal f o r age . H i s motor development was r e t a r d e d . H i s muscle t o n e was reduced. CT-scan w a s normal. Bone a g e w a s n o t advanced then . A d i a g n o s i s o f c e r e b r a l g i g a n t i s m was made. Chromosome i n v e s t i g a t i o n s (TC medium 199 w i t h 5% f e t a l calf serum) showed 6% f ra (X) (q27) cells .

Cerebral Gigantism in Fra(X) Syndrome 223

Fig . 1. P a t i e n t 1 a t 4 months o f age .

P a t i e n t 2

MM was born on Feb.21, 1971 after a g e s t a t i o n complicated by toxemia. He w a s t h e f i r s t c h i l d o f h e a l t h y , u n r e l a t e d p a r e n t s who were 30 and 26 years o l d , r e s p e c t i v e l y . D e l i v e r y was a t term and normal. H i s b i r t h weight w a s 4730 g ( 9 7 t h c e n t i l e ) , l e n g t h 51 c m ( 5 0 t h c e n t i l e ) , OFC unknown. I n t h e f i r s t months o f l i f e h e had f e e d i n g d i f f i c u l t i e s due t o g e n e r a l i z e d hypotonia . A t 7 , 5 months h i s weight w a s 9180 g (50-75th c e n t i l e ) , l e n g t h 81 cm (above 97th c e n t i l e ) and OFC 48.5 cm (above 97th c e n t i l e ) . Bone a g e was 1 year i n advance. He had a h i g h f o r e h e a d , f r o n t a l boss ing , t e l e c a n t h u s , ant imongoloid s l a n t of p a l p e b r a l f i s s u r e s and a high-arched p a l a t e . H i s s k u l l was d o l i c h o c e p h a l i c ; h i s ears appeared l a r g e . H i s psychomotor development was r e t a r d e d l e a d i n g t o i n s t i t u t i o n a l i s a t i o n a t 4 y e a r s . A t t h a t t i m e c e r e b r a l g i g a n t i s m ( S o t o s syndrome) w a s diagnosed.

A t 1 4 y e a r s he w a s reexamined (F ig . 2 a ) . H i s h e i g h t w a s 166.5 c m ( 7 5 t h c e n t i l e ) , span 162.5, lower body segment 88 cm. H i s weight w a s 39.7 kg (10-25th c e n t i l e ) , OFC 53.2 c m . H i s hands were 17.3 c m (25th-50th c e n t i l e ) . I n n e r c a n t h a l d i s t a n c e appeared t o be 3.1 c m ( 5 0 t h c e n t i l e ) , i n t e r p u p i l l a r y d i s t a n c e 5.4 c m ( 2 5 t h c e n t i l e ) , o u t e r c a n t h a l d i s t a n c e 8 .4 c m (25th c e n t i l e ) . The o t h e r anomal ies were

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comparable t o t h o s e o f p a t i e n t 1. H i s testis volume was 4 m l . Chromosomal i n v e s t i g a t i o n showed 4% f r a ( X ) ( q 2 7 ) cel ls (TC B e s i d e s a normal b r o t h e r h e had a b r o t h e r who was m e n t a l l y r e t a r d e d , however, w i thou t unusua l growth c h a r a c t e r i s t i c s . Chromosomal i n v e s t i g a t i o n o f t h i s boy (Fig.2b) demonstrated 18% f r a ( X )

Beemer, Veenema, and de Pater

medium 199 w i t h 5% f e t a l c a l f serum).

Figs .2a ( l e f t , p a t i e n t 2 ) and 2b ( r i g h t , b r o t h e r o f p a t i e n t 2 )

(q27) p o s i t i v e ce l l s ; he h a s classic Mart in-Bel l syndrome.

DISCUSSION

The c l i n i c a l m a n i f e s t a t i o n s o f c e r e b r a l g i g a n t i s m are w e l l d e f i n e d (Wit e t a l , 1985) . Although t h e d i a g n o s i s is o f t e n made a t f i r s t g l a n c e , t h e minor f a c i a l anomal i e s p e r se are n o n s p e c i f i c . Reviewing t h e f a c e s o f t h e 22 p a t i e n t s i n t h e pape r by W i t e t a1 (1985) , many i m p o r t a n t d i f f e r e n c e s i n phenotype c a n be d i s c r i m i n a t e d , even i n p a t i e n t s w i t h a n i d e n t i c a l l i s t of symptoms. A s shown i n t h a t pape r , se r ia l photographs i n long-term follow-up show marked changes i n t h e i n d i v i d u a l phenotype. T h i s i s o b v i o u s i n t h e 2 cases who were fo l lowed f o r a l o n g p e r i o d o f t i m e . G e n e r a l l y , a

Cerebral Gigantism in Fra(X) Syndrome 225

d i a g n o s i s o f c e r e b r a l g i g a n t i s m depends on r a t h e r s u b j e c t i v e cri teria. Pe rhaps more o b j e c t i v e ev idence w i l l emerge from a n a l y s i n g metacarpophalangeal p a t t e r n p r o f i l e s (MCPP) ( B u t l e r e t a l , 1985; D i j k s t r a 1985) . However, a n a l y s i s a t v a r i o u s a g e s a p p e a r s t o be n e c e s s a r y ( D i j k s t r a 1985) . Mental r e t a r d a t i o n i s p r e s e n t i n many - though n o t a l l - p a t i e n t s . I f t h e d i a g n o s i s o f c e r e b r a l g i g a n t i s m h a s n o t been e s t a b l i s h e d b e f o r e a d o l e s c e n c e t h e men ta l r e t a r d a t i o n can be e a s i l y c o n s i d e r e d n o n - s p e c i f i c . Although by d e f i n i t i o n n o n s p e c i f i c r e t a r d a t i o n d o e s n o t show c o n s i s t e n t p h y s i c a l correlates, c a r e f u l examina t ion o f t e n d i s c o v e r s p h y s i c a l a b n o r m a l i t i e s and d e v i a t i o n s o f normal growth as h a s been c l e a r l y demonstrated by P a r t i n g t o n (1984) . He found a c h a r a c t e r i s t i c fac ia l appea rance w i t h l a r g e OFC, l a r g e ears and jaws t o be p r e s e n t i n 60-70% of f r a ( X ) p a t i e n t s , a l l symptoms being a l s o p r e s e n t i n c e r e b r a l g i g a n t i s m ( S o t o s syndrome). We a g r e e wi th Dr.J. O p i t z , as quo ted by B u t l e r e t a1 1985 when he sugges t ed t h a t ( q u o t e ) " c e r e b r a l g i g a n t i s m may be a sequence and n o t a syndrome. The p a t t e r n of m u l t i p l e anomal i e s i n c l u d i n g macrocephaly, c r a n i o f a c i a l a b n o r m a l i t i e s , men ta l r e t a r d a t i o n , language d e f i c i t s and l a r g e s ize may n o t b e a syndrome b u t , r a t h e r , be d e r i v e d from a s i n g l e anomaly such a s a n e n l a r g e d cerebrum" (end o f q u o t e ) . We s u g g e s t t h a t i n c e r e b r a l g i g a n t i s m a c e r t a i n number o f cases may show up w i t h f r a ( X ) chromosomes. T h i s cou ld e x p l a i n a t l eas t i n p a r t t h e male preponderance i n S o t o s syndrome (Smith, 1982) . A s a consequence, f r a ( X ) s t u d i e s are schedu led i n a l l p a t i e n t s w i t h c e r e b r a l g i g a n t i s m ( S o t o s syndrome) known t o us .

ACKNOWLEDGEMENTS We wish t o thank D r s . J . B . Bylsma, W.Croughs and J . J .P .

van de Kamp f o r h e l p f u l h i n t s and r e f e r r a l o f t h e p a t i e n t s and R . van d e r Hors t and G.Korthof f o r c y t o t e c h n o l o g i c a l c o l l a b o r a t i o n .

REFERENCES

Bale AE, D r u m M A , P a r r y DM, M u l v i h i l l JJ (1985) :Fami l i a l S o t o s syndrome ( C e r e b r a l g i g a n t i s m ) : C r a n i o f a c i a l and p s y c h o l o g i c a l c h a r a c t e r i s t i c s . A m J Med Genet 20:613-624

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B u t l e r MG,Meaney F J , K i t t u r S , Hersh J H , H o r n s t e i n L(1985): Metacarpophalangeal p a t t e r n p r o f i l e a n a l y s i s i n S o t o s syndrome. Am J Med Genet 20:625-629.

Metacarpophalangeal p a t t e r n p r o f i l e s . F o r t s c h r Ron tgens t r

P a r t i n g t o n MW (1984): The f r a g i l e X syndrome 1 I : P r e l i m i n a r y Am J Med Genet

Smith DW (1982) :"Recognizable P a t t e r n s i n Human Malformation". 3rd ed. P h i l a d e l p h i a , Saunders , pp 122.

S o t o s J F , Dodge PR, Muirhead D , Crawford J D , T a l b o t NB (1964): C e r e b r a l g i g a n t i s m i n ch i ldhood : A syndrome of e x c e s s i v e l y r a p i d growth w i t h ac romega l i c f e a t u r e s and a non p r o g r e s s i v e n e u r o l o g i c a l d i s o r d e r . N Engl J Med 271:

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D i j k s t r a PF (1985): C e r e b r a l g i g a n t i s m ( S o t o s ' syndrome).

143~183-185.

d a t a on growth and development i n males. 17:175-194.

109-1 16. W i t J M , Beemer FA, B a r t h PG, Oorthuys JWE, D i j k s t r a PF, Van

den Brande J L , Leschot N J (1985): C e r e b r a l g i g a n t i s m ( S o t o s syndrome). Compiled d a t a of 22 cases. A n a l y s i s o f c l i n i c a l f e a t u r e s , growth and plasma somatomedin. Eur J P e d i a t r 144:131-141.

Edited by John M. Opitz and James F. Reynolds

Received for publication September 17, 1985; revision received September 30, 1985.