11
ROGER, P. CANLORBE, P. BORNICHE::, M. CASTANIE*:
and
R . S C H O L L E ~ . Fondation de Recherche en Hormonologie
M.
.4
12
F. LORENZEN+, S.PANG+,
M.I.NEW,
B.DUPONT+, M.POLLACK~
D.cHoW).,
and L.S.LEVINE+,
C o r n e l l U n i v e r s i t y Medical
H. SCHEDEWIE, M.J. ELDERS*, V. MACLEOD*, & L. DEFTOS*
Dept. P e d i a t r i c s , University o f Arkansas Medical Sci.
L i t t l e Rock, AR., & VA Hospital, La J o l l a , CA.
Parathormone and c a l c i t o n i n i n the pathogenesis o f neonatal
hypocal cemia
Hypocalcemia (HOC) i s comnon i n i n f a n t s o f d i a b e t i c mothers
(IDM), premature newborns (NB), and asphyxiated i n f a n t s . I n
addition, i t i s m r e frequent i n boys than i n g i r l s . To invest i g a t e the cause o f HOC, we have measured serum calcium, RIAparathormone (PTH), and c a l c i t o n i n (CT) i n IDM, premature, and
asphyxiated NB during the f i r s t week o f l i f e . These subjects
were compared to healthy term i n f a n t s as w e l l as a group o f neonates w i t h documented HOC ( C a q 7.5 mp/dl ). Mean PTH and CT concentrations were s i m i l a r i n both sexes and i n vaginal (n=188)
and cesarean section d e l i v e r i e s ( 1 2 4 ) , and there was no d i f f e r ence between small ( 1 8 ) . appropriate (144), and l a r g e ( 4 2 ) for
date term NB. Serum PTH i n premature NB, however, was s i g n i f i c a n t l y lower (p<0.05) and CT concentrations were higher (p<0.01)
than i n term NB. IDM had low PTH l e v e l s (p<0.05), but CT concentrations were not d i f f e r e n t from controls. Asphyxiated
i n f a n t s had both, elevated PTH and CT l e v e l s (p<0.01). Mean
PTH concentrations i n hypocalcemic NB were not d i f f e r e n t from
controls, but CT l e v e l s were higher than i n any o t h e r i n f a n t
group (p<0.001). These data suggest t h a t hypercalcitoninemia
and hypoparathyroidism alone may cause HOC, but t h a t the r i s k
o f HOC i s p a r t i c u l a r l y high i n i n f a n t s w i t h combined hypoparathyroidism and hypercalci toninemia.
15
C o l l e g e and S l o a n - K e t t e r i n g I n s t i t u t e , New York, USA.
S t u d i e s of t h e 17-desoxy, 17-hydroxy, and C19 androgens i n conj u n c t i o n w i t h c o n g e n i t a l a d r e n a l h y p e r p l a s i a (21 -OH d e f i c i e n c y ) .
Honnonal r e s p o n s e t o 6 h o u r ACTH s t i m u l a t i o n was d e t e r m i n e d i n
24 s i b s p r e d i c t e d t o b e heterozygous c a r r i e r s o f t h e gene f o r
21-OH-def. by HLA genotyping and 14 p a r e n t s , o b l i g a t e h e t e r o z y g o t e s . Confirming t h e f i n d i n g s of Grosse-Wilde, e t a 1 (Inmunog e n e t i c s , 8:41, 1979) i n p r e - p u b e r t a l c h i l d r e n and post-pubert a l m a l e s p r e d i c t e d t o b e h e t e r o z y g o u s c a r r i e r s of t h e gene
based on HLP genotyping, t h e mean 17-OH-P l e v e l s (13, 1 7 ng/ml
r e s p e c t i v e l y ) were s i g n i f i c a n t l y h i g h e r (p<.OOl) t h a n i n t h e
c o n t r o l c h i l d r e n and a d u l t s (3.9, 5.3 ng/ml r e s p e c t i v e l y ) . I n
post-menarchal f e m a l e s t h e mean 17-CYI-P r e s p o n s e i n t h e h e t e r o z y g o t e s (12.1 ng/ml) was s i g n i f i c a n t l y h i g h e r ( ~ 4 . 0 0 5 ) t h a n i n
t h e g e n e r a l p o p u l a t i o n (5.2 ng/ml); however t h e o v e r l a p p i n g
v a l u e s d i d n o t p e r m i t a c l e a r d i f f e r e n t i a t i o n o f t h e hormonal
r e s p o n s e s i n t h e s e two groups. Plasma ACTH l e v e l s and a l l
o t h e r ACTH s t i m u l a t e d s t e r o i d s i n c l u d i n g 17-OH pregnenolone,
11-desoxycortisol, c o r t i s o l , p r o g e s t e r o n e , DOC, B, a l d o s t e r o n e ,
A-4-androstenedione, dehydroepiandrosterone, and t e s t o s t e r o n e
whether a n a l y z e d a l o n e o r i n combination d i d n o t d i s c r i m i n a t e
between t h e c o n t r o l p o p u l a t i o n and t h e h e t e r o z y g o t e s . I n summary, i n s i b s p r e d i c t e d t o b e h e t e r o z y g o u s by HLP g e n o t y p i n g
and o b l i g a t e h e t e r o z y g o t e p a r e n t s , m i l d 21 h y d r o x l a s e d e f i c i e n cy was e x p r e s s e d i n t h e 1 7 hydroxy pathway b u t was n o t e v i d e n t
i n t h e 17-desoxy pathway o r C1g androgens a f t e r ACTH s t i m u l a t i o n .
.
V . PUCHOLT, J . S . FITZSIMMONS, M.A. REYNOLDS,
K . GELSTHORPE ( I n t r . b y W. T e l l e r ) .
City
Hospital, Nottingham, C h i l d r e n ' s Hospital and
N.B.T.S.
Sheffield,England.
Location o f t h e s e n e f o r 21-hydroxylase d e f i c i e n c y
W e h a v e s t u d i e d 3 4 f a m i l i e s - i n whom t h e propositus
h a d CAH a n d c o n f i r m t h e o r i g i n a l o b s e r v a t i o n ( 1 ) t h a t
t h e g e n e r e s p o n s i b l e i s c l o s e l y r e l a t e d t o t h e HLA
l o c i . I n one f a m i l y t h e p a t e r n a l HLA a n t i g e n s w e r e A l
B8, B 3 7 , DRW5 a n d t h e maternal a n t i g e n s A3, A9,CW3,CWS
8 1 2 , 8 4 0 , DRW1, DRW5.
Two a f f e c t e d d a u g h t e r s h a d A l ,
A3, CW3, B8, B 4 0 , DRW1, DRW5 a n d A l , A 3 , CW3, B 8 , B 4 0 ,
DRW5.
F r o m t h e s e r e s u l t s we d e d u c e t h e h a p l o t y p e s o f
t h e f a m i l y t o b e : f a t h e r A l l B 8 , DRW5/Al1 B 3 7 , DRW5;
m o t h e r A3, CW3, B 4 0 , DRWl/A9, CW5, B 1 2 , DRW5; f i r s t
d a u g h t e r A l , B 8 , DRW5/A3, CW3, 8 4 0 , DRW1; s e c o n d
These
d a u g h t e r A l , B8, DRWS/A3, CW3, B 4 0 , DRW5.
findings a r e explicable on t h e b a s i s o f recombination
E a r l i e r work
b e t w e e n t h e B a n d DR l o c i i n t h e m o t h e r .
( 2 ) h a d l o c a t e d t h e gene r e s p o n s i b l e f o r 2 1 - h y d r o x y l a s e d e f i c i e n c y t o l i e between l o c u s A a n d t h e GLO
l o c u s . CONCLUSION: T h e p r e s e n t r e s u l t s n a r r o w t h e
locus o f t h e 2 1 - h y d r o x y l a s e d e f i c i e n c y g e n e t o b e t w e e n
t h e A a n d DR l o c i o f t h e major h i s t o c o m p a t i b i l i t y
r e g i o n o n chromosome 6 .
16
13
1.
D u p o n t , B.
2.
Levine,
L.S.
al.
Lancet,
2.New
1977,
1978,
299,
K.ZUPPINGER,U.WIESMANN,H.P.SIEGRIST,T.SCHAEFER,
H . P .SCHWARZ&N.HERSCHKOWITZ,Department o f P e d i a t r i c s
U n i v e r s i t y o f Bern,Switzerland
E f f e c t o f g l u c o s e d e p r i v a t i o n on s u l f a t i d e s y n t h e s i s i n
d i s s o c i a t e d b r a i n c e l l c u l t u r e s o f newborn mice.
S u l f a t i d e s y n t h e s i s (SFS) i n b r a i n c e l l s i s a . m a r k e r f o r c e l l
d i f f e r e n t i a t i o n . SFS was measured by i n c o r p o r a t i o n o f 35504
i n t o s u l f a t i d e i n c u l t u r e d b r a i n c e l l s o f newborn mice a t
1 3 days i n c u l t u r e a f t e r exposure t o v a r i o u s g l u c o s e conc e n t r a t i o n s f o r t h e preceding 7 2 h r s . T h i s a g e range c o r r e s ponds t o an i n vivo developmental s t a g e o f r a p i d m y e l i n a t i o n .
Glucose e x t r a c t i o n f r . o m t h e medium d u r i n g t h e f i r s t 24hrs
was independent from t h e i n i t i a l g l u c o s e l e v e l down t o 1 m M .
Thus t h e d u r a t i o n o f s e v e r e g l u c o s e d e f i c i e n c y (below ImH)
was r e l a t e d t o t h e i n i t i a l g l u c c s e supply. SFS was p r o g r e s s i v e l y reduced with i n c r e a s i n g d u r a t i o n o f s e v e r e g l u c o s e
d e p r i v a t i o n r e a c h i n g 3.5% o f c o n t r o l s a f t e r 48hrs o f g l u c o s e
d e f i c i e n c y . I n t h e c e l l homogenates t h e s u l f a t i d e s y n t h e t i z i n g enzyme c e r e b r o s i d e s u l f o t r a n s f e r a s e was s i m i l a r l y reduced f o l l o w i n g g l u c o s e d e p l e t i o n keeping a r e s i d u a l a c t i v i t y o f 10%. T h i s i n d i c a t e s t h a t a l a c k o f p r e c u r s o r s o r subs t r a t e s was n o t t h e o n l y cause o f SFS r e d u c t i o n . Replenishment o f g l u c o s e s t o r e s i n t h e medium a f t e r a s t a r v a t i o n peri o d o f l 4 h r s o n l y f a i l e d t o r e c o v e r SFS. Reexposure o f g l u c o s e deprived c e l l s t o g l u c o s e even l e d t o a f u r t h e r dec r e a s e of' SFS s u g g e s t i n g a p o s s i b l e t o x i c e f f e c t o f g l u c o s e
on b r a i n c e l l s p r e v i o u s l y damaged by g l u c o s e d e p l e t i o n .
2, 1 3 0 9 .
E n g l J Med.
G.F.RONDANINI*,F.BUSETTO',G.PELLEGRIS*o,~~.T.ILLENI*o
and G.CHIUMELL0. Dpt. o f P e d i a t r i c s , Endocrine U n i t ,
U n i ~ e r s i t y o f M i 1 a n ; ~ N a t i o n aCancer
l
Inst.,Milan , I t a l y .
Linkage between HLA a n t i g e n s and o b e s i t y .
WeperformedHLAtypingin122obese c h i l d r e n , 4 7 w i t h a h i s t o r y
o f f a m i l i a l o b e s i t y and 75 with a n e g a t i v e h i s t o r y . The c o n t r o l
group c o n s i s t e d o f 905 s u b j e c t s , w i t h o u t f a m i l y r e l a t i o n w i t h
p a t i e n t s , l i v i n g i n t h e same g e o g r a p h i c a l a r e a . O u r r e s u l t s show:
1 ) i n t h e 47 p a t i e n t s w i t h f a m i l i a l o b e s i t y a s i g n i f i c a n t i n c r e a s e
i n HLA 813 a n t i g e n a s compared t o c o n t r o l s ( p < . 0 5 ) , w i t h a
r e l a t i v e r i s k of 3.45; 2 ) i n t h e 75 p a t i e n t s w i t h o u t a h i s t o r y o f
f a m i l i a l o b e s i t y a s i g n i f i c a n t f a l l i n HLA A2 a n t i g e n ( p < .OR)
a s c o m p a r e d t o c o n t r o l s . 3 ) A l l obese p a t i e n t s evidenced a h i g h l y
s i g n i f i c a n t i n c r e a s e i n HLA -A and -B b l a n k s a s compared t o
c o n t r o l s , t h e i n c r e a s e b e i n g h i g h e r f o r l o c u s A ( c h i square=17.83,
p<.0001) than f o r l o c u s B ( c h i square=9.20, p < . 0 0 3 ) . T h i s seems
t o s u p p o r t t h e h y p o t h e s i s t h a t a t l e a s t i n a number of p a t i e n t s
h e r e d i t a r y p r e d i s p o s i t i o n p l a y s an important r o l e i n t h e
a e t i o l o g y o f o b e s i t y and t o i n d i c a t e t h a t such p r e d i s p o s i t i o n
i n v o l v e s genes c o n t r o l l e d by t h e HLA chromosomic r e g i o n . The
h i g h e r frequency of b l a n k s i n obese s u b j e c t s might be connected
w i t h a diminished phenotypic e x p r e s s i o n of HLA a n t i g e n s o r w i t h
t h e p r e s e n c e i n t h e serum o f obese p a t i e n t s of a HLA a n t i g e n s
masking f a c t o r .
and H d p i t a l Saint-Vincent-de-Paul, P a r i s , France.
T e s t o s t e r o n e (T) d e c r e a s e a f t e r ACTH : a g l u c o c o r t i c o i d mediated
process.
I n a p r e v i o u s r e p o r t (ESPE 1977, a b s t . 67) it was shown t h a t
i n boys a t p u b e r t a l s t a g e ( P ) 2, T l e v e l s were s i g n i f i c a n t l y r e duced by dexamethasone (DXM). As T p r o d u c t i o n a t P2 may b e b o t h
from a d r e n a l and gonadal s o u r c e s , t h e s i g n i f i c a n c e o f this i n h i b i t i o n was f u r t h e r i n v e s t i g a t e d i n advanced p u b e r t a l s t a g e s .
20 boys a t P2 and 15 boys a t P3-4 were s t u d i e d a f t e r informed
c o n s e n t o f p a r e n t s . At P2, T morning l e v e l s ( j i f sem) b e f o r e DXM,
a f t e r 1 mg DXM g i v e n a t 9 p.m. and 60 mn a f t e r Synacthen 250 pg
/ m 2 , were r e s p e c t i v e l y i n nmol/l : 2.7 f 0.46, 1 . 5 ?. 0.27, 1.5 f
0.31 ( p < 0 . 0 0 2 ) . At P3-4 T l e v e l s were reduced by DXM from 9.8
f 1 . 1 t o 6 . 6 f 1.0 ( p < 0.01) and f u r t h e r reduced a f t e r Synacthen
up t o 4.9 f 0.9 ( p = 0 . 0 2 ) . I n n i n e a d u l t male v o l u n t e e r s morning
T l e v e l s were reduced from 21 f 1.7 t o 18 f 1.7 ( p = 0.05) by DXM
( 3 mg x 3 d a y s ) . 5000 I U hCG g i v e n i n t r a m u s c u l a r l y under DXM
t r e a t m e n t induced a r e s p o n s e n o t d i f f e r i n g from c o n t r o l group (34
f 1.7, 30 f 2.1, p > 0 . 1 0 ) . These f i n d i n g s s u p p o r t t h e conception
t h a t ACTH induced i n h i b i t i o n of T p r o d u c t i o n i s mediated by g l u c o c o r t i c o i d s . The e f f e c t of DXM seems t o be d o s e - r e l a t e d s i n c e i n
boys w i t h l a r g e r body s i z e (P3-4). Synacthen induced a f u r t h e r
d e c r e a s e o f T, b u t n o t i n boys a t P2 where i n h i b i t i o n i s maximal
w i t h t h e same DXM dosage. The u n a l t e r e d r e s p o n s i v e n e s s t o hCG i n
a d u l t does n o t s u p p o r t an i n h i b i t o r y e f f e c t o f DXM upon LH a c t i o n
on Leydig c e l l s .
911
1186