A RING D CHROMOSOME IN ASSOCIATION WITH DOWN'S
SYNDROME-LIKE PHENOTYPE
A . WAJNTAL*; A . J . D I A M E N T * * ; P . H . SALDANHA*
T h e first ring c h r o m o s o m e w a s described by Morgan (1933) 9
and ori-ginated f r o m a crossing-over b e t w e e n a t t a c h e d X - c h r o m o s o m e s containing an inversion in Drosophila. Since then ring chromosome have been studied specially in Drosophila, m a i s e and Man. I n t e r e s t on ring c h r o m o s o m e s arises from the f a c t t h a t s o m e information m a y be disclosed regarding m e -c h a n i s m of -chromatid splitting during mitosis and meiosis as w e l l as on sister-strand crossing-over (McClintock, 1 9 3 87
; S m i t h W h i t e et al., 1 9 6 31 0 ) . In man, ring c h r o m o s o m e s m i g h t be valuable in assigning loci to specific chromosomes not only because of the original deletion involved in the for-mation of the ring but also because of t h e deficiencies and duplications t h a t m i g h t arise during mitotic divisions (Lejeune, 1967) 6
. Thus, studying patients w i t h a ring D chromosome, the locus t h a t determines t h e s y n t h e s i s of the alpha chain of haptoglobin has been s h o w n to belong to t h e chromosome 13 (Gerald et al.4
, 1967; B l o o m et al.2
, 1967).
T h e present paper reports on a p a t i e n t w i t h Down's syndrome-like characteristics a n d w h o s e caryotype analysis revealed a m o s a i c i s m involving a ring D chromosome.
CASE R E P O R T
S . F . B . , w h i t e f e m a l e born on 6-1-1959, a d m i t t e d a t t h e Clinical H o s p i t a l of t h e U n i v e r s i t y of S ã o P a u l o in 20-6-65. She w a s t h e e i g h t h p r e g n a n c y of a sibship w i t h 4 b r o t h e r s and 3 sisters b e i n g all h e a l t h y , e x c e p t t h e third p r e g n a n c y t h a t w a s a m a l e stillbirth. T h e p a r e n t s are not r e l a t e d and, a t birth, her f a t h e r w a s 44 a n d h e r m o t h e r 34 years old. T h e course and l e n g h t of p r e g n a n c y w e r e n o r m a l . D e l i v e r y w a s u n r e m a r k a b l e . B i r t h w e i g h t w a s 1.800 g. N e u r o m o t o r d e v e l o p m e n t during child-hood w a s a p p a r e n t l y normal, a c c o r d i n g to h e r mother's i n f o r m a t i o n . A t c l i n i c a l admission, b e c a u s e of t h e m o n g o l o i d a s p e c t of her face, t h e p a t i e n t w a s referred for n e u r o l o g i c a l a n d g e n e t i c a l studies. T h e p a t i e n t w a s r e e x a m i n e d w h e n s h e w a s ten y e a r s old and h e r p h o t o g r a p h s t a k e n a t t h a t t i m e are s h o w n in fig. 1. T h e r e w a s l i g h t t y m p a n i c sound by c r a n i a l p e r c u s s i o n and e v o l u t i o n a l d y s l a l i a . P h y s i c a l r e e x a m i n a t i o n at 11 y e a r s of a g e r e v e a l e d h e i g h t 1.60 m, w e i g h t 4 4 . 5 kg, s p a n 1 . 5 7 m, microcephaly, nose f l a t t e n i n g , b i l a t e r a l e p i c a n t h u s , h i g h a r c h e d p a l a t e , b i l a -teral s t r a b i s m u s , t h o r a c i c ciphosis, l o m b a r lordosis, acne, l i g h t breast d e v e l o p m e n t , ulna r d e f l e c t i o n of hands, l i g h t radial r o t a t i o n ( c l i n o d a c t y l y ) of t h u m b s , l o n g fingers
* L a b o r a t ó r i o d e G e n é t i c a M é d i c a e * * D e p a r t a m e n t o d e N e u r o p s i q u i a t r i a , F a c u l d a d e d e M e d i c i n a , U n i v e r s i d a d e d e S ã o P a u l o .
Aknowledgements — T h e a u t h o r s a r e d e e p l y i n d e b t e d t o M r s . T i y o T. M a t s u o ,
r e s e m b l i n g a r a c n o d a c t y l y , a b s e n c e of pubic hair, and confirmed e v o l u t i o n a l d y s l a l i a and a u d i t o r y deficit. Vertebral and h a n d X - r a y s e x a m i n a t i o n s w e r e normal. Mastoid a n d p y r a m i d a l X - r a y films s u g g e s t e d b i l a t e r a l i n c r e a s e d l u m e n of t h e inner a c o u s t i c d u c t s and m a s t o i d a l p n e u m a t i z a t i o n . S k u l l X - r a y films w e r e n o r m a l e x c e p t for v e i l i n g of r i g h t a n t r o m a x i l l a and a s s y m e t r y of r i g h t r e t r o - p y r a m i d a l bone ( m a x i l l a r s i n u s o p a t h y ) . P s y c h o l o g i c a l e x a m i n a t i o n ( G o o d e n o u g h and T e r m a n - M e r r i l l ) indicated IQ = 57 w i t h childish l a n g u a g e . S e r u m protein electrophoresis s h o w e d r e l a t i v e and a b s o l u t e d e c r e a s e of a l p h a g l o b u l i n . I s h i h a r a t e s t s r e v e a l e d n o r m a l color vision. R e d cell G6PD a c t i v i t y w a s a l s o n o r m a l ( 7 . 4 U . C l . B t y p e ) .
Chromosome and dermatoglyphic studies — C h r o m o s o m e s t u d y w a s carried o u t
by a modified m e t h o d based on Moorhead e t al. (1960) s
: 0 . 1 m l of h e p a r i n i z e d peripheral blood w e r e c u l t u r e d in 60% of H a n k s s a l i n e s u p p l e m e n t e d w i t h 20% of a 2 . 5 % l a c t o a l b u m i n h i d r o l i s a t e s o l u t i o n , 20% of calf serum, 0 . 5 % P h y t o c l i n *, 0 . 0 0 1 % glicose and a n t i b i o t i c s . T h e c u l t u r e s w e r e i n c u b a t e d for 96 hours, t r e a t e d w i t h l x 1 0 -7
M Colcemid (Ciba) and s l i d e s prepared by t h e air d r y i n g m e t h o d . B u c c a l s m e a r s for s e x c h r o m a t i n s t u d i e s w e r e fixed in 1:1 e t h a n o - 1 : e t h e r and F e u l g e n stained. D e r m a t o g l y p h i c s w e r e t a k e n by s t a n d a r d ink m e t h o d .
Chromosome a n a l y s i s of 30 m e t a p h a s e p l a t e s r e v e a l e d 28 c e l l s w i t h 46 c h r o m o -s o m e -s a n d n o r m a l f e m a l e c o n -s t i t u t i o n (fig. 2) a n d 2 c e l l -s w i t h 46 c h o r o m o -s o m e -s a n d o n e c h r o m o s o m e m i s s i n g in t h e D group (1313) w i t h t h e e x t r a c r o m o s o m e s h o w -i n g a r -i n g - l -i k e a p p e a r e n c e (f-ig. 3 ) . Scor-ing for r-ing c h r o m o s o m e s -in 60 c e l l s of a second c u l t u r e r e v e a l e d 8 r i n g - b e a r i n g c e l l s g i v i n g a t o t a l of 10 r i n g c e l l s in
90 m i t o s e s . It w a s not found c e l l s w i t h t w o ring c h r o m o s o m e s o r c e l l s w i t h 5 D c h r o m o s o m e s w i t h o u t a n y ring. T h e 10 r i n g c h r o m o s o m e s w e r e of a u n i f o r m s i z e a n d in t h e r a n g e of n o r m a l D c h r o m o s o m e s (fig. 4 ) .
T h e p a t i e n t h a d a n o r m a l n u c l e a r s e x w i t h 20% of p o s i t i v e s e x - c h r o m a t i n n u c l e i . There w e r e s o m e a b n o r m a l i t i e s in t h e d e r m a l r i d g e s : t h e r e w e r e a r a d i a l loop o n R2
, u l n a r loops on R3
, J?4
, R°, L* and L5
D I S C U S S I O N
T h e clinical findings regarding 16 patients h a v i n g a D-ring c h r o m o s o m e
have been r e v i e w e d by Alderdice e t a l .
1(1969). Most of the parents of such
children w e r e b e l o w 25 years old at birth t i m e of the affected child s u g g e s t i n g
t h a t parental age a t t i m e of conception is not an important factor in t h e
origin of this chromosome aberration. T h e m o s t c o m m o n defects correlated
w i t h ring D c h r o m o s o m e a r e : microcephaly, large ears, epicanthic folds, ocular
hipertelorism, micrognathia, high arched palate, abnormalities of external
genitalia, congenital heart defects. T h e variability b e t w e e n the different cases
m i g h t be due to either different chromosomes involved in the D group, or
to deletions and duplications involved in the different ring chromosomes.
T h o u g h only 1 1 % of the calls carried a ring chromosome and the size
of the rings is in the size range of a normal D chromosome, the patient's
phenotype is suficiently abnormal to be included in a m o n g o l i s m study. As a
m a t t e r of fact, t h e patient has m o s t of t h e m a i n diagnostic characteristics
for Down's s y n d r o m e : m e n t a l deficiency, microcephaly, epicanthic folds, small
and low set ears, high arched palate, atipical palmar creases, clinodactyly
of the 5th finger, displaced axial triradiis, increased distance b e t w e e n h a l u x
and second toe. T h e patient did not h a v e a protuberant scrotal tongue, short
bulky neck, hipoplastic nasal bone, short hand and feet, short s t a t u r e or a
typical mongoloid facies.
T h e clinical features of this patient w e r e similar to those described by
J a c o b s e n
5(1966) and E m b e r g e r et a l .
3(1971). All other cases of ring D
chromosome w e r e associated w i t h a m u c h m o r e deviant phenotype. B o t h
cases w e r e disclosed to have the chromosome 15 involved in the ring formation.
T h e replication pattern of the ring chromosome from patients h e r e w i t h
des-cribed has not been studied yet. As this patient has a low frequency of cells
carrying the ring chromosome (11%) it is rather difficult to establish w h e t h e r
the minor deviations involved are consequence of a mosaicism w i t h a majority
of normal cells or t h e y are specific for rings involving chromosome 15.
U n l e s s it is a s s u m e d that part of a G chromosome is included in the
ring formation, w h a t s e e m s very unlikely, this case calls attention by t h e
f a c t t h a t the s a m e abnormalities m i g h t be c o m m o n to different chromosome
aberrations. W h e t h e r this indicated that the normal phenotype for the
abnor-malities involved is conditioned by a large number of genes spread out on
different chromosomes or alternatively, t h a t the particular abnormalities
m i g h t be caused by genie imbalance, c o m m o n to any chromosomal aberration,
is still an open question that will be a n s w e r e d only after more is k n o w n on
t h e correlation b e t w e e n different chromosomal aberrations and the phenotypes
abnormalities involved.
S U M M A R Y
r e p o r t e d . T h e c l i n i c a l f e a t u r e s of t h e p a t i e n t w e r e c o n s i d e r e d s i m i l a r t o t h o s e
d e s c r i b e d b y J a c o b s e n (1966) a n d E m b e r g e r e t a l . (1971) w h o i n t e r p r e t e d
t h e r i n g c h r o m o s o m e p r e s e n t in t h e i r p a t i e n t s a s b e i n g c h r o m o s o m e 15.
R E S U M O
R e l a t a - s e u m c a s o d e u m a m e n i n a c o m 10 a n o s d e i d a d e , m e n t a l m e n t e
r e t a r d a d a e c o m s e m e l h a n ç a s c o m a s í n d r o m e d e D o w n , c u j a a n á l i s e c r o m o s s ô ¬
m i c a r e v e l o u u m m o s a i c i s m o p o u c o f r e q ü e n t e , i n c l u i n d o 1 0 % d e m i t o s e s c o m
u m c r o m o s s o m a e m a n e l s u b s t i t u i n d o u m c r o m o s s o m a D . O q u a d r o clínico
d a p a c i e n t e é s i m i l a r a o d e s c r i t o p o r J a c o b s e n (1966) e E m b e r g e r e t a l . (1971)
q u e i n t e r p r e t a r a m a p r e s e n ç a do c r o m o s s o m a e m a n e l e m s e u s p a c i e n t e s c o m o
s e n d o o c r o m o s s o m a 1 5 .
R E F E R Ê N C I A S
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8 . M O O R H E A D , P . S.; N O W E L L , P . C.; M E L L M A N , W. J . ; B A T T I P S , D . M . & H U N G E R F O R D , D . A. — C h r o m o s o m e p r e p a r a t i o n s of l e u k o c y t e s c u l t u r e d f r o m h u m a n p e r i p h e r a l blood. E x p t . Cell. R e s . 2 0 : 6 1 3 , 1960.
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