Eur J Pediatr (1992) 151 : 586-589

EuropeanJournalof

Pediatrics

9 Springer-Verlag 1992

Robinow syndrome in two siblings from consanguineous parents D. F. Schorderet 1, S. D a h o u n 1, I. Defrance 2, D. Nussl6 3, and M. A. Morris ~ Departments of i Microbiology and Genetics, : Paediatrics, 3P aediatric Radiology, University of Geneva and H6pital cantonal Universitaire, 9, ave de Champel, CH-1211 Geneva, Switzerland Received August 7, 1991 / Accepted after revision January 13, 1992

Abstract. A K u r d i s h f a m i l y h a d two c h i l d r e n a f f e c t e d with R o b i n o w s y n d r o m e . T h e d a u g h t e r h a d s h o r t stature, m a c r o c e p h a l y , h y p e r t e l o r i s m , h e p a t o s p l e n o m e g a l y , short forearms and marked vertebral anomalies. Her b r o t h e r h a d hypertelorism, h y p e r t r o p h i e d alveolar ridges, h e p a t o s p l e n o m e g a l y , s h o r t f o r e a r m s , rib a n o m a l y a n d a m b i g u o u s genitalia. T h e k a r y o t y p e o f t h e a f f e c t e d m a l e sibling s h o w e d m o s a i c i s m for 45X, 4 6 , X , d i c Y ( q 1 1 . 2 2 ) , 47,X, d i c Y ( q l l . 22) ,dicY(q11.22).

Key words: R o b i n o w s y n d r o m e - A u t o s o m a l recessive occurrence - Chromosomal abnormalities - Y chromosome

Introduction I n 1969, R o b i n o w et al. d e s c r i b e d f o u r cases of a n e w l y r e c o g n i z e d s y n d r o m e c h a r a c t e r i z e d b y m e s o m e l i c dwarfism, g e n i t a l a m b i g u i t y a n d p e c u l i a r facies ( " f e t a l f a c e " ) [13]. A l t h o u g h it was s u g g e s t e d a n d s h o w n in s o m e instances t h a t this d i s o r d e r was d o m i n a n t l y i n h e r i t e d [1, 8, 13, 18, 20, 23], m o s t cases s e e m to b e s p o r a d i c [1, 4, 21, 23]. A n a u t o s o m a l recessive m o d e has also b e e n p r o p o s e d [5, 11, 14, 19, 22]. W e d e s c r i b e h e r e two f u r t h e r cases o f a u t o s o m a l recessive R o b i n o w s y n d r o m e in a K u r d i s h family f r o m T u r k e y w h o s e m a l e child has a 45X,46,X,dicY(q11.22),47,X,dicY(qll.22),dicY(q11.22) karyotype.

Case reports Case 1 She was the female product of an uneventful pregnancy. The parents, 1.83 cm and 1.57 cm tall respectively, are first cousins through their mothers and are of Kurdish origin. The baby girl was 2 years 3 months old when we first examined her. Her height, weight and head circumference were 72cm ( - 5 S D ) , 10kg ( - 1 . 8 S D ) and 49.5 cm (+0.7 SD) respectively. The physical examination revealed pronounced dwarfism with severe scoliosis and deformation of the thoracic cage. Her facies was round and characterized by frontal Offprint requests to: D. E Schorderet

Fig. 1. Male and female sibs with their mother

bossing, hypertelorism (5.5cm; > 97th percentile), bilateral epicanthus, flat nasal root and macrostomia (Fig. 1). Her head seemed macrocephalic when compared to the rest of the body, although measurements were normal. The neck was short, and the thorax grossly deformed with scoliosis, marked lordosis and reduced ampliation. No heart murmurs were recorded. There was a marked hepatosplenomegaly. The genitalia were normal for age. The forearm was short on both sides. The hands were small, with short fingers and bilateral simian creases. The 5th fingers showed brachymesophalangia and clinodactyly; nails were normal. Neurological development was normal. Radiological studies. The head was brachycephalic with an abnormal cervico-occipital junction and hypoplastic axis. The spine showed gross malformations with hemi- and fused vertebrae and marked scoliosis (Fig. 2a, b). The limbs presented mild shortening of the humerus. The radius and, to some extend the ulna, were hypoplastic on both sides. The metacarpals were reduced in length. (Fig. 2c). Brachymesophalangia and clinodactyly of the 5th fingers were confirmed. The metatarsals and the toes were also short. Both femurs and tibiae were shorter than normal. Osseous maturation was slightly delayed. Exact measurements were taken and showed the following values: humerus: 10.9 cm (mean: 13.7; normal range: 12.6-14.9); ulna: 7.9cm (mean: 11.3; normal range: 9.8-12.4); radius: 6.8cm (mean: 10.1,; normal range: 8.7-11.1);

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Fig. 3. Case 2, X-ray films, a Thorax with bifid rib (3rd right). b Mesomelic shortening of the upper limb with fused metacarpals

Radiological examination. The head was brachycephalic. The Fig. 2. Case 1, X-ray films, a Numerous vertebral anomalies with marked scoliosis, b Fused cervical vertebrae, c Mesomelic shortening of the upper limb

femur: 16.0cm (mean: 19.0; normal range: 17.0-20.0); tibia: 12.7cm (mean: 15.4; normal range 13.7-16.4) [10].

spine was normal. One bifurcation was found at the anterior segment of the 3rd rib of the right side (Fig. 3a). The upper limbs showed mesomelic shortening. The hands had fused carpal bones with short metacarpals and short fingers (Fig. 3b). The lower limbs were also shorter than normal but without asymmetry between the femora and the tibiae. Osseous maturation was slightly delayed for age. The length of the long bones were: humerus: 10.0 cm (mean: 10.5, normal range: 9.4-11.6); ulna: 8cm (mean: 9.08; normal range: 8.5-10.3); radius: 7.2cm (mean: 8.2; normal range: 7.69.3); femur: 12.5 cm (mean 13.5, normal range: 12.8-14.9, tibia: 9.5 cm (mean: 10.8; normal range: 9.9-12.2).

Karyotype 46,XX.

Case 2 He was the younger brother and only sibling of case 1 (Fig. 1). He was examined at 9 months of age because of sexual ambiguity. His height, weight and head circumference were all at - 1 SD. The face was round, with frontal bossing and hypertelorism (5.1 cm; 97th percentile). The mouth was large and showed hypertrophied alveolar ridges. The thorax was normal and there was no heart murmur nor scoliosis. Pronounced hepatosplenomegaly was found on abdominal palpation. The external genitalia were ambiguous with a short penis, shawl scrotum and penile hypospadias. The right testis was palpable at the inguinal level, the left was absent. The hands were short and the limbs did not appear grossly reduced. Neurological development was normal.

Karyotype Three abnormal cell populations were found in the peripheral blood: 62% of the 60 tested cells were 45,X; 33% presented one dicentric Y chromosome 46,X,dicY(q11.22), and 5% had two dicentric Y chromosomes 47,X,dic Y(q11.22), dic Y(q11.22) (Fig. 4). Extensive biochemical and serological investigations were performed in order to explain the hepatosplenomegaly found in both siblings, with no significant findings.

Discussion T h e R o b i n o w s y n d r o m e , also k n o w n as t h e fetal face s y n d r o m e , is n o w a w e l l - e s t a b l i s h e d e n t i t y . I t is c h a r a c t e r i z e d b y m e s o m e l i c d w a r f i s m , a s s o c i a t e d w i t h facial a n o m a l i e s ( h y p e r t e l o r i s m , flat a n d r o u n d facies), v e r t e -

588

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Y dic Y ( q l 1 . 2 2 ) Fig. 4. Karyotype showing Y chromosomes from the affected male sib and from his father and diagram of normal and dicentric chromosomes. (GTG, G-banding; CBG, C-banding; QFG, Q-banding)

bral and rib defects, and hypoplastic genitalia. The literature has recently been reviewed by Butler and Wadlington [2]. The description of the two cases presented here fits well with the diagnosis of Robinow syndrome. The association of mesomelic dwarfism, hypertelorism, vertebral anomalies and hypoplastic genitalia is rare enough so that this diagnosis could be made. In addition, the dysmorphic features of these two patients were entered in S Y N D R O C , an expert system in dysmorphology [17]. The program listed Robinow syndrome as the most probable diagnosis in both search algorithms. It is, however, possible that some parts of the phenotype found in the boy, especially the ambiguous genitalia, are due to the abnormal Y chromosome and that case 2 does not have Robinow syndrome. When a rare disorder occurs in a consanguineous family there is an a priori assumption that its mode of inheritance is recessive. This supposition is probably correct in this case for several families with autosomal recessive inheritance have been reported. Delineation of a recessive or dominant form is not trivial because it bears important consequences at the counselling level. Bain et al. tried to separate the phenotypes of both forms of Robinow syndrome [1]. They proposed that vertebral anomalies were more frequent and more pronounced in

the recessive form. The female patient described here fits well with this hypothesis and could have been diagnosed by prenatal ultrasound. H e r brother, however, shows only very minor rib involvement and has no spine defect. He would not be classified as having the recessive form had his parents not been consanguineous. It seems, as reported earlier [19], that the Robinow phenotype is too variable to allow accurate discrimination between dominant and recessive forms. Therefore it is important not to overlook a recessive form carrying a recurrence risk of 25%. We report here the first abnormal karyotype in a Robinow syndrome patient. In case 2, three abnormal cell populations were found in the blood. It is probable that this anomaly of the Y chromosome is not related to Robinow syndrome and that it occurred purely by chance. Several associations between Robinow syndromes and rare dysmorphic entities have recently been reported: Crigler-Najjar syndrome [11]; congenital heart disease [24]; androgen receptor deficiency [16]; cystic kidney disease [25]. Saal et al. [14] found an association between Robinow syndrome and anterior chamber cleavages anomalies. Although the latter authors favour a new diagnosis, it is not known whether this indeed represents a new entity. The fact that this anomaly is of the Y chromosome almost excludes it from being considered as a general cause of Robinow syndrome. It is, however, interesting to note that ambiguous genitalia is one of the major characteristics of Robinow syndrome. In their review, Butler and Wadlington [2] reported hypoplastic genitalia in 94% of cases. The mechanism(s) by which this ambiguity develops is not clear but it could well involve one or several genes, including genes from the Y chromosome. In one case of Robinow syndrome, sexual ambiguity was traced back to an androgen receptor deficiency [16]. The androgen receptor gene has been mapped to Xql2. In our case, we found a mosaicism for 45X/46,X,dicY(q11.22)/ 47,X,dicY(q11.22), dicY(q11.22) with an abnormal Y chromosome. As for the case presented by Sch6nau et al, this fact in itself could explain the sexual ambiguity [12]. It is therefore difficult to evaluate which parts of this feature originate from the Robinow syndrome and from the chromosomal mosaicism. It could also be speculated that a gene with alleles present on the missing part of the Y chromosome and close to the androgen receptor gene on the X chromosome regulates some aspects of the Robinow syndrome. Several genes with alleles on both sexual chromosomes have recently been reported [3, 6, 7, 9, 15, 26] and it will be interesting to map at the molecular level any deletion found in male patients with sexual ambiguity.

Acknowledgements. D.F.S. is supported by the Swiss National Science Foundation (grant 3.754-0.87) and is grateful to Ms. Barman and Mr. Furrer for expert photographic assistance.

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