Hum. Genet. 50, 231--235 (1979)
© by Springer-Vedag 1979
A Ring Chromosome 9 in an Infant with Malformations T. I n o u y e 1*, H. M a t s u d a ~, K. S h i m u r a ~, M. H a m a z a k i ~, I. K i k u t a ~, K. I i n u m a ~, a n d Y. N a k a g o m e 2 1Division of Neonatology, Clinical Genetics and Pathology, Shizuoka Children's Hospital, Shizuoka, 420, Japan 2Department of Human Genetics, National Institute of Genetics, Mishima, 411, Japan
Summary. A l o w - b i r t h - w e i g h t infant with m a l f o r m e d u p p e r extremities a n d congenital h e a r t disease was observed. C y t o g e n e t i c analysis revealed a 46,XY,r(9)(p24q34) c o m p l e m e n t .
Introduction To o u r knowledge, six cases o f ring c h r o m o s o m e 9 a s s o c i a t e d with v a r i o u s clinical features have been r e p o r t e d ( K i s t e n m a c h e r et al., 1975; J a c o b s e n et al., 1973; F r a i s s e et al., 1974; Z d a n s k y et al., 1975; N a k a j i m a et al., 1976; M e t a x o t o u a n d K a l p i n i - M a v r o u , 1977). W h e t h e r a well-defined clinical s y n d r o m e is ass o c i a t e d with the ring is n o t yet clear. W e o b s e r v e d ring c h r o m o s o m e 9 in a low-birth-weight infant with m a l f o r m e d u p p e r extremities, s h o r t stature, m i c r o c e p h a l y , a n d severe congenital h e a r t disease. His k a r y o t y p e was 46,XY,r(9)(p24q34).
Case Report The patient, born uneventfully after 32 weeks of gestation, was admitted to the Shizuoka Children's Hospital on his first day of life because of frequent apneic spells. He was the second offspring of his 28-year-old mother. His parents, grandparents, and elder sister were phenotypically normal. His birth weight was 1090 g, height 37.0 cm, and head circumference 25.5 cm (all below the 3rd percentile). Both of his forearms were extremely short and both hands were radially deviated (Fig. 1). The thumbs were rudimentary, each attached to its hand by a stringlike structure. There was pectus excavatum; systolic heart murmurs were audible. Roentgenograms of the arms showed aplasia of the left radius and hypoplasia of the right (Fig. 2). Routine hematologic and biochemical tests were within normal limits. On his ninth day of life, he developed severe bradycardia followed by cardiac arrest. * To whom offprint requests should be sent
0 3 4 0 - 6 7 1 7 / 7 9 / 0 0 5 0 / 0 2 3 1 / $ 01.00
232
T. Inouye et al.
Fig. 1. Patient at age 5 days. Note malformed upper extremities
Fig. 2. X-ray of the left upper extremity, showing radial aplasia and lack of ossification in the rudimentary thumb
Post-mortem examination revealed atrial septal defect, ventricular septal defect, pulmonary atresia, right ventricular hypertrophy, overriding aorta, and patent ductus arteriosus. Macroscopic studies of other organs including brain and kidneys, disclosed no anomaly.
Cytogenetic Analysis All 100 metaphases, obtained f r o m standard leukocyte cultures, showed a 46,XY karyotype with one of the C - g r o u p c h r o m o s o m e s being replaced by a ring (Fig. 3). Giemsa banding ( G T G ) identified the ring as r(9)(p24q34) (Fig. 4). The rings appeared stable and most of them, as far as examined, were single sized; a small n u m b e r (7 o f 100) were double-sized rings.
Ring Chromosome 9 with Peculiar Malformations
233
Fig. 3. G-banded karyotype of the patient
Fig. 4. a G-banded normal chromosome 9; b G-banded ring chromosome 9. Double-sized ring is shown for easy demonstration of G-bands; e C-banded ring chromosome 9. Large heterochromatin blocks can be seen in the double-sized ring
Discussion Clinical features of six reported cases a n d the present case are s u m m a r i z e d in Table 1. A p p a r e n t l y the present case is the only one showing hypoplasia (or aplasia) of radii a n d t h u m b s . The association of congenital heart disease with these a b n o r m a l i t i e s is reminiscent of the H o l t - O r a m syndrome.
234
T. I n o u y e et al.
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Ring Chromosome 9 with Peculiar Malformations
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Mosaicism as well as instability of the ring m a y cause differences in phenotype. F o r example, cells with a double-sized ring are, in fact, partially trisomic for a segment involved in the ring and partially m o n o s o m i c for the distal ends of both arms. Cells with a single-sized ring do not have a trisomic segment. Thus, the p r o p o r t i o n of cells with a double-(sometimes triple- or even larger) sized ring has implications in the phenotypes of particular patients (Serra and Singh-Kahlon, 1976; Schmid et al., 1978). The phenotype may also depend largely on the size o f deletion in each c h r o m o s o m e arm. N a k a g o m e et al. (1973) were the first to identify successfully points o f breakage within a h u m a n ring chromosome. I n f o r m a t i o n on breakpoints and on the p r o p o r t i o n of cells of different ring sizes should be included in any papers describing cases with a ring. Further case reports are needed to establish phenotype-karyotype correlation in cases with ring 9 c h r o m o s o m e .
References Fraisse, J., Lauras, B., Ooghe, M.-J., Freycon, F., Rethor6, M.-O.: Apropos d'un cas de chromosome 9 en anneau. Identification par d6naturation m6nag6e. Ann. Genet. (Paris) 17,175--180 (1974) Jacobsen, P., Mikkelsen, M., Rosleff, F.: A ring chromosome, diagnosed by quinacrine fluorescence as No.9, in a mentally retarded girl. Clin. Genet. 4, 434--441 (1973) Kistenmacher, M. L., Punnett, H. H.: Comparative behavior of ring chromosomes. Am. J. Hum. Genet. 22, 304--318 (1970) Kistenmacher, M. L., Punnett, H. H., Aronson, M., Miller, R. C., Greene, A. E., Coriell, L. L.: A ring 9 chromosome. Repository identification No. GM-166. Cytogenet. Cell Genet. 15, 122--123 (1975) Metaxotou, C., Kalpini-Mavrou, A.: Ring chromosome 9.46,XY,r(9) in a male with ambiguous external genitalia. Hum. Genet. 37, 351--354 (1977) Nakagome, Y., Iinuma, K., Taniguchi, K.: Points of exchange in a human No. 5 ring chromosome. Cytogenet. Cell Genet. 12, 35--39 (1973) Nakajima, S., Yanagisawa, M., Kamoshita, S., Nakagome, Y.: Mental retardation and congenital malformations associated with a ring chromosome 9. Hum. Genet. 32, 289--293 (1976) Schmid, M., Henrichs, I., Nestler, H., Knorr-Gartner, H., Teller, W. H., Krone, W.: Analysis of banding patterns and mosaic configurations in a case of ring chromosome 15. Hum. Genet. 41,289--299 (1978) Serra, A., Singh-Kahlon, D. P.: 21 ring chromosome in a girl with stigmata of Down's and G deletion I syndromes. Hum, Genet. 33, 47--53 (1976) Zdansky, R., Andrle, M., Btihler, E., Tsuchimoto, T., Mayr, W. R., Rett, A.: Irregular phenotypic expression of ring chromosomes. Humangenetik 26, 193--198 (1975) Received February 12, 1979
© by Springer-Vedag 1979
A Ring Chromosome 9 in an Infant with Malformations T. I n o u y e 1*, H. M a t s u d a ~, K. S h i m u r a ~, M. H a m a z a k i ~, I. K i k u t a ~, K. I i n u m a ~, a n d Y. N a k a g o m e 2 1Division of Neonatology, Clinical Genetics and Pathology, Shizuoka Children's Hospital, Shizuoka, 420, Japan 2Department of Human Genetics, National Institute of Genetics, Mishima, 411, Japan
Summary. A l o w - b i r t h - w e i g h t infant with m a l f o r m e d u p p e r extremities a n d congenital h e a r t disease was observed. C y t o g e n e t i c analysis revealed a 46,XY,r(9)(p24q34) c o m p l e m e n t .
Introduction To o u r knowledge, six cases o f ring c h r o m o s o m e 9 a s s o c i a t e d with v a r i o u s clinical features have been r e p o r t e d ( K i s t e n m a c h e r et al., 1975; J a c o b s e n et al., 1973; F r a i s s e et al., 1974; Z d a n s k y et al., 1975; N a k a j i m a et al., 1976; M e t a x o t o u a n d K a l p i n i - M a v r o u , 1977). W h e t h e r a well-defined clinical s y n d r o m e is ass o c i a t e d with the ring is n o t yet clear. W e o b s e r v e d ring c h r o m o s o m e 9 in a low-birth-weight infant with m a l f o r m e d u p p e r extremities, s h o r t stature, m i c r o c e p h a l y , a n d severe congenital h e a r t disease. His k a r y o t y p e was 46,XY,r(9)(p24q34).
Case Report The patient, born uneventfully after 32 weeks of gestation, was admitted to the Shizuoka Children's Hospital on his first day of life because of frequent apneic spells. He was the second offspring of his 28-year-old mother. His parents, grandparents, and elder sister were phenotypically normal. His birth weight was 1090 g, height 37.0 cm, and head circumference 25.5 cm (all below the 3rd percentile). Both of his forearms were extremely short and both hands were radially deviated (Fig. 1). The thumbs were rudimentary, each attached to its hand by a stringlike structure. There was pectus excavatum; systolic heart murmurs were audible. Roentgenograms of the arms showed aplasia of the left radius and hypoplasia of the right (Fig. 2). Routine hematologic and biochemical tests were within normal limits. On his ninth day of life, he developed severe bradycardia followed by cardiac arrest. * To whom offprint requests should be sent
0 3 4 0 - 6 7 1 7 / 7 9 / 0 0 5 0 / 0 2 3 1 / $ 01.00
232
T. Inouye et al.
Fig. 1. Patient at age 5 days. Note malformed upper extremities
Fig. 2. X-ray of the left upper extremity, showing radial aplasia and lack of ossification in the rudimentary thumb
Post-mortem examination revealed atrial septal defect, ventricular septal defect, pulmonary atresia, right ventricular hypertrophy, overriding aorta, and patent ductus arteriosus. Macroscopic studies of other organs including brain and kidneys, disclosed no anomaly.
Cytogenetic Analysis All 100 metaphases, obtained f r o m standard leukocyte cultures, showed a 46,XY karyotype with one of the C - g r o u p c h r o m o s o m e s being replaced by a ring (Fig. 3). Giemsa banding ( G T G ) identified the ring as r(9)(p24q34) (Fig. 4). The rings appeared stable and most of them, as far as examined, were single sized; a small n u m b e r (7 o f 100) were double-sized rings.
Ring Chromosome 9 with Peculiar Malformations
233
Fig. 3. G-banded karyotype of the patient
Fig. 4. a G-banded normal chromosome 9; b G-banded ring chromosome 9. Double-sized ring is shown for easy demonstration of G-bands; e C-banded ring chromosome 9. Large heterochromatin blocks can be seen in the double-sized ring
Discussion Clinical features of six reported cases a n d the present case are s u m m a r i z e d in Table 1. A p p a r e n t l y the present case is the only one showing hypoplasia (or aplasia) of radii a n d t h u m b s . The association of congenital heart disease with these a b n o r m a l i t i e s is reminiscent of the H o l t - O r a m syndrome.
234
T. I n o u y e et al.
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Ring Chromosome 9 with Peculiar Malformations
235
Mosaicism as well as instability of the ring m a y cause differences in phenotype. F o r example, cells with a double-sized ring are, in fact, partially trisomic for a segment involved in the ring and partially m o n o s o m i c for the distal ends of both arms. Cells with a single-sized ring do not have a trisomic segment. Thus, the p r o p o r t i o n of cells with a double-(sometimes triple- or even larger) sized ring has implications in the phenotypes of particular patients (Serra and Singh-Kahlon, 1976; Schmid et al., 1978). The phenotype may also depend largely on the size o f deletion in each c h r o m o s o m e arm. N a k a g o m e et al. (1973) were the first to identify successfully points o f breakage within a h u m a n ring chromosome. I n f o r m a t i o n on breakpoints and on the p r o p o r t i o n of cells of different ring sizes should be included in any papers describing cases with a ring. Further case reports are needed to establish phenotype-karyotype correlation in cases with ring 9 c h r o m o s o m e .
References Fraisse, J., Lauras, B., Ooghe, M.-J., Freycon, F., Rethor6, M.-O.: Apropos d'un cas de chromosome 9 en anneau. Identification par d6naturation m6nag6e. Ann. Genet. (Paris) 17,175--180 (1974) Jacobsen, P., Mikkelsen, M., Rosleff, F.: A ring chromosome, diagnosed by quinacrine fluorescence as No.9, in a mentally retarded girl. Clin. Genet. 4, 434--441 (1973) Kistenmacher, M. L., Punnett, H. H.: Comparative behavior of ring chromosomes. Am. J. Hum. Genet. 22, 304--318 (1970) Kistenmacher, M. L., Punnett, H. H., Aronson, M., Miller, R. C., Greene, A. E., Coriell, L. L.: A ring 9 chromosome. Repository identification No. GM-166. Cytogenet. Cell Genet. 15, 122--123 (1975) Metaxotou, C., Kalpini-Mavrou, A.: Ring chromosome 9.46,XY,r(9) in a male with ambiguous external genitalia. Hum. Genet. 37, 351--354 (1977) Nakagome, Y., Iinuma, K., Taniguchi, K.: Points of exchange in a human No. 5 ring chromosome. Cytogenet. Cell Genet. 12, 35--39 (1973) Nakajima, S., Yanagisawa, M., Kamoshita, S., Nakagome, Y.: Mental retardation and congenital malformations associated with a ring chromosome 9. Hum. Genet. 32, 289--293 (1976) Schmid, M., Henrichs, I., Nestler, H., Knorr-Gartner, H., Teller, W. H., Krone, W.: Analysis of banding patterns and mosaic configurations in a case of ring chromosome 15. Hum. Genet. 41,289--299 (1978) Serra, A., Singh-Kahlon, D. P.: 21 ring chromosome in a girl with stigmata of Down's and G deletion I syndromes. Hum, Genet. 33, 47--53 (1976) Zdansky, R., Andrle, M., Btihler, E., Tsuchimoto, T., Mayr, W. R., Rett, A.: Irregular phenotypic expression of ring chromosomes. Humangenetik 26, 193--198 (1975) Received February 12, 1979
