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Trisomy 9 mosaicism in a newborn infant with multiple malformations
Volume 85 Number l DISCUSSION Trisomy for the short arm of c h r o m o s o m e 9 resulting from an inherited translocation has been reported in several subjects who presented with multiple abnormalities) -s In comparing our present patients there are c o m m o n findings such as mental retardation, deep-set eyes, abnormal ears, d o w n t u r n e d corners of the m o u t h , clinodactyly, transverse palmar creases, unusual dermatoglyphics, and s o m e hypoplastic phalanges and nails (Table I). Rethor~ and associates I presented four patients and reviewed 11 cases of translocations involving a c h r o m o s o m e in the C group and believed four represented trisomy o f the short arms of c h r o m o s o m e 9. T h e most p r o m i n e n t findings were mental retardation, deepset eyes, hypertelorism, abnormal ears, s o m e hypoplastic phalanges, clinoclactyly, and unusual dermatoglyphics. Other findings noted in s o m e cases were microcephaly, hypoplastic nails, partial webbing of the toes and fingers, hernia, epicanthal folds, small eyes, and narrow auditory canals. Gerald 6 has recently studied two patients with trisomy for the short arms of c h r o m o s o m e 9 demonstrated by fluorescent microscopy: Both exhibit mental retardation, occulomotor abnormalities, cup-shaped external ears, hypoplastic phalanges of the second and fifth digits, hypoplastic nails, and various bony abnormalities.
Trisomy 9 mosaicism in a newborn infant with multiple malformations P. Bowen, M.D., F.R.C.P.(C),* K. L. Ying, Ph.D., and G. S. H. Chung, M.D., F.R.C.P.(C), Alberta and Saskatchewan, Canada
N E W E R METHODS for identification of individual chrom o s o m e s afford an opportunity to subclassify cases of congenital C (6-12) trisomy according to the particular a u t o s o m e i n v o l v e d ~ a n d t h e r e b y to d e v e l o p m o r e m e a n i n g f u l clinical d e s c r i p t i o n s . In this r e p o r t w e From the Department of Pediatrics, University of AIberta, Edmonton, and the Department of Pediatrics, Section of Medical Genetics, University of Saskatchewan. *Reprint address." 4-120. ClinicalSciences Bldg., Edmonton, AIberta, Canada T6G 2G3.
Brief clinical and laboratory observations
95
A l t h o u g h the n u m b e r of cases o f trisomy for the short arms of c h r o m o s o m e 9 is limited, w e feel these t w o p a tients are consistent with the clinical s y n d r o m e o f trisomy for the short arms of c h r o m o s o m e 9 as reported by Rethor6 and associates) The authors express their gratitude to Park S. Gerald, M.D., Children's Hospital, Boston, Mass., for the fluorescent microscopy studies and counsel. REFERENCES 1. Rethor~, M.-O., Larget-Piet, L., Abonyi, D., Boeswillwald, M., Berger, R., Carpentier, S., Cruveiller, J., Dutrillaux, B., Lafourcade, J., Penneau, M., and Lejeune, J.: Sur quartre cas de trisomie pur le bras court du chromosome 9. Individualisation d'une nouvelle entlte morb~de, Ann. Genet. (Paris) 13: 217, 1970. 2. Lejeune, J., Berger, R., Rethor6, M.-O., Salmon, Ch., and Kaplan, M.: Translocation Cc-F familiale determinant une trisomie pour le bras court du chromosome 12, Ann. Genet. (Paris) 9: 12, 1966. 3. Edwards, J. H., Fracearo, M., Davies, P., and Young, R. B.: Structural heterozygosis in man: analysis of two families, Ann. Genet. (London)26: I63, 1962. 4. Butler, L. J., Eades, S. M., and France, N. E.: Transmission of a translocation t(Cp+;Dq-) through three generations, Ann. Genet. (Paris) 12: 15, 1969. 5. Baccichetti, C., and Tenconi, R.: A new case of trisomy for the short arm of No. 9 chromosome, J. Med. Genet. 10: 296, 1973. 6. Gerald, P. S.: Personal communications.
describe a newborn male infant with multiple congenital anomalies and trisomy 9 mosaicism. CASE R E P O R T The mother was a gravida 1, para 0, 17-year-old single girl and the father was 19 years of age. The mother had recurrent epileptic seizures until she was 10 years of age. The baby was born after 39 weeks of gestation and weighed 2,211 gin. The pregnancy was unremarkable except for spotting of blood for one day during the thirteenth week. The amniotic fluid was meconiumstained and resuscitation was difficult. The placenta was described as "small" and the umbilical cord contained three blood vessels. The baby's head circumference was 32.5 cm (twentyfifth percentile) and the length was 49 cm (fiftieth percentile). He had the following anomalies (Fig. 1): posterior rotation of the ears; hypotelorism; small, upward-slanting palpebral fissures; prominent nose; receding chin; long fingers maintained in persistent flexion over the thumbs; transitional simian creases; small penis; undescended testes; restricted hip mobility; gross misalignment of the right lower limb at the knee; and calcaneovalgus deformity of the right foot. The palate was high but intact and the cry was feeble. There was no heart murmur. The dermal configurations are summarized in Table I. The electrocardiograph showed a pattern consistent with right ventricu-
96
B r i e f clinical and laboratory observations
The Journal of Pediatrics July 1974
T a b l e I. D e r m a l p a t t e r n s Left fingers Area
Interdigital area IV Thenar Hypothenar Hallucal
5 UL *
4 W
3 UL
Right fingers 2 RL
1 W
1 RL
Loop No pattern No pattern Loop distal O 20 ridges)
2 UL
3 UL
4 W
5 UL
Loop No pattern No pattern Loop distal () 20 ridges)
*Key to abbreviations: UL, ulnar loop; RL, radial loop; W, whorl.
complete closure by tethering to the septum. The right testis and epididymis were located in the inguinal canal and were histologically normal. The left epididymis was situated at the external inguinal ring and microscopic sections taken from this site showed no adjacent testicular tissue. There was a diverticulum on the left lateral wall of the bladder and a double ureter on the left. The kidneys contained a number of microscopic cysts lined with epithelium. The gross and microscopic appearances of the brain were not remarkable. Chromosome studies. Twelve of 100 cells from the baby's cultured peripheral blood were trisomic for a member of the Cgroup and the remainder had a normal 46,XY karyotype. The karyotype of cultured skin fibroblasts was 46,XY, no trisomic cells being present among 100 cells counted. A buccal smear was negative for sex chromatin bodies. Chromosome preparations with Q and C-bands made by methods outlined in Evans, Buckton, and Sumner 2 showed the trisomic chromosome to be a No. 9 (Fig. 2). The mother's karyotype, determined in 30 cells from cultures of peripheral blood lymphocytes, was 46,XX. The mother is heterozygous for an unusual C-band variant on a No. 9 chromosome that may have resulted from a small pericentric inversion. A similar No. 9 chromosome is present in all ceils in her baby and is represented twice in the baby's trisomic cells (Fig. 2, b). The father's karyotype has not been determined. DISCUSSION
Fig. 1. Propositus at age 5 weeks. lar hypertrophy and the heart appeared to be slightly enlarged on roentgen films of the chest. Radiographs of the lower extremities showed dislocation of both hips and the right knee, normal acetabula, and an unusual configuration of both femurs. The clinical course was characterized by refractory congestive heart failure and gradual deterioration. Cardiac catheterization, performed on day 38 (Dr. Neil Duncan), showed no abnormality other than a persistent left superior vena cava. The baby died on his forty-second day of life. Autopsy findings. Gross anatomic defects of the viscera were confined to the cardiovascular and genitourinary systems. The heart was enlarged and the ductus arteriosus was patent. The tricuspid valve had only two leaflets that were prevented from
Relatively few cases of c o n g e n i t a l C - t r i s o m y h a v e b e e n i n v e s t i g a t e d w i t h specific b a n d i n g t e c h n i q u e s , a n d in t h e s e t h e t r i s o m y h a s i n v o l v e d e i t h e r a No. 8 or a No. 9 c h r o m o s o m e . A l t h o u g h distinctive s y n d r o m e s h a v e n o t yet e m e r g e d t h e r e is a n early suggestion of diverg e n c e in t h e p h e n o t y p e s associated with t r i s o m y 8 a n d t r i s o m y 9. Caspersson and associates I described four cases of c o n g e n i t a l t r i s o m y 8, o n e of w h i c h was a n a p p a r e n t l y normal 30-year-old woman studied because of two m i s s e d abortions. T h e r e m a i n i n g t h r e e p a t i e n t s were m e n t a l l y r e t a r d e d boys 8, 13, a n d 15 years o f age. T r i s o m y 8 has also b e e n r e p o r t e d in a 10-year-old m e n tally r e t a r d e d boy 3 a n d in a 3 - m o n t h - o l d girl w i t h multiple congenital a n o m a l i e s . 4 R e c u r r e n t features in t h e s e latter five cases were m e n t a l r e t a r d a t i o n (5/5), s t r a b i s m u s (2/5), clinodactyly (3/5), v e r t e b r a l a n o m a l i e s (2/5), a n o m a -
Volume 85 Number 1
Brief clinical and laboratory observations
97
b I I
1 ! I t t 1
NORMAL (9) It
? INV (9)
Fig. 2. (a) Karyotype of a trisomic cell from the propositus with the No. 9 chromosomes identified by Q-bands. (b) The No. 9 chromosomes in a trisomic and normal cell from the propositus (top two rows) and a cell from the mother. Variant C-band, possibly the result of a small pericentric inversion, serves as a marker on the maternal No. 9 chromosomes of the propositus.
lies of the great vessels (3/5), and mosaicism (2/5). Two cases of congenital trisomy 9 have been reported previously. One was a n o n m o s a i c male infant who survived for 28 days 5 and the other was a mentally retarded boy who died at the age of eight years due to complications of congenital heart disease. 6 Recurrent features were small palpebral fissures (2/3), sagging or low-set ears (3/3), micrognathia (3/3), congenital heart disease (3/3), s m a l l p e n i s (2/3), u n d e s c e n d e d testes (3/3), bypotonia (2/3), anatomic defects in the brain (2/3), multiple joint dislocations (3/3), a n d mosaicism (2/3). Variant C-bands have been observed with relatively high frequency in control subjects] The variant on the No. 9 c h r o m o s o m e observed in the mother and baby results in little if any displacement of the centromere, in contrast with the more frequently observed pericentric inversion on this chromosome. 7,8 As it is unlikely that the father has a similar variant, the presence of the marker on two of the three No. 9 chromosomes in the baby's trisomic cells probably indicates that nondisjunction involved a maternal No. 9. The simplest of several theoretical m e c h a n i s m s would be mitotic n o n d i s j u n c t i o n of a maternal, ?inv (9) c h r o m o s o m e during early cleavage in a 46,XY embryo, resulting in a viable 47,XY,+9 stemcell and an inviable m o n o s o m i c cell.
We are grateful to Dr. Jean Leriche for a description of the autopsy findings. Technical assistance was provided by Mrs. Frances Williams, Mrs. Carol Flint, Mr. Paulino Pabello, and Mrs. Dorothy Reeve. REFERENCES
1.
2.
3.
4.
5. 6.
7.
8.
Caspersson, T., Lindsten, J., Zech, L., Buckton, K. E., and Price, W. H.: Four patients with trisomy 8 identified by the fluorescence and Giemsa banding techniques, J. Med. Genet. 9: 1, 1972. Evans, H. J., Buckton, K. E., and Sumner, A. T.: Cytological mapping of human chromosomes: Results obtained with quinacrine fluorescence and the acetic saline Giemsa techniques, Chromosoma 35: 310, 1971. Grouchy, J. de, Turleau, C., and Leonard, C.: Etude en fluorescence d'une trisomie C mosaique, probablement 8: 46,XY/47,XY,?8+, Ann. Genet. (Paris) 14: 69, 1971. Kakati, S., Nihill, M., and Sinha, A. K.: An attempt to establish trisomy 8 syndrome, Humangenetik 19: 293, 1973. Feingold, M., and Atkins, L: A case of.trisomy 9, J. Med. Genet. 10: 184, 1973. Haslam, R. H. A., Broske, S. P , Moore, C. M., Thomas, G. H., and Neill, C. A.: Trisomy 9 mosaicism with multiple congenital anomalies, J. Med. Genet. 10: 180, 1973. Craig-Holmes, A. P., Moore, F. B., and Shaw, M. W.: Polymorphism of human C-band heterochromatin. I. Frequency of variants, Am. J. Hum. Genet. 181, 1973. Ferguson-Smith, M. A.: Personal communication, Glasgow, 1973.
Trisomy 9 mosaicism in a newborn infant with multiple malformations P. Bowen, M.D., F.R.C.P.(C),* K. L. Ying, Ph.D., and G. S. H. Chung, M.D., F.R.C.P.(C), Alberta and Saskatchewan, Canada
N E W E R METHODS for identification of individual chrom o s o m e s afford an opportunity to subclassify cases of congenital C (6-12) trisomy according to the particular a u t o s o m e i n v o l v e d ~ a n d t h e r e b y to d e v e l o p m o r e m e a n i n g f u l clinical d e s c r i p t i o n s . In this r e p o r t w e From the Department of Pediatrics, University of AIberta, Edmonton, and the Department of Pediatrics, Section of Medical Genetics, University of Saskatchewan. *Reprint address." 4-120. ClinicalSciences Bldg., Edmonton, AIberta, Canada T6G 2G3.
Brief clinical and laboratory observations
95
A l t h o u g h the n u m b e r of cases o f trisomy for the short arms of c h r o m o s o m e 9 is limited, w e feel these t w o p a tients are consistent with the clinical s y n d r o m e o f trisomy for the short arms of c h r o m o s o m e 9 as reported by Rethor6 and associates) The authors express their gratitude to Park S. Gerald, M.D., Children's Hospital, Boston, Mass., for the fluorescent microscopy studies and counsel. REFERENCES 1. Rethor~, M.-O., Larget-Piet, L., Abonyi, D., Boeswillwald, M., Berger, R., Carpentier, S., Cruveiller, J., Dutrillaux, B., Lafourcade, J., Penneau, M., and Lejeune, J.: Sur quartre cas de trisomie pur le bras court du chromosome 9. Individualisation d'une nouvelle entlte morb~de, Ann. Genet. (Paris) 13: 217, 1970. 2. Lejeune, J., Berger, R., Rethor6, M.-O., Salmon, Ch., and Kaplan, M.: Translocation Cc-F familiale determinant une trisomie pour le bras court du chromosome 12, Ann. Genet. (Paris) 9: 12, 1966. 3. Edwards, J. H., Fracearo, M., Davies, P., and Young, R. B.: Structural heterozygosis in man: analysis of two families, Ann. Genet. (London)26: I63, 1962. 4. Butler, L. J., Eades, S. M., and France, N. E.: Transmission of a translocation t(Cp+;Dq-) through three generations, Ann. Genet. (Paris) 12: 15, 1969. 5. Baccichetti, C., and Tenconi, R.: A new case of trisomy for the short arm of No. 9 chromosome, J. Med. Genet. 10: 296, 1973. 6. Gerald, P. S.: Personal communications.
describe a newborn male infant with multiple congenital anomalies and trisomy 9 mosaicism. CASE R E P O R T The mother was a gravida 1, para 0, 17-year-old single girl and the father was 19 years of age. The mother had recurrent epileptic seizures until she was 10 years of age. The baby was born after 39 weeks of gestation and weighed 2,211 gin. The pregnancy was unremarkable except for spotting of blood for one day during the thirteenth week. The amniotic fluid was meconiumstained and resuscitation was difficult. The placenta was described as "small" and the umbilical cord contained three blood vessels. The baby's head circumference was 32.5 cm (twentyfifth percentile) and the length was 49 cm (fiftieth percentile). He had the following anomalies (Fig. 1): posterior rotation of the ears; hypotelorism; small, upward-slanting palpebral fissures; prominent nose; receding chin; long fingers maintained in persistent flexion over the thumbs; transitional simian creases; small penis; undescended testes; restricted hip mobility; gross misalignment of the right lower limb at the knee; and calcaneovalgus deformity of the right foot. The palate was high but intact and the cry was feeble. There was no heart murmur. The dermal configurations are summarized in Table I. The electrocardiograph showed a pattern consistent with right ventricu-
96
B r i e f clinical and laboratory observations
The Journal of Pediatrics July 1974
T a b l e I. D e r m a l p a t t e r n s Left fingers Area
Interdigital area IV Thenar Hypothenar Hallucal
5 UL *
4 W
3 UL
Right fingers 2 RL
1 W
1 RL
Loop No pattern No pattern Loop distal O 20 ridges)
2 UL
3 UL
4 W
5 UL
Loop No pattern No pattern Loop distal () 20 ridges)
*Key to abbreviations: UL, ulnar loop; RL, radial loop; W, whorl.
complete closure by tethering to the septum. The right testis and epididymis were located in the inguinal canal and were histologically normal. The left epididymis was situated at the external inguinal ring and microscopic sections taken from this site showed no adjacent testicular tissue. There was a diverticulum on the left lateral wall of the bladder and a double ureter on the left. The kidneys contained a number of microscopic cysts lined with epithelium. The gross and microscopic appearances of the brain were not remarkable. Chromosome studies. Twelve of 100 cells from the baby's cultured peripheral blood were trisomic for a member of the Cgroup and the remainder had a normal 46,XY karyotype. The karyotype of cultured skin fibroblasts was 46,XY, no trisomic cells being present among 100 cells counted. A buccal smear was negative for sex chromatin bodies. Chromosome preparations with Q and C-bands made by methods outlined in Evans, Buckton, and Sumner 2 showed the trisomic chromosome to be a No. 9 (Fig. 2). The mother's karyotype, determined in 30 cells from cultures of peripheral blood lymphocytes, was 46,XX. The mother is heterozygous for an unusual C-band variant on a No. 9 chromosome that may have resulted from a small pericentric inversion. A similar No. 9 chromosome is present in all ceils in her baby and is represented twice in the baby's trisomic cells (Fig. 2, b). The father's karyotype has not been determined. DISCUSSION
Fig. 1. Propositus at age 5 weeks. lar hypertrophy and the heart appeared to be slightly enlarged on roentgen films of the chest. Radiographs of the lower extremities showed dislocation of both hips and the right knee, normal acetabula, and an unusual configuration of both femurs. The clinical course was characterized by refractory congestive heart failure and gradual deterioration. Cardiac catheterization, performed on day 38 (Dr. Neil Duncan), showed no abnormality other than a persistent left superior vena cava. The baby died on his forty-second day of life. Autopsy findings. Gross anatomic defects of the viscera were confined to the cardiovascular and genitourinary systems. The heart was enlarged and the ductus arteriosus was patent. The tricuspid valve had only two leaflets that were prevented from
Relatively few cases of c o n g e n i t a l C - t r i s o m y h a v e b e e n i n v e s t i g a t e d w i t h specific b a n d i n g t e c h n i q u e s , a n d in t h e s e t h e t r i s o m y h a s i n v o l v e d e i t h e r a No. 8 or a No. 9 c h r o m o s o m e . A l t h o u g h distinctive s y n d r o m e s h a v e n o t yet e m e r g e d t h e r e is a n early suggestion of diverg e n c e in t h e p h e n o t y p e s associated with t r i s o m y 8 a n d t r i s o m y 9. Caspersson and associates I described four cases of c o n g e n i t a l t r i s o m y 8, o n e of w h i c h was a n a p p a r e n t l y normal 30-year-old woman studied because of two m i s s e d abortions. T h e r e m a i n i n g t h r e e p a t i e n t s were m e n t a l l y r e t a r d e d boys 8, 13, a n d 15 years o f age. T r i s o m y 8 has also b e e n r e p o r t e d in a 10-year-old m e n tally r e t a r d e d boy 3 a n d in a 3 - m o n t h - o l d girl w i t h multiple congenital a n o m a l i e s . 4 R e c u r r e n t features in t h e s e latter five cases were m e n t a l r e t a r d a t i o n (5/5), s t r a b i s m u s (2/5), clinodactyly (3/5), v e r t e b r a l a n o m a l i e s (2/5), a n o m a -
Volume 85 Number 1
Brief clinical and laboratory observations
97
b I I
1 ! I t t 1
NORMAL (9) It
? INV (9)
Fig. 2. (a) Karyotype of a trisomic cell from the propositus with the No. 9 chromosomes identified by Q-bands. (b) The No. 9 chromosomes in a trisomic and normal cell from the propositus (top two rows) and a cell from the mother. Variant C-band, possibly the result of a small pericentric inversion, serves as a marker on the maternal No. 9 chromosomes of the propositus.
lies of the great vessels (3/5), and mosaicism (2/5). Two cases of congenital trisomy 9 have been reported previously. One was a n o n m o s a i c male infant who survived for 28 days 5 and the other was a mentally retarded boy who died at the age of eight years due to complications of congenital heart disease. 6 Recurrent features were small palpebral fissures (2/3), sagging or low-set ears (3/3), micrognathia (3/3), congenital heart disease (3/3), s m a l l p e n i s (2/3), u n d e s c e n d e d testes (3/3), bypotonia (2/3), anatomic defects in the brain (2/3), multiple joint dislocations (3/3), a n d mosaicism (2/3). Variant C-bands have been observed with relatively high frequency in control subjects] The variant on the No. 9 c h r o m o s o m e observed in the mother and baby results in little if any displacement of the centromere, in contrast with the more frequently observed pericentric inversion on this chromosome. 7,8 As it is unlikely that the father has a similar variant, the presence of the marker on two of the three No. 9 chromosomes in the baby's trisomic cells probably indicates that nondisjunction involved a maternal No. 9. The simplest of several theoretical m e c h a n i s m s would be mitotic n o n d i s j u n c t i o n of a maternal, ?inv (9) c h r o m o s o m e during early cleavage in a 46,XY embryo, resulting in a viable 47,XY,+9 stemcell and an inviable m o n o s o m i c cell.
We are grateful to Dr. Jean Leriche for a description of the autopsy findings. Technical assistance was provided by Mrs. Frances Williams, Mrs. Carol Flint, Mr. Paulino Pabello, and Mrs. Dorothy Reeve. REFERENCES
1.
2.
3.
4.
5. 6.
7.
8.
Caspersson, T., Lindsten, J., Zech, L., Buckton, K. E., and Price, W. H.: Four patients with trisomy 8 identified by the fluorescence and Giemsa banding techniques, J. Med. Genet. 9: 1, 1972. Evans, H. J., Buckton, K. E., and Sumner, A. T.: Cytological mapping of human chromosomes: Results obtained with quinacrine fluorescence and the acetic saline Giemsa techniques, Chromosoma 35: 310, 1971. Grouchy, J. de, Turleau, C., and Leonard, C.: Etude en fluorescence d'une trisomie C mosaique, probablement 8: 46,XY/47,XY,?8+, Ann. Genet. (Paris) 14: 69, 1971. Kakati, S., Nihill, M., and Sinha, A. K.: An attempt to establish trisomy 8 syndrome, Humangenetik 19: 293, 1973. Feingold, M., and Atkins, L: A case of.trisomy 9, J. Med. Genet. 10: 184, 1973. Haslam, R. H. A., Broske, S. P , Moore, C. M., Thomas, G. H., and Neill, C. A.: Trisomy 9 mosaicism with multiple congenital anomalies, J. Med. Genet. 10: 180, 1973. Craig-Holmes, A. P., Moore, F. B., and Shaw, M. W.: Polymorphism of human C-band heterochromatin. I. Frequency of variants, Am. J. Hum. Genet. 181, 1973. Ferguson-Smith, M. A.: Personal communication, Glasgow, 1973.