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21 translocation
Volume 74 Number 2
Brie[ clinical and laboratory observations
tarded and ossification centers of the sternum were prematurely fused. A voiding cystourethrogram indicated bilateral vesicoureteral reflux, and an intravenous urogram revealed a hypoplastic right kidney. Chromosomal analysis of peripheral leukocytes revealed a normal 46, XY karyotype. The plasma growth hormone response to infusion of 1-arginine monochloride by radioimmunoassay was within normal limits. DISCUSSION T h e p r o b a n d has most of the c o m m o n clinical findings described in the i n t r o d u c tion. T h e following m a l f o r m a t i o n s seen in our case were not described in previously rep o r t e d cases: tibial torsion with metatarsus varus, facial a n d p a l a t a l paralysis, radiog r a p h i c findings of a b e r r a n t right subclavian artery, p r e m a t u r e fusion of sternal ossification centers, bilateral vesicoureteral reflux, a n d hypoplastic kidney. T o our knowledge this is the first N e g r o infant described with the S m i t h - L e m l i Opitz syndrome. We wish to express our gratitude to Dr. W. Webster Riggs for the special radiographic stud-
Familial 21/21 translocation S h e r m a n B. L a w t o n , M.D.,* Gayle R. S t o d d a r d , B.S., a n d J. R o d m a n Seely, M . D . , Ph.D. OKLAHOMA
CITY~ OKLA.
From the Department o[ Pediatrics and the Clinical Research Center, Children's Memorial Hospital, University o[ Oklahoma Medical Center. *Senior medical student during tenure of these studies .who was recipient of a medical student summer fellowship sponsored by Training Grant No. T1-HD-O0064 ]rom the National Institute o] Child Health and Human Development. Requests for reprints: ]. Rodman Seely, M.D., Children's Memorial Hospital, 800 N.E. 13, Oklahoma City, Okla. 73104.
30 5
ies and to Dr. Alvro M. Camacho for measurement of plasma growth hormone. REFERENCES 1. Smith, D. W., Lemll, L., and Opitz, J. M.: A newly recognized syndrome of multiple congenital anomalies. J. P~mAT. 64:~210, 1964. 2. Pinskey, L., and DiGeorge, A. M.: A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female, J. P~DIAT. 66: 1049, 1965. 3. Blair, H. R., and Martin, J. K.: A syndrome characterized by mental retardation, short stature, craniofacial dysplasla, and genital anomalies occurring in siblings, J. PEDIAT. 69: 457, 1966. 4. Dallaire, L., and Fraser, F. C.: The syndrome of retardation with urogenital and skeletal anomalies in siblings, J. PEmAT. 69': 459, 1966. 5. Gibson, R.: A case of the Smith-Lem!i-Opitz syndrome of multiple congenital anoma!ies in association with dysplasia epiplysialis punetata, Canad. M. A. J. 92- 574, 1965. 6. Kenis, H., and Hustinx, T. W. J.: A familial syndrome of mental retardation in association with multiple congenital anomalies resembling the syndrome of Smith-Lemli-Opitz, Maandsehr. kindergeneesk. 35: 37, 1967. 7. Fine, R. N., Gwinn, J. L., and Young, E. F.: Smith-Lemi-Opitz syndrome, Am. J. Dis. Child. 115: 483, 1968.
A
D E F I N I T E , albeit
small, percentage
of
cases of Down's syndrome (mongolism) are attributable to translocation of a G - g r o u p chromosome to a n o t h e r chromosome, usually one of the D or G-groups. A l t h o u g h there have been numerous reports of G / G translocations since the initial one in 1960,1 very few ~, 3 have h a d sufficient d a t a to allow a further presumptive designation as 21/21 translocation. T h e purpose of this report is to present a family in which demonstration of a G / G translocation in 3 children with mongolism a n d the phenotypically n o r m a l m o t h e r is a c c o m p a n i e d by sufficient evidence to indicate the presence of 21/21 translocation. These studies were supported in part by Grant No. CRCS-28 ]tom the National Foundation and Public Health Service Grant No. FR-62 [rom the General Clinical Research Centers Branch, National Institutes o[ Health.
306
Brief clinical and laboratory observations
The Journal of Pediatrics February 1969
Fig. 1. Karyotype of the mother showing the G/G translocation carrier state. There are 45 chromosomes present with only 2 normal G-group chromosomes and an extra small meta~ centric chromosome (arrow). The Chicago classification is 45,XX,G-G-,t(GqGq).
CASE
REPORT
The family was composed of phenotypically normal parents and 3 children, all of whom had the typical stigmas of mongolism. Although intellectual development had been evaluated formally only in the eldest child (intelligence quotient of 42), each was obviously functioning at a retarded level. They had typical dermatoglyphic findings: Each child had distally placed axial triradii and a predominance of digital ulnar loops (8 such loops in" the eldest and 9 in each of the 2 younger patients). Only the 2 younger siblings had simian creases, and these were found on only the right hand. None of the 3 had overt cardiovascular disease. The mother, who was 2 years older than the father, gave birth to the first affected child in 1949 at 28 years of age. The other children were born in 1955 and 1961. There were 4 known abortions at 8 to 10 week's gestation bet@een the pregnancies of the middle and eldest child and another at a maternal age of 19 years. There
was no further history of mongolism in the family. The mother had 4 siblings with a total of 11 children, all of whom were living and well. The maternal grandmother had 5 siblings, who had 6 offspring, and the maternal grandfather had 6 siblings, who had 14 offspring; all of these persons were considered to be "normal." The paternal family history was noncontributory. The mother sought therapeutic abortion during the pregnancy of each of the latter two children and was refused because of the medical view that the previous events were spontaneous in nature and the chance of recurrence was, therefore, remote. CYTOLOGIC
INVESTIGATION
Peripheral blood samples were obtained from the affected children a n d from both parents: the leukocytes were cultured a n d prepared for chromosome analyses accordi n g to a method modified from that of Moorhead a n d associates. 4 T h e father had a
Volume 74 Number 2
Brie[ clinical and laboratory observations
307
Fig. 2. Karyotype from the youngest propositus; it is representative of those of the other 2 children. There are 46 chromosomes with 3 normal G-group chromosomes and an extra small metacentric chromosome (arrow). The Chicago classification is 46,XX,G-,t(GqGq)mat.
normal 46,XY chromosome complement, while analysis of the maternal cells revealed a modal number of 4 5 and an abnormal karyotype with only 2 G-group chromosomes instead of the normal 4 and an extra metacentric chromosome resembling those in the F-group but larger in size. Results from each of the 3 children were essentially identical; the modal chromosome count was 46 and the karyotypes contained 0nly 3 G-group chromosomes and the same extra metacentric chromosome as observed in the mother. The mother's karyotype is shown in Fig. 1; a representative karyotype of the children, in Fig. 2. It is believed that the extra metacentric chromosome represents a translocation between 2 members of the G-group; however, morphologic detail does not provide suffi-
cient distinction between the G-group pairs to allow differentiation of the abnormal chromosome as a 21/21 or 21/22 translocation. DISCUSSION Although numerous cases of transmission of G / G translocations have been reported in the literature, designation of them as 21/21 translocations has remained a rarity because of difficulties in distinguishing between the 2 pairs of G-group chromosomes. It is generally conceded that such distinction cannot be made on morphologic grounds alone. Although Yunis and associates 5 were able to demonstrate chronologic differences in the uptake of tritiated thymidine by chromosomes Nos. 21 and 22 in autoradiographic replication studies, this technique
3 08
Brie[ clinical and laboratory observations
does not yet appear sufficiently reliable to allow consistent separation of the G-group pairs, de Capoa and associates 3 came to the conclusion that autoradiography did not provide meaningful designation of the nature of a transmitted G/G21 translocation. For the present, classification of G/G21 translocations as 21/21 or 21/22 depends on the different nature of the respective inheritance pattern. Random selection in the mating of a phenotypically normal 21/22 translocation carrier would produce zygotes divided into groups of normal offspring, phenotypically normal carriers, trisomy-21, and monosomy-2t. However, a 21/21 translocation carrier, normally fertilized, is able to produce only translocation trisomy-21 or monosomy-21. Since autosomal monosomy has been reported in only 3 living patients, 6-8 for practical purposes it may be considered a lethal condition. Thus, a 21/21 translocation carrier would be expected to abort all fetuses not afflicted with Down's syndrome. The production of a normal child by a G / G translocation carrier allows identification of the abnormal chromosome as 21/22, but designation of a 21/21 translocation is presumptive only and depends on the presence of a sufficient number of involved children and abortions to mal~e such designation statistically probable. Only 2 previous cases were found, those of Dallaire and associates 2 and de Capoa and associates, s which appear to provide such evidence. In the present case, assumption that each abortion was the result of monosomy-21 allows consideration of the probability of 8 consecutive pregnancies without the appearance of a phenotypically normal child if the translocation we.re a 21/22. Assuming a random distribution among the possibilities, namely that "one half of the offspring would be normal or phenotypicalIy normal carriers while the remainder would be abortuses or affected with Down's syndrome, the probability would be ([~21 s) or 1/256. Thus, it appears likely that this case is indeed one of 21/21 translocation. This assumption is strengthened by evidence that a greater percentage of normals and phenotypically nor-
The ]ourna! o[ Pediatrics February 1969
mal carriers occur than would be expected theoretically. The unfortunate aspects of this case demonstrate the need for standards for performing chromosome analysis on children born with Down's syndrome. Sufficient data are now available to indicate the probability of inherited translocation in such cases2, 10 It seems reasonable to perform chromosome analysis routinely in all instances in which the maternal age is less than 30 years or when there is a positive family history of the anomaly; as recently discussed by McKay 11 and Wright and associates, 9 adoption of such criteria would potentially prevent most occurrences of multiple affected births to the same mother. SUMMARY
A family is presented in which 8 consecutive pregnancies produced 3 children affected with Down's syndrome and 5 spontaneous abortions. The 3 siblings were demonstrated to have translocation trisomy-21 of the G / G type; analysis of maternal cells revealed a modal chromosome number of 45 and presence of a G / G translocation carrier state. Morphologic detail does not at present provide differentiation between chromosomes of the G-group; however, statistical analysis demonstrates the probability that this represents a 21/21 translocation; only 2 similar cases were found in the literature. REFERENCES
1. Fraccarro, M., Kaijser, K., and Lindsten, J.: Chromosomal abnormalities in father and mongol child, Lancet h 724, 1960. 2. Dallaire, L., and Fraser, F. C.: Two unusual cases of familial mongolism, Canad. J. Genet. & Cytol. 6: 540, 1964. 3. de Capoa, A., Miller, O. J., Mukherjee, B. B., and Warburton, D.: Autoradiographlc studies on a mother and aborted fetus from a family with four mongoloid children and a presumptive 21/21 translocation, Ann. Human Genet. 3h 243, 1967. 4. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., and Hungerford, D. A.: Chromosome preparations of leukocytes cultured from human peripheral blood, Exper. Cell Res. 20: 613, 1960. 5. Yunis, J. J., Hook, E. B., and Mayer, M.: Identification of the mongolism chromosome
Volume 74 Number 2
by DNA replication analysis, Am. J. Human Genet. 17: 191, 1965. 6. Ai-Aish, M. S., de la Cruz, 17., Goldsmith, L. A., Volpe, J., Mella, G., and Robinson, J. C.: Autosomal monosomy in man, New England J. Med. 277" 777, 1967. 7. Seely, J. R.: Unpublished data, reported at Clinical Research Center Day, University of Oklahoma School of Medicine, April 19, 1968. 8. Thorburn, M. J., and Johnson, B. E.: Apparent monosomy of a G-group chromosome
Brie[ clinical and laboratory observations
3 09
in a Jamaican infant, J. M. Genet. 3" 290, 1966. 9. Wright, S. W., Day, R. W., Muller, H., and Weinhouse, R.: The frequency of trisomy and translocation in Down's snydrome, J. PEDIAT. 70: 420, 1967. I0. Mikkelsen, M.: Down's syndrome at young maternal age: cytogenetical and genealogical study of eighty-one families, Ann. Human Genet. 31: 51, 1967. 11. McKay, J. R.: Whose chromosomes to count in mongolism, Pediatrics 36: 620, 1965.
Brie[ clinical and laboratory observations
tarded and ossification centers of the sternum were prematurely fused. A voiding cystourethrogram indicated bilateral vesicoureteral reflux, and an intravenous urogram revealed a hypoplastic right kidney. Chromosomal analysis of peripheral leukocytes revealed a normal 46, XY karyotype. The plasma growth hormone response to infusion of 1-arginine monochloride by radioimmunoassay was within normal limits. DISCUSSION T h e p r o b a n d has most of the c o m m o n clinical findings described in the i n t r o d u c tion. T h e following m a l f o r m a t i o n s seen in our case were not described in previously rep o r t e d cases: tibial torsion with metatarsus varus, facial a n d p a l a t a l paralysis, radiog r a p h i c findings of a b e r r a n t right subclavian artery, p r e m a t u r e fusion of sternal ossification centers, bilateral vesicoureteral reflux, a n d hypoplastic kidney. T o our knowledge this is the first N e g r o infant described with the S m i t h - L e m l i Opitz syndrome. We wish to express our gratitude to Dr. W. Webster Riggs for the special radiographic stud-
Familial 21/21 translocation S h e r m a n B. L a w t o n , M.D.,* Gayle R. S t o d d a r d , B.S., a n d J. R o d m a n Seely, M . D . , Ph.D. OKLAHOMA
CITY~ OKLA.
From the Department o[ Pediatrics and the Clinical Research Center, Children's Memorial Hospital, University o[ Oklahoma Medical Center. *Senior medical student during tenure of these studies .who was recipient of a medical student summer fellowship sponsored by Training Grant No. T1-HD-O0064 ]rom the National Institute o] Child Health and Human Development. Requests for reprints: ]. Rodman Seely, M.D., Children's Memorial Hospital, 800 N.E. 13, Oklahoma City, Okla. 73104.
30 5
ies and to Dr. Alvro M. Camacho for measurement of plasma growth hormone. REFERENCES 1. Smith, D. W., Lemll, L., and Opitz, J. M.: A newly recognized syndrome of multiple congenital anomalies. J. P~mAT. 64:~210, 1964. 2. Pinskey, L., and DiGeorge, A. M.: A familial syndrome of facial and skeletal anomalies associated with genital abnormality in the male and normal genitals in the female, J. P~DIAT. 66: 1049, 1965. 3. Blair, H. R., and Martin, J. K.: A syndrome characterized by mental retardation, short stature, craniofacial dysplasla, and genital anomalies occurring in siblings, J. PEDIAT. 69: 457, 1966. 4. Dallaire, L., and Fraser, F. C.: The syndrome of retardation with urogenital and skeletal anomalies in siblings, J. PEmAT. 69': 459, 1966. 5. Gibson, R.: A case of the Smith-Lem!i-Opitz syndrome of multiple congenital anoma!ies in association with dysplasia epiplysialis punetata, Canad. M. A. J. 92- 574, 1965. 6. Kenis, H., and Hustinx, T. W. J.: A familial syndrome of mental retardation in association with multiple congenital anomalies resembling the syndrome of Smith-Lemli-Opitz, Maandsehr. kindergeneesk. 35: 37, 1967. 7. Fine, R. N., Gwinn, J. L., and Young, E. F.: Smith-Lemi-Opitz syndrome, Am. J. Dis. Child. 115: 483, 1968.
A
D E F I N I T E , albeit
small, percentage
of
cases of Down's syndrome (mongolism) are attributable to translocation of a G - g r o u p chromosome to a n o t h e r chromosome, usually one of the D or G-groups. A l t h o u g h there have been numerous reports of G / G translocations since the initial one in 1960,1 very few ~, 3 have h a d sufficient d a t a to allow a further presumptive designation as 21/21 translocation. T h e purpose of this report is to present a family in which demonstration of a G / G translocation in 3 children with mongolism a n d the phenotypically n o r m a l m o t h e r is a c c o m p a n i e d by sufficient evidence to indicate the presence of 21/21 translocation. These studies were supported in part by Grant No. CRCS-28 ]tom the National Foundation and Public Health Service Grant No. FR-62 [rom the General Clinical Research Centers Branch, National Institutes o[ Health.
306
Brief clinical and laboratory observations
The Journal of Pediatrics February 1969
Fig. 1. Karyotype of the mother showing the G/G translocation carrier state. There are 45 chromosomes present with only 2 normal G-group chromosomes and an extra small meta~ centric chromosome (arrow). The Chicago classification is 45,XX,G-G-,t(GqGq).
CASE
REPORT
The family was composed of phenotypically normal parents and 3 children, all of whom had the typical stigmas of mongolism. Although intellectual development had been evaluated formally only in the eldest child (intelligence quotient of 42), each was obviously functioning at a retarded level. They had typical dermatoglyphic findings: Each child had distally placed axial triradii and a predominance of digital ulnar loops (8 such loops in" the eldest and 9 in each of the 2 younger patients). Only the 2 younger siblings had simian creases, and these were found on only the right hand. None of the 3 had overt cardiovascular disease. The mother, who was 2 years older than the father, gave birth to the first affected child in 1949 at 28 years of age. The other children were born in 1955 and 1961. There were 4 known abortions at 8 to 10 week's gestation bet@een the pregnancies of the middle and eldest child and another at a maternal age of 19 years. There
was no further history of mongolism in the family. The mother had 4 siblings with a total of 11 children, all of whom were living and well. The maternal grandmother had 5 siblings, who had 6 offspring, and the maternal grandfather had 6 siblings, who had 14 offspring; all of these persons were considered to be "normal." The paternal family history was noncontributory. The mother sought therapeutic abortion during the pregnancy of each of the latter two children and was refused because of the medical view that the previous events were spontaneous in nature and the chance of recurrence was, therefore, remote. CYTOLOGIC
INVESTIGATION
Peripheral blood samples were obtained from the affected children a n d from both parents: the leukocytes were cultured a n d prepared for chromosome analyses accordi n g to a method modified from that of Moorhead a n d associates. 4 T h e father had a
Volume 74 Number 2
Brie[ clinical and laboratory observations
307
Fig. 2. Karyotype from the youngest propositus; it is representative of those of the other 2 children. There are 46 chromosomes with 3 normal G-group chromosomes and an extra small metacentric chromosome (arrow). The Chicago classification is 46,XX,G-,t(GqGq)mat.
normal 46,XY chromosome complement, while analysis of the maternal cells revealed a modal number of 4 5 and an abnormal karyotype with only 2 G-group chromosomes instead of the normal 4 and an extra metacentric chromosome resembling those in the F-group but larger in size. Results from each of the 3 children were essentially identical; the modal chromosome count was 46 and the karyotypes contained 0nly 3 G-group chromosomes and the same extra metacentric chromosome as observed in the mother. The mother's karyotype is shown in Fig. 1; a representative karyotype of the children, in Fig. 2. It is believed that the extra metacentric chromosome represents a translocation between 2 members of the G-group; however, morphologic detail does not provide suffi-
cient distinction between the G-group pairs to allow differentiation of the abnormal chromosome as a 21/21 or 21/22 translocation. DISCUSSION Although numerous cases of transmission of G / G translocations have been reported in the literature, designation of them as 21/21 translocations has remained a rarity because of difficulties in distinguishing between the 2 pairs of G-group chromosomes. It is generally conceded that such distinction cannot be made on morphologic grounds alone. Although Yunis and associates 5 were able to demonstrate chronologic differences in the uptake of tritiated thymidine by chromosomes Nos. 21 and 22 in autoradiographic replication studies, this technique
3 08
Brie[ clinical and laboratory observations
does not yet appear sufficiently reliable to allow consistent separation of the G-group pairs, de Capoa and associates 3 came to the conclusion that autoradiography did not provide meaningful designation of the nature of a transmitted G/G21 translocation. For the present, classification of G/G21 translocations as 21/21 or 21/22 depends on the different nature of the respective inheritance pattern. Random selection in the mating of a phenotypically normal 21/22 translocation carrier would produce zygotes divided into groups of normal offspring, phenotypically normal carriers, trisomy-21, and monosomy-2t. However, a 21/21 translocation carrier, normally fertilized, is able to produce only translocation trisomy-21 or monosomy-21. Since autosomal monosomy has been reported in only 3 living patients, 6-8 for practical purposes it may be considered a lethal condition. Thus, a 21/21 translocation carrier would be expected to abort all fetuses not afflicted with Down's syndrome. The production of a normal child by a G / G translocation carrier allows identification of the abnormal chromosome as 21/22, but designation of a 21/21 translocation is presumptive only and depends on the presence of a sufficient number of involved children and abortions to mal~e such designation statistically probable. Only 2 previous cases were found, those of Dallaire and associates 2 and de Capoa and associates, s which appear to provide such evidence. In the present case, assumption that each abortion was the result of monosomy-21 allows consideration of the probability of 8 consecutive pregnancies without the appearance of a phenotypically normal child if the translocation we.re a 21/22. Assuming a random distribution among the possibilities, namely that "one half of the offspring would be normal or phenotypicalIy normal carriers while the remainder would be abortuses or affected with Down's syndrome, the probability would be ([~21 s) or 1/256. Thus, it appears likely that this case is indeed one of 21/21 translocation. This assumption is strengthened by evidence that a greater percentage of normals and phenotypically nor-
The ]ourna! o[ Pediatrics February 1969
mal carriers occur than would be expected theoretically. The unfortunate aspects of this case demonstrate the need for standards for performing chromosome analysis on children born with Down's syndrome. Sufficient data are now available to indicate the probability of inherited translocation in such cases2, 10 It seems reasonable to perform chromosome analysis routinely in all instances in which the maternal age is less than 30 years or when there is a positive family history of the anomaly; as recently discussed by McKay 11 and Wright and associates, 9 adoption of such criteria would potentially prevent most occurrences of multiple affected births to the same mother. SUMMARY
A family is presented in which 8 consecutive pregnancies produced 3 children affected with Down's syndrome and 5 spontaneous abortions. The 3 siblings were demonstrated to have translocation trisomy-21 of the G / G type; analysis of maternal cells revealed a modal chromosome number of 45 and presence of a G / G translocation carrier state. Morphologic detail does not at present provide differentiation between chromosomes of the G-group; however, statistical analysis demonstrates the probability that this represents a 21/21 translocation; only 2 similar cases were found in the literature. REFERENCES
1. Fraccarro, M., Kaijser, K., and Lindsten, J.: Chromosomal abnormalities in father and mongol child, Lancet h 724, 1960. 2. Dallaire, L., and Fraser, F. C.: Two unusual cases of familial mongolism, Canad. J. Genet. & Cytol. 6: 540, 1964. 3. de Capoa, A., Miller, O. J., Mukherjee, B. B., and Warburton, D.: Autoradiographlc studies on a mother and aborted fetus from a family with four mongoloid children and a presumptive 21/21 translocation, Ann. Human Genet. 3h 243, 1967. 4. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D. M., and Hungerford, D. A.: Chromosome preparations of leukocytes cultured from human peripheral blood, Exper. Cell Res. 20: 613, 1960. 5. Yunis, J. J., Hook, E. B., and Mayer, M.: Identification of the mongolism chromosome
Volume 74 Number 2
by DNA replication analysis, Am. J. Human Genet. 17: 191, 1965. 6. Ai-Aish, M. S., de la Cruz, 17., Goldsmith, L. A., Volpe, J., Mella, G., and Robinson, J. C.: Autosomal monosomy in man, New England J. Med. 277" 777, 1967. 7. Seely, J. R.: Unpublished data, reported at Clinical Research Center Day, University of Oklahoma School of Medicine, April 19, 1968. 8. Thorburn, M. J., and Johnson, B. E.: Apparent monosomy of a G-group chromosome
Brie[ clinical and laboratory observations
3 09
in a Jamaican infant, J. M. Genet. 3" 290, 1966. 9. Wright, S. W., Day, R. W., Muller, H., and Weinhouse, R.: The frequency of trisomy and translocation in Down's snydrome, J. PEDIAT. 70: 420, 1967. I0. Mikkelsen, M.: Down's syndrome at young maternal age: cytogenetical and genealogical study of eighty-one families, Ann. Human Genet. 31: 51, 1967. 11. McKay, J. R.: Whose chromosomes to count in mongolism, Pediatrics 36: 620, 1965.