Clinical Genetics 1975: 8: 370-375
Ring chromosome 6 in a malformed boy FABIO SALAMANCA-GONEZ, SARA NAVA, AND SALVADOR ARMENDARES
Departamento de GenCtica, Hospital de Pediatria, Centro MCdico Nacional and Seccibn de GenCtica del Departamento de Investigaci6n Cientifica, Instituto Mexican0 del Seguro Social, MCxico City, Mexico In a mentally retarded and malformed boy who died at 6 months of age a ring chromosome 6 was identified by G banding. Clinical, cytogenetical and post-mortem findings are discussed. Received 14 April, accepted for publication 30 April 1975
ments are far below the 3rd percentile). Physical examination (Fig. 1) disclosed a peculiar facies with microphthalmia, hyperthelorism, bilateral epicanthic folds, flat nose, asymmetric low-set and malformed ears, micrognathia and a fish-shaped, small mouth. There was a high-arched palate. The neck was short and webbed. A systolic and diastolic murmur (grade 111-IV) was heard Case Report in the precordial area and in the left subThe propositus was the term product of the clavian region. The penis was small and first normal pregnancy and delivery of a bilateral hydrocele was observed. There 24-year-old mother and 27-year-old father. was bilateral congenital hip dislocation and The parents are not consanguineous. The bilateral tallus valgus. A simian crease on mother reported taking 12 capsules of the left palm, with an equivalent crease on diazepam (7-chloro-1,3-dihydro-l-methyl-5- the right palm, were observed. The dermal phenyl-2H-1, 4-benzodiazepine-2-one) dur- ridges were hypoplastic and no dermatoging the first month of pregnancy and lyphic patterns could be identified. dimethyl-pyrazolone (dosis not noted) durOphthalmologic examination revealed, in ing the first quarter of pregnancy. Birth addition to the microphthalmia, bilateral weight was 1960 g and the length was 40 megalocornea and embryotoxon, bilateral optic atrophy, chorioretinitis on the right cm. At 5 months of age he measured 45 cm, side and coloboma of the iris on the left. his weight was 2200 g, and his head The patient died at 6 months of age circumference was 28.5 cm (these measure- because of an acute pneumonic process. Constitutional ring chromosomes involving the C group are rare and only two cases have been described involving chromosome number 6 (Moore et al. 1973, Van den Berghe et al. 1974). In this report we present a third case, inchding a description of the post-mortem findings.
RING CHROMOSOME 6 IN A MALFORMED BOY
Laboratory lnvestigatlon
At 5 months of age laboratory studies, including blood cell count, urinalysis, and serum phosphorus, calcium, creatinine, uric
Fig. 1. Post-mortem pictures of the patient.
371
acid, urea and bilirubins, were normal or negative. The toxoplasmosis test (Sabin-Feldman) and rubella antibodies were negative in the patient and his mother.
372
SALAMANCA-GOMEZ, NAVA, AND ARMENDARES
Fig. 2. A) Portions of three metaphases showing ring chromosomes. Note open and multicentric rings. B) The normal chromosome No. 6 and rings from three different cells with G banding.
Roentgenological examination revealed retarded bone age. Cervical and thoracic hemivertebras were observed. Necropsy Studies
The necropsy findings included: persistent ductus arterious and hypoplasia of the arch of the aorta; dysplastic pulmonary valve, interatrial septa1 defect, insufficiency of the tricuspid valve and hypertrophy of the right ventricle. There was right pulmonary isomerism. The origin of the left renal artery was localized on the right side from a
common branch from the superior mesenteric artery. There was cerebral atrophy, polymicrogyria, atrophy of the first gyrus on the left side and hydrocephalus. Exostoses of the xiphoid appendix and cervical and thoracic hemivertebrae were seen. Cytogenetic Investigations
X-chromatin was negative. Chromosome studies in the patient and in both parents were carried out on cultures of peripheral blood lymphocytes according to usual procedures. The propositus had a modal num-
RING CHROMOSOME 6 IN A MALFORMED BOY
373
Flg. 3. Full karyotype of the patient showing the ring 6 chromosome with G banding.
ber of 46 chromosomes but one of the C group chromosomes was replaced by a ring chromosome. The ring was present in all of 100 analyzed cells. One cell showed two rings and dicentric and open rings were observed in two cells (Fig. 2A). Chromosome complements from the parents were normal. A second study was performed in the proband’s blood obtained by a post-mortem cardiac aspiration. G (Sumner et al. 1971) and C (Salamanca & Armendares 1974) banding techniques were performed. The G banding pattern revealed that the abnormal chromosome was a ring 6 (Figs. 2B and 3) with the break points probably located on bands p23 or p24 and q26 or q27 (Paris
Conference 1971). The C banding revealed a normal pattern of constitutive heterochromatin. Dlscusslon
The phenotypic characteristics of patients with ring chromosomes are quite variable because the behavior of the rings in mitotic divisions produces a variation of gene dose from cell to cell, and because the deletion of genetic material depends upon the position of the break points. The new banding techniques have made it possible to establish a more precise identification of the ring chromosomes and to ascertain the position of the break point, thus enabling the
374
SALAMANCA-GOMEZ, NAVA. A N D A R M E N D A R E S
Table 1 Comparative clinical features in cases with ring 6 chromosome
Low birth weight Mental and physical retardation Microcephaly Microphthalmia Epicanthal folds Hypertelorism Strabismus Nystagmus Coloboma of the iris Optic atrophy Megalocornea Embryotoxon Flat nose Low-set, malformed ears Micrognathia Microstomia High-arched palate Short neck Congenital heart defect Hemivertebras Pes equinus Tallus valgus Hyperkeratosis of the soles Nevus pigmentosus
Case of Moore et al. (1973)
Case of Van den Berghe et al. (1974)
Present case
+
+
+
+ + + +
+ + +
+
-
+ +
-
-
+ + +
+ +
-
-
-
+ -
+ +
+ + -
-
+ + + +
+
comparison of phenotypes of patients having this type of abnormal chromosome. The clinical findings observed in the three patients with a ring chromosome 6 reported so far are summarized in Table 1. In the three cases there is concurrence of the following signs: mental and physical retardation, low birth weight, microcephaly, peculiar facies, microphthalmia and higharched palate. In two of the cases epicanthal folds, embryotoxon, flat nose, lowset ears, micrognathia, microstomia and short neck were also observed. It is premature to judge if the postmortem features are due to the chromo-
some abnormality or if they are a fortuitous association. More studies are needed to clarify this problem. Salamanca et al. (1972) reported that in cases with ring chromosome 13 the position of the index case in the sibship was generally the first and no effect of advanced parental age was observed. In two out of three cases with ring chromosome 6, the propositus is the first born and the mean parental age is 25 years for the mothers and 27 for the fathers. It is interesting to comment that in the present case, as well as those of Moore et al. (1973) and Van den Berghe et al. (1974), the ring was relatively stable, contrary to what has been described, for example in the D group ring chromosome (Salamanca et al. 1972). Kistenmacher ,& Punnett (1970) compared the behavior of D and C ring chromosomes, and found important differences in their stability. Chromosome 13 has late replicating DNA in a large distal segment of the long arm while chromosome 6 has no similar late replicating segment. This segment is largely heterochromatin (Brown 1966). It is thus possible that the relative proportion between heterochromatin and euchromatin and their localization in a specific chromosome may play some role in the behavior of the rings, as hypothesized by Kistenmacher #&Punnet (1970). Acknowledgment
This work was partially supported by a grant from The Ford Foundation.
References
Brown, S. W. (1966). Heterochromatin. Science 151, 417-425.
Kistenmacher, M. L. & H. H. Punnett (1970). Comparative behavior of ring chromosomes. Amer. J . hum. Genet. 22, 304-318.
Moore, C.M., R . H . Heller & G.H. Thomas (1973). Developmental abnormalities associ-
RING CHROMOSOME 6 IN A MALFORMED BOY
ated with a ring chromosome 6. J . med. Genet. 10, 299-303. Paris Conference 1971 (1972). Standardization in human cytogenetics. Birth Dejects: Original Article Series V l l l , No. 7 . Salamanca, F., L. Buentello & S. Armendares (1972). Ring D, chromosome with remarkable morphological variation in a boy with mental retardation. Ann. Ge'ne't. 15, 183-186. Salamanca, F. & S. Armendares (1974). C. bands in human metaphase chromosomes treated by barium hydroxide. Ann. Ge'nkt. 17, 135-136. Sumner, A.T., H. J. Evans & R. A. Buckland (1971). New technique for distinguishing between human chromosomes. Nature New Biol. 232, 31-32.
3 75
Van den Berghe, H., J. P. Fryns, J. J. Cassiman & G. David (1974). Chromosome 6 en anneau caryotype 16,XY,r(6)/45,XY,-6. Ann. Ce'ne't. 17, 29-35.
Address: Fabio Salamanca-Gdmez, M . D . Departamento de Gene'tica Hospital de Pediatria Seccidn de Gene'tica Departamento de lnvestigacidn lnstituto Mexican0 det Seguro Social Apartado Postal 73-032 M h i c o 73, D.F. Mexico
Ring chromosome 6 in a malformed boy FABIO SALAMANCA-GONEZ, SARA NAVA, AND SALVADOR ARMENDARES
Departamento de GenCtica, Hospital de Pediatria, Centro MCdico Nacional and Seccibn de GenCtica del Departamento de Investigaci6n Cientifica, Instituto Mexican0 del Seguro Social, MCxico City, Mexico In a mentally retarded and malformed boy who died at 6 months of age a ring chromosome 6 was identified by G banding. Clinical, cytogenetical and post-mortem findings are discussed. Received 14 April, accepted for publication 30 April 1975
ments are far below the 3rd percentile). Physical examination (Fig. 1) disclosed a peculiar facies with microphthalmia, hyperthelorism, bilateral epicanthic folds, flat nose, asymmetric low-set and malformed ears, micrognathia and a fish-shaped, small mouth. There was a high-arched palate. The neck was short and webbed. A systolic and diastolic murmur (grade 111-IV) was heard Case Report in the precordial area and in the left subThe propositus was the term product of the clavian region. The penis was small and first normal pregnancy and delivery of a bilateral hydrocele was observed. There 24-year-old mother and 27-year-old father. was bilateral congenital hip dislocation and The parents are not consanguineous. The bilateral tallus valgus. A simian crease on mother reported taking 12 capsules of the left palm, with an equivalent crease on diazepam (7-chloro-1,3-dihydro-l-methyl-5- the right palm, were observed. The dermal phenyl-2H-1, 4-benzodiazepine-2-one) dur- ridges were hypoplastic and no dermatoging the first month of pregnancy and lyphic patterns could be identified. dimethyl-pyrazolone (dosis not noted) durOphthalmologic examination revealed, in ing the first quarter of pregnancy. Birth addition to the microphthalmia, bilateral weight was 1960 g and the length was 40 megalocornea and embryotoxon, bilateral optic atrophy, chorioretinitis on the right cm. At 5 months of age he measured 45 cm, side and coloboma of the iris on the left. his weight was 2200 g, and his head The patient died at 6 months of age circumference was 28.5 cm (these measure- because of an acute pneumonic process. Constitutional ring chromosomes involving the C group are rare and only two cases have been described involving chromosome number 6 (Moore et al. 1973, Van den Berghe et al. 1974). In this report we present a third case, inchding a description of the post-mortem findings.
RING CHROMOSOME 6 IN A MALFORMED BOY
Laboratory lnvestigatlon
At 5 months of age laboratory studies, including blood cell count, urinalysis, and serum phosphorus, calcium, creatinine, uric
Fig. 1. Post-mortem pictures of the patient.
371
acid, urea and bilirubins, were normal or negative. The toxoplasmosis test (Sabin-Feldman) and rubella antibodies were negative in the patient and his mother.
372
SALAMANCA-GOMEZ, NAVA, AND ARMENDARES
Fig. 2. A) Portions of three metaphases showing ring chromosomes. Note open and multicentric rings. B) The normal chromosome No. 6 and rings from three different cells with G banding.
Roentgenological examination revealed retarded bone age. Cervical and thoracic hemivertebras were observed. Necropsy Studies
The necropsy findings included: persistent ductus arterious and hypoplasia of the arch of the aorta; dysplastic pulmonary valve, interatrial septa1 defect, insufficiency of the tricuspid valve and hypertrophy of the right ventricle. There was right pulmonary isomerism. The origin of the left renal artery was localized on the right side from a
common branch from the superior mesenteric artery. There was cerebral atrophy, polymicrogyria, atrophy of the first gyrus on the left side and hydrocephalus. Exostoses of the xiphoid appendix and cervical and thoracic hemivertebrae were seen. Cytogenetic Investigations
X-chromatin was negative. Chromosome studies in the patient and in both parents were carried out on cultures of peripheral blood lymphocytes according to usual procedures. The propositus had a modal num-
RING CHROMOSOME 6 IN A MALFORMED BOY
373
Flg. 3. Full karyotype of the patient showing the ring 6 chromosome with G banding.
ber of 46 chromosomes but one of the C group chromosomes was replaced by a ring chromosome. The ring was present in all of 100 analyzed cells. One cell showed two rings and dicentric and open rings were observed in two cells (Fig. 2A). Chromosome complements from the parents were normal. A second study was performed in the proband’s blood obtained by a post-mortem cardiac aspiration. G (Sumner et al. 1971) and C (Salamanca & Armendares 1974) banding techniques were performed. The G banding pattern revealed that the abnormal chromosome was a ring 6 (Figs. 2B and 3) with the break points probably located on bands p23 or p24 and q26 or q27 (Paris
Conference 1971). The C banding revealed a normal pattern of constitutive heterochromatin. Dlscusslon
The phenotypic characteristics of patients with ring chromosomes are quite variable because the behavior of the rings in mitotic divisions produces a variation of gene dose from cell to cell, and because the deletion of genetic material depends upon the position of the break points. The new banding techniques have made it possible to establish a more precise identification of the ring chromosomes and to ascertain the position of the break point, thus enabling the
374
SALAMANCA-GOMEZ, NAVA. A N D A R M E N D A R E S
Table 1 Comparative clinical features in cases with ring 6 chromosome
Low birth weight Mental and physical retardation Microcephaly Microphthalmia Epicanthal folds Hypertelorism Strabismus Nystagmus Coloboma of the iris Optic atrophy Megalocornea Embryotoxon Flat nose Low-set, malformed ears Micrognathia Microstomia High-arched palate Short neck Congenital heart defect Hemivertebras Pes equinus Tallus valgus Hyperkeratosis of the soles Nevus pigmentosus
Case of Moore et al. (1973)
Case of Van den Berghe et al. (1974)
Present case
+
+
+
+ + + +
+ + +
+
-
+ +
-
-
+ + +
+ +
-
-
-
+ -
+ +
+ + -
-
+ + + +
+
comparison of phenotypes of patients having this type of abnormal chromosome. The clinical findings observed in the three patients with a ring chromosome 6 reported so far are summarized in Table 1. In the three cases there is concurrence of the following signs: mental and physical retardation, low birth weight, microcephaly, peculiar facies, microphthalmia and higharched palate. In two of the cases epicanthal folds, embryotoxon, flat nose, lowset ears, micrognathia, microstomia and short neck were also observed. It is premature to judge if the postmortem features are due to the chromo-
some abnormality or if they are a fortuitous association. More studies are needed to clarify this problem. Salamanca et al. (1972) reported that in cases with ring chromosome 13 the position of the index case in the sibship was generally the first and no effect of advanced parental age was observed. In two out of three cases with ring chromosome 6, the propositus is the first born and the mean parental age is 25 years for the mothers and 27 for the fathers. It is interesting to comment that in the present case, as well as those of Moore et al. (1973) and Van den Berghe et al. (1974), the ring was relatively stable, contrary to what has been described, for example in the D group ring chromosome (Salamanca et al. 1972). Kistenmacher ,& Punnett (1970) compared the behavior of D and C ring chromosomes, and found important differences in their stability. Chromosome 13 has late replicating DNA in a large distal segment of the long arm while chromosome 6 has no similar late replicating segment. This segment is largely heterochromatin (Brown 1966). It is thus possible that the relative proportion between heterochromatin and euchromatin and their localization in a specific chromosome may play some role in the behavior of the rings, as hypothesized by Kistenmacher #&Punnet (1970). Acknowledgment
This work was partially supported by a grant from The Ford Foundation.
References
Brown, S. W. (1966). Heterochromatin. Science 151, 417-425.
Kistenmacher, M. L. & H. H. Punnett (1970). Comparative behavior of ring chromosomes. Amer. J . hum. Genet. 22, 304-318.
Moore, C.M., R . H . Heller & G.H. Thomas (1973). Developmental abnormalities associ-
RING CHROMOSOME 6 IN A MALFORMED BOY
ated with a ring chromosome 6. J . med. Genet. 10, 299-303. Paris Conference 1971 (1972). Standardization in human cytogenetics. Birth Dejects: Original Article Series V l l l , No. 7 . Salamanca, F., L. Buentello & S. Armendares (1972). Ring D, chromosome with remarkable morphological variation in a boy with mental retardation. Ann. Ge'ne't. 15, 183-186. Salamanca, F. & S. Armendares (1974). C. bands in human metaphase chromosomes treated by barium hydroxide. Ann. Ge'nkt. 17, 135-136. Sumner, A.T., H. J. Evans & R. A. Buckland (1971). New technique for distinguishing between human chromosomes. Nature New Biol. 232, 31-32.
3 75
Van den Berghe, H., J. P. Fryns, J. J. Cassiman & G. David (1974). Chromosome 6 en anneau caryotype 16,XY,r(6)/45,XY,-6. Ann. Ce'ne't. 17, 29-35.
Address: Fabio Salamanca-Gdmez, M . D . Departamento de Gene'tica Hospital de Pediatria Seccidn de Gene'tica Departamento de lnvestigacidn lnstituto Mexican0 det Seguro Social Apartado Postal 73-032 M h i c o 73, D.F. Mexico
