Hum. Genet. 50, 145--149 (1979) © by Springer-Verlag 1979
Original Investigations Ring Chromosome 6: Case Report and Review of Literature K. R. Kini, D. L. Van Dyke*, L. Weiss, and M. S. Logan Departments of Pediatrics and Pathology, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, M. 48202, USA
Summary. A ring chromosome 6 has been identified by GTG-banding in a male with microcephaly, growth retardation, seizures, epicanthus, hypertelorism, micrognathia, and other congenital anomalies. Cytogenetic studies indicate the instability of the ring chromosome. The most common findings in subjects with ring 6 include: profound to moderate mental retardation, microcephaly, prenatal growth failure, retarded bone age, epicanthal folds, flat nasal bridge, short neck, ears low-set or malformed, microphthalmia, and micrognathim Linkage studies, including HLA, are consistent with reported maps of chromosome 6.
Introduction Only with the advent of chromosome banding has it been possible to identify accurately C-autosome rings or deletions. Location by chromosome number is essential to delineate syndromes, to relate the clinical effects of aneuploidy to particular chromosome regions, and to attempt deletion mapping of genes. The present case broadens the clinical spectrum of the ring chromosome 6 syndrome which may consist of profound growth and mental retardation, convulsions; micrOgnathia, microphthalmia, short neck, low-set or malformed ears, flat nasal bridge, and epicanthus.
Case Report The proband (Lab.-No. 138-0001) is a 41/2year old black male, one of a set of twins born to nonconsanguineous parents. The patient weighed 2525g at term, his twin 2809g. He had mild respiratory distress and CNS depression at birth and was in intensive care for 5 days. His mother was 18 and his father 22 years old. His twin sister and four year old brother are normal. This study was supported in part by grant number 1-442 from the National Foundation -March of Dimes * To whom offprint requests should be sent
0340-6717/79/0050/0145/$ 01.00
146
K.R. Kini et al.
His mother was treated during this pregnancy with magensium sulfate for preeclampsia, but took no other drugs. Since early infancy he has had multiple episodes of afebrile grand mal seizures, which have been controlled by phenobarbitol. Electroencephalogram revealed diffuse slowing without epileptiform or focal activity. He has remained spastic, lies in a "frog-leg" position, and has had intermittent opisthotonus. At 4~ years his IQ is approximately 20, in the range of profound mental retardation. At 7 weeks of age he was microcephalic (OFC =34,5 cm), his length (51 cm) and weight (2608 g) were below the third percentile; his bone age was delayed, and he was failing to thrive. He had disproportionate facial features with a wide nasal bridge, epicanthal folds, hypertelorism, micrognathia, low-set ears, and high-arched palate. He had an umbilical hernia, and bilateral undescended testes. Audiological and ophthalmological evaluations were within normal limits, as were many metabolic studies.
Cytogenetics The proband was karyotyped in September, 1974 (peripheral blood), November, 1974 (fibroblast culture from skin biopsy), and in March, 1976 (peripheral blood) with GTG-banding (G-bands by trypsin using Giemsa). Of 64 peripheral blood lymphocyte metaphases analyzed, 5 cells had a 46,XY karyotype, and 48 cells (Fig. 1) had 46,XY,r(6)(p25q26) or (p24q27). Nine other cells had 45 chromosomes with apparently random losses, and two cells were 45,XY,-6.
#6
Fig. 1. a The karyotype 46,XY, r(6) was present in most cells from peripheral blood and fibroblast cultures. See text for details, b Breakpoints in the formation of the ring chromosome appear to be 6p25 and 6q26, or at 6p24 and 6q27. The origin of the light band between 6p24 and 6q26 is open to question
Ring Chromosome 6
147
In addition, 15 fibroblast metaphase cells were 46,XY, r(6) and 5 had a 45,XY,-6 karyotype. One cell had a small ring, two cells had tiny fragments without a r(6), and another cell appeared to have two rings. The ring chromosomes appeared to be of uniform size in all other cells from both tissues. The karyotpye of the twin sister was 46,XX in all of15 cells. The parents were not karyotyped; in all likelihood they have no r(6) cell line since a normal cell line was observed in the boy.
Genotyping Family studies and somatic cell hybridization studies have been used to map and assign the linkage group including HLA, complement, PGM, and other genes to chromosome 6, at band 6p21 to 6p22 (Bodmer, 1976; Francke and Pellegrino, 1977; Breuning et al., 1977). Nance and Engel (1967) point out that whenever a patient with a deletion is heterozygous for co-dominant alleles, that locus is excluded from the region deleted. This permits mapping by exclusion even when other family members are unavailable. In the present case, only the affected child has been studied by genotyping; his parents refused to be studied. The boy was HLA A26, A28, B12, CW4. He is also heterozygous in acid phosphatase (AB), Rh(ccDEe), and Duffy (Fy"/Fy b) types. Since he is heterozygous, the HLA-A locus is excluded from the deleted regions (i.e., distal to bands 6p24 and 6q25). For the HLA-B and C loci we cannot distinguish from among the three possibilities: an undetected antigen, homozygosity, and hemizygosity. Thus the present findings are consistent with the established location of HLA.
Discussion In the case of ring 6 chromosome described by Wurster et al. (1969) and WursterHill and Hoefnagel (1975) the breakpoints were given as p25 and q27. The breakpoints were given as p23 or p24 and q26 or q27 in the case described by SalamancaGomez et al. (1975). The present case has breakpoints at p25 and q26, or p24 and q27, but again the breakpoints cannot be defined with certainty because we cannot distinguish between the light bands p25 and q27. Other cases of r(6) have shown mosaicism with normal cells or 45,-6 cells (Wurster et al., 1969; Moore et al., 1973; Van den Berghe et al., 1974; Fried et al., 1975). Similarly, the ring chromosome 6 described here was absent in a few cells (45,XY,-6) presumably due to mitotic instability. We observed no dicentric rings but in three fibroblast metaphase cells the ring appeared unusually small, which suggests a breakagereunion cycle. The presence of normal 46,XY cells indicates post-zygotic formation of the ring. In no reported case was the ring observed in a parent.
Ring 6 Phenotype Five other patients have been described with a ring chromosome 6 identified by banding (Table 1). The present case becomes the sixth fully described in the
148
K . R . K i n i et al.
T a b l e 1. C l i n i c a l f i n d i n g s in six c a s e s o f r i n g c h r o m o s o m e
6
Reference
Moore et al., 1973
Van den Berghe et al., 1974
Salamanca- Fried Gomez et al., et al., 1975 1975
Wurster et al., 1969 and Wurster-Hill et al., 1 9 7 5
Present case
2525
B i r t h w e i g h t (g)
2910
2900
1960
3380
2433
Mental retardation
+
+
+
+
+
+
Development
+
+
+
+
+
+
+
+
retardation
Bone age retardation
+
Seizures
.
.
.
.
.
Microcephaly
+
+
+
+
+
Microphthalmia
+
+
+
-
-
Strabismus
-
+
-
-
-
Nystagmus
-
+
-
-
-
Iris coloboma
-
-
+
-
-
Optic atrophy
-
-
+
-
-
Megalocornea
-
-
+
-
-
Embryotoxon
-
+
+
-
-
Epicanthus bilateral
+
-
+
+
+
+
Hypertelorism
-
-
+
-
+
+
+
+
Flat or broad nasal bridge
+
-
+
+
Ears low and/or
+
+
+
+
+
+
Micrognathia
+
-
+
-
+
+
Microstomia
+
-
+
-
+
+
+
-
+
+
-
+
+
+
Congenital heart defect
-
-
+
-
Hemivertebrae
-
-
+
+
-
-
malformed
Palate high-arched Neck short and/or
webbed
+
-
Talipes equinovarus Pes equinus Con. hip dislocation
+
-
+
-
-
+
Talus valgus
-
-
+
-
Soles-hyperkeratosis
+
-
-
-
Nevus pigmentosus
-
+
-
-
Cephalohematoma
literature.
+
Parental
six males
and
The
common
most
mental
two
a g e is n o t females findings
retardation,
epicanthal
folds,
microphthalmia,
obviously
affected,
in subjects
microcephaly, flat and
Acknowledgements. W e
nasal
bridge,
increased
and
over
normal.
we are unaware with ring 6 include:
prenatal short
growth neck,
-
of any
profound
failure, ears
There
retarded
low-set
have
affected
or
been
siblings.
to moderate bone
age,
malformed,
micrognathia.
w o u l d like t o t h a n k H a j i m e H a y a s h i , P h . D . f o r t h e h i s t o c o m p a t i b i l i t y typing, the laboratory of C. Eugene Jackson, M.D. for genotyping, Juanita Clark, George Henry, and Nona Lightman for expert technical assistance, and Debbie N. Anderson for typing the manuscripts.
Ring Chromosome 6
149
References Bodmer, W. F.: Report of the committee on the genetic constitution of chromosome 6. Cytogenet. Cell Genet. 16, 24--30 (1976) Breuning, M. H., van den Berg-Loonen, E. M., Bernini, L. F., Bijlsma, J. B., van Loghem, E., Khan, P. M., Nijenhuis, L. E.: Localization of HLA on the short arm of chromosome 6. Hum. Genet. 37, 131--139 (1977) Francke, U., Pellegrino, M. A.: Assignment of the major histocompatibility complex to a region of the short arm of human chromosome 6. Proc. Natl. Acad. Sci. 74, 1147--1151 (1977) Fried, K., Rosenblatt, M., Mundel, G., Krikler, R.: Mental retardation and congenital malformations associated with a ring chromosome 6. Clin. Genet. 7, 192--196 (1975) Moore, C. M., Heller, R. H., Thomas, G. H.: Developmental abnormalities associated with a ring chromosome 6. J. Med. Genet. 10, 299--303 (1973) Nance, W. E., Engel, E.: Autosomal deletion mapping in man. Science 155,692--694 (1967) Salamanca-Gomez, F., Nava, S., Armendares, S.: Ring chromosome 6 in a malformed boy. Clin. Genet. 8, 370--375 (1975) Van den Berghe, H., Fryns, J. P., Cassiman, J. J., David, G.: Chromosome 6 en anneau caryotype 46,XY,r(6)/45,XY,-6. Ann. Genet. 17, 29--35 (1974) Wurster, D., Pomeroy, J., Benirschke, K., Hoefnagel, D.: Mental deficiency and malformations in a boy with a group-C ring chromosome: 46,XY,Cr. J. Ment. Defic. Res. 13, 184--190 (1969) Wurster-Itill, D. H., Hoefnagel, D.: Banding identification of chromosomal abnormalities in four patients: ring (6), translocation (2q-;15q+), translocation (21q;21q) and deletion (22q-). J. Ment. Defic. Res. 19, 145--150 (1975)
Received November 3, 1978 / Revised March 13, 1979
Original Investigations Ring Chromosome 6: Case Report and Review of Literature K. R. Kini, D. L. Van Dyke*, L. Weiss, and M. S. Logan Departments of Pediatrics and Pathology, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, M. 48202, USA
Summary. A ring chromosome 6 has been identified by GTG-banding in a male with microcephaly, growth retardation, seizures, epicanthus, hypertelorism, micrognathia, and other congenital anomalies. Cytogenetic studies indicate the instability of the ring chromosome. The most common findings in subjects with ring 6 include: profound to moderate mental retardation, microcephaly, prenatal growth failure, retarded bone age, epicanthal folds, flat nasal bridge, short neck, ears low-set or malformed, microphthalmia, and micrognathim Linkage studies, including HLA, are consistent with reported maps of chromosome 6.
Introduction Only with the advent of chromosome banding has it been possible to identify accurately C-autosome rings or deletions. Location by chromosome number is essential to delineate syndromes, to relate the clinical effects of aneuploidy to particular chromosome regions, and to attempt deletion mapping of genes. The present case broadens the clinical spectrum of the ring chromosome 6 syndrome which may consist of profound growth and mental retardation, convulsions; micrOgnathia, microphthalmia, short neck, low-set or malformed ears, flat nasal bridge, and epicanthus.
Case Report The proband (Lab.-No. 138-0001) is a 41/2year old black male, one of a set of twins born to nonconsanguineous parents. The patient weighed 2525g at term, his twin 2809g. He had mild respiratory distress and CNS depression at birth and was in intensive care for 5 days. His mother was 18 and his father 22 years old. His twin sister and four year old brother are normal. This study was supported in part by grant number 1-442 from the National Foundation -March of Dimes * To whom offprint requests should be sent
0340-6717/79/0050/0145/$ 01.00
146
K.R. Kini et al.
His mother was treated during this pregnancy with magensium sulfate for preeclampsia, but took no other drugs. Since early infancy he has had multiple episodes of afebrile grand mal seizures, which have been controlled by phenobarbitol. Electroencephalogram revealed diffuse slowing without epileptiform or focal activity. He has remained spastic, lies in a "frog-leg" position, and has had intermittent opisthotonus. At 4~ years his IQ is approximately 20, in the range of profound mental retardation. At 7 weeks of age he was microcephalic (OFC =34,5 cm), his length (51 cm) and weight (2608 g) were below the third percentile; his bone age was delayed, and he was failing to thrive. He had disproportionate facial features with a wide nasal bridge, epicanthal folds, hypertelorism, micrognathia, low-set ears, and high-arched palate. He had an umbilical hernia, and bilateral undescended testes. Audiological and ophthalmological evaluations were within normal limits, as were many metabolic studies.
Cytogenetics The proband was karyotyped in September, 1974 (peripheral blood), November, 1974 (fibroblast culture from skin biopsy), and in March, 1976 (peripheral blood) with GTG-banding (G-bands by trypsin using Giemsa). Of 64 peripheral blood lymphocyte metaphases analyzed, 5 cells had a 46,XY karyotype, and 48 cells (Fig. 1) had 46,XY,r(6)(p25q26) or (p24q27). Nine other cells had 45 chromosomes with apparently random losses, and two cells were 45,XY,-6.
#6
Fig. 1. a The karyotype 46,XY, r(6) was present in most cells from peripheral blood and fibroblast cultures. See text for details, b Breakpoints in the formation of the ring chromosome appear to be 6p25 and 6q26, or at 6p24 and 6q27. The origin of the light band between 6p24 and 6q26 is open to question
Ring Chromosome 6
147
In addition, 15 fibroblast metaphase cells were 46,XY, r(6) and 5 had a 45,XY,-6 karyotype. One cell had a small ring, two cells had tiny fragments without a r(6), and another cell appeared to have two rings. The ring chromosomes appeared to be of uniform size in all other cells from both tissues. The karyotpye of the twin sister was 46,XX in all of15 cells. The parents were not karyotyped; in all likelihood they have no r(6) cell line since a normal cell line was observed in the boy.
Genotyping Family studies and somatic cell hybridization studies have been used to map and assign the linkage group including HLA, complement, PGM, and other genes to chromosome 6, at band 6p21 to 6p22 (Bodmer, 1976; Francke and Pellegrino, 1977; Breuning et al., 1977). Nance and Engel (1967) point out that whenever a patient with a deletion is heterozygous for co-dominant alleles, that locus is excluded from the region deleted. This permits mapping by exclusion even when other family members are unavailable. In the present case, only the affected child has been studied by genotyping; his parents refused to be studied. The boy was HLA A26, A28, B12, CW4. He is also heterozygous in acid phosphatase (AB), Rh(ccDEe), and Duffy (Fy"/Fy b) types. Since he is heterozygous, the HLA-A locus is excluded from the deleted regions (i.e., distal to bands 6p24 and 6q25). For the HLA-B and C loci we cannot distinguish from among the three possibilities: an undetected antigen, homozygosity, and hemizygosity. Thus the present findings are consistent with the established location of HLA.
Discussion In the case of ring 6 chromosome described by Wurster et al. (1969) and WursterHill and Hoefnagel (1975) the breakpoints were given as p25 and q27. The breakpoints were given as p23 or p24 and q26 or q27 in the case described by SalamancaGomez et al. (1975). The present case has breakpoints at p25 and q26, or p24 and q27, but again the breakpoints cannot be defined with certainty because we cannot distinguish between the light bands p25 and q27. Other cases of r(6) have shown mosaicism with normal cells or 45,-6 cells (Wurster et al., 1969; Moore et al., 1973; Van den Berghe et al., 1974; Fried et al., 1975). Similarly, the ring chromosome 6 described here was absent in a few cells (45,XY,-6) presumably due to mitotic instability. We observed no dicentric rings but in three fibroblast metaphase cells the ring appeared unusually small, which suggests a breakagereunion cycle. The presence of normal 46,XY cells indicates post-zygotic formation of the ring. In no reported case was the ring observed in a parent.
Ring 6 Phenotype Five other patients have been described with a ring chromosome 6 identified by banding (Table 1). The present case becomes the sixth fully described in the
148
K . R . K i n i et al.
T a b l e 1. C l i n i c a l f i n d i n g s in six c a s e s o f r i n g c h r o m o s o m e
6
Reference
Moore et al., 1973
Van den Berghe et al., 1974
Salamanca- Fried Gomez et al., et al., 1975 1975
Wurster et al., 1969 and Wurster-Hill et al., 1 9 7 5
Present case
2525
B i r t h w e i g h t (g)
2910
2900
1960
3380
2433
Mental retardation
+
+
+
+
+
+
Development
+
+
+
+
+
+
+
+
retardation
Bone age retardation
+
Seizures
.
.
.
.
.
Microcephaly
+
+
+
+
+
Microphthalmia
+
+
+
-
-
Strabismus
-
+
-
-
-
Nystagmus
-
+
-
-
-
Iris coloboma
-
-
+
-
-
Optic atrophy
-
-
+
-
-
Megalocornea
-
-
+
-
-
Embryotoxon
-
+
+
-
-
Epicanthus bilateral
+
-
+
+
+
+
Hypertelorism
-
-
+
-
+
+
+
+
Flat or broad nasal bridge
+
-
+
+
Ears low and/or
+
+
+
+
+
+
Micrognathia
+
-
+
-
+
+
Microstomia
+
-
+
-
+
+
+
-
+
+
-
+
+
+
Congenital heart defect
-
-
+
-
Hemivertebrae
-
-
+
+
-
-
malformed
Palate high-arched Neck short and/or
webbed
+
-
Talipes equinovarus Pes equinus Con. hip dislocation
+
-
+
-
-
+
Talus valgus
-
-
+
-
Soles-hyperkeratosis
+
-
-
-
Nevus pigmentosus
-
+
-
-
Cephalohematoma
literature.
+
Parental
six males
and
The
common
most
mental
two
a g e is n o t females findings
retardation,
epicanthal
folds,
microphthalmia,
obviously
affected,
in subjects
microcephaly, flat and
Acknowledgements. W e
nasal
bridge,
increased
and
over
normal.
we are unaware with ring 6 include:
prenatal short
growth neck,
-
of any
profound
failure, ears
There
retarded
low-set
have
affected
or
been
siblings.
to moderate bone
age,
malformed,
micrognathia.
w o u l d like t o t h a n k H a j i m e H a y a s h i , P h . D . f o r t h e h i s t o c o m p a t i b i l i t y typing, the laboratory of C. Eugene Jackson, M.D. for genotyping, Juanita Clark, George Henry, and Nona Lightman for expert technical assistance, and Debbie N. Anderson for typing the manuscripts.
Ring Chromosome 6
149
References Bodmer, W. F.: Report of the committee on the genetic constitution of chromosome 6. Cytogenet. Cell Genet. 16, 24--30 (1976) Breuning, M. H., van den Berg-Loonen, E. M., Bernini, L. F., Bijlsma, J. B., van Loghem, E., Khan, P. M., Nijenhuis, L. E.: Localization of HLA on the short arm of chromosome 6. Hum. Genet. 37, 131--139 (1977) Francke, U., Pellegrino, M. A.: Assignment of the major histocompatibility complex to a region of the short arm of human chromosome 6. Proc. Natl. Acad. Sci. 74, 1147--1151 (1977) Fried, K., Rosenblatt, M., Mundel, G., Krikler, R.: Mental retardation and congenital malformations associated with a ring chromosome 6. Clin. Genet. 7, 192--196 (1975) Moore, C. M., Heller, R. H., Thomas, G. H.: Developmental abnormalities associated with a ring chromosome 6. J. Med. Genet. 10, 299--303 (1973) Nance, W. E., Engel, E.: Autosomal deletion mapping in man. Science 155,692--694 (1967) Salamanca-Gomez, F., Nava, S., Armendares, S.: Ring chromosome 6 in a malformed boy. Clin. Genet. 8, 370--375 (1975) Van den Berghe, H., Fryns, J. P., Cassiman, J. J., David, G.: Chromosome 6 en anneau caryotype 46,XY,r(6)/45,XY,-6. Ann. Genet. 17, 29--35 (1974) Wurster, D., Pomeroy, J., Benirschke, K., Hoefnagel, D.: Mental deficiency and malformations in a boy with a group-C ring chromosome: 46,XY,Cr. J. Ment. Defic. Res. 13, 184--190 (1969) Wurster-Itill, D. H., Hoefnagel, D.: Banding identification of chromosomal abnormalities in four patients: ring (6), translocation (2q-;15q+), translocation (21q;21q) and deletion (22q-). J. Ment. Defic. Res. 19, 145--150 (1975)
Received November 3, 1978 / Revised March 13, 1979
