Clinical Genetics 1975: 7 : 192-196

Mental retardation and congenital ma Iformations associated with a ring chromosome 6 K. FRIED,M. ROSENBLATT,G. MUNDEL,AND R. KRIKLER

Departments of Genetics and Pediatrics, Asaf Harofe Government Hospital, Tel-Aviv University Medical School, Zerifin, Israel A boy, in whom a ring chromosome 6 was found, presented with mental retardation and odd facies. He had a small head, bilateral epicanthus, broad nasal bridge, low set prominent ears, short neck and clasped thumbs. The ring chromosome was identified by the ASG banding technique. Received I August, accepted f o r publication 16 September 1974

A C ring chromosome, most frequently in association with congenital abnormalities and mental retardation, has been reported in a few cases (Turner et al. 1962, SmithWhite et al. 1963, Atkins et al. 1966a,b, Butler et al. 1967, Bueno et al. 1969, Wurster et al. 1969, Gacs et al. 1970, Kistenmacher & Punnett 1970, Therkelsen et al. 1971, de Chieri et al. 1972, Moore et al. 1973, Zackai & Breg 1973, van den Berghe et al. 1974). Identification of the ring by the recently available banding techniques has been described in these individuals only since 1973. These reports identified ring chromosome 7 (Zackai & Breg 1973) and ring chromosome 6 (Moore et al. 1973, van den Berghe et al. 1974). The present report identifies a further case of ring chromosome 6 and describes the congenital malformations associated with it. We hope that detailed descriptions of the malformations and the publication of

photographs of many individuals with identified ring chromosome will make it possible in the future, to suspect the cytogenetic diagnosis of some specific ring chromosomes on clinical grounds. Case Report

The proband was born 23 June 1971. He is the only child of healthy, unrelated Jewish parents. The father and mother were 27 and 24 years of age, respectively, at the time of his birth. Pregnancy (the only pregnancy of the mother) was normal and there was no exposure to drugs or radiation. The birthweight was 3380 g at full term. He had a large cephalohematoma. In early infancy, the mother did not notice any health problem. At the age of 11 months the child developed stridor and was hospitalized because of acute laryngitis. During hospitalization bilateral acute otitis media appeared. Because of the relapse of bilateral puruIent otitis media he underwent

R I N G C H R O M O S O M E 6 :A C A S E R E P O R T

bilateral mastoidectomy at the age of 12 months. Since then the child has had a few episodes of upper respiratory infection or laryngitis that did not require hospitalization. At the age of 26 months the child was referred for investigation because of suspected psychomotor retardation and delayed speech development. Psychological evaluation at the age of 27 months revealed the following developmental attainments: body movements 18 months; understanding of speech 17 months; attention 16 months; play 18 months; use of hands 19 months; verbal expression 18 months (he said only a few short words); and social adaptability 17 months. Physical examination at age 2 K years revealed a mentally retarded child with odd facies (Fig. l ) , bilateral epicanthus, broad nasal bridge, low set prominent ears and short neck. The thumbs were clasped much of the time. Head circumference was 46 cm (below 2nd percentile). Ophthalmological examination was normal except for epicanthic folds. The child had great difficulties with eating solid food and had a strange voice, although the mouth, tongue, palate and pharynx were found to be normal. Electroencephalogram was normal. Hematological investigation revealed slight anemia: Hemoglobin 10.4 gm %, Hematocrit 33 %, with slight anisocytosis and hypochromia. The dermatoglyphic findings are shown in Table 1.

193

Fig. 1. Face of patient. Note the bilateral epicanthus. broad nasal bridge, low set prominent ears and short neck.

Methods

Chromosome preparations were made from cultures of peripheral blood by the method of Moorhead et al. (1960). Colchicine was added to the cultures 2 h prior to harvest. The hypotonic solution used was 0.075 mol/l KCI for 10 min. The fixative, 3:l methanol acetic acid, was added and slides were prepared by the air drying technique. The ASG (AcetidSalinelGiemsa) technique

Table 1 Dermatoglyphics of the patient Left

Fingertip pattern Finger ridge count ~

Total ridge count = 60

~~

Right

I

II

Ill

IV

v

I

II

111

IV

v

L' 1410

A 010

LU 310

Lu 410

Lu 610

L" 1710

Lu 310

Lu 710

A 010

610

~

atd: Left 68"; Right 45"

LU

194

FRIED, ROSENBLATT, MUNDEL, AND KRIKLER Table 2 Results of chromosome analysis

Chromosome count No. of cells Monocentric ring Dicentric ring Two rings Ring absent

> 46

< 45

45

46

6 6 0 0 0

12 4 0 0 8

152 138 7 0 7

0 1 0

was used for banding chromosomes. The slides were incubated for 1 h at 60°C in 2 X SSC (0.3 molA sodium chloride plus 0.03 mol/l tri-sodium citrate), after which they were rinsed briefly with deionized water and stained in Giemsa for 30 min (Gurr’s Giemsa R. 66, 2 ml t o 50 ml of buffer pH 6.8 made with Gurr’s buffer

Polyploid

Total

1

3

a

2 0 1

174 150 7 2

0

15

tablets). Finally, they were rinsed again briefly in deionized water and dried by blotting. Cytogenetic Investigation

A buccal smear from the patient was examined and, as expected, no X-chromatin was

Fig. 2. Karyotype of cell with 46 chromosomes showing ring chromosome 6. ASG staining.

RING CHROMOSOME 6 : A CASE REPORT

195

cells in metaphase (Fig. 4). No interlocking rings were observed. Discussion

The majority of cells contain one monocentric ring chromosome 6. For the ring m. 3. Ring chromosome 6 from a furthor 12 dif- chromosome to occur so extensively in the ferent cells. The last four to the right of the bottom different cultures, it must have arisen either line are dicentric. during parental meiosis or very early in embryogenesis. The mechanism of ring found; on fluorescent staining Y-bodies production is presumably by simultaneous were observed. Peripheral blood leukocyte breakage of both the long and short arms cultures of both parents showed normal of the chromosome near their ends, followed karyotypes. Three peripheral blood leuko- by the union of both arms. In the process, cyte cultures of the patient taken on three the distal ends of both the long and short separate occasions were studied, and, as the arms are lost so that the ring chromosome results of analysis were similar, the findings has a partial deletion of both the long and were pooled (Table 2). A modal number short arm. In the present case, the amount of 46 chromosomes is apparent; 95 % of of genetic material lost must be small, bethe cells containing this number are missing cause the circumference of this ring chroa chromosome 6. Counting all cells, chro- mosome 6 is not much less than the total mosome 6 was replaced in 87 % by a mono- length of an ordinary chromosome 6 and all centric ring chromosome 6 (Fig. 2), in 1 % bands seem to be present in the ring chroby two rings and in 4 % by a dicentric mosome. The relatively minor malformaring (Fig. 3). By chance, a cell in late tions and moderate retardation also sugprophase was observed among the many gest that the patient is monosomic for only a very small part of chromosome 6. With the present banding techniques, it is unlikely to be possible to estimate the exact amount of chromosomal material lost when it is less than 10 %. In chromosome 6, since the dista! ends of both the long and short arms stain similarly by the banding technique used, it is impossible to recognize whether the deleted segment is mainly from the long or the short arm. The occasional production of an unstable dicentric ring is expected if “crossing over” occurs between chromatids in the monocentric ring chromosome during mitosis (producing a “MObius ring”). However, at the next mitosis, such a dicentric ring is expected to produce Fig. 4. Late prophase spread of a cell observed by an interlocking ring, which is cven more chance among the many cells in metaphase. Note unstable and will soon disappear. the ring chromosome 6 i n an extended form. ASG The findings, as in our case, of a few staining.

196

FRIED, ROSENBLATT, MUNDEL. AND KRIKLER

apparently normal cells among the large majority with a ring chromosome is reported in several cases and discussed by van den Berghe e t al. (1974). T h e partial similarity between this patient and the o n e reported by Moore e t al. (1973) is consistent with the inherently variable loss of genetic material from ring chromosome 6 from o n e case to another. W e were unable t o investigate genetic markers, since the parents declined to cooperate. W e regret the omission of this irnportant information.

References

Atkins, L., S. S. Pant, G. W. Hazard & E. M. Quellette (1966a). Two cases with a C group ring autosome. Ann. hum. Genet. 30, 1-6. Atkins, L., R. T. Sceery & M. E. Keenan (1966b). An unstable ring chromosome in a female infant with hypotonia, seizures and retarded development. J . med. Genet. 3, 134-138. Bueno, M., A. del Amo & F. Hermida (1969). Primordial dwarfism and mental deficiency associated with a group C annular chromosome. Genetica Iberica 21, 63-80. Butler, L. J., N. E. France & N. M. Jacoby (1967). An infant with multiple congenital anomalies and a ring chromosome in group C(X-6-12). J . m e d . Genet. 4, 295-298. de Chieri, P. R., J. M. Albores, A. Cosin & J. M. Cosin (1972). A human ring C chromosome associated with multiple congenital abnormalities. J . med. Genet. 9, 239-242. Gacs, G., D. Schuler & M. Sellyei (1970). Familial occurrence of congenital malforma-

tions and ring chromosome (46,XX,Cr). J . med. Genet. 7 , 177-179. Kistenmacher, M. L. & H. H. Punnett (1970). Comparative behavior of ring chromosomes. Amer. .I. hum. Genet. 22, 304-318. Moore, C. M., R. H. Heller & G. H. Thomas (1973). Developmental abnormalities associated with a ring chromosome 6. J . med. Genet. 10, 299-303. Moorhead, P. S., P. C . Nowell, W. J. Mellm-.n, D. M. Batipps & D. A. Hungerford (1960). Chromosome preparations of leukocytes cultured from human peripheral blood. Exp. Cell Res. 20, 613616. Smith-White, S., W. J. Peackock, B. Turner & G. M. den Dulk (1963). A ring chromosome in man. Nature (Lond.) 197, 102-103. Therkelsen, A. J., B. Moller & K. Henningsen (1971). A group C ring chromosome in a mentally deficient male. J . med. Genet. 8, 227-230. Turner, B., A. N. Jennings, G. M. den Dulk & T. Stapleton (1962). A self-perpetuating ring chromosome. M e d . J . Aust. 49, 56-58. Van den Berghe, H., J. P. Fryns, J. J. Cassiman & G. David (1974). Chromosome 6 en anneau caryotype 46,XY,r(6)/45,XY,d. Ann. Gknkt. 17, 29-35. Wurster, D., J. Pomeroy, K. Benirschke & D. Hoefnagel (1969). Mental deficiency and malformation in a boy with a group C ring chromosome: 46,XY,Cr. J . ment. Defic. Res. 13, 184-190. Zackai, E. H. & W. R. Breg (1973). Ring chromosome 7 with variable phenotypic expression. Cytogenet. Cell Genet. 12, 40-48. Address: K . Fried M . D . , Ph.D. University Department of Genetics Asnf Harofe Governrnent Hospital Zerifin Israel