Journals    
Present Issue 
Past Issues 
 

THESMANEWS   
Present Issue 
Past Issues 
 

SMJ Editorial Board 

Letters to the Editor

Instructions to Authors 
 

Singapore Med J 1999; Vol 40(04):

Ring Chromosome 22 Resulting in Partial monosomy in a Mentally Retarded Boy
B Gibbons, S Y Tan, P Y Tam

ABSTRACT

Ring chromosomes are a rare occurrence, and their abnormal morphology makes characterisation by conventional G-banding analysis difficult, resulting in few reports of well characterised rings. Most cases of ring chromosome 22 would be expected to show loss of part or all of the short arm in addition to loss of some long arm material. Loss of short arm material is unlikely to have any phenotypic effect. However, partial monosomy resulting from deletion of part of the long arm is known to be associated with a syndrome involving global developmental delay, mental retardation, severe delay in speech and language skills but only minor facial dysmorphology(1). Patients with ring chromosome 22 may have clinically significant deletions of 22q and application of fluorescent in situ hybridisation (FISH) techniques to ring chromosomes in order to confirm that deletion has occurred, is a useful adjunct to conventional cytogenetic studies.

Karyotyping was performed on G-banded metaphase chromosomes after routine PHA stimulated peripheral blood culture. Synchronisation by thymidine block(2) was used to obtain high resolution chromosomes. Chromosome analysis showed 59 of 62 cells to have a ring chromosome 22 (Fig 3). The remaining three cells were missing the ring chromosome and were therefore monosomic for chromosome 22. However, these cells probably represent mitotic instability rather than true mosaicism. The morphology of the ring chromosome did not allow for determination of any deleted segments. However, it was thought likely that the ring chromosome would have lost the 22q telomeric segment. In order to test this hypothesis, in situ hybridisation with the cosmid probe N85A3 (Cytocell)(3) was performed. This probe is the last unique cosmid on 22q(4) lying approximately 70 - 110 kb from the telomere in band 22q13.3(3). The TUPLE-1 probe mapping to 22q11 acted as a control and marker for chromosome 22. The procedure used was in accordance with the manufacturer’s instructions. In all 25 cells analysed, the TUPLE-1 probe gave positive signal on both the normal chromosome 22 and the ring chromosome. The N85A3 probe gave positive signal only on the normal chromosome 22 in all cells examined. No signal was present on the ring chromosome, confirming deletion of the distal part of 22q13 (Fig 4). Parental karyotypes were normal, no evidence of mosaicism was detected in 30 cells from each parent.

Ring chromosome 22 is a rare occurrence. Early publications(5) dismissed the idea of a ring chromosome 22 syndrome. However, Hunter et al(6) suggested that the most commonly reported features of mental retardation with disproportionate verbal delay, reduced head circumference, hypotonia, unsteady gait, large ears with abnormal configuration and epicanthic eye folds did in fact suggest a r(22) syndrome. Teyssier and Moreau(7) reported familial transmission of a r(22) from a phenotypically normal woman to her daughter, a 27-year-old woman, without dysmorphic features or mental retardation, indicating that significant deletion is not universal in the production of ring chromosomes. Gustavson et al(8) reported a ring chromosome 22 in a mentally retarded boy, and also produced evidence for a deleted ring 22 by way of gene dosage effect for arylsulphatase A activity.

It would be expected that the clinical features associated with ring chromosome 22 would be similar to those seen in association with pure deletion of the terminal region of chromosome 22. Deletions involving 22q13.3 are generally associated with a common phenotype which includes global developmental delay, hypotonia, severe delays in expressive speech and mild facial dysmorphic features. It would seem appropriate to consider r(22) as a special subset of deletion 22q with the proviso that rings, like deletions, can vary in the size of the deleted segment and thus can vary in their phenotypic effect. Small deletions are associated with minimal dysmorphology although mental impairment can be profound. The patient described here exhibits the microcephaly, global developmental delay, severe delay in expressive speech, mild facial dysmorphology and large ears seen in the del(22)(q13) and r(22) syndromes. However, hypotonia was not noted. Large hands and feet have been noted previously in only one patient with del(22)(q13.3)(1).

Small deletions may not be cytologically detectable in a ring chromosome, therefore additional techniques are required to demonstrate deletion in such patients. Recent studies of patients with deletions of chromosome 22 have utilised FISH(9,10) or molecular genetic techniques(1) to fully characterise the deletion. In this paper, we describe a similar FISH strategy to demonstrate deletion in a ring chromosome 22. The probe used, cosmid N85A3 is particularly valuable for identifying small terminal deletions due to its proximity to the telomere.

Cytogenetics Laboratory
6A Napier Road
Gleneagles Hospital
Singapore 258500

Royal Free Hospital School of Medicine
Pond St
London NW3 2QG, UK