Ring chromosome 22: a review of the literature and first report from India.

Ring chromosome 22 [r(22)], a rare cytogenetic finding, has been described in nearly 70 cases to date. Cytogenetic investigations were carried out on a 5-year-old male child with microcephaly and intellectual disability. Cytogenetic investigations revealed his karyotype to be 46,XY,r(22). To the best of our knowledge, this is the first report of an r(22) anomaly from India.

INTRODUCTION

Ring chromosome 22 [r(22)] was first described by Weleber et al. in 1968 [1]. Ring chromosomes arise from terminal breaks on both arms of a chromosome followed by fusion. The amount of genetic material lost in this process depends upon the breakpoints. Ring chromosome 22 is usually caused by spontaneous or de novo errors very early in the development of the embryo that appear to occur randomly for unknown reasons. Since r(22) is a rare disorder, its incidence is not known. Apart from the usual clinical manifestations, some variations have also been reported in some studies such as arachnoid cyst in posterior cerebellum [2]. Further investigations by the authors revealed deletion in 22q13.3 (Arylsulphatase A region) visualized by fluorescent in situ hybridization (FISH). Hypertension, large ears, hand and feet and torticollis were the other varied features reported [3] (Table 1).

Table 1

Clinical features for ring chromosome 22 syndrome ([+]: present; [−]: not reported).

ReferencesClinical Features	15	17	18	38	26	39	3	40	30	31	32	35	36	37	2	6	This Study
Growth retardation	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[−]	[+]	[+]
Absent to severe speech impairment	[+]	[−]	[−]	[+]	[+]	[+]	[+]	[+]	[−]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]
Microcephaly	[+]	[−]	[−]	[−]	[−]	[+]	[+]	[+]	[+]	[−]	[−]	[−]	[−]	[+]	[+]	[+]	[+]
Hypotonia	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[−]	[+]	[+]	[+]	[−]	[+]	[+]	[−]	[+]
Autistic features	[+]	[−]	[−]	[−]	[−]	[+]	[+]	[+]	[−]	[+]	[−]	[+]	[+]	[+]	[+]	[+]	[+]
Hydrocephaly	[−]	[−]	[+]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Craniofacial anomalies	[−]	[+]	[−]	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[−]	[+]	[−]
Epicanthal folds	[+]	[−]	[−]	[−]	[+]	[+]	[+]	[+]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[+]	[+]
Long eye lashes	[−]	[−]	[−]	[−]	[+]	[+]	[−]	[+]	[+]	[+]	[−]	[−]	[−]	[−]	[−]	[+]	[+]
Full eyebrows	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[+]	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[+]	[−]
Hypertelorism	[−]	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Flat nasal bridge	[−]	[−]	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Second and third toe syndactyly	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[+]
Large ears	[+]	[−]	[−]	[−]	[−]	[−]	[+]	[+]	[+]	[−]	[+]	[−]	[−]	[−]	[+]	[−]	[−]
Dental malocclusion	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[+]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
High arched palate	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Unsteady gait	[+]	[−]	[−]	[+]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Lymphedema	[−]	[−]	[+]	[−]	[+]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Hypertension	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]
Seizures	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[+]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]

CASE REPORT

The proband, a 5-year-old male with microcephaly and intellectual disability, was referred to the Centre for Genetic Disorders, Guru Nanak Dev University, Amritsar, Punjab, India, for cytogenetic investigations. He was born to healthy, non consanguineous parents aged 32 (mother) and 35 (father) years old, respectively. His older sister (9 years old) was normal. The pregnancy, delivery and neonatal period were uneventful. The mother had one spontaneous abortion and one of her pregnancies was terminated as the fetal heart was absent. The present subject presented delayed milestones with microcephaly. On examination, his head circumference was found to be 46 cm (normal 52.1 cm). Physical features included brachycephalic head, flat face, pointed chin, almond shaped eyes, long eye lashes and epicanthal folds (Figure 1a). His ears were placed higher than the normal position and syndactyly of the second and third toes of right foot was present. He had hypotonia, absence of speech and only started walking at the age of 3 years. Autistic behavior and aggressive nature was also noted. A magnetic resonance imaging (MRI) and urine test for metabolic screening revealed no abnormality.

Figure 1

(a) Facial features of r(22) male;

RESULTS

Informed parental consent was obtained before the investigations were begun. Peripheral blood of the proband and his parents was cultured in an RPMI 1640 (Biological Industries, Kubbutz Baet Haemek 25225, Israel) using standard protocols. Slides were banded using standard GTG-banding techniques with some modifications [4] such as normal saline was used to wash the slides instead of buffer. Examination of 100 metaphases revealed 46,XY, r(22) in all cells (Figure 1c) of the proband. The parental karyotypes were normal. To the best of our knowledge, this is the first reported case with r(22) from India.

Figure 1

(c) karyotype showing 46,XY, r(22).

DISCUSSION

The clinical findings of our case were similar to the description in the literature (Table 1). These features overlap with patients presenting terminal 22q13.3 deletion syndrome (Table 2) except for dental malocclusion, seizures, unsteady gait, etc. Microcephaly may also be a part of a well recognized syndrome and intellectual disability is a common feature in these individuals [5]. Fluorescent in situ hybridization could not be carried out in present case due to some technical reasons.

Table 2

Common clinical features of ring chromosome 22 and 22q deletion syndrome ([+]: present; [−]: not reported).

ReferencesCommon Clinical Features	42	43	3	40	43	30	31	35	44	45	36	37	This Study
Mental retardation	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[+]	[−]	[+]	[+]	[+]	[+]
Microcephaly	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[−]	[+]	[−]	[+]	[−]	[+]
Absent to severe speech impairment	[+]	[+]	[+]	[−]	[+]	[−]	[+]	[+]	[−]	[+]	[+]	[+]	[+]
Hypotonia	[+]	[+]	[+]	[−]	[+]	[−]	[−]	[+]	[−]	[+]	[+]	[+]	[+]
Autistic features	[−]	[+]	[+]	[+]	[−]	[−]	[+]	[+]	[−]	[−]	[+]	[+]	[+]
Pointed chin	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[−]	[+]	[−]	[+]

Ring chromosomes are formed as a result of breakage and reunion in the distal p and q arms accompanying loss of the p arm and satellite materials in these regions. Ring chromosomes, though a rare chromosomal abnormality involves telomere pairing or deletion. The size of the deleted distal q arm segment affects the overall phenotype. In addition to ring formation, deletion of the 22q13 region of chromosome 22 represents a cytogenetic microdeletion syndrome with severe speech delay, autism, hypotonia, developmental delay and minimal facial dysmorphism [6-8].

Most of the cases reported with r(22) are males and the ratio of females is very much less. There is one report of a 3-year-old girl and another is a case of familial transmission of r(22) from a phenotypically normal mother to her daughter [9,10].

Cases of ring chromosomes usually show a non specific pattern of clinical symptoms; therefore, the presence of growth retardation, microcephaly, speech delay should provide sufficient reason to consider performing a karyotype determination on the patient. Severe growth delay is more common in cases in larger chromosomal rings. The ring behavior and structure causes growth failure, which is often the sole major physical abnormality in many cases of ring syndromes [5,11].

As both the parents of proband showed a normal chromosomal constitution, the aberration found in the proband was considered to be a de novo event. Ring formation is associated with deletion of the terminal regions of the chromosome involved. Fluorescent in situ hybridization and molecular analyses would be helpful to fully characterize the present case. Testing of the proband helped both in counseling the parents regarding the cause of disease in their child as well as prevention of recurrence of the abnormality in future pregnancies.