가족성 Ring Chromosome 21 모자이크현상 1예
A Case of Familial Ring Chromosome 21 Mosaicism
계명대학교 의과대학 진단검사의학교실1, 소아청소년과학교실2
Departments of Laboratory Medicine1 and Pediatrics2, Keimyung University School of Medicine, Daegu, KoreaCorrespondence to:
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Lab Med Online 2021; 11(2): 132-134
Published April 1, 2021
Copyright © The Korean Society for Laboratory Medicine.
Ring chromosome (RC) is a circular DNA that results from breaks at the ends of both the chromosome arms followed by fusion of the broken ends . During ring formation, genetic material might be lost or a complete ring with no deletion can be created by fusion of subtelomeric sequences or telomere–telomere fusion . Most RCs are formed
Here, we report a rare case of familial RC 21 mosaicism where mother had mos 46,XX,r(21)(p13q22.3)/46,XX. Her daughter inherited RC 21 from her, but had a more complex mosaicism, mos 47,XX,+r(21)(p13q22.3)mat/45,XX,-21/46,XX,r(21)(p13q22.3)mat/47,XX,+dic r(21)/46,XX.
The proband, a 2-month-old girl, was the second-born child of unrelated parents. Her parents and 5-year-old sister had normal phenotype and intelligence. Her mother, aged 38, without any dysmorphism, had a history of spontaneous abortion (4 times) and a heart surgery due to atrial septal defect (ASD). To find out the reason for recurrent abortions, karyotyping was performed, which revealed mos 46,XX,r(21)(p13q22.3)/46,XX (Fig. 1). Microarray analysis using a CytoScan 750K array (Affymetrix, Santa Clara, CA, USA) detected no loss or gain of genetic material.
Figure 1. Partial karyotype of mother showing normal 21 (A) and ring chromosome 21 (B).
The proband was born at 38 weeks of gestation by caesarean section, with birth weight of 3,200 g. Karyotype by amniocentesis was normal at 16 weeks of gestation. However, after birth, low nasal bridge, mild facial dysmorphism, hypotonia, and a 2.3 mm ASD were detected. Conventional karyotyping revealed mos 47,XX,+r(21)(p13q22.3)mat/45,XX,-21/46,XX,r(21)(p13q22.3)mat/47,XX,+dic r(21)/46,XX (Fig. 2). Re-analysis of the same amniotic fluid sample revealed very low-level mosaicism of RC 21 (8 of the 100 metaphase cells examined).
Figure 2. Partial karyotype of daughter showing normal 21 (A), ring chromosome 21 (B), loss 21 (C), additional ring chromosome 21 (D), and additional dicentric ring chromosome 21 (E).
Inheritance of RC is a very rare phenomenon. RC 22, RC 21, RC 20, and RC 14 are the most common among inherited RCs [3, 5]. This preference might be because of their relative stability during cell division and less phenotypic effect of these small chromosomes than the larger ones . Particularly, high rate of mother-to-child RC transmission than father-to-child has been observed, although there are no sex differences in the prevalence of RC in general [3, 8]. This difference is thought to be due to the deleterious effect of RC on spermatogenesis in male. However, no distinct effect on fertility has been reported in female .
In a review article, 9 out of 30 families with ring transmission showed that both the parent and the child were mosaic . In our case of RC 21, both the mother and the daughter showed mosaicism. As the germline transmission of an RC should produce a non-mosaic karyotype, the reproduction of mosaicism in the offspring should be rare. Several hypotheses have been proposed to explain the co-occurrence of normal karyotype with RC in the offspring who has mosaic RC carrier parents: 1) early postzygotic loss of the ring and subsequent reduplication (monosomy rescue), 2) ring opening during early embryogenesis, and 3) postzygotic ring re-formation [3, 10, 11]. However, in addition to normal clone, our patient had several derivative clones, which could be explained by “dynamic mosaicism” [12, 13]. During cell division, if a ring replicates without sister chromatid exchange in the prophase, the separation of the ring results in the equal-sized rings. If sister chromatid exchange occurs through dicentric ring or interlocked ring formation, followed by asymmetric breakage, variable unbalanced products such as ring loss, dicentric RC, and duplication or additional RC could be produced in the daughter cells. This continuous production of aberrations in the daughter cells is referred as “dynamic mosaicism” [12-14].
Generally, inherited RC shows milder symptoms than sporadic case, which is more striking in the familial RC cases that rarely show major malformation . However, formation of an additional RC 21 or duplication of Down syndrome critical region by dynamic mosaicism can lead to Down syndrome in RC 21 carriers [15, 16]. In a report, the authors reviewed 26 cases of RC 21 carriers and found that 5 (21%) of them had Down syndrome offspring, whose karyotype were either duplication of RC 21 or additional RC 21 . Our patient had additional RC 21 (16% by fluorescence
Here, we report a very rare case of a familial RC 21 mosaicism. When a new case of RC 21 is detected, detailed karyotyping for many metaphase cells should be performed to detect the mosaicism with variable RC 21 derivative clones. In addition, we recommend genetic counseling and family study, including parental and prenatal tests, because of the possibility of inheritance and recurrence of RC.
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