Ring chromosomes arise following breakage and rejoining in both chromosome arms. They are heterogeneous with variable size and genetic content and can originate from any chromosome. Phenotypes associated with ring chromosomes are highly variable as apart from any deletion caused by ring formation, imbalances from ring instability can also occur. Of interest is ring chromosome 20 which has a significant association with epilepsy with seizure onset in early childhood. Severe growth deficiency without major malformations is a common finding in the ring chromosome carrier. This phenotype associated with ring behaviour and mitotic instability and independent of the chromosome involved has been termed the “ring syndrome”. Precise genotype-phenotype correlations for ring chromosomes may not be possible as influencing factors vary depending on the extent of deletion in ring formation, ring instability and the level of mosaicism. Although ring chromosomes usually arise as de novo events, familial transmission of rings from carrier to offspring has been described and prenatal diagnosis for any pregnancies should always be considered.

Autosomal ring chromosomes in human genetic disorders

Ring chromosomes are rare entities, usually associated with phenotypic abnormalities in correlation with the loss of genetic material. There are various breakpoints and sometimes there is a dynamic mosaicism that is reflected in clinical features. Most of the ring chromosomes are de novo occurrences. Our study reflects the experience of three Romanian cytogenetic laboratories in the field of ring chromosomes. We present six cases with ring chromosomes involving chromosomes 5, 13, 18, and 21. All ring chromosomes were identified after birth in children with plurimalformative syndromes. The ring chromosome was present in mosaic form in three cases, and this feature reflects the ring’s instability. In case of ring chromosome 5, we report a possible association with oculo-auriculo-vertebral spectrum.

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Ring Autosomes: Some Unexpected Findings

Major neurological disorders may accompany rare chromosomal abnormalities. As an example of this rare condition, we present a case with microcephaly, mental retardation, developmental delay, hyperactivity, stereotypic movements, seizures and dysmorphic facial appearance in whom a mosaic ring chromosome 18 was found [45,XX,-18/46,XX,r(18)/46,XX,dicr(18)]. Although ring chromosome 18 phenotype has been known for a long time, this is the third reported patient with a dicentric ring chromosome 18 mosaicism. The presented case will contribute to the identification of the genotype-phenotype correlation in chromosome 18 anomalies.

An unexpected finding in a child with neurological problems: mosaic ring chromosome 18

We report two prenatal and two postnatal diagnosed cases (the latter monozygotic twins) with ring chromosomes after GTG banding. All four, de novo r(18), cases turned out to be more complex after application of high-resolution molecular cytogenetics techniques such as use of fluorescence in situ hybridization, centromeric probes, multicolor banding, and locus-specific probes for chromosome 18. All four cases are mosaics involving chromosome 18 in up to five different cell lines, including 46,r(18); 46,dr(18); 47,r(18)x2; 46,mar(18); and 45,-18. Mosaicism sharing both numerical and structural anomalies is rare, but rings often appear as mosaics due to their mitotic instability. Overall, patients with ring chromosome 18 usually share clinical features of 18q- syndrome and, less frequently, those of 18p- syndrome. High-resolution molecular cytogenetics techniques were useful in the characterization of cases with dynamic mosaicism and in establishing the relationship between loss or gain of chromosomal material and the phenotype.

Three unusual but cytogenetically similar cases with up to five different cell lines involving structural and numerical abnormalities of chromosome 18.

Constitutional jumping translocations (JT) are rare, especially in phenotypically normal individuals. We report on an adult male with partial hypogonadism as the sole phenotypic abnormality with an unusual chromosome abnormality. In this patient, centric fission of chromosome 18 lead to formation of a ring 18q chromosome, while 18p formed a JT through centromere-telomere fusion with chromosome 8q (66%) or 20q (13%). In 21% of cells, the 18p fragment was missing. Fluorescent in situ hybridization revealed the presence of interstitial telomeres at the junction site of the fusion and unequal distribution of the alphoid sequences through the centric fission, leaving a small, yet functional centromere within the ring. We discuss the phenotype of the patient in light of this unusual karyotype.

Ring chromosome 18q and jumping translocation 18p in an adult male with hypergonadotrophic hypogonadism.

First familial case of ring chromosome 18 and monosomy 18 mosaicism.

We report the case of a woman who carried two reciprocal translocations. Her karyotype was 46,XX,t(3;12)(q12;q21)(4;17)(p14;p13). She had two children, a phenotypically normal daughter (karyotype (46,XX,t(3;12)(q12;q21)) and a son with partial 4p trisomy (karyotype 46,XY,t(3;12) (q12;q21),-17,+maternal der(17)). She was pregnant with a female fetus who had the same karyotype as her son. She also reported a history of two spontaneous abortions. This viable recurrent abnormality was due to the maternal (4;17) translocation with meiotic segregation type 2:2 adjacent 1. In this case of the two reciprocal translocations carried by the mother, one led to imbalances, whereas the other remained balanced in the viable offspring.

Identical chromosome imbalance in two siblings born to a mother with a double reciprocal translocation.

We report the case of a female child presented at birth with hypotonia, growth retardation and respiratory distress. Chromosome study from peripheral blood showed a 46,XX,del(5)(p14pter) karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced paracentric inversion of long arms of one chromosome 5, giving the karyotype 46,XX,inv(5)(q12q32), whereas paternal karyotype was normal. The maternal abnormality was confirmed by fluorescence in situ hybridization (FISH) and was not present in the daughter’s metaphases. Microsatellite analysis in the proposita and her parents permitted us to conclude that the deleted chromosome 5 was paternal in origin, as usually described. Therefore, as might have been expected, maternal paracentric inversion of chromosome 5q and “cri-du-chat syndrome” presented by the daughter were not related.

Dominique Barthe

Papers

First familial case of ring chromosome 18 and monosomy 18 mosaicism.

Identical chromosome imbalance in two siblings born to a mother with a double reciprocal translocation.

"Cri-du-chat" syndrome in a patient born to a mother with a paracentric inversion of chromosome 5q.

Revaluation twenty-three years later of a supernumerary derivative chromosome 9.