Ring chromosome 12 and severe oligospermia: a case report

Abstract

Objective

To describe an unusual presentation of ring chromosome 12, which manifested as severe azoospermia, resulting in male infertility.

Design

Case report.

Setting

In vitro fertilization center at a tertiary care hospital.

Patient(s)

A 27-year-old man diagnosed with unexplained azoospermia and ring chromosome 12 abnormality during a workup for primary infertility.

Intervention(s)

In vitro fertilization with preimplantation genetic diagnosis.

Main Outcome Measure(s)

To confirm the importance of obtaining karyotypes in individuals with severe oligospermia.

Result(s)

Full-term pregnancy after IVF using donor sperm.

Conclusion(s)

Severe oligospermia and male infertility should be included in the spectrum of findings found in ring chromosome 12.

The formation of ring chromosomes is rare but has been identified in many chromosomes. Hamerton et al. (1) were the first to report a case of a patient with phenotypic dysmorphism and ring chromosome 12. Ring chromosome 12 is a rare structural chromosome abnormality that causes the 12th chromosome to form a ring structure and is the cause of widely variable phenotypic characteristics. There are only 8 previously reported cases in the literature. Various investigators have found that 3%–18% of men with severe abnormalities of sperm production, including azoospermia, will have Y chromosome deletions (2). In addition, a large number of studies have shown that the prevalence of somatic chromosome abnormalities detectable with karyotype is 10-fold higher in infertile men with impaired spermatogenesis (3).

At present there are no definitive phenotypic abnormalities for ring chromosome 12, and there is a wide array of phenotypic characteristics due to varying amounts of truncated telomeric ends. The few case reports in the literature note recurring phenotypic characteristics, such as mental retardation, developmental delays, behavioral problems, and epilepsy, and have been labeled “ring chromosome 12 syndrome” (4). Other features, such as learning disabilities, microcephaly, short stature, facial dysplasias, clinodactyly of the fifth fingers, multiple café-au-lait spots, and sebaceous acne, have also been noted.

Here we report a case of a patient with ring chromosome 12 who presented with azoospermia in the setting of an infertility evaluation. This association has not previously been reported in the literature.

CASE REPORT

A 27-year-old man and his 26-year-old gravida 0 wife with polycystic ovary syndrome presented to the Yale Fertility Center for evaluation for primary infertility after failing to become pregnant after 1 year of unprotected intercourse. The patient’s initial semen analysis revealed a volume of 1.5 mL, low viscosity, a very low sperm concentration of 0.01 (total sperm: 0.01 × 1.5 mL), and 10% motility, which is consistent with severe oligospermia. A repeat sperm analysis confirmed the diagnosis of azoospermia, with no sperm identified. His FSH level was elevated at 29.5 IU/L, and the T, PRL, and LH levels were normal. The patient denied any trauma to his testes or viral illnesses and tested negative for cystic fibrosis. The patient underwent a complete urologic evaluation for infertility, and no identifiable etiology was identified. Karyotype evaluation revealed a ring chromosome 12 in 85% of peripheral leukocytes. His karyotype is 46,XY,r (12) (p13q24.3)/46,XY. Multiplex polymerase chain reaction was used to rule out sY86, sY84, sY127, sY134, sY255, and sY524 microdeletions of the Y chromosome. These tested microdeletions detect more than 90% of the microdeletions in the three AZF regions.

The karyotype prompted a more detailed history of the patient. He noted that he had always been self-conscious of a perceived small head in relation to his body size but was not diagnosed with microcephaly. His pediatrician noted the lag in head size during yearly evaluations. In addition, the patient noted difficulty in school and comprehension and was considered “learning delayed” throughout childhood. The patient also had been diagnosed with neurofibromatosis 1 on the basis of biopsies of multiple café-au-lait spots.

After a complete infertility evaluation and consultation with the geneticist and urologist, the couple was offered IVF with intracytoplasmic sperm injection and preimplantation genetic diagnosis. The couple decided instead to use donor sperm with IUI and had a successful full-term pregnancy.

COMMENT

The formation of a ring chromosome can be the result of loss of genetic information from both ends of the chromosome. Ring chromosomes are specific deletion chromosomes resulting from breaks occurring at the two telomeric ends with subsequent loss of deleted segments devoid of centromeres and the reunion of the remaining two “sticky ends” (7). Rings seem to undergo difficulties at mitosis, at which point breakage of the ring followed by fusion generates smaller and larger rings. Because of this mitotic instability, ring chromosomes often occur in only a proportion of cells. There are multiple causes for ring formation that range from sporadic, spontaneous breakage to exposure to radiation or chemicals. Kosztolanyi (8) noted that 99% of ring chromosomes are sporadic in origin. Pezzolo et al. (9) showed the presence of telomeric and subtelomeric sequences at the fusion points of the ring chromosomes by fluorescence in situ hybridization. This suggested that ring formation may be caused by ring instability and is not necessarily due to the intrinsic loss of genetic information. The diversity and severity of physical manifestations is likely due to subtle differences in the breakpoints, which create difficulty in establishing a genotype–phenotype correlation (8).

Our patient had some typical phenotypic findings consistent with “ring syndrome,” such as learning disabilities and undiagnosed microcephaly. Microcephaly has been reported to be associated with ring chromosome 12. All previous ring 12 cases in the literature reported significant learning disabilities and mental disabilities, with varying phenotypic variations and developmental delays. However, inconsistent with documented ring 12 patients, our patient has nearly normal phenotypic cognitive functions, aside from learning disabilities and scholastic difficulty. Although there are varying degrees of cognitive impairment and mental retardation in ring chromosome patients in the literature, those with ring 12 tend to have more severe impairments.

The patient also has documented café-au-lait spots and was diagnosed with neurofibromatosis 1. The presence of multiple café-au-lait spots is important in the diagnosis of patients with chromosomal rings and has been described in patients with ring chromosome 7, 11, and 15 (10, 6, 11). Café-au-lait spots were also noted on patients with ring chromosome 12 and their family members in 2 prior case reports, by Hajianpour et al. (12) and Zen et al. (13). To date, 4 of the 8 documented cases of ring chromosome 12 have had café-au-lait spots (5, 6).

Azoospermia has previously been documented in patients with ring Y chromosome but has not previously been noted with autosomal ring chromosomes (14). Our patient had an elevated FSH level of 29.5 IU/L but normal LH, PRL, and T levels and was negative for Y chromosome microdeletion. Eighty-five percent of leukocytes analyzed had ring chromosome 12. Preimplantation genetic diagnosis was offered to the couple to prevent the transmission of the ring 12 chromosome to the offspring. However, the couple opted to use donor sperm.

The reported incidence of somatic chromosomal abnormalities in the infertile male population is approximately 10%, and this number increases as the sperm concentration decreases (15). The incidence is consistent with recent literature. It has been well established, however, that Y chromosome abnormalities also result in decreased sperm production. The findings presented here imply that ring chromosome 12 may also result in oligospermia. A gene on chromosome 12 may influence spermatogenesis; however, this linkage has not been previously investigated. This case illustrates the importance of karyotype testing after a diagnosis of unexplained oligospermia.

In summary, we report an unusual presentation of ring chromosome 12. Severe oligospermia and male infertility should be included in the spectrum of findings in this syndrome.