Prenatal diagnosis of ring chromosome 13: a rare chromosomal aberration

Introduction

Chromosomal aberrations, such as trisomy 13 and 18, are poor prognostic factors for the fetus and neonate. When a chromosomal aberration is suspected, chromosomal analysis using amniotic fluid is used for the diagnosis. We encountered a case of ring chromosome 13, an extremely rare chromosomal aberration [1], and faced the clinical challenge of making the prenatal diagnosis and counseling the parents regarding this disease.

Case

The patient was 24 years old, gravida 2, para 1. Her personal and family histories were not remarkable. She became pregnant spontaneously. At 24 weeks of gestation, the patient was referred to our hospital because of fetal growth restriction and oligohydramnios. The estimated fetal weight was 514 g [−2.8 standard deviation (SD)], which indicated severe fetal growth restriction. The amniotic fluid pocket was within the normal range. The fetus had various abnormalities, including holoprosencephaly and congenital heart disease (Figure 1). From these ultrasonographic findings, a fetal chromosomal aberration, in particular, trisomy 13, was suspected. Then, after genetic counseling, amniocentesis for chromosomal analysis was performed at 28 weeks of gestation. To allow for discussion of the clinical management as soon as possible, we added fluorescent in situ hybridization (FISH) to the G-banding analysis. The results of amniotic fluid analysis by FISH showed no numeric abnormalities of chromosomes 13, 18, 21, X and Y. However, based on the ultrasonographic findings, we still could not exclude the possibility of a fetal chromosomal aberration, and G-banding analysis revealed a ring chromosome 13; 46, XX, r (13) (p13q32) (Figure 2). We explained to the patient that the developmental prognosis for a fetus with a ring chromosome 13 is known to be poor. At 41 weeks of gestation, she delivered a baby girl weighing 2240 g with Apgar scores of 7 and 7 points at 1 and 5 min, respectively. The umbilical cord blood arterial pH was 7.359. The baby was diagnosed with holoprosencephaly, microcephaly, micrognathia, anal atresia, anocutaneous fistula, congenital heart disease [atrial septal defect (ASD), ventricular septal defect (VSD)], hypoplastic kidney and hypoplastic fingers and toes (Figure 3). The general condition and respiratory status of the neonate was stable except for dehydration due to poor feeding. The neonate received surgical treatment to correct the anal atresia and anocutaneous fistula at 16 days and was discharged at 30 days after birth.

Figure 1:

Ultrasonographic findings for the fetus at 24 weeks of gestation.

The lateral ventricles were widened on both sides (A), and a dorsal sac was noted (B), indicating holoprosencephaly. Ant = Anterior, Post = posterior.

Figure 2:

The results of G-banding analysis for this case.

A ring chromosome 13 was noted.

Figure 3:

Clinical features of the neonate.

The micrognathia and hypoplastic toes of the neonate are shown.

Discussion

Numeric abnormalities of chromosomes 13, 18, 21, X and Y are often encountered in clinical practice. Among them, trisomy 13 is a poor prognostic factor for the fetus and neonate. In general, when a fetus has various abnormalities, including holoprosencephaly, congenital heart disease and facial dysmorphism, trisomy 13 is suspected, and chromosomal analysis with genetic counseling is often performed. In our case, the fetus had holoprosencephaly and congenital heart disease, so at first, we suspected that the fetus had trisomy 13, but the fetus was found to have a ring chromosome 13. The ring chromosome 13 was first reported by Lejeune in 1968, and it has an estimated incidence of approximately 1 in 58,000 [1]. This structural chromosomal aberration occurs when the chromosome is cut in two places, and the amputated stumps recombine to form a ring. All chromosomes can possibly become ring chromosomes. Individuals with a ring chromosome 13 may present with various clinical features, including abnormal brain structures, congenital heart disease, renal anomalies, anal atresia and hypoplastic fingers and toes [2], [3], [4], [5]. According to the review by Brandt [6], ring chromosome 13 was recently categorized into three groups based on the position of the ring breakpoint, and the clinical features of each group are described in Table 1. Each breakpoint group tends to show the characteristic clinical features. While no stillbirth has been reported for fetuses with breakpoints at 13q33 or 34 and 13q31 or 32, all fetuses with breakpoints at more proximal positions have resulted in stillbirth. The clinical features such as holoprosencephaly, microcephaly and hypoplastic fingers and toes in our case matched those typically observed in the group with a breakpoint at 13q31 or 32. Compared with the known poor prognosis for trisomy 13, though the great majority of cases with ring chromosome 13 result in developmental delay, neonates with ring chromosome 13 have a chance of surviving to adolescence or adulthood [7], [8], [9]. Although both chromosomal anomalies involve chromosome 13, the clinical features and prognoses differ. In an affected fetus or neonate with ring chromosome 13, the number of lost genes depends on the location of the breakpoint; therefore, obstetricians should take into consideration the position of the chromosome breakpoint when counseling the parents regarding the fetal and neonatal prognosis.

In contrast to the results from G-banding analysis, those from FISH analysis are quickly available, and the method can reliably detect clinically suspected numeric abnormalities. In FISH analysis, probes are used to detect structural abnormalities, but ring chromosomal aberrations may not always be detected by FISH analysis, as in our case. The possibility of detection depends on the location of probes. To detect numeric anomalies with FISH analysis, a centromere probe is usually used. However, by using a telomere probe or adding a specific probe for 13q34 or 13q12, the structural chromosomal anomalies such as ring chromosomes can be detected by FISH analysis. Recently, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have recommended microarray analysis as the first-line genetic test [10]. Although chromosomal microarray analysis is not yet routinely used in Japan, this method can enable rapid diagnosis of numeric and structural anomalies in chromosomes, including that of ring chromosomes. In this case, if this technique were used for the analysis, the result might reveal the monosomy at both ends of chromosome 13, indicative of a ring chromosome 13.

In conclusion, as a ring chromosome is an extremely rare aberration, obstetricians should note that this structural chromosomal aberration cannot be detected solely by FISH analysis and that G-banding or microarray analysis is also required. Additionally, information on the position of the chromosomal breakpoint should be obtained before counseling the parents regarding the fetal prognosis.