Background

Genotype–phenotype analyses have revealed several critical regions related to specific anomalies in 13q deletion syndrome [1]. Brown et al. categorized 13q deletions into three groups: group 1, proximal deletions not extending into q32; group 2, more distal deletions including at least part of q32; and group 3, most distal deletions involving q33–34 [2]. They also suggested that the severely malformed 13q phenotype results from the deletion of a critical region in 13q32 [3], which was later verified by others [4, 5]. However, genotype–phenotype correlations are still not completely understood. Since 13q deletion syndrome is exceedingly rare and presents as multiple phenotypic symptoms, the collection and analysis of findings regarding genotype–phenotype correlations are necessary to better understand this condition.

In the present report, the patient was an infant with a prenatal diagnosis of 13q deletion syndrome, defined as the deletion of 13q32.1–qter, consistent with the most severe form of group 2 deletions. The neonate exhibited several related symptoms, including fetal growth restriction (FGR), congenital anomalies of microphthalmia, Dandy–Walker malformation (DWM), overlapping finger, and esophageal atresia. Esophageal atresia is a rare symptom. The comparative genomic hybridization (CGH) array revealed a breakpoint of 13q31.3.

Case presentation

A 28-year-old Japanese primigravid woman was referred at 31 weeks of gestation for abnormal ultrasound findings including FGR, absence of a gastric bubble, and polyhydramnios. She had no history of abortion or complications. The couple had no family history of genetic diseases. The fetus showed an estimated fetal body weight of −3.2 standard deviations at the first ultrasound survey, had a score of 26 on the amniotic fluid index, exhibited no gastric bubble, and had cerebellar hypoplasia (Fig. 1a, b, arrows) and overlapping fingers. Microphthalmia was also detected in the right eye on fetal magnetic resonance imaging (MRI) (Fig. 1b). Amniocentesis was performed, and Giemsa banding (Fig. 2a) and fluorescence in situ hybridization (Fig. 2b) revealed a 46,XX,del(13)(q32.1–qter) karyotype. At 38 + 0 weeks gestation, an infant girl weighing 1774 g was born and examined by pediatric doctors. She presented with isolated esophageal atresia (Gross type A), DWM, right microphthalmia, left coloboma, overlapping fingers, pleurocentrum in the thoracic vertebrae, reduced anogenital distance, and hearing loss. At 48 days after birth, the infant underwent radical surgery for esophageal atresia and was discharged from the hospital uneventfully at 7 months age. The CGH array (SurePrint G3 human CGH 1 × 1 M; Agilent Technologies, CA, USA) using villus sampling after birth revealed that the region stretching from 13q31.3 to the terminus was deleted (22.12 Mb; from 92,973,314 to 115,097,664 bp, GRCh37, Fig. 2c). The parents both had normal karyotypes, indicating that the infant’s 13q deletion was de novo. The couple later had three healthy children.

Fig. 1
figure 1

Fetal magnetic resonance imaging scans. Sagittal (a) and axial (b) views at 34 weeks of gestation. Arrows indicate the cerebellum

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Fig. 2
figure 2

Chromosomal analyses. a Results of Giemsa banding by amniocentesis. The arrow indicates the abnormal chromosome 13, as del(13)(q32.1). b The result of fluorescent in situ hybridization by amniocentesis. The normal chromosome 13 had both 13q14 (blue) and 13qter (yellow), but no signal indicative of 13qter was detected on the chromosome del(13)(q32.1). c Array CGH analysis reveals the deleted region of 13q31.2–qter (92973314–115097664). The right panel shows an enlarged view of the gene deletion site in the left panel

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Discussion and conclusion

Esophageal atresia is a rare phenotype of 13q deletion syndrome. CGH array analysis determined that the breakdown point was 13q31.3. The patient also exhibited various phenotypes that matched with group 2 of 13q deletion syndrome, including overlapping finger, DWM, right microphthalmia, left coloboma, hearing loss, reduced anogenital distance, and pleurocentrum in the thoracic vertebrae (Fig. 3). She had no cardiac anomaly.

Fig. 3
figure 3

Candidate genes are related to the phenotype of the present patient. The red line shows the deleted region of the present patient. The numbers shown in the parentheses are consistent with the reference numbers

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The relation between haploinsufficiency of EFNB2 and vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L) (VATER/VACTERL) associations in 13q deletion syndrome have recently been reported [6,7,8]. Esophageal atresia without tracheoesophageal fistula (Gross A), vertebra anomalies, and reduced anogenital distance in the present patient also indicate VATER/VACTERL association-like symptoms. We found no previous reports demonstrating esophageal atresia (Gross A) with 13q deletion syndrome, but esophageal atresia (Gross A) might be a symptom of VATER/VACTER [9]. Our review found three 13q deletion patients with esophageal atresia, including the present patient (Table 1) [8, 10]. All of these patients showed partial symptoms of VATER/VACTER. Therefore, the present patient and our literature review suggest that 13q deletion syndrome with esophageal atresia would show VATER/VACTERL association-like symptoms. Two of the three patients had 13.32q deletion, which results in the haploinsufficiency of EFNB2. However, the specific region associated with esophageal fistula/atresia remains undetermined. Therefore, further studies are needed to clarify the association between insufficiency of the 13q region and tracheoesophageal fistula/atresia. For this purpose, it would be helpful to determine the deleted region in detail using the CGH array.

Table 1 Comparison of clinical and chromosomal features in 13q deletion syndrome with esophageal atresia
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Finger anomalies are related to loss of the GPC5 gene in 13q31.3 [5] and the GPC6 gene in 13q31.3–q32.1 [11], consistent with the present patient. However, one report showed that limb abnormalities may not be related to any specific genomic region [12].

DWM is well known to be associated with haploinsufficiency of the ZIC2 and ZIC5 located in the 13q32.3 [4, 12,13,14,15], which is consistent with the findings of the present patient. In addition, the 13q33.1 may also be associated with DWM [14], which is also consistent with our patients.

Previous reports suggested that eye malformation might be associated with the EFNB2 gene [4], and deletion of the 13q32 region [2]. Recently, the 13q33.3–q34 deletion (110,302,002–11,394,979, GPCh37) has been shown to be associated with microphthalmia or anophthalmia with/without coloboma in 15 patients [16], and 13 genes were encoded in the region: IRS2[110405042–110438930], COL4A1[110801310–110959504], COL4A2[110959631–111165556], CARS2[111293757–111358862], ING1[111364970–111375686], SOX1[112721463–112726020], ATP11A[113344352–113541482], MCF2L[113623528–113754056], F7[113760102–113774999], F10[113777113–113803843], PROZ[113812962–113826700], PCID2[113831850–113862983] and CUL4A[113862507–113921422] (GpCh37) [7]. In our review of these genes, IRS2 was reported to be involved in retina function [17, 18]. COLA1 and/or COLA2 mutations are involved in ocular defects [19,20,21,22]. The present patient and our literature review suggest that IRS2, COLA1, and COLA2 in the 13q33.3–q34 would also have a pathological role in eve malformation, including microphthalmia or anophthalmia with/without coloboma.

It has been reported that EFNB2 haploinsufficiency [23,24,25] or 13q32 deletion [15], is involved in hearing loss, although deafness has been reported in the patients with deletions of the 13q13.1–q14.3 and 13q12.3–q21.1 [26]. Furthermore, EFNB2 is involved in the morphogenesis of the endolymphatic sac and duct epithelia in the mouse inner ear, which requires normal hearing [27]. Our data also supports the role of the EFNB2 haploinsufficiency in hearing loss.

The present patient showed no cardiac defect without the distal 13q34 region, which has been reported to be associated with cardiac defect [7, 28].

This study presented a case that indicated an association between esophageal atresia, a rare phenotype, with deletion of the 13q31.3–qter region. The present case and the literature review suggest that it is part of VATER/VACTERL association-like symptoms and suggests the association between haploinsufficiency of EFNB2 and VATER/VACTERL association-like symptoms. These findings support the previous findings on pathological roles of haploinsufficiency of ZIC2/ZIC5 on DWM, and EFBN2 haploinsufficiency on eye malformation and hearing loss. Furthermore, we identify the possible involvement of IRS2, COLA1, and COLA2 in eye malformation. We hope that these findings will help identify the causal genes of various phenotypes of 13q deletion and provide more precise information during prenatal counseling, although further accumulation of such reports is required.