Key Clinical Message
We present a case of a fetus with unbalanced 46, XY, der(10)t(6;10)(p22;q26.1) translocation. Prenatal genetic diagnosis can provide useful information about postnatal complications, prognosis, and subsequent pregnancy.
1. INTRODUCTION
The frequency of unbalanced translocations is generally 0.03% in neonates.1 In 82% of cases of unbalanced translocations, one of the parents harbors a balanced translocation. Furthermore, among families harboring an unbalanced translocation, 19.2% of the translocation carriers may bear a child with an unbalanced translocation.2
Unbalanced translocations typically result in phenotypes with multiple malformations, growth disorders, or intellectual impairment, similar to other chromosomal abnormalities. Fetuses with moderate malformations may be born; however, those with severe malformations may result in miscarriage or the occurrence of intrauterine fetal death.
Here, we report the case of an unbalanced translocation between chromosomes 6p22 and 10q26, detected before birth, resulting in severe fetal growth restriction (FGR) and congenital heart disease (CHD) determined through chromosome analysis, and present a review of the related literature.
2. CASE REPORT
The mother was 29 years old, gravida 1, para 0, with no family history of chromosomal abnormalities. The father was 40 years old, with no family history (parents and two younger siblings) of phenotypic and chromosomal abnormalities; however, his previous partners experienced multiple miscarriages. He did not have a history of medication or smoking.
The mother conceived naturally and underwent regular pregnancy checkups at other hospitals from early pregnancy. The FGR was -1.5 standard deviations (SD) from 23 weeks of gestation. The mother was referred to our hospital at 27 weeks of gestation owing to the suspicion of fetal cardiac malformation. The fetus was diagnosed with FGR with an estimated fetal weight (EFW) of 641 g (-3.7 SD), and CHD (ventricular septal defect [VSD] and pulmonary stenosis) was suspected. However, no arterial obstruction or reflux was observed in the umbilical cord, and the cause of FGR was unclear. The mother was therefore hospitalized for prenatal management. Isosorbide dinitrate was administered to improve blood flow in the uterine artery.
We performed chromosome analysis using amniotic-fluid cells at 29 weeks of gestation and detected a chromosomal aberration of 46, XY, add(10)(q26) (Figure 1). To identify the origin of the additional chromosome, we conducted additional chromosome analysis for the parents at 32 weeks of gestation, which revealed a normal karyotype in the mother and an unbalanced 46, XY, t(6;10)(p22;q26.1) translocation in the father (Figure 2). The 46, XY, der(10)t(6;10)(p22;q26.1) translocation was detected in the fetus. The growth rate of the fetus was slow, and the EFW was -4.9 and -3.6 SD thereafter.
The fetus was delivered through selective caesarian sectioning at 37 weeks of gestation owing to abnormalities in blood flow through the umbilical artery, fetal monitoring abnormalities with non-stress test (NST), and severe FGR. The neonate was a boy weighing 1,470 g, and the Apgar scores were 3, 7, and 8 in the first, fifth, and eighth min, respectively, with an umbilical cord arterial blood pH of 7.21.
Internal malformations including VSD, pulmonary atresia (PA), and pulmonary hypoplasia; facial malformations including low set ears and high arched palate; and other external malformations including scrotal hypoplasia were detected in the fetus. Neurological abnormalities could not be assessed; however, hypotonia, overlapping toes, and cryptorchidism were detected. However, urinary tract/renal anomalies were not detected (Table 1). We attempted to improve the respiratory status through intubation; however, the neonate died at 14 days of age owing to multiple organ failure due to pulmonary hypoplasia and circulatory failure.
3. DISCUSSION
Phenotypic abnormalities observed as a result of trisomy of chromosome 6 were first reported as “the trisomy 6p syndrome” by Therkelsen in 1971, and are particularly infrequent chromosomal abnormalities.3 Phenotypic abnormalities observed in partial trisomy of chromosome 6 include craniofacial malformations, mental retardation, cardiac abnormalities, and other complications. Castiglione reported cephalic abnormalities: craniosynostosis, tall forehead, ear anomalies, strabismus, long philtrum, thin vermilion of the lips, and a high arched palate; neurological abnormalities: developmental delay, intellectual disability, and behavioral issues; cardiac malformations; hydronephrosis; overlapping toes; low birth weight (LBW); and immunodeficiency.4 Table 1 enlists the malformations in trisomy 6p syndrome reported by Castiglione and Ferrando.5
Multiple malformations have been reported in patients with a partial deletion in chromosome 10. In particular, cases with chromosome 10q26 deletion syndrome exhibited several malformations including craniofacial anomalies, developmental delay/intellectual disability, urinary tract abnormalities, cardiac malformations, and neurodevelopmental deficits, and shared numerous common clinical characteristics.
Table 1 partially displays the phenotypes of 10 cases with 10q26 deletion syndrome reported previously.6 Among these, the most common facial malformations are microcephaly, tall forehead, bitemporal narrowing, ear anomalies, strabismus, broad/prominent nose, long philtrum, and thin vermilion of the lips, posterior cleft palate, and a broad chin. Furthermore, neurological abnormalities were observed at a 95% frequency, especially during developmental delay and intellectual disability and hypotonia in >80% cases. Furthermore, behavioral issues and hypotonia were frequent. Although certain limb abnormalities were observed in half of the cases, no specific morphological abnormality was noted, including clinodactyly and tapering of the fingers. Moreover, cardiac malformations are observed in more than half of the cases, especially atrial septal defect (ASD) and VSD. Minor malformations and urinary abnormalities, although infrequent, have also been reported in individual cases.6
Patients with trisomy 6 and monosomy 10 have common craniofacial abnormalities, especially ear anomalies, strabismus, long philtrum, and thin vermilion of the lips. Notwithstanding, a small number of cases revealed that microcephaly, bitemporal narrowing, broad/prominent nose, posterior cleft palate, broad chin, and hypotonia are unique to monosomy 10.4,6
Mutations in FGFR2 (10q26) are associated with craniosynosis, Crouzon syndrome, Pfeiffer syndrome, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, and Saethre-Chotzen syndrome.4 However, Lin et al. reported a low frequency of the 10q26 deletion, probably owing to trisomy 6 because it was observed in the cases reported by Castiglione and Ferrando.4,5 Cardiac and urinary malformations have been reported in both chromosomal abnormalities; however, their pathological roles are unclear. However, since low birth weight and immunodeficiency have not been reported during monosomy 10, chromosome 6 was considered responsible for this phenotype.
Low birth weight; cephalic abnormalities including microcephaly, low set ears, high arched palate, and ambiguous genitalia including scrotal hypoplasia and cryptorchidism were observed in the present case. CHDs including VSD and PA were also observed herein. No kidney or renal malformations were observed. Mental retardation could not be evaluated owing to neonatal death. Microcephaly, ear anomalies, hypotonia, and VSD, the most common external malformations in 10q26 deletion syndrome reported by Lin et al.6, were observed herein. However, tall forehead, bitemporal narrowing, strabismus, broad/prominent nose, choanal atresia, posterior cleft palate, and broad chin were not observed. Furthermore, the mortality rate and frequency of low birth weight in previously reported infants were not very high. In the present case, early neonatal death may have resulted from severe cardiac malformation and LBW. Perinatal death, LBW, and overlapping toes may have resulted from trisomy 6, as few have been reported for 10q26 deletion syndrome.
During gametogenesis, a chromosomal pattern opposite to that in our case may occur; thus, there is a possibility of trisomy 10 and monosomy 6. In the present case, abortion would have been possible owing to significant chromosome loss. Previous studies have reported phenotypes including preterm birth, delayed growth, mental retardation, microcephaly, craniosynostosis, internal organ abnormalities, digital abnormalities, short neck, flat face, arched eyebrows, ocular hypertelorism, flat nose, micrognathia, and cleft palate.7 A funnel chest and congenital cardiac anomalies (ASD, VSD, patent ductus arteriosus) were reported particularly in cases of monosomy 6p.7 With regard to 10q trisomies, the 10q24 → qter trisomy has been most frequently reported, accompanied by LBW, growth retardation, and severe mental retardation.8 Approximately half of the carriers have been reported to die during infancy.8
In conclusion, in the present case, chromosome analyses of the parents and the fetus with severe FGR and CHD revealed an unbalanced translocation in the father. Fetal prenatal malformations and postpartum neuropsychiatric developmental disorders could be predicted to some extent through chromosome analysis. Furthermore, chromosomal abnormalities could be investigated during subsequent pregnancy and, if desired, preimplantation genetic diagnosis can be implemented to obtain useful information.
ABBREVIATIONS
FGR: fetal growth restriction, CHD: congenital heart disease, SD: standard deviations, EFW: estimated fetal weight, VSD: ventricular septal defect, NST: non-stress test, PA: pulmonary atresia, LBW: low birth weight, ASD: atrial septal defect
CONSENT
The patient consented.
FUNDING
None.
AVAILABILITY OF DATA AND MATERIAL
All medical data were obtained from hospital electronic medical records.
ACKNOWLEDGMENTS
We would like to thank Editage (www.editage.com) for English language editing.
CONFLICT OF INTEREST
None declared.
AUTHOR CONTRIBUTIONS
MI: drafted the manuscript. TW: performed genetic counseling and approved the manuscript. HK, AY, KS, MS, HG, MH, and KF: performed the clinical assessment.
REFERENCES
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  3. Therkelsen AJ, Klinge T, Henningsen K, Mikkelsen M, Schmidt G. A family with a presumptive C–F translocation in five generations.Ann Genet.  1971;14:13-21.
  4. Castiglione A, Guaran V, Astolfi L, et al. Karyotype-phenotype correlation in partial trisomies of the short arm of chromosome 6: a family case report and review of the literature. Cytogenet Genome Res. 2013;141:243-259.
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  7. Palmer CG, Bader P, Slovak ML, Comings DE, Pettenati MJ. Partial deletion of chromosome 6p: delineation of the syndrome. Am J Med Genet. 1991;39:155-160.
  8. Han JY, Kim KH, Jun HJ, Je GH, Glotzbach CD, Shaffer LG. Partial trisomy of chromosome 10 (q22–q24) due to maternal insertional translocation (15; 10). Am J Med Genet A. 2004;131:190-193.