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.
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