Partial trisomy of chromosome 15q and partial monopsony of 6q due to maternal balanced translocation.

A 7-month-old male presented with developmental delay and multiple congenital anomalies. He was found to have partial trisomy for the distal segment of chromosome 15 (q22-qter). Chromosome analysis of the mother showed a reciprocal balanced translocation between long arms of chromosome 6 and 15, t (6;15)(q26;q22).

Introduction

Partial trisomy of chromosome 15 was first reported by Fujimoto et al. in 1974.[1] Since then, over 20 such cases have been reported in the medical literature.[2] Most of the cases involved distal segment of chromosome 15, with the breakpoints at q22 or distal to it.[34] We report a case of a 7-month-old male with partial trisomy 15 due to balanced translocation involving chromosomes 6 and 15 in the mother.

Case Report

A 7-month-old male was brought with developmental delay. He was born to nonconsanguineous parents, mother aged 36 years and father aged 38 years, with three normal elder daughters. The fourth baby was a male, who died 6 h after birth. He had dysmorphism, and the parents were told that the baby had some genetic disorder. However, no documentation of dysmorphic features or karyotype was available. The fifth pregnancy, 1-year later, was a spontaneous abortion at 3 months gestation.

The proband was conceived as the sixth pregnancy. The family came to medical attention at 23 weeks 3 days of pregnancy when an ultrasound had detected bilateral club feet, thickened nuchal skin fold, cerebral ventriculomegaly, hypoplastic cerebellum, unilateral right renal pelviectasis. The findings suggested chromosomal anomaly and amniocentesis was done for fluorescent in-situ hybridization for chromosome 21 and karyotype analysis. The fluorescent in-situ hybridization for chromosome 21 showed two signals in each cell. Karyotype showed an “extra genetic material” on a long arm of chromosome 6 [Figure 1]. The parents were counseled about the risk of mental retardation in the baby and were advised to undergo chromosomal analysis. They, however, decided to continue the pregnancy in view of advanced gestational age.

Figure 1

Karyotype of the baby (prenatal sample) showing an extra chromosomal material on chromosome 6

At term, the mother went into labor. Fetal distress was detected in the form of fetal bradycardia and meconium stained liquor. The baby was delivered by a lower segment cesarian section. He cried immediately at birth. He developed fast breathing and received oxygen and intravenous fluids. He improved gradually and was discharged after 6 days. There was no history of seizures, encephalopathy, or jaundice in the neonatal period.

He developed social smile at 3 months, and was recognizing his mother and reaching out for objects at the time of presentation. He had achieved partial neck holding. Vision and hearing were normal. There was no history of seizures.

On examination, the infant had an abnormal posture with his legs in abducted and flexed position. He weighed 7.5 kg (<25th centile for age), measuring 72.5 cm in crown-heel length (>75th centile for age). The child had microcephaly (head circumference of 40 cm, <−3 standard deviation). He had facial asymmetry, strabismus involving the left eye, narrow down-slanting palpebral fissures, prominent nose, overhanging columella, long philtrum, small pointed chin, midline crease in the lower lip and high arched palate [Figure 2]. He also had club feet, and long tapering fingers, with middle finger being overlapped by other fingers. The neurological and systemic examination was normal.

Figure 2

(a) Facial asymmetry, strabismus involving the left eye, narrow down-slanting palpebral fissures, prominent nose, overhanging columella, long philtrum, small pointed chin, midline crease in the lower lip. (b) Long and tapering fingers, with middle finger being overlapped by other fingers. (c) Club feet

Investigations revealed a normal hemogram, liver, and kidney function tests. Ultrasonographical evaluation of the abdomen revealed no abnormality. Magnetic resonance imaging of the brain revealed mild thinning of the corpus callosum without any other abnormalities. Echocardiography was normal.

Karyotype analyses of parents were carried out in view of previous sibling death with dysmorphism and history of spontaneous abortion in mother. Father's karyotype was normal. Karyotype of the mother revealed a balanced translocation between chromosomes 6 and 15; t (6;15)(q26;q22) [Figure 3].

Figure 3

Karyotype of the mother showing a balanced translocation between chromosomes 6 and 15; t(6;15)(q26;q22)

From the above dysmorphic features, physical findings and the patient's and his mother's karyotype, a diagnosis of partial trisomy of chromosome 15 (q22 → qter) due to balanced translocation in the mother was made. As the child inherited the derivative chromosome 6 from the mother, it was clear that, he also had terminal deletion of 6q (q26 and q27). The child was started on physical and occupational therapy.

Genetic counseling was provided to the family. The family was able to understand that the anomalies and developmental delay are due to the chromosomal imbalances in the affected child. They also were able to understand that the chromosomal anomaly in this child and probably some of the previous pregnancy losses are related to the balanced translocation in one of the parents. The recurrence risk and availability of prenatal testing early in pregnancy has been explained. Other reproductive options like use of a donor ovum have also been discussed. The importance of extended family screening for the same balanced translocation on the mother's side; and its importance for the prevention of recurrences in the extended family has been explained.

Discussion

The karyotype of our patient contained an extra genetic material on a long arm of chromosome 6 (46, XY, 6q+). Chromosomal analysis of the parents showed the mother to be a balanced translocation carrier, with the karyotype 46, XX, t (6;15)(q26;q22). The extra genetic material was thus found to be a segment of chromosome 15, which was attached to the long arm of chromosome 6 in the proband. The congenital anomalies and the global developmental delay in our case were thus, due to a partial distal trisomy of chromosome 15. Partial distal trisomy of chromosome 15, in some cases, has been reported to be due to a balanced translocation in one of the parents.

The range and severity of symptoms and physical findings may vary from case to case, depending upon the length and location of the duplicated portion of chromosome 15 and the second chromosome involved in the translocation.[34] Even though the breakpoint in the second chromosome is often in the terminal region, modifying effects of an undetectable deletion or duplication of genetic material involving the second chromosome may still occur. As is evident from the clinical profile, all the cases reported until date, the phenotype due to a partial distal trisomy of chromosome 15 is clinically distinguishable. It is usually characterized by a delay in language development and motor skills such as walking or sitting up, growth and mental retardation. Distinctive craniofacial features may include microcephaly, antimongoloid slant, epicanthal folds, micrognathia, flattened nasal bridge, long philtrum, puffy cheeks and high arched palate.[4567] Other abnormalities may include hypotonia, seizures, skeletal deformities and abnormal fingers and toes. Cardiomyopathy, renal anomalies or abnormal genitalia may also be found.[67]

Our patient had microcephaly, micrognathia, long philtrum and high arched palate, which was consistent with the physical appearance described in this anomaly. Also, our patient had strabismus and flexion deformities of fingers and toes, which have been reported in very few patients with this disorder.[8] The second chromosome involved in our case is chromosome 6 and some features like ventriculomegaly and hypoplasia of corpus callosum, might be contributed by the terminal monosomy of chromosome 6.[910] Our case thus helps in expanding the spectrum of partial trisomy 15. Unlike our case, there can be translocations leading to smaller imbalances in the offspring. Prenatal karyotype by Giemsa banding might miss such small imbalances, which might have unfavorable consequences. Multiplex ligation-dependent probe amplification, fluorescence in-situ hybridization or cytogenetic microarray may be used as an adjunct diagnostic technique to look for small cryptic imbalances in the fetus. Importance of detection of such chromosomal anomalies lies in the fact that the family can be provided genetic counseling so that the family can adapt to the problem and also take a decision regarding future pregnancies. As mother is a carrier of balanced translocation; she is likely to produce gametes with chromosomal imbalance during meiosis. The overall chance of having normal children is around 60-70%. The private risk for the balanced translocation described by us is not available. Prenatal testing early in pregnancy by chromosomal analysis from chorionic villus sample (9-11 weeks) or amniotic fluid (15-16 weeks) or by ultrasonography to look for associated physical anomalies as described in the affected child, are viable methods to prevent recurrences.