Double Trisomy 48,XXY,+21 in a Neonate with Congenital Heart Disease

Received: October 17, 2018, Accepted: December 11, 2019, ePublished: May 1, 2020 Abstract Double trisomy 48, XXY, +21 or Down-Klinefelter syndrome is a rare occurrence and presents clinical manifestation of trisomy 21 in early life and of Klinefelter syndrome after 10 months of age. The phenotypic and karyotyping characteristics of a 2-month-old boy were reported. He had mild clinical feature of Down syndrome and echocardiographic features of atrioventricular (AV) septal defects with severe pulmonary valve stenosis.


Introduction
As an abnormal number of a genomic region copies, fetal aneuploidy is the most common mechanism of human chromosomal diseases. Along with other chromosomal aberrations, it affects 9 out of 1000 live births. 1 As the most common chromosomal disorder in humans, Down syndrome (trisomy 21) has an incidence of one in 770 live births; and Klinefelter syndrome (47, XXY), in which there is one extra X chromosome resulting in the karyotype is also the most common disorder of sex chromosomes in humans, with prevalence of one in 500 males. 2 About 45% of trisomy 21 patients are affected by congenital heart diseases (CHDs) and half of them have balanced complete atrioventricular (AV) canal (complete endocardial cushion defect), a complex condition that needs cardiac repair by open heart surgery. 3 Double aneuploidy, the presence of two chromosomal abnormalities in the same individual, is a rare phenomenon and occurs because of two meiotic nondisjunctional events. Double aneuploidy of 48,XXY,+21 is the most commonly described double aneuploidy whose coincidence rate is estimated to lie in the range 0.27-0.7 × 10 -5 . 4,5 After reviewing the available literatures, Shen et al revealed that since the first case reported by Ford et al in 1959, sixty-three cases of 48,XYY,+21 chromosome pattern were reported until 2012, and only 9 cases had CHD. 2 Following that, seven cases of 48, XXY,+21 were reported, out of whom one case presented CHD. [6][7][8][9] In the current report, the clinical features of a 2-monthold infant who exhibited 48,XXY,+21 double aneuploidy karyotype were presented.

Case Report
A 2-month-old male infant was referred for chromosomal analysis due to dysmorphic features suggestive of Down syndrome in cytogenetic laboratory of Shafa educational hospital, Ahvaz, Iran, on June 2018; informed consent was obtained from the patient's parent. He was the third child of consanguineous couple (second cousins). The mother was 39 years old and the father was 40. After 10 years of infertility and related medications, the couple has a healthy 7-year-old girl and a 5-year-old son.
His mother had no history of perinatal medically significant problems such as diabetes mellitus, systemic lupus erythematous, infections, using alcohol and smoking, but she was using oral ranitidine and aluminum MGS for her gastritis. She did not carry out prenatal chromosomal trisomies screening as generally used for diagnosis of 13, 18 and 21 trisomies in Iran.
The proband was born after 41 weeks of gestation via caesarian section following an uncomplicated pregnancy and with post-partum cyanosis. He was born with 3350 g of weight, 52 cm of length and 34.5 cm of head circumference and had active crying and was fed normally. Now the patient and his family stay in Haftgel city of Khuzestan province, Iran and he is Lor, ethnically.
Mild cyanosis, generalized hypotonia and simian crease were noted. Face appearance was overall suggestive of Down syndrome. He has low set and small ears, epicanthic folds, protruding tongue, upward sloping palpebral fissures and strabismus. There was a load systolic murmur in heart auscultation on mitral and pulmonary focal areas. The genitalia was normal. He showed no other malformation (Figure 1).
Cytogenetic study from peripheral blood cultures showed a complement of 48 chromosomes with two extra chromosomes X and 21 in the C and G groups. Chromosomal preparations obtained from peripheral blood cultures stimulated by phytohemagglutinin, were subjected to Giemsa banding and karyotyping result was 48,XXY,+21 ( Figure 2) with no evidence of mosaicism.
The Doppler echocardiogram detection showed complete balanced AV canal presented by premium atrial septal defect (ASD1), large inlet ventricular septal defect (inlet VSD: 12 mm), common AV valve with regurgitation and significant pulmonary stenosis (PS) with 65 mm Hg pressure gradient as well as an additional secundum atrial septal defect or ASD2 (Figure 3). This complex CHD could be described as complete balanced AV canal plus tetralogy of Fallot. Clinically, coexisting PS could save the patient from pulmonary overflow and heart failure.
His development was delayed in all of the domains and he could not walk and talk, but he reacts normally to his parents.

Discussion
The incidence of trisomies is directly related to ma ternal age; this may play a more important role in the etiology of the most com mon double aneuploidy 48,XXY,+21. 10 Kovaleva and Mutton reported a mean maternal age of 33 years and a mean paternal age of 38 years for the risk of 48,XXY,+21. 5 In the current case, mother's and father's age of proband were 39 and 40 years respectively, which indicates this age dependent manner.
Aneuploidies are genetic disorders generally created due to meiotic non-disjunctional events. Considering history of our case's mother prominences old history of fertility inducer drugs during infertility period, compared to other teratogens such as histamine-2 blockers consumption.
Published cases of 48,XXY,+21 generally showed typical feature of Down syndrome and the Klinefelter syndrome characteristic feature not apparent until the pubertal   stage. According to the Down-Klinefelter case reports, neonates and infants younger than 10 months show few or no clinical appearance of Klinefelter syndrome. 2 The current case had features of trisomy 21, but not Klinefelter syndrome, which is consistent with other case reports. On the other hand, our proband had mild clinical feature of Down syndrome and it can be resulted from the presentation of X trisomy in the verge of trisomy 21.
Although Cyril et al 4 and Eid et al 10 did not report cardiac manifestation in their X, 21 double trisomy cases, Neu et al 11 reported an endocardial cushion defect of the AV canal type with large ASD and VSD. Down-Klinefelter case of Shen et al 2 had ASD and VSD with patent ductus arteriosus, pulmonary hypertension and mild tricuspid regurgitation. ASD and VSD are the common grounds of our case with the last two case reports.
Although prenatal trisomies screening currently became compulsory for all pregnant women in Iran, it was not carried out during the pregnancy of our case's mother. American College of Obstetricians and Gynecologists (ACOG) strongly recommended that all pregnant mothers implement Down syndrome screening tests. 12 Regarding familial problems, our proband was not prone to screening, which resulted in sustaining life without worried about termination of pregnancy.
Unlike Klinefelter syndrome, Down syndrome is well known for CHD, occurring in 40%-50% of patients including AV, ventricular and isolated atrial septal defect and other anomalies. 13 Our case suffered from AV canal and pulmonary stenosis too.