Double Aneuploidy (48,Xxy,+21) of Maternal Origin in a Child Born to a 13-Year-Old Mother: Evaluation of the Maternal Folate Metabolism

Summary: Double aneuploidy (48.XXY.+21) of maternal origin in a child born to a 1 3-year-old mother: evaluation of the maternal folate metabolism: The occurrence of non-mosaic double trisomy is exceptional in newborns. In this paper, a 48,XXY,+21 child, the parental origin of the extra chromosomes and the evaluation of the maternal folate metabolism are presented. The infant was born to a 13-year-old mother and presented with the typical clinical features of Down syndrome (DS). The origin of the additional chromosomes was maternal and most likely resulted from errors during the first meiotic division. Molecular analysis of 12 genetic polymorphisms involved in the folate metabolism revealed that the mother is heterozygous for the MTHFR C677T and TC2 A67G polymorphisms, and homozygous for the mutant MTRR A66G polymorphism. The maternal homocysteine concentration was 4.7 µmol/L, a value close to the one considered as a risk factor for DS in our previous study. Plasma methylmalonic acid and serum folate concentrations were 0.17 µmol/L and 1 8.4 ng/mL, respectively. It is possible that the presence of allelic variants for the folate metabolism and Hey concentration might have favored errors in chromosomal disjunction during gametogenesis in this young mother. To our knowledge, this is the first patient with non-mosaic Down-Klinefelter born to a teenage mother, resulting from a rare fertilization event combining an abnormal 25,XX,+2 1 oocyte and a 23,Y spermatozoon. Key-words: Aneuploidy - Down syndrome - Folic acid - Genetic Nondisjunction - Genetic Polymorphisms - Klinefelter syndrome. INTRODUCTION The occurrence of single trisomy is common, being found in around 50% of the karyotyped spontaneous abortions occurred before 1 5 weeks of gestation (20). However, the occurrence of double aneuploidy in the same individual is a relatively rare phenomenon, detected in about 0.7% of all miscarriages and exceptionally rare in liveborns (39). Double aneuploidy leading to trisomy and/or monosomy of two different chromosomes arises due to two nondisjunction events, and these two aneuploidies may have the same or different parental origin (18), and occur during meiosis I (MI), meiosis II (Mil), or during an early mitotic division in the developing zygote. Advanced maternal age is a well-established risk factor for nondisjunction of both autosomes and sex chromosomes (8, 25). More recently, the abnormal maternal folate metabolism has been pointed as a maternal risk factor for chromosome 21 nondisjunction by several studies (7, 13, 23, 33, 44). In addition, studies have associated the occurrence of chromosomal nondisjunction with altered patterns of meiotic recombination (28, 42). In this paper, we describe a 48,XXY,+21 infant with double aneuploidy, born to a 13-year-old mother. The parental origin of the extra chromosomes and the meiosis stage of the chromosomal nondisjunctions were determined. The association of two nondisjunction events in such a young mother provides a good opportunity for an insight into the role of folate metabolism deficiency in the etiology of chromosomal malsegregation. We analyzed 12 polymorphisms of genes involved in the folate metabolic pathway, and measured serum folate and plasma homocysteine (Hey) and methylmalonic acid (MMA), an indicator of the status of vitamin B12, in the mother of the affected child, in order to investigate possible maternal risk factors for chromosomal nondisjunction. MATERIALS AND METHODS This study was approved by the Research Ethics Committee of the Sao Jose do Rio Preto Medical School (CEP-FAMERP), in the State of Sao Paulo, and by the National Research Commission (CONEP), Brazil. CLINICAL REPORT A 3-month-old male patient was referred for chromosomal analysis to the General Outpatient Service of Hospital de Base in Sao Jose do Rio Preto, due to dysmorphic features suggestive of DS. The child was born at 32 weeks of gestation, the first child of young, nonconsanguineous parents (13-year-old mother and 24-year-old father). …