Double paternal nondisjunction in an infant with transient neonatal diabetes mellitus and Klinefelter syndrome

Transient neonatal diabetes mellitus (TNDM) is a relatively rare disorder, with an incidence of approximately 1 in 400,000 live births. Infants typically present as growth-restricted neonates with persistent hyperglycemia and inappropriately low insulin levels. Insulin therapy is initially required but patients are usually weaned from exogenous insulin around 4 months of age. Despite the transient nature of TNDM, approximately 40% of patients develop type II diabetes later in life. TNDM has been associated with abnormalities of chromosome 6 [Temple and Shield, 2002], including partial or complete paternal uniparental disomy (UPD) [Temple et al., 1995; Gardner et al., 1998; Cave et al., 2000; Das et al., 2000], paternal duplication of a region of 6q24 [Temple et al., 1996], and loss of maternal methylation in the 6q24 region [Gardner et al., 2000]. These associations strongly suggest that TNDM is caused by the overexpression of an imprinted paternal gene. Two possible candidate genes that have been identified for this condition are PLAGL1 (previously known as ZAC), a regulator of apoptosis and the cell cycle [Varrault et al., 2001], andHYMAI, a gene imprinted in hydatidiform mole [Arima et al., 2000]. The PLAGL1 and HYMAI genomic sequences overlap [Arima et al., 2001; Mackay et al., 2002]. Altered expression of both PLAGL1 and HYMAI has been demonstrated in fibroblasts isolated from a patient with TNDM [Mackay et al., 2002]. More recently, transient neonatal hyperglycemia has been reproduced in transgenic mice expressing the human TNDM locus [Ma et al., 2004]. Hyperglycemia occurs in the offspring of these mice following paternal but not maternal transmission of the TNDM locus, with litters exhibiting a defective insulin secretory response. The origins of the many chromosomal abnormalities associated with TNDM are complex and have only rarely been associated with anomalies of other chromosomes. A search of the current literature on this subject reveals one report of an infant with TNDM and Trisomy X syndrome resulting from paternal isodisomy of chromosome 6 and maternal disomy of the X chromosome [Valerio et al., 2001]. We report on the case of a male infant with TNDM who was born at 39 weeks gestation with a birth weight of 1,835 g. The pregnancy was complicated by both oligohydramnios and fetal growth restriction. He was delivered by cesarean secondary to decreased fetal movement and poor intrauterine growth. Apgar scores were 8 at 1 min and 9 at 5 min. His initial physical examination revealed a small for gestational age male infant that appeared emaciated, with significant macroglossia and hypertelorism. On day 1 of life he fed very poorly and his glucose level was 44.6 mmol/L (811 mg/dl) with an insulin level of less than 0.2 mU/ml. Chromosomal analysis revealed a 47, XXY karyotype with no visible abnormalities of chromosome 6. Intravenous insulin therapy was initiated on day 1 of life at a rate of 0.05 units/kg/hr to decrease his serum glucose by 3.3–4.4 mmol/L (60–80 mg/dl) every hour to reach a goal of 5.5– 11 mmol/L (100–200 mg/dl). He remained on IV