Neonatal diabetes mellitus (NDM) is extremely rare (1/400 000–1/500 000 newborns), and most cases are sporadic.1 NDM is defined as persistent hyperglycaemia developing in the first month of life, lasting at least 2 weeks, and requiring insulin treatment. In several epidemiological studies, two forms of NDM have been clinically recognised—one transient (TNDM, 50–60%) and the other permanent (40–50%)—which differ in the duration of insulin dependence.1 2

Recently, advances have been made in understanding the clinical and genetic characteristics of TNDM. Most patients of TNDM have intrauterine growth retardation (IUGR) at birth and fail to thrive.1^–6 Also, an open-eyed, alert face and macroglossia are clinically observed.2 3 5 It is considered that overexpression of an imprinted gene located on chromosome 6q24 causes TNDM.2^–6 With this condition, infants develop persistent hyperglycaemia that requires insulin in the first month of life (median 3–6 days; range1–81).2 3 Insulin administration is necessary as treatment, but the need ends at about 3 months of age and the remission persists.2 3 However, a significant number of patients with TNDM relapse in late childhood or adolescence (range 4–28 years) with type 2 diabetes.1^–4 It is probable that pancreatic dysfunction dependent on the severity of the β-cell defect is initiated at times of metabolic stress such as puberty.3 4

To the best of our knowledge, no reports of preterm infants with TNDM have been published. In this report, we describe an extremely preterm infant with TNDM who received neonatal intensive care for prematurity and insulin treatment for hyperglycaemia. The purpose of this report was to determine whether the clinical course of TNDM (such as features at birth, age at hyperglycaemia development, and treatment) in an extremely preterm infant differs from that in term infants.

CASE REPORT

A female infant was born by vaginal delivery to a 27-year-old woman (gravida 2, para 2) at 27 weeks’ gestation. The pregnancy was uneventful and the mother had received no steroids during pregnancy. Her family members were healthy, with no family history of IUGR or diabetes mellitus (DM). Apgar scores were 1 and 2 at 1 and 5 minutes, respectively, and resuscitation was necessary. The neonate was transported to our neonatal intensive care unit because of extreme prematurity and low birth weight. Birth weight was 718 g, and IUGR was present. Physical examination on admission showed no anomalies. She developed respiratory distress syndrome, chronic lung disease (CLD) and retinopathy of prematurity, but severe intraventricular haemorrhage, periventricular leucomalacia, sepsis or meningitis did not develop. The infant was mechanically ventilated until 79 days of life, but steroids for treatment of CLD were not used because of hyperglycaemia.

Although no hypoglycaemia or hyperglycaemia were seen just after birth, laboratory studies demonstrated hyperglycaemia (>22.2 mmol/l) at 12 hours after birth, so continuous insulin infusion was started.. Until the infant was around 50 days old (34 weeks post-conceptual age), the insulin dosage varied from 0.01 to 0.075 U/kg/day and the blood glucose level varied greatly from 5.6 to 27.8 mmol/l (fig 1). When the infant was between 50 and 70 days old (34–37 weeks after conceptual age), the insulin dosage was reduced to 0.025–0.05 U/kg/day and the blood glucose level began to stabilise at 11.1–22.2 mmol/l. Insulin administration was discontinued on the 89th day of life (39 weeks post-conceptual age), which was one day before the original due date. Serum insulin, C-peptide or proinsulin were not measured during the hyperglycaemic episode.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1 Changes in blood glucose level and insulin dosage while patient was in the neonatal intensive care unit.

Subsequently, weight gain was poor, and on the 90th day of life, which was the original due date, was low at 1513 g. An open-eyed, alert face and macroglossia were noted. Paternal uniparental isodisomy of chromosome 6 was identified. Therefore, TNDM was diagnosed.

Currently, the child is 4 years old and her physique is small. Her post-hospital clinical course was unremarkable. Open-eyed, alert face and macroglossia have already disappeared. She does not have cerebral palsy, but has mental retardation (IQ = 72). It is unclear if the mental retardation is due to the unstable blood glucose levels from TNDM or due to the premature birth. She has not had a recurrence of DM.

DISCUSSION

Transient hyperglycaemia in extremely preterm infants is commonly observed, especially during the first week of life. Sepsis, meningitis, severe intracranial haemorrhage, necrotising enterocolitis, severe respiratory distress syndrome are common causes of hyperglycaemia. Hyperglycaemia is also seen as a side effect of drugs, such as steroids for CLD and theophylline for apnoea of prematurity. Moreover, extremely preterm infants develop hyperglycaemia when receiving inappropriately high rates of glucose infusion or parenteral nutrition. In this case, however, these causes were ruled out.

This is the first report of TNDM in the extremely preterm infant. There are a few new observations in this case. First, this extremely premature infant had already exhibited IUGR at birth and developed hyperglycaemia on the first day of life. The high rate of IUGR is associated with failure of insulin secretion, in fetal life, especially during the third trimester of pregnancy. This suggests that insufficient insulin secretion is occurring from the early stages and that insulin is a potent growth factor even at this early age in TNDM, at least from the second trimester of the pregnancy. Second, about 3 months were required to improve the hyperglycaemia. This agreed with the duration reported in full-term infants.2 3 5 6 It seemed that the duration needed for recovery of insulin secretion was not dependent on the maturity. Third, the time at which insulin treatment was completed was around the due date.

The clinical course of this patient is interesting. Might there be cases with TNDM in which hyperglycaemia develops during pregnancy, but resolves by the time of birth, and recurs as DM in late childhood or adolescence? Is there a possibility that TNDM is hidden among patients with young onset DM? However, a previous study has examined whether imprinting defects within the TNDM locus are associated with early onset type 2 DM, as a result of two patients who carried a paternal unbalanced duplication of 6q24 with no history of neonatal diabetes but with onset of DM at age 25 years. The authors finally concluded that a chromosomal anomaly is not positive in patients with young onset DM.7 The disappearance of hyperglycaemia at term might be coincident in this preterm infant with TNDM. Further studies are necessary to clarify the hypothesis that hyperglycaemia might resolve by the time of birth in some cases with TNDM.