A retrospective analysis of case records of children admitted with neonatal diabetes mellitus in the Department of Pediatrics and Endocrinology of Kanchi Kamakoti CHILDS Trust hospital, Chennai from January 2004 to December 2014 were analyzed. The study was approved by the institutional review board. A diagnosis of neonatal diabetes mellitus was established in infants who had their onset of diabetes within the first 6 months of life and presented with features of polyuria, polydipsia, weight loss, DKA and had their fasting blood sugar >126 mg/dL with HbA1C >6.5%. The case records of infants with neonatal diabetes mellitus were analyzed for birth weight, the age at onset of symptoms, the clinical features, laboratory investigations (FBS, HbA1C values), Genetic mutation testing results, treatment and follow-up details. We collected 3 mL of whole blood in EDTA tube from the proband and their parents, and sent it to Royal Devon and Exeter NHS Foundation Trust laboratory, Exeter, UK for genetic analysis. Molecular genetic testing included gene sequencing by PCR technique. All infants were treated with subcutaneous insulin at 05 -0.8 U/kg/day and were followed up.

During the study period, a total of 137 children were diagnosed as Type 1 diabetes mellitus as per WHO diagnostic criteria and 10 (5 boys) were diagnosed as neonatal diabetes mellitus. The age range at onset was from 3 days to 160 days. Six children were born to parents with consanguineous marriage and none had history of diabetes in their first degree relatives. All were born at term and six were born with a birth weight <2.5 kg. Diabetic ketoacidosis was the mode of presentation in 3 (30%) children (INS,EIF2AK3 and NEUROD1 gene). Glutamic acid decarboxylase and islet cell autoantibodies were negative in all children. The mean blood sugar was 499 mg/dL. Of the 10 children, one child had transient neonatal diabetes mellitus and nine had permanent neonatal diabetes mellitus. The child with transient neonatal diabetes presented with hyperglycemia on D3 of life, required insulin for 5 months, and mutation analysis revealed complete loss of methylation on chromosome 6 q24. She is off insulin and at her 16 month follow-up, she is growing well. Of the nine children with permanent neonatal diabetes mellitus, KCNJ11 gene mutation was positive in 1, ABCC 8 gene and INS gene mutation in 2 each, PDX1 gene mutation in 1, NEURO D1 mutation in 1, EIF2AK3 mutation in 1 and SLC19A2 gene mutation in 1 child. Children with KCNJ11 gene mutation and ABCC 8 gene mutation were treated with oral sulfonyl urea and others were treated with Insulin. On follow up, the child with Wolcott Rallison Syndrome died and other patients are growing well without problems. The details are shown in Table I.

TABLE 1 Clinical and Genetic Profile of Children With Neonatal Diabetes Mellitus

Nine children were diagnosed with permanent NDM in the present series. Heterozygous activating mutations in the KCNJ11 gene, that encodes the KATP channel subunit Kir6.2, accounts for 47% of permanent NDM [5,6] and a few cases of treatment NDM [7,8]. Similarly mutations in ABCC8 gene which encodes the SUR1 regulatory subunit of the ATP-sensitive potassium channels in beta cells can cause both permanent and transient neonatal diabetes. In clinical practice it is difficult to differentiate between patients with KCN J11or ABCC8 mutations and oral sulfonyl urea becomes the treatment of choice for diabetes resulting from both these mutations [9,10]. Our patients were switched on treatment from insulin to oral glibenclamide (0.5 mg/kg/day) once the genetic diagnosis was established, and on follow up their glycemic control was good.

The present study describes the clinical and genetic profile of children with neonatal diabetes mellitus. As the molecular genetic testing is expensive, we suggest an algorithm to approach a child with neonatal diabetes for ordering genetic testing in resource limited setting like ours (Fig. 1). Molecular genetic testing has a big impact on management of NDM as switching over to oral sulfonyl urea is required in children with KCNJ11/ABCC 8 gene mutation. Complete history, thorough clinical examination with a high suspicion and correlation with physical findings may help us to guide further the genotype work up of neonatal diabetes mellitus.

Fig. 1 Proposed algorithm for ordering genetic mutation testing in patients with neonatal diabetes (NDM).

Acknowledgements: Prof Sian Ellard, Consultant Molecular Geneticist, Peninsula Medical School (Royal Devon and Exeter NHS Foundation Trust, Exeter) and Professor Karen Temple, Wessex Regional Genetics laboratory, University of Southampton School of Medicine for carrying out the molecular genetic work-up.

Contributors: RG, NS, TV: reviewed literature, drafted manuscript and were involved in patient management; KGR: reviewed manuscript for intellectual content and will act as the guarantor.

Funding: None; Competing interests: None stated.