Permanent neonatal diabetes mellitus (NDM) is a debilitating condition. In couples with consanguineous marriage, and especially with multiple children being affected, a strong possibility of genetic causes should be kept and evaluated appropiately. Wolcott-Rallison syndrome is one such syndrome, now being more commonly diagnosed in Indian families. A couple presented to the fetal medicine unit for genetic counselling at a gestational age of 9 weeks, because of two previous babies being affected with early onset type 1 diabetes mellitus. There was a 3rd degree consanguinity. The elder child was 6 year-8 month-old girl, with hyperglycemia detected at 1 month of age. She was evaluated by the pediatrician. She had history of multiple episodes of seizures, unconsciousness and developmental delay in all fields, with a motor age of 2 years and social and language age of 4 years. Parents were not compliant with either regular insulin administration or home blood glucose monitoring. On examination, she was stunted (height 86 cm, <3rd centile), underweight (weight 11.4 kg, <3rd centile) and had microcephaly (head circumference 43 cm, <3rd centile). The child had a chubby look, round facies, delayed dentition, dental caries and short stubby fingers. There was firm hepatomegaly with liver span of 12 cm. We evaluated for hypothyroidism, celiac disease, polyendocrinopathies and genetic syndromes causing type 1 diabetes mellitus. There were no clinical features suggestive of exocrine pancreatic insufficiency. The younger sibling was a female child who was diagnosed as type 1 diabetes mellitus at 1 month of life and succumbed the following month. Medical records were unavailable. A detailed three-generation pedigree did not reveal any other family member with similar manifestations.

The skeletal survey revealed a bone age >4 years, with small carpals, hypo-mineralized metacarpals, and notching of anterior vertebrae, suggestive of skeletal dysplasia (Fig. 1). The laboratory evaluation did not reveal any abnormalities in hemoglobin, leucocyte counts, thyroid function tests and liver enzymes. Blood urea nitrogen was 15.3 mmol/L, creatinine was 61.9 µmol/L, and glycosylated hemoglobin was 12.7%. A genetic panel for causes of PNDM and maturity-onset diabetes of the young (MODY) was done. It revealed a homozygous non-sense variation in exon 17 of the EIF2AK3 gene (chr2:g. 88857412G>A), consistent with Wolcott-Rallison syndrome. Subsequently, we carried out sanger variant analysis for the same gene in the fetus by chorionic villus sampling at 14 weeks of gestation. It also revealed homozygosity for chr2:g. 88857412G>A and c.3193C>T. The couple were advised termination of pregnancy and were counseled regarding recurrence risk and need for antenatal diagnosis. The importance of home blood glucose monitoring and insulin administration was explained for the older child and management plan with concerned specialist was arranged.

Fig. 1 (a) X-ray wrist anteroposterior view of the index child, and (b) X-ray showing thoracic spine, ribs and humerus.

Neonatal diabetes mellitus is a rare form of type 1 diabetes mellitus, with onset in first 6 months of life and an incidence of 1 in 90,000 to 1,60,000 live births [1]. Most NDMs are monogenic, and can be either transient or permanent. The most common mutations causing NDM worldwide are related to defects in potassium channel subunit genes, namely KCNJ11 and ABCC8 [2]. Similarly, in India, most published literature shows that the commonest mutations are related to potassium channel mutations [3]. In the setting of parental consanguinity, most common causes related to an autosomal recessive inheritance. These include mutations in EIF2AK3, GCK, GLIS3, RFX6, IER31P1 and MNX1 genes. Except GCK1, the remaining mentioned mutations result in syndromic forms of type 1 diabetes mellitus, with extra-pancreatic involvement [1,4]. Thus, it becomes important to get focused evaluation for autosomal recessive conditions in such a scenario. Wolcott-Rallison syndrome is being recognized as an important cause of syndromic permanent NDM in Indian subcontinent [5,6]. This syndrome has high mortality and several associated morbidities including skeletal dysplasia, episodic liver failure, renal dysfunction, exocrine pancreas insufficiency and developmental delay. The frequency of extra-pancreatic manifestations increases with increasing age, with initial appearance of skeletal abnormalities, followed by liver and renal dysfunction. In the index child, we could note developmental delay and skeletal dysplasia.

Evaluation for monogenic causes should be done in all cases of permanent NDM. When associated with consanguinity and extra-pancreatic manifestations, syndromic neonatal diabetes mellitus with autosomal recessive inheritence is most likely. Timely genetic diagnosis and prenatal confirmation can avert birth of an affected progeny.

1. Lemelman MB, Letourneau L, Greeley SAW. Neonatal diabetes mellitus: An update on diagnosis and management. Clin Perinatol. 2018;45:41-59.

2. De Franco E, Flanagan SE, Houghton JAL, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386:957-63.

3. Jain V, Satapathy A, Yadav J, et al. Clinical and molecular characterization of children with neonatal diabetes mellitus at a tertiary care center in northern India. Indian Pediatr. 2017;54:467-71.

4. Flannick J, Johansson S, Njølstad PR. Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat Rev Endocrinol. 2016;12:394-406.

5. Jahnavi S, Poovazhagi V, Kanthimathi S, Gayathri V, Mohan V, Radha V. EIF2AK3 mutations in South Indian children with permanent neonatal diabetes mellitus associated with Wolcott-Rallison syndrome. Pediatr Diabetes. 2014;15:313-8.