Transient Neonatal Diabetes Mellitus is a rare condition characterized by transient hyperglycemia, intrauterine growth retardation, dehydration and a severe failure to thrive. Patients require insulin therapy to maintain glucose levels and symptoms usually undergo spontaneous remission. About 70% of TNDM cases are caused by imprinting defects of chromosome 6q24, known as TNDM1. Other subsets of the disorder include TNDM2 (associated with ABCC8 gene mutations) and TNDM3 (caused by KCNJ11 gene mutations). In the case of TNDM1, the disorder typically has an onset in the first week of life and patients undergo remission at a mean age of 12 weeks. In some cases, TNDM1 patients relapse during adolescence. Around 40% of cases have extra-pancreatic congenital anomalies due to mosaic DNA hypomethylation at other imprinted loci throughout the genome.
While the prognosis of TNDM is positive, some patients may develop type 2 diabetes mellitus later in life. The condition is diagnosed based on clinical features, age at onset and evidence of spontaneous remission. It is initially treated with intravenous insulin therapy and rehydration. Early diagnosis and treatment is essential to prevent complications.
TNDM1 is caused by imprinting defects of chromosome 6q24. This can be due to paternal Isodisomy or duplication, or due to loss of maternal methylation. As mentioned above, individuals with methylation loss at one maternally-methylated locus might also manifest methylation loss at other loci, resulting in several extra-pancreatic congenital anomalies and confounding the clinical presentation. The disorder is associated with two genes located at this position: PLAGL1 at 6q24.2 and ZFP57 at 6p22.1.
Deeb et al. (2016) found 25 cases of Neonatal Diabetes Mellitus in Abu Dhabi between the years 1985-2013, giving an incidence rate of 1:29,241 live births. Of these, 2 patients had Transient Neonatal Diabetes Mellitus (TNDM, incidence rate 1:350,903). The first patient, a male child born at term to consanguineous parents (birth weight 1.9 kg) was diagnosed at 6 weeks of age. At the time of this report, he was 8 years old and had remitted, no longer requiring insulin. However, he suffered from global developmental delay, brain atrophy, agenesis of corpus callosum, absent septum pelucidum, nystagmus and dysmorphic features. Genetic analysis found loss of methylation on the maternal allele at 6q24. The second patient, a female child from a consanguineous family (birth weight 1.4 kg), was diagnosed at 2 days old. She remitted at 6 weeks and had been off insulin since then. Genetic analysis revealed a c.-331C>G in the INS gene. Interestingly, she had 3 siblings with the same mutation who were all diagnosed with hyperglycemia at 2 days old. They did not undergo remission and remained on insulin leading to a PNDM diagnosis. The INS mutation thus has a highly variable presentation even within families.
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