NKX2-2 mutation causes congenital diabetes and infantile obesity with paradoxical glucose induced ghrelin secretion.

CONTEXT NKX2-2 is a crucial transcription factor that enables specific β-cell gene expression. Nkx2-2(-/-) mice manifest with severe neonatal diabetes and changes in β-cell progenitor fate into ghrelin-producing cells. In humans, recessive NKX2-2 gene mutations have been recently reported as a novel etiology for neonatal diabetes, with only 3 cases known worldwide. This study describes the genetic analysis, distinctive clinical features, the therapeutic challenges, and the unique pathophysiology causing neonatal diabetes in human NKX2-2 dysfunction. CASE DESCRIPTION An infant with very low birth weight (VLBW) and severe neonatal diabetes (NDM) presented with severe obesity and developmental delay already at age 1 year. The challenge of achieving glycemic control in a VLBW infant was unexpectedly met by a regimen of 3 daily doses of long-acting insulin analogues. Sanger sequencing of known NDM genes (such as ABCC8 and EIF2AK3) was followed by whole-exome sequencing that revealed homozygosity of a pathogenic frameshift variant, c.356delG, p.P119fs64*, in the islet cells transcription factor, NKX2-2. To elucidate the cause for the severe obesity, an oral glucose tolerance test was conducted at age 3.5 years and revealed undetectable C-peptide levels with a paradoxically unexpected 30% increase in ghrelin levels. CONCLUSION Recessive NKX2-2 loss of function causes severe NDM associated with VLBW, childhood obesity, and developmental delay. The severe obesity phenotype is associated with postprandial paradoxical ghrelin secretion, which may be related to human β-cell fate change to ghrelin-secreting cells, recapitulating the finding in Nkx2-2(-/-) mice islet cells.