Transient Neonatal Diabetes Mellitus Potentially Associated With a Novel Homozygous MS4A6A Gene Variant: A Case Report

Neonatal diabetes mellitus (NDM) is a rare metabolic disorder characterised by hyperglycemia within the first six months of life. While commonly monogenic, the <i>MS4A6A</i> gene, known for immune modulation and calcium signalling, has not previously been linked to NDM. We report a case of transient NDM (TNDM) potentially associated with a novel homozygous variant in the <i>MS4A6A</i> gene. A male infant born at 27 weeks of gestation (720 g) developed severe hyperglycemia (>200 mg/dL) and polyuria on day 14 of life, following the resolution of suspected meningitis. Investigations confirmed insulin-deficient diabetes with low C-peptide (0.3 ng/mL) and negative antibodies. While standard NDM genetic panels were negative, whole-exome sequencing identified a homozygous <i>MS4A6A</i> variant (c.162G>C; p.Leu54Phe). Chromosomal microarray confirmed a region of loss of heterozygosity (LOH) at 11q12.1q12.2, encompassing the <i>MS4A6A</i> gene, consistent with identity by descent. The variant is extremely rare in population databases and is predicted to be damaging by multiple <i>in silico</i> tools. Both asymptomatic parents were confirmed as heterozygous carriers. The infant was treated with insulin, achieving excellent catch-up growth. However, by day 92, insulin requirements decreased, and the patient spontaneously maintained euglycemia off therapy by day 95. Remission was biochemically confirmed by normalised serum insulin levels (3.97 μIU/mL). This clinical course suggests a potential mechanism involving transient islet inflammation or defective calcium signalling. This case identifies <i>MS4A6A</i> as a potential candidate gene for TNDM, necessitating lifelong surveillance for relapse and highlighting a "dual-risk" profile for the heterozygous parents.