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

Neonatal diabetes mellitus (NDM) is a rare metabolic disorder characterised by hyperglycemia within the first six months of life. While commonly monogenic, the MS4A6A 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 MS4A6A 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 MS4A6A variant (c.162G>C; p.Leu54Phe). Chromosomal microarray confirmed a region of loss of heterozygosity (LOH) at 11q12.1q12.2, encompassing the MS4A6A gene, consistent with identity by descent. The variant is extremely rare in population databases and is predicted to be damaging by multiple in silico 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 MS4A6A as a potential candidate gene for TNDM, necessitating lifelong surveillance for relapse and highlighting a "dual-risk" profile for the heterozygous parents.