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.

Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes presenting before 6 months of age. It may be permanent (PNDM) or transient (TNDM). Individuals with KATP channel variants may respond to oral sulphonylurea instead of insulin. The study aimed to review the presentation, genotype, phenotype, management, and outcomes of patients diagnosed with NDM in Ireland over 19 years. Data on Irish NDM cases from 2006 to 2024 were collated through paediatric endocrinologists nationally and electronic databases. Analyses were performed using SPSS, with ethical approval obtained. Nineteen cases were identified: twelve PNDM and seven TNDM. Age at diagnosis ranged from 1 day to 11 months. Among PNDM cases, KCNJ11 (n = 6), EIF2AK3 (n = 3) and INS (n = 1) variants were identified, while two lacked a genetic diagnosis. Six TNDM cases had 6q24 methylation defects, and one had an ABCC8 variant. Genetic diagnosis informed familial risk and prompted changes to a parent's medical management. Sulphonylurea therapy was most effective when initiated early. This national case series highlights the genetic and phenotypic spectrum of NDM in Ireland. Early genetic diagnosis enables precision therapy, with timely sulphonylurea initiation improving outcomes in KATP-related NDM.

Background/Objectives: Transient neonatal diabetes mellitus (TNDM) is a form of neonatal diabetes mellitus (NDM) arising in the first weeks of life and remitting in infancy. Epigenetic aberrations at the imprinted 6q24 locus (overexpression of PLAGL1/HYMAI) are the most common causes of TNDM. The aim of this study was a retrospective clinical and genetic analysis of a Polish pediatric cohort, emphasizing the role of methylation-specific MLPA (MS-MLPA) in the diagnosis of TNDM. Methods: We conducted a retrospective analysis of the medical records of 22 patients with diabetes diagnosed at 1 year of age. The molecular studies included an analysis of the NDM gene panel by a targeted NGS and MS-MLPA for the 6q24 imprinting region. Results: 6q24-TNDM was confirmed in five patients, with a median age of diabetes remission of 4 months (IQR: 3-6 months). The MS-MLPA identified paternal UPD6 or isolated maternal hypomethylation of PLAGL1 in three patients, and two had a paternal 6q24 duplication. Conclusions: In our group, changes in the 6q24 region were confirmed in 22.7% of NDM patients, indicating the usefulness of the MS-MLPA technique in the diagnosis and detection of imprinting defects. We acknowledge key limitations, including diagnostic delays and incomplete parental testing, which precluded trio-based confirmation of paternal UPD6 versus epimutation in some cases; future diagnostic workflows should incorporate an early trio-based SNP array or STR confirmation. A methylation analysis should be included early in the NDM genetic diagnosis process to provide genetic counseling and monitor patients for diabetes recurrence.

Neonatal diabetes is commonly defined by presentation in the first 6 months of life, with subsets of permanent and transient neonatal diabetes mellitus (TNDM) distinguished by spontaneous resolution of hyperglycemia in the latter. Infants with TNDM frequently require hospitalization for rehydration but characteristically do not present with a severe clinical course with ketoacidosis. Here we present a 19-day-old infant with a history of intrauterine growth restriction, small for gestational age, and normal blood sugars in the first 25 hours of life who presented with respiratory distress that rapidly progressed to shock and multiorgan failure. Diagnostic studies on presentation revealed severe hyperglycemia, metabolic acidosis, transaminitis, acute kidney injury, hyperammonemia, and thalamic hyperintensities that collectively raised suspicion for a metabolic/mitochondrial disorder. The patient's clinical course and genetic studies, however, converged on a diagnosis of TNDM due to uniparental disomy of chromosome 6. Diabetes has resolved, but the patient has endured permanent motor deficits associated with thalamic hemorrhage at presentation. This case highlights that TNDM can escape detection by blood glucose measurements in the first days of life and indeed present in severe diabetic ketoacidosis, which can further progress to shock and multiorgan failure that may mimic a metabolic/mitochondrial disorder.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction. Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed. Hepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient. Early diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.