Acta Diabetol. 2025 Apr 19. doi: 10.1007/s00592-025-02506-2. Online ahead of print.
ABSTRACT
BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS1) is characterized by chronic mucocutaneous candidiasis, hypoparathyroidism and autoimmune adrenal insufficiency and sporadically by other autoimmune conditions including thyroiditis and diabetes mellitus. APS1 is usually caused by recessive mutations in the AIRE gene, though rare dominant mutations can result in mild, late-onset clinical manifestations. Whether and to what extent autoimmune diabetes is present in these latter forms has been poorly addressed.
METHODS: Genetic testing for monogenic diabetes in an Italian child with early onset diabetes (at the age of 18 months), positive IA2 antibodies and negative insulin GAD antibodies was performed by Next Generation Sequencing, using direct Sanger sequencing as a confirmatory test.
RESULTS: A heterozygous AIRE inframe likely pathogenic deletion (c.64_69del, p.Val22_Asp23del, rs752303080 in exon 1; NM_000383.4) was identified. The proband's father carried the same AIRE mutation and presented with subclinical hypothyroidism and coeliac disease but normal glucose level.
CONCLUSIONS: To the best of our knowledge this is the first case of early onset diabetes as the only autoimmune manifestation related to AIRE heterozygous variants. In a broader context, our report indicates the need for genetic testing in individuals with isolated autoimmune hyperglycemia whose very early onset makes the diagnosis of type 1 diabetes unlikely. Our finding also highlights the heterogeneity of clinical expression of AIRE heterozygous variants, with two carriers of the same pedigree showing different organs involved and age of disease onset, in the absence of the most typical APS1 clinical abnormalities.
PMID:40252101 | DOI:10.1007/s00592-025-02506-2