Autoimmune hyperglycemia: beyond type 1 diabetes.

Area of Science:

• Endocrinology
• Genetics
• Immunology

Background:

• Autoimmune Polyglandular Syndrome type 1 (APS1) typically involves candidiasis, hypoparathyroidism, and adrenal insufficiency, often due to recessive AIRE gene mutations.
• Dominant AIRE mutations can cause milder, later-onset autoimmune conditions, but their association with autoimmune diabetes is understudied.

Purpose of the Study:

• To investigate the genetic basis of early-onset diabetes in a child with suspected autoimmune etiology.
• To explore the role of AIRE gene variants in isolated autoimmune hyperglycemia.

Main Methods:

• Next Generation Sequencing and Sanger sequencing were used for genetic testing in a pediatric patient with early-onset diabetes and specific autoantibodies.
• Analysis focused on identifying monogenic diabetes causes, particularly AIRE gene mutations.

Main Results:

• A heterozygous, likely pathogenic in-frame deletion in the AIRE gene (c.64_69del, p.Val22_Asp23del) was identified in the proband.
• The proband's father, carrying the same mutation, exhibited subclinical hypothyroidism and celiac disease, but normal glucose levels.

Conclusions:

• This is the first reported case of early-onset diabetes as the sole autoimmune manifestation linked to heterozygous AIRE variants.
• The findings underscore the importance of genetic testing for AIRE variants in unexplained autoimmune hyperglycemia, especially in very young patients.
• The study demonstrates significant clinical heterogeneity in AIRE heterozygous variants, with differing organ involvement and onset ages within the same family.