Dual genetic diagnoses: AIRE and FOXRED1-Related Syndromes in two brothers

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disorder caused by mutations in the AIRE gene. While the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency defines the syndrome, its phenotypic spectrum can be broad and complex. While a single genetic etiology is typically assumed, the co-occurrence of a second monogenic disorder can complicate the clinical picture. Here, we report two brothers from a non-consanguineous family who presented with a complex multisystem phenotype including hypocalcemia, seizures, and neurodevelopmental impairments. Whole-exome sequencing revealed a homozygous AIRE deletion in both siblings, confirming APS-1. Notably, the elder brother was also found to carry a homozygous variant in the FOXRED1 gene, which explained his severe neurological features, including cerebral atrophy and lactic acidosis, consistent with a dual diagnosis of APS-1 and FOXRED1-related mitochondrial encephalopathy. This case highlights that atypical or compounded clinical presentations should raise suspicion for dual genetic disorders, underscoring the critical role of comprehensive genetic analysis in reaching a precise diagnosis.