Allgrove syndrome in Colombia: clinical characterization and evidence of a possible founder effect

Abstract

Abstract Objectives Allgrove syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the AAAS gene, characterized by achalasia, alacrima, and adrenal insufficiency, with variable neurological involvement. Genotype–phenotype correlations remain poorly characterized. This study aimed to describe the clinical and genetic features of Colombian patients with Allgrove syndrome and to explore potential genotype–phenotype differences. Methods A multicenter retrospective cohort study was conducted between January 2010 and July 2025. A total of 1,587 clinical records were screened across three tertiary referral centers in Antioquia, complemented with structured telephone interviews, identifying 30 patients meeting diagnostic criteria. Genetic testing results, including whole-exome sequencing or targeted AAAS gene analysis retrieved from clinical records, were analyzed by genotype. Results Twenty-nine of 30 patients (96.7 %) presented the complete classical triad. Median age at diagnosis was 5.5 years, glucocorticoid and mineralocorticoid deficiencies were diagnosed at a median of 4 and 3 years, respectively; achalasia at a mean of 7.75 years. Among 19 genotyped patients, two homozygous pathogenic variants were identified: c.1331+1G>A and c.1300C>T (p.Arg434*) in one patient, who exhibited earlier onset and more severe neurological involvement. Clustering in the Paisa region suggests a potential founder effect. Conclusions This is the largest reported Colombian cohort of Allgrove syndrome. A highly prevalent AAAS variant suggestive of a possible founder effect was identified in the Paisa population. Clinically meaningful differences in disease severity were observed between variants. These findings expand the phenotypic spectrum and underscore the importance of early genetic testing and systematic multidisciplinary surveillance.