Correlation of Phenotype with Genetic Variants of Allgrove Syndrome in Colombian Patients
Keywords:
Syndrome, Genotype, PhenotypeAbstract
Introduction: Allgrove syndrome is an autosomal recessive disorder (AAAS gene) characterized by acalasia, alacrimia, and adrenal insufficiency. In fewer cases, the presence of peripheral neuropathy and dysautonomia has also been documented. However, a genotype-phenotype relationship has not been documented (1-6).
Objective: To describe the clinical and genetic features in Colombian patients with Allgrove syndrome.
Methodology: A cross-sectional study with consecutive sampling was conducted. Clinical records from pediatric endocrinology services were evaluated. Face-to-face/telephone interviews were conducted to collect data on demographic and clinical variables (symptoms, treatment, complications, and diagnostic aids). Whole exome sequencing of the AAAS gene was performed.
Results: The patients came from Manizales, Bogotá, Valle de Aburrá, Santa fe de Antioquia, Amaga, and Liborina. All patients (14) presented with alacrimia, acalasia, and adrenal insufficiency. Additionally, the majority had polyneuropathy, developmental delay, and dysautonomia. Less frequently, mineralocorticoid deficiency, cognitive impairment, and amyotrophy were observed. Approximately 23% of the patients had a history of consanguinity or early deaths among siblings. Nucleotide sequencing revealed three pathogenic variants in the AAAS gene. None of the patients carried the c.1331+1G>A variant. One patient had the c.1201C>T (p.Arg401*) variant, and another had the c.1232+1G>A variant.
Conclusion: Three pathogenic variants in the AAAS gene were identified in Colombian patients with Allgrove syndrome. The c.1201C>T (p.Arg401*) variant was associated with early symptom onset, dysautonomia, and neurodevelopmental impairment. The c.1331+1G>A variant is the most common, suggesting a widespread founder effect (5). Additionally, this variant was associated with respiratory symptoms not previously reported.
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