Beyond the classic triad: three novel AAAS variants expand the genetic spectrum of triple A syndrome and reveal marked phenotypic heterogeneity in five families

Triple A syndrome (TAS), also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by the classical triad of achalasia, alacrima, and adrenal insufficiency, often accompanied by neurological involvement affecting the central, peripheral, and autonomic nervous systems. TAS exhibits marked clinical heterogeneity in age at onset (AAO), symptom presentation, and disease severity. The disorder is caused by pathogenic variants in the AAAS gene, encoding ALADIN, a nuclear pore complex protein involved in nucleocytoplasmic transport. Following clinical and paraclinical assessments of six patients from five different families, candidate variants were identified using whole-exome sequencing (WES) and validated through Sanger sequencing. Clinical assessment revealed considerable variability in AAO and manifestations, including among patients carrying the same variant. Neurological involvement was observed in all patients. One patient presented with neurological manifestations in the absence of the classic triad features and was described as having an AAAS -related disorder with predominant neurological manifestations. Genetically, we identified five variants in the AAAS gene, including three novel, c.470_471delTT; p.Phe157Cysfs*16, c.626T > C; p.Leu209Ser, and c.1222G > C; p.Gly408Arg, and two known variants, c.463 C > T; p.Arg155Cys, and c.1066_1067del; p.Leu356Valfs*8. All patients were homozygote, except for one patient, who was a compound heterozygote. Our findings expanded both the genetic and phenotypic spectrum of TAS by identifying three novel AAAS variants and demonstrating substantial phenotypic heterogeneity, even among individuals carrying the same pathogenic variant. The presence of neurological manifestations and the absence of the classic triad in one patient suggest that such patients be classified as having an AAAS -related disorder and emphasize the importance of considering this disorder in patients with unexplained neurological disorders and support the value of WES for establishing an accurate diagnosis.