Neurological manifestations of Allgrove syndrome in patients carrying a potentially founder p.Ser263Pro variant in the AAAS gene

Allgrove syndrome (AS) is a rare, multisystem, autosomal recessive disorder characterized by the triad of symptoms: achalasia, alacrimia and ACTH-resistant adrenal insufficiency. Various and nonspecific neurological symptoms can also develop over time, "blurring" the typical course of this underdiagnosed condition. The incidence of Allgrove syndrome is unknown. Orphanet database reports fewer than 100 published cases, but according to the literature review, at least 206 patients have already been described. The pathogenic variant p.Ser263Pro is one of the most recurrent aberrations affecting the AAAS gene and has been reported in several families of Slavic origin. We investigated genotype-phenotype correlation in 206 patients with AS described in literature (including two novel Polish siblings carrying a homozygous p.Ser263Pro variant in the AAAS gene) and found that neurological symptoms were significantly more common among carriers of p.Ser263Pro variant (33 out of 34, 97.1%) as compared to other AAAS variant carriers (133 out of 172, 77.3%, p = 0.006). While the incidence of the classical clinical triad of AS was similar and observed in 110 out of 206 AS patients (53.4%) and in 18 out of 34 (52.9%) among p.Ser263Pro variant carriers. Furthermore, our report supports the hypothesis of a founder origin of the p.Ser263Pro variant in AAAS gene in a European Caucasian population. Slavic origin was found in 25 out of 36 reported variant carriers (69.4%) and 17 out of 23 (73.9%) who were homozygous for p.Ser263Pro variant. Summarizing, neurological manifestations of AS predominate in patients carrying a potentially founder p.Ser263Pro variant within the AAAS gene.