Clinical and genetic heterogeneity of Triple A syndrome: a multicenter study.

Abstract

Triple A syndrome (AAAS) is a rare autosomal recessive neuroendocrine disorder caused by pathogenic variants in the AAAS gene and characterized by marked clinical heterogeneity. In this multicenter retrospective study, we analyzed 23 patients from 18 families diagnosed across nine centers in Türkiye to characterize the molecular and clinical features of AAAS. Six distinct vari-ants in the AAAS gene were identified in this cohort, with truncating variants predominating. The most frequent variant was c.1066_1067delCT (p.Leu356Valfs*8), detected in 7 of 18 families, followed by the nonsense variant c.1432C>T (p.Arg478*), identified in 6 families. Clinically, the most common initial presenting complaints were alacrima (6/23), achalasia (5/23), and ad-renal insufficiency (4/23). Cumulative assessment during follow-up revealed the complete clas-sic triad in 15/23 patients. Neurological involvement was frequent and showed an age-dependent pattern, with manifestations such as dysarthria (5/23) and autonomic dysfunction in-cluding anhidrosis (7/23); gait disturbance (8/23) was also commonly observed. Other frequent clinical findings included hyperpigmentation (12/23), short stature (11/23), palmoplantar hyper-keratosis (6/23), and microcephaly (4/23). Mineralocorticoid deficiency was reported in 7/23 patients based on physician documentation, six of whom had concomitant glucocorticoid defi-ciency. This multicenter cohort highlights the marked clinical variability of AAAS, including progressive neurological involvement and heterogeneity in the recognition and biochemical presentation of mineralocorticoid dysfunction. Keywords: Triple A syndrome; AAAS variant; adrenal insufficiency; mineralocorticoid deficien-cy; alacrima; achalasia.