Abstract
BACKGROUND. Primary adrenal insufficiency (PAI) is commonly caused by autoimmunity in adults, known as autoimmune Addison’s disease (AAD). Autoantibodies against 21-hydroxylase are a hallmark of AAD but are absent in some patients diagnosed with AAD, posing a challenge to their clinical management. METHODS. We tested a polygenic risk score for AAD (PRS14AAD) to prioritize seronegative patients for etiologic reevaluation. The PRS14AAD was calculated in patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n = 124). Patients with low (n = 35) or high (n = 10) genetic susceptibility to AAD underwent clinical re-evaluation and whole-genome sequencing. RESULTS. Of the 34 patients with low PRS14AAD, 14 (41%) were re-diagnosed with non-autoimmune adrenal insufficiency, whereas no alternative etiologies were identified in patients with high PRS14AAD. The low PRS group included six patients (17%) with confirmed monogenic PAI and eight patients (23%) with adrenal insufficiency due to either tuberculosis or non-primary causes. Notably, four of the six confirmed monogenic cases developed PAI in adulthood, consistent with late-onset disease caused by hypomorphic variants. Additionally, seven patients (20%) carried genetic variants suspected of causing monogenic disease. CONCLUSION. These findings support considering genetic evaluation in patients with seronegative PAI, regardless of the age at diagnosis.
Authors
Maribel Aranda-Guillén, Ileana Ruxandra Botusan, Venuja Fernando, Michela Barbaro, Maria Blomqvist, Ellen Christine Røyrvik, Anette Susanne Bøe Wolff, Eystein Sverre Husebye, Stephan Kemp, Anna Wedell, Olov Ekwall, Magnus Isaksson, Jeanette Wahlberg, Ola Lindgren, Jakob Skov, Ragnhildur Bergthorsdottir, Per Dahlqvist, Sophie Bensing, Olle Kämpe, Daniel Eriksson
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ISSN: 0021-9738 (print), 1558-8238 (online)