Hailey-Hailey Disease is Associated with Diabetes: A Population-based Cohort Study, Clinical Cohort Study, and Pedigree Analysis

Hailey-Hailey disease is a rare hereditary skin disease caused by mutations in the ATP2C1 gene encoding the secretory pathway Ca(2+)/Mn(2+)-ATPase 1 (SPCA1) protein. Extracutaneous manifestations of Hailey-Hailey disease are plausible but still largely unknown. The aim of this study was to explore the association between Hailey-Hailey disease and diabetes. A population-based cohort study of 347 individuals with Hailey-Hailey disease was performed to assess the risks of type 1 diabetes and type 2 diabetes, using Swedish nationwide registries. Pedigrees from 2 Swedish families with Hailey-Hailey disease were also investigated: 1 with concurrent type 1 diabetes and HLA-DQ3, the other with type 2 diabetes. Lastly, a clinical cohort with 23 individuals with Hailey-Hailey disease and matched healthy controls was evaluated regarding diabetes. In the register data males with Hailey-Hailey disease had a 70% elevated risk of type 2 diabetes, whereas no excess risk among women could be confirmed. In both pedigrees an unusually high inheritance for diabetes was observed. In the clinical cohort, individuals with Hailey-Hailey disease displayed a metabolic phenotype indicative of type 2 diabetes. Hailey-Hailey disease seems to act as a synergistic risk factor for diabetes. This study indicates, for the first time, an association between Hailey-Hailey disease and diabetes and represents human evidence that SPCA1 and the Golgi apparatus may be implicated in diabetes pathophysiology. SIGNIFICANCE This study showed, for the first time, a manifestation of the severe skin disorder Hailey-Hailey disease outside the skin. By studying 2 Swedish nationwide registers, 2 family pedigrees with concurrent diabetes type 1 and 2, and a clinical cohort with matched healthy controls, the results show that there is an association between Hailey-Hailey disease and diabetes. This information potentially has great impact for the care and management of patients with Hailey-Hailey disease and provides interesting insight into the multi-faceted pathophysiology of diabetes.