Darier disease : more than skin deep

Darier disease (DD) is a severe, inherited dermatological disorder with a characteristic clinical and histopathological appearance. It is caused by mutations in the ATP2A2 gene, encoding a Ca2+ pump in the endoplasmic reticulum, Sarco/Endoplasmic Reticulum Ca2+-ATPase 2 (SERCA2), which has been found to be an essential regulator of cellular Ca2+ homeostasis. SERCA2 is expressed in all cells of the body, not just the skin, and has been implicated in physiological and pathophysiological mechanisms in several organs, thus rendering the occurrence of extra-dermal presentations plausible. DD has so far only been associated with brain-related disorders. The overall aim of this thesis was to investigate comorbidities associated with DD. In study I, II and III, experimental, matched case-control designs were used to evaluate broad cognitive function, heart disease and diabetes in individuals with DD compared with matched healthy controls. Individuals with DD were found to exhibit a widespread, significant impairment in cognitive function assessed with the Cambridge Neuropsychological Test Automated Battery, evaluating general cognitive function. A possible defect in serum lipid handling was also seen, as well as evidence of pancreatic β-cell dysfunction indicating a metabolic state seen during the development of type 2 diabetes. In study II and IV, a population-based cohort design, comparing data on individuals with DD taken from the National Patient Register with matched comparison subjects from the Total Population Register, was used. Individuals with DD displayed a 59% risk increase of heart failure (risk ratio [RR] 1.59, confidence interval [CI] 1.16-2.19) and a 32% risk increase of any heart diagnosis (RR 1.32, CI 1.02-1.70). Female DD patients had a 59% risk increase of any heart diagnosis (RR 1.59, CI 1.13-2.25). The first heart diagnosis also occurred almost seven years earlier in individuals with DD (70.0 vs. 76.9 years). A 74% increased risk of type 1 diabetes diagnosis was also seen (RR 1.74, CI 1.13-2.69). In study V, immune cell markers were evaluated in a small cohort of DD patients. The values of CD19+ B cells were found to be lower than the normal laboratory range on average, which together with the evidence of the importance of SERCA2 in B cell development indicates a possible immune system defect. This finding can help explain the recurring secondary infections often troubling individuals with DD. In conclusion, DD has been found to be associated with impaired cognitive function, heart disease and diabetes, as well as a possible defect in the immune system. The range of comorbidities associated with DD has been expanded to include several organs, resulting in the confident conclusion that DD should be viewed as a systemic disorder. This has several important implications, both for the individual patient and in routine care for this group of patients. Looking forward, it will quite possibly influence the way DD is treated

Extensive Amyloid Purpura: An Unusual Presentation of Myeloma-associated Light Chain Amyloidosis

Abstract is missing (Short communication

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 Ca2+/Mn2+-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