Our attempt to explore the molecular mechanism underlying HHD indicates a complex puzzle in which multi-hit combinations of altered signal pathways may explain the wide spectrum of defects in HHD.

Hailey-Hailey disease (HHD) is a rare autosomal dominant disorder characterized by recurrent skin lesions predominantly involving the body folds. It is caused by heterozygous mutations in the ATP2C1 gene, encoding the human secretory pathway Ca2+/Mn2+-ATPase protein 1 (hSPCA1). In this report we describe the molecular studies performed in eight HHD cases from Italy that led us to identify six different mutations scattered through the ATP2C1 gene in seven of eight cases. Four of the detected mutations were novel. Our results confirm the high allelic heterogeneity of the ATP2C1 gene and support the notion that HHD is a genetically homogeneous disorder. Furthermore, we created a table summarizing all previously reported ATP2C1 mutations, adapting the nomenclature, if needed, according to the guidelines of the Human Genome Variation Society.

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Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in ATP2A2 and characterized by multiple warty papules coalescing in seborrheic areas and specific histological skin changes. Rare patients are described with variable bone involvement, but this association has never been sufficiently emphasized. Aniridia is a developmental disorder of the eye due to heterozygous mutations in PAX6. DD and aniridia are Mendelian traits mapping on independent loci and have never been reported in association. Here, we describe a 14-year-old girl showing the unique combination of DD, multiple bone cysts, and bilateral aniridia. Molecular investigations demonstrated that such a complex phenotype is due to double de novo heterozygous mutations in ATP2A2 and PAX6. Review of the literature indicates that, in DD, bone cysts are true developmental abnormalities of the skeleton. This finding suggests a role for ATP2A2 in bone biology. More systematic studies are expected in order to estimate the true prevalence of bone cysts in DD and the relationship between skeletal changes and ATP2A2 perturbation.