Allelic loss underlies type 2 segmental Hailey-Hailey disease, providing molecular confirmation of a novel genetic concept

Abstract

Hailey-Hailey disease (HHD) is an autosomal dominant trait characterized by erythematous and oozing skin lesions preponderantly involving the body folds. In the present unusual case, however, unilateral segmental areas along the lines of Blaschko showing a rather severe involvement were superimposed on the ordinary symmetrical phenotype. Based on this observation and similar forms of mosaicism as reported in other autosomal dominant skin disorders, we postulated that in such cases, 2 different types of segmental involvement can be distinguished. Accordingly, the linear lesions as noted in the present case would exemplify type 2 segmental HHD. In the heterozygous embryo, loss of heterozygosity occurring at an early developmental stage would have given rise to pronounced linear lesions reflecting homozygosity or hemizygosity for the mutation. By analyzing DNA and RNA derived from blood and skin samples as well as keratinocytes of the index patient with various molecular techniques including RT-PCR, real-time PCR, and microsatellite analysis, we found a consistent loss of the paternal wild-type allele in more severely affected segmental skin regions, confirming this hypothesis for the first time, to our knowledge, at the molecular and cellular level.

Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN nullizygosity

“…15 A similar mechanism with a second hit occurring earlier during development was postulated for autosomal-dominant genodermatoses 16 and such a phenomenon was recently confirmed for Hailey-Hailey disease. 17 Cowden disease is another example in which a germline dominant mutation can be associated with mosaic inactivation of the wild-type allele, resulting in segmental exacerbations of the disease.…”

Cutaneous mosaicism: right before our eyes

“…In 2004, we showed at the cellular and molecular level that the type 2 segmental manifestation of Hailey-Hailey disease, being superimposed on the ordinary nonsegmental lesions of this autosomal dominant trait, results from postzygotic loss of heterozygosity (LOH) (11). These data provided the first molecular evidence supporting this genetic concept, which was postulated ten years ago (12).…”

“…These include decreased or impaired growth factor production (6-8), angiogenic response (8,9), macrophage function (10), collagen accumulation, epidermal barrier function, quantity of granulation tissue (8), keratinocyte and fibroblast migration and proliferation, number of epidermal nerves (11), bone healing, and balance between the accumulation of ECM components and their remodeling by MMPs (12). Wound healing occurs as a cellular response to injury and involves activation of keratinocytes, fibroblasts, endothelial cells, macrophages, and platelets.…”

Piecing together the puzzle of cutaneous mosaicism

“…In contrast to many autosomal dominant disorders of the skin in which lesions are widespread and, upon clinical examination, no skin appears to be spared, the red, crusted plaques of Hailey-Hailey disease tend to be symmetrically distributed primarily at intertriginous areas, where opposing skin surfaces may touch and rub, such as skin folds of the groin, underarm, and breast. The patient studied by Poblete-Gutiérrez et al developed widely distributed, severely erythematous, and crusted plaques along Blaschko's lines on the left side of her body (16,17). In contrast to the typical onset of plaques largely confined to intertriginous areas in late childhood or young adulthood, these extensive plaques were first noted when the patient was 3 months of age (17).…”

“…The patient studied by Poblete-Gutiérrez et al developed widely distributed, severely erythematous, and crusted plaques along Blaschko's lines on the left side of her body (16,17). In contrast to the typical onset of plaques largely confined to intertriginous areas in late childhood or young adulthood, these extensive plaques were first noted when the patient was 3 months of age (17).…”