385 Patterning of linear morphea on the face and neck: Blaschkoid or not?

Abstract

Netherton Syndrome (NS) is a rare autosomal recessive skin disorder caused by mutations in the gene encoding Serine Protease Inhibitor Kazal-type 5 (SPINK5), a protease inhibitor expressed in the stratum corneum of the epidermis. In NS patients, the inhibitory activities of SPINK5 are abolished, triggering hyperactivity of epidermal proteases which leads to skin dryness, hair shaft defects, elevated IgE levels, chronic skin inflammation and scaling that predisposes the patient to life-threatening infections. Currently, there are no curative treatments for NS, and novel targeted therapeutics are necessitated. To this end, we have developed KB104, a replication-defective HSV-1 gene therapy vector encoding human SPINK5 for direct topical application to the skin. Here we show that KB104 efficiently transduces target skin cells in vitro and in vivo and produces functional SPINK5. Human keratinocytes infected with KB104 at varying multiplicities of infection produced and secreted full-length SPINK5 in a dose-dependent manner, as determined by real time PCR, immunocytochemistry, ELISA, and western blotting. Importantly, the KB104-expressed SPINK5 was functional, being capable of inhibiting a native target of SPINK5, the serine protease Kallikrein 5, in an enzymatic inhibition assay. KB104 also efficiently expressed human SPINK5 after either topical or intradermal administration in immunocompetent mice, as assessed by real time PCR and immunohistochemistry. Human SPINK5 co-localized with mouse filaggrin, a protein expressed in the stratum corneum, indicating that KB104 successfully transduced the targeted epidermal layer. Moreover, no inflammatory infiltration or structural changes were observed at the KB104-treated site, confirming that KB104 is well-tolerated. Taken together, these preclinical studies support the potential for KB104 to be a convenient, safe, and efficacious gene therapy vector for direct molecular correction of SPINK5 deficiency in Netherton Syndrome.(33%) by all investigators. The concordance rate was 60% (free-marginal k¼0.59, moderate agreement). Non-blaschkoid lesions primarily coursed perpendicular to or lacked the curvilinear nature of Blaschko's lines. These results suggest that factors beyond segmental mosaicism must underlie linear morphea patterning. Further analysis is planned to gain consensus and seek "morpheatomes" that better characterize disease patterning.

Unravelling morphoea aetiopathogenesis by next-generation sequencing of paired skin biopsies

“…There are several clinical complexities of LM supporting more multifaceted aetiopathogenesis. LM may not be truly Blaschkoid [ 8 ], morphoea is a dermal pathology, has vast clinical heterogeneity with complex patterning and morphology [ 4 , 30 ] and is not congenital.…”

En Coup De Sabre in 16-Year-Old Girls: A Case Report

“…Common symptoms seen with en coup de sabre are straight lines or depressions on the scalp or face, discolored or swollen skin, and baldness of the affected areas. [9][10][11] En coup de sabre is a subtype of morphea.…”

Pediatric morphea state‐of‐the‐art literature review: Reframing morphea as a systemic disease

“…17,18 Linear morphea presents on the head, neck, trunk, or extremities, potentially following Blaschko lines. [19][20][21] Although linear morphea usually presents as a single linear band, multilesional or bilateral…”

“…24,25 Genetic susceptibility and autoimmunity are hypothesized to yet to be found. 21,26 Ten to 30% percent of individuals with morphea report a family history of autoimmune disease, which is significantly elevated relative to the general population. 9,16,27,28 In pediatric morphea, up to 10% of patients have a concomitant autoimmune disorder, most commonly, vitiligo, alopecia areata, and juvenile rheumatoid arthritis.…”

“…Genetic susceptibility and autoimmunity are hypothesized to play a role in the development of pediatric morphea. The Blaschkoid distribution of skin lesions raises the possibility of somatic mutations contributing to morphea pathogenesis, though a causative gene has yet to be found 21,26 . Ten to 30% percent of individuals with morphea report a family history of autoimmune disease, which is significantly elevated relative to the general population 9,16,27,28 .…”