Loss of RhoE Function in Dermatofibroma Promotes Disorganized Dermal Fibroblast Extracellular Matrix and Increased Integrin Activation.

Dermatofibromas (DFs) are common, benign fibrous skin tumors that can occur at any skin site. In most cases, DFs are solitary and sporadic, but a few are multiple and familial, and the mechanisms leading to these lesions are currently unclear. Using exome sequencing, we have identified a heterozygous variant in a pedigree with autosomal dominant multiple familial DF within RND3 (c.692C>T,p.T231M) that encodes for the small GTPase RhoE, a regulator of the actin cytoskeleton. Expression of T231M-RhoE or RhoE depletion using CRISPR in human dermal fibroblasts increased proliferation and adhesion to extracellular matrix through enhanced ß1 integrin activation and more disorganized matrix. The enzyme PLOD2 was identified as a binding partner for RhoE, and the formation of this complex was disrupted by T231M-RhoE. PLOD2 promotes collagen cross-linking and activation of ß1 integrins, and depleting PLOD2 in T231M-RhoE-expressing cells reduced T231M-RhoE-mediated ß1 integrin activation and led to increased matrix alignment. Immunohistochemical analysis revealed reduced expression of RhoE but increased expression of PLOD2 in the dermis of DF skin samples compared with that of the controls. Our data show that loss of RhoE function leads to increased PLOD2 activation, enhancing integrin activation and leading to a disorganized extracellular matrix, contributing to DF.

A possible role for second-hit postzygotic GJB2 mutation in porokeratotic eccrine ostial and dermal duct nevus.

Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare type of epidermal nevus involving the eccrine acrosyringia. It typically presents as asymptomatic linear keratotic papules and plaques along the lines of Blaschko and predominantly affects the extremities. This disease has recently been linked to somatic mutations within the GJB2 locus. Only four GJB2 mutations have been previously documented for PEODDN, and the underlying genetic basis remains inconclusive. Herein, we report an 18-year-old female with a hyperkeratotic plaque on the dorsa of the proximal interphalangeal joint of her right ring finger, as well as multiple small hyperkeratotic papules linearly distributed on the lateral sides of her fingers occurring since birth. Histopathological results revealed prominent parakeratotic cornoid lamella-like tiers at the opening of the eccrine secretory ducts. Whole-exome sequencing of the affected skin tissue revealed a heterozygous germline mutation and a postzygotic somatic mutation in GJB2. In summary, this study presents a case of PEODDN with compound heterozygous mutations in GJB2, which broadens the genetic spectrum of this disease entity and implies a possible role for second-hit mutations in the pathogenesis of PEODDN.

Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas.

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4ß1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4ß1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

Treatment of epidermal growth factor receptor inhibitor-induced severe paronychia with pyogenic granuloma-like lesions with topical betaxolol: an open-label observation study.

BACKGROUND: Paronychia is a common adverse event caused by epidermal growth factor receptor (EGFR) inhibitors. However, high rates of post-treatment discomfort, infection, recurrence, and increased time to return to work have been noted after nail plate avulsion for EGFR inhibitor-induced paronychia. Furthermore, poor wound healing and malnutrition were common conditions found in cancer patients. The aim of this study is to find an effective, pain-relieving, and noninvasive treatment for patients with severe paronychia induced by EGFR inhibitors. METHODS: Data from a series of 35 non-small cell lung cancer cases suffering from EGFR inhibitor-induced paronychia with pyogenic granuloma-like lesions of digits treated with betaxolol 0.25% ophthalmic solution once daily were collected and analyzed. RESULTS: Of the 35 patients suffering from grade 2 or 3 paronychia with pyogenic granuloma-like lesions induced by EGFR inhibitors, 34 (97.1%) demonstrated complete resolution and only one (2.9%) had partial resolution after 12 weeks of topical betaxolol treatment. The grading of paronychia according to the Common Terminology Criteria for Adverse Events decreased from an average of 2.29 to 0.63 after 4 weeks of treatment (P = 5.55 × 10-16 ). All the patients had significant improvement (50% pain reduction), as their pain visual analogue scale scores decreased from an average of 7.06 to 2.26 after one week of treatment (P = 6.11 × 10-25 ). CONCLUSION: Betaxolol 0.25% ophthalmic solution is an effective, safe, and pain-relieving treatment for patients suffering from EGFR inhibitor-induced paronychia with pyogenic granuloma-like lesions and deep fissures.