Systemic CXCL10 is a predictive biomarker of vitiligo lesional skin infiltration, PUVA, NB-UVB and corticosteroid treatment response and outcome.

Vitiligo is an acquired pigmentary skin disorder that currently lacks standardized treatment and validated biomarkers to objectively evaluate disease state or therapeutic response. Although prior studies have linked vitiligo autoimmunity with CXCL10/CXCL9-mediated recruitment of leukocytes to the skin, only limited clinical data are available regarding CXCL10 as vitiligo biomarker. To evaluate the utility of systemic CXCL10 as a predictor of disease progression and treatment response on a large cohort of vitiligo patients. CXCL10 levels in lesional, perilesional, and unaffected skin of vitiligo patient (n = 30) and in the serum (n = 51) were measured by quantitative ELISA. CXCL10 expression, recruitment of leukocytes, and inflammatory infiltrates were evaluated by histochemical (n = 32) and immunofluorescence (n = 10) staining. Rigorous cross-sectional and longitudinal biostatistical analysis were employed to correlate CXCL10 levels with disease variables, treatment response, and outcome. We demonstrated that elevated CXCL10 level (2 pg/mm2 and higher) in lesional skin correlates with increased leukocytic infiltrate, disease duration (< 2 year), and its higher level in the serum (50 pg/ml and higher). Changes in CXCL10 serum levels in patients treated with psoralen plus UVA (PUVA) phototherapy, narrowband UVB (NB-UVB) phototherapy, and systemic steroids (SS) correlated with changes in the intralesional CXCL10 levels in repigmented skin. NB-UVB and SS regimens provided most consistent CXCL10 mean change, suggesting that these regimens are most effective in harnessing CXCR3-mediated inflammatory response. Serum CXCL10 is a useful vitiligo biomarker, which predicts lesional skin leukocytic infiltration, and vitiligo treatment response and outcome.

Ichthyosis, psoriasiform dermatitis, and recurrent fungal infections in patients with biallelic mutations in PERP.

BACKGROUND: Germline autosomal dominant and autosomal recessive mutations in PERP, encoding p53 effector related to PMP-22 (PERP), a component of epidermal desmosomes, have been associated with a spectrum of keratodermas. Monoallelic nonsense mutations cause Olmsted syndrome with severe periorificial keratoderma and palmoplantar keratoderma (PPK). Biallelic recessive frameshift and missense mutations are associated with milder forms of the disease, including generalised erythrokeratoderma and PPK. OBJECTIVES: To add new insights into the genotype-phenotype correlations as a consequence of PERP mutations and to provide a comprehensive review of the literature. METHODS: Among 26 previously unresolved families within a cohort of 180 extended Iranian families with syndromic or non-syndromic ichthyosis, two families with shared clinical features were examined by whole-exome sequencing and genome-wide homozygosity mapping. Mycological and dermatopathological studies were performed to further characterise their atypical phenotypic presentations. RESULTS: In two unrelated multiplex consanguineous families affected by ichthyosis, two novel biallelic PERP variants, NM_022121.5, c.89T > C, p.Leu30Pro and c.466G > C, p.Gly156Arg, located inside of genomic homozygosity regions of the probands were detected. Interestingly, some patients had areas of scaly psoriasiform plaques on the background of generalised ichthyosis that appeared during active cutaneous fungal infections. Mycological examinations of these lesions revealed infections caused by Candida albicans, Epidermophyton floccosum, or Trichophyton rubrum. Histopathology of the psoriasiform lesions shared some features with psoriasis, which when combined with clinical presentation, led to incorrect diagnosis of guttate psoriasis or pustular psoriasis. CONCLUSIONS: PERP variants in ichthyosis patients can confer susceptibility to recalcitrant cutaneous fungal infections. Additionally, patients with episodic psoriasiform dermatitis in the setting of keratoderma should be considered for PERP genotyping and cutaneous fungal examinations.

GGCX mutations in a patient with overlapping pseudoxanthoma elasticum/cutis laxa-like phenotype.

Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and the cardiovascular system. The classic forms of PXE are caused by mutations in the ABCC6 gene encoding the ABCC6 protein, expressed primarily in the liver. Cutis laxa (CL) manifests with loose and sagging skin with loss of recoil. In 2009 we investigated a 19-year-old patient with overlapping cutaneous features of PXE and CL, together with alpha thalassaemia. Genetic analysis failed to identify pathogenic mutations in ABCC6. More recently we developed a gene-targeted panel of next-generation sequencing technology. This panel has 29 genes, 22 of which, including ABCC6 and GGCX, are associated with ectopic mineralization phenotypes. Mutation analysis in the patient identified two heterozygous GGCX mutations: c.200_201delTT in exon 2 and c.763G>A, p.V255M in exon 7. The GGCX gene encodes a γ-glutamyl carboxylase necessary for activation of blood coagulation factors in the liver. The p.V255M mutation was previously reported to result in reduced γ-glutamyl carboxylase activity in vitro, while the c.200_201delTT mutation is novel. Previous studies reported that mutations in GGCX cause overlapping PXE/CL skin phenotypes in association with or without multiple vitamin K-dependent coagulation factor deficiency. Our patient had loose redundant skin, moderate-to-severe angioid streaks and characteristic calcification of elastic structures in the mid dermis, consistent with PXE/CL overlap, but no coagulation abnormalities. Our studies expand the GGCX mutation landscape in patients with PXE-like phenotypes.

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.

BACKGROUND: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). OBJECTIVES: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. METHODS: This was a consensus expert review. RESULTS: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. CONCLUSIONS: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.

Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.

BACKGROUND: Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations. OBJECTIVES: We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation. METHODS: Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing. RESULTS: Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. CONCLUSIONS: These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

Pachyonychia congenita: a case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation.

Pachyonychia congenita (PC) is a rare autosomal dominant disorder characterized by nail dystrophy and palmoplantar keratoderma with severe plantar pain affecting quality of life. There is no effective treatment. Heterozygous mutations in the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17 have been reported as a cause of PC. Herein we present a female patient with an amino acid substitution mutation in KRT6A (c.1381G>A, p.Glu461Lys in exon 7) and classic features of PC associated with oral leucokeratosis and follicular hyperkeratosis. We also demonstrate successful treatment of the patient with rosuvastatin. A 3.6-mm reduction in plantar callosity thickness was demonstrated by sonography. Our patient also experienced significant pain relief that allowed her to increase physical activity (Children's Dermatology Life Quality Index score dropped nine points following treatment). Collectively, these improvements suggest that rosuvastatin may offer a promising treatment for PC. What's already known about this topic? Pachyonychia congenita (PC) is an autosomal dominant disease characterized by nail dystrophy and painful plantar keratoderma. Keratolytics, emollients, retinoids and steroids have been used for treatment but with limited benefits. What does this study add? A patient with PC who had a KRT6A mutation was treated with rosuvastatin with significant improvement in plantar hyperkeratosis and pain. Statins could be a promising treatment for PC with long-term safety, but further studies are needed.

Seven novel COL7A1 mutations identified in patients with recessive dystrophic epidermolysis bullosa from Mexico.

Recessive dystrophic epidermolysis bullosa (RDEB; OMIM #226600) is one of the most devastating subtypes of epidermolysis bullosa, a group of skin and mucous membrane blistering disorders often associated with extracutaneous manifestations. RDEB is caused by mutations in COL7A1, the gene encoding type VII collagen (C7), and to date over 700 different mutations in the 8835 nucleotides constituting the open reading frame or adjacent exon-intron boundaries of COL7A1 have been described. We used targeted next-generation sequencing to identify seven previously unreported mutations in a cohort of 17 Mexican patients who were diagnosed with RDEB based on clinical presentation and immunoepitope mapping. Our study expands the spectrum of mutations identified in this cohort, including those suitable for emerging therapies reliant on precise genotyping.

Infantile systemic hyalinosis in an Iranian family with a mutation in the CMG2/ANTXR2 gene.

Infantile systemic hyalinosis (ISH) is an extremely rare genodermatosis, characterized by thickened skin, joint contractures and subcutaneous nodules. ISH is caused by mutations in the CMG2 gene, which encodes a protein of unknown function. In this report, we describe a patient with ISH, who was a twin born to a consanguineous Iranian couple, and who demonstrated unusual skin findings in addition to the characteristic features of ISH. Mutation analysis disclosed a homozygous deletion mutation, c.1074delT in CMG2, resulting in a frameshift and premature termination codon 50 amino acids downstream of the deletion. This information adds to the recurring nature of this mutation in ISH, with implications for genetic counselling in extended families with a history of this disease.

Phenotypic characterization of the KK/HlJ inbred mouse strain.

Detailed histopathological diagnoses of inbred mouse strains are important for interpreting research results and defining novel models of human diseases. The aim of this study was to histologically detect lesions affecting the KK/HlJ inbred strain. Mice were examined at 6, 12, and 20 months of age and near natural death (ie, moribund mice). Histopathological lesions were quantified by percentage of affected mice per age group and sex. Predominant lesions were mineralization, hyperplasia, and fibro-osseous lesions. Mineralization was most frequently found in the connective tissue dermal sheath of vibrissae, the heart, and the lung. Mineralization was also found in many other organs but to a lesser degree. Hyperplasia was found most commonly in the pancreatic islets, and fibro-osseous lesions were observed in several bones. The percentage of lesions increased with age until 20 months. This study shows that KK/HlJ mice demonstrate systemic aberrant mineralization, with greatest frequency in aged mice. The detailed information about histopathological lesions in the inbred strain KK/HlJ can help investigators to choose the right model and correctly interpret the experimental results.