Oral candidiasis and seborrheic dermatitis in an 8-year-old female with a heterozygous variant of the IL-17RC gene.

An 8-year-old female with chronic oral candidiasis and severe seborrheic dermatitis was found to have a heterozygous mutation (p.R14X c.40 C>T) of the IL-17RC gene, which was predicted to possibly represent a new pathogenic variant via truncation or nonsense-mediated mRNA decay. Given previously reported IL-17RC-related disorders are autosomal recessive, we would expect an affected individual to have two mutated alleles whereas our patient was heterozygous. Given the overlapping clinical picture, this variant could be responsible for altered immunity against both Candida and Malassezia species. This is the first report to our knowledge of chronic oral candidiasis and severe seborrheic dermatitis in a patient with a heterozygous variant (p.R14X c.40 C>T) for the IL-17RC gene.

Differential microRNA profiles in elderly males with seborrheic dermatitis.

Seborrheic dermatitis (SD) is one of the most common skin diseases characterized by inflammatory symptoms and cell proliferation, which has increased incidence in patients older than 50 years. Although the roles of microRNAs (miRNAs) have been investigated in several diseases, miRNA profiles of patients with SD remain unknown. This study aimed to identify differentially expressed miRNAs (DEMs) in lesions of elderly male patients with SD. We used a microarray-based approach to identify DEMs in lesions compared to those in non-lesions of patients with SD. Furthermore, Gene Ontology and pathway enrichment analysis were performed using bioinformatics tools to elucidate the functional significance of the target mRNAs of DEMs in lesions of patients with SD. Expression levels of two miRNAs-hsa-miR-6831-5p and hsa-miR-7107-5p-were downregulated, whereas those of six miRNAs-hsa-miR-20a-5p, hsa-miR-191-5p, hsa-miR-127-3p, hsa-miR-106b-5p, hsa-miR-342-3p, and hsa-miR-6824-5p-were upregulated. Functions of the SD-related miRNAs were predicted to be significantly associated with typical dermatological pathogenesis, such as cell proliferation, cell cycle, apoptosis, and immune regulation. In summary, SD alters the miRNA profile, and target mRNAs of the DEMs are related to immune responses and cell proliferation, which are the two main processes in SD pathogenesis.

An update on the microbiology, immunology and genetics of seborrheic dermatitis.

The underlying mechanism of seborrheic dermatitis (SD) is poorly understood but major scientific progress has been made in recent years related to microbiology, immunology and genetics. In light of this, the major goal of this article was to summarize the most recent articles on SD, specifically related to underlying pathophysiology. SD results from Malassezia hydrolysation of free fatty acids with activation of the immune system by the way of pattern recognition receptors, inflammasome, IL-1ß and NF-kB. M. restricta and M. globosa are likely the most virulent subspecies, producing large quantities of irritating oleic acids, leading to IL-8 and IL-17 activation. IL-17 and IL-4 might play a big role in pathogenesis, but this needs to be further studied using novel biologics. No clear genetic predisposition has been established; however, recent studies implicated certain increased-risk human leucocyte antigen (HLA) alleles, such as A*32, DQB1*05 and DRB1*01 as well as possible associations with psoriasis and atopic dermatitis (AD) through the LCE3 gene cluster while SD, and SD-like syndromes, shares genetic mutations that appear to impair the ability of the immune system to restrict Malassezia growth, partially due to complement system dysfunction. A paucity of studies exists looking at the relationship between SD and systemic disease. In HIV, SD is thought to be secondary to a combination of immune dysregulation and disruption in skin microbiota with unhindered Malassezia proliferation. In Parkinson's disease, SD is most likely secondary to parasympathetic hyperactivity with increased sebum production as well as facial immobility which leads to sebum accumulation.

A novel frameshift truncation mutation in the V2 tail domain of KRT1 causes mild ichthyosis hystrix of Curth-Macklin.

Ichthyosis hystrix, Curth-Macklin type (IHCM) is an extremely rare autosomal dominant dermatosis caused by mutations in the keratin genes, KRT1 or KRT10, which often manifests as extensive, dark, spiky or verrucous plaques and severe palmoplantar keratoderma. We report a novel frameshift truncation mutation, c.1596_1597insAT (p.Gly533Metfs*82) in exon 7 (V2 tail domain) of KRT1, which, by replacing the glycine-serine-rich tail of KRT1 with a series of 75 alanine-rich amino acids, produces a mild IHCM phenotype. The patient with the mutation presented with localized ichthyosis and progressive hyperkeratosis of the palms and soles with no history of blistering.

Cutaneous findings in Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, pleiotropic syndrome and member of a diverse group of disorders known as ciliopathies. Improved understanding of dermatoses in BBS will further understanding of the syndrome and will help define the role of dermatologists in providing care for patients with BBS. The purpose of this study was to describe the cutaneous phenotype of BBS in patients attending a large, multispecialty BBS clinic. METHODS: All patients attending the multispecialty BBS Clinic at the Marshfield Medical Center over a 12-month period were invited to participate. Complete cutaneous examinations were performed by a board-certified dermatologist, and comprehensive physical examinations were performed by clinic physicians. Molecular genetic results were obtained when available. Comprehensive laboratory studies were performed in each patient including fasting blood sugar and thyroid and renal function. RESULTS: Thirty-one individuals ranging in age between 2 and 69 years (median age, 12 years) participated in the study. Cutaneous findings were present in all subjects. Keratosis pilaris was present in 80.6% of subjects, and seborrheic dermatitis was present in 19.3%. Obesity, a cardinal feature of BBS, was present in the majority of subjects (90.3%) and was accompanied by known obesity-related dermatologic disorders. CONCLUSIONS: Cutaneous disorders are common in BBS and suggest disturbance of keratinization and keratinocyte function as well as systemic consequences of BBS on skin health. Increased prevalence of skin barrier dysfunction in this ciliopathy demonstrates the importance of dermatologist contribution to health care in BBS.

Analysis of gene expression profiles of multiple skin diseases identifies a conserved signature of disrupted homeostasis.

Triggers of skin disease pathogenesis vary, but events associated with the elicitation of a lesion share many features in common. Our objective was to examine gene expression patterns in skin disease to develop a molecular signature of disruption of cutaneous homeostasis. Gene expression data from common inflammatory skin diseases (eg psoriasis, atopic dermatitis, seborrhoeic dermatitis and acne) and a novel statistical algorithm were used to define a unifying molecular signature referred to as the "unhealthy skin signature" (USS). Using a pattern-matching algorithm, analysis of public data repositories revealed that the USS is found in diverse epithelial diseases. Studies of milder disruptions of epidermal homeostasis have also shown that these conditions converge, to varying degrees, on the USS and that the degree of convergence is related directly to the severity of homeostatic disruption. The USS contains genes that had no prior published association with skin, but that play important roles in many different disease processes, supporting the importance of the USS to homeostasis. Finally, we show through pattern matching that the USS can be used to discover new potential dermatologic therapeutics. The USS provides a new means to further interrogate epithelial homeostasis and potentially develop novel therapeutics with efficacy across a spectrum of skin conditions.

Role of the keratin 1 and keratin 10 tails in the pathogenesis of ichthyosis hystrix of Curth Macklin.

Ichthyosis Hystrix of Curth-Macklin (IH-CM) is a rare manifestation of epidermolytic ichthyosis (EI) that is characterised by generalised spiky or verrucous hyperkeratosis. The disorder is further distinguished by the presence of binucleated cells in the affected skin, whereas epidermolysis and clumping of tonofilaments, as seen in EI, are absent. While IH-CM is associated with mutations in the keratin 1 (KRT1) gene, reports to date have indicated that mutations in the KRT1 gene result in an aberrant and truncated protein tail, essentially affecting the function of the V2 domain. Here, we studied a female sporadic patient who was born with diffused erythrodermic hyperkeratosis and who presented at the age of 13 months with an intense and widespread hyperkeratosis with a papillomatous appearance and typical palmoplantar keratoderma. Genetic analysis demonstrated a "de novo" mutation in the keratin 10 gene (KRT10) consisting of a three-base-pair deletion, resulting in the substitution of amino acids p.Glu445 and p.Ile446 by Asp at the end of the 2B domain of the protein. We performed structural and functional studies showing that this mutation modifies the structure of the paired 2B and V2 K1/10 domains, leading to the disease phenotype. Our results highlight the importance and complexity of the KRT1/10 V2 domain in keratin dimer formation and the potential consequences of its alteration.

The genetic basis of seborrhoeic dermatitis: a review.

Seborrhoeic Dermatitis (SD) is a common inflammatory skin disease that presents as itchy, flaking skin in the seborrhoeic areas. Various environmental and intrinsic factors have been identified as predisposing factors for SD, but its aetiology remains poorly understood. Although it was recognized that genetic factors play a role in SD aetiology, there have not been studies that systematically review the literature specifically for causal mutations or protein deficiencies in SD. In this review, we searched various databases for gene mutations and protein deficiencies that cause SD or SD-like phenotype in humans and experimental animals, and summarize 11 gene mutations or protein deficiencies that were described in the literature. Most of the encoded proteins play a role either in the immune response (ACT1, C5, IKBKG/NEMO, STK4, 2C TCR) or epidermal differentiation (ZNF750, MPZL3). Understanding the genetic basis of SD can impart knowledge of the pathobiology of the disease and help identify novel therapeutic targets.

Dandruff/seborrhoeic dermatitis is characterized by an inflammatory genomic signature and possible immune dysfunction: transcriptional analysis of the condition and treatment effects of zinc pyrithione.

BACKGROUND: Dandruff/seborrhoeic dermatitis is a common scalp condition that is characterized by flakes, pruritus and sometimes mild erythema. These symptoms reflect tissue level events that are poorly understood at the molecular level. OBJECTIVES: The purpose of this work was: (i) to compare gene expression profiles in subjects with dandruff vs. those of subjects without dandruff to determine the key physiological disruptions manifest in the condition; and (ii) to determine the effect on this profile of treatment with a shampoo containing potentiated zinc pyrithione (ZPT). METHODS: In study 1, scalp biopsies were taken from 16 normal subjects and from involved and uninvolved sites in 15 subjects with dandruff. In study 2, 30 subjects with dandruff were treated for 3 weeks with a commercial ZPT shampoo (n = 15) or a vehicle (n = 15), and scalp lesional biopsies were collected at baseline and end of study for transcriptomic analysis. RNA was extracted from all biopsies and Affymetrix gene chips were used to analyse transcriptomic profiles, followed by bioinformatic analysis. RESULTS: Analysis of study 1 biopsies revealed more than 7000 individual probes differentially regulated in dandruff lesional skin relative to normal. Enriched Gene Ontology categories included: lipid metabolism, immune response, response to stimulus, apoptosis, cell proliferation, and epidermal development. The most striking feature of lesional skin relative to normal was the reciprocal expression of induced inflammatory genes and repressed lipid metabolism genes. Induced inflammatory genes were also enriched in dandruff uninvolved skin, suggesting the existence of predisposing factors associated with inflammation. Many genes increased in lesional skin were increased at the level of protein in stratum corneum samples (e.g. IL-1RA, S100A8, S100A9, S100A11, IL-8). Under conditions known to improve overall scalp condition, the ZPT shampoo treatment in study 2 produced a transcriptomic profile resembling that of normal scalp skin. CONCLUSIONS: These data provide novel insights into the nature of dandruff and the therapeutic action of potentiated ZPT-containing shampoo, and provide a basis to explore many new mechanistic questions related to these topics.

Seborrhea-like dermatitis with psoriasiform elements caused by a mutation in ZNF750, encoding a putative C2H2 zinc finger protein.

We describe an Israeli Jewish Moroccan family presenting with autosomal dominant seborrhea-like dermatosis with psoriasiform elements, including enhanced keratinocyte proliferation, parakeratosis, follicular plugging, Pityrosporum ovale overgrowth and dermal CD4 lymphocyte infiltrate. We mapped the disease gene to a 0.5-cM region overlapping the PSORS2 locus (17q25) and identified a frameshift mutation in ZNF750, which encodes a putative C2H2 zinc finger protein. ZNF750 is normally expressed in keratinocytes but not in fibroblasts and is barely detectable in CD4 lymphocytes.

A novel T cell receptor transgenic animal model of seborrheic dermatitis-like skin disease.

We have characterized a novel animal model of the common inflammatory skin disease seborrheic dermatitis (SD) that involves the expression of the self-specific 2C transgenic T cell receptor on the DBA/2 genetic background. Opportunistic fungal pathogens are present in the primary histological lesions and severe disease can be mitigated by the administration of fluconazole, demonstrating a role for infection in disease pathogenesis. Spontaneous disease convalescence occurs at 70-90 d of age and is preceded by an expansion of CD4+ T cells that partially restores the T cell lymphopenia that occurs in these animals. The adoptive transfer of syngeneic CD4+ T cells into pre-diseased DBA/2 2C mice completely abrogates the development of cutaneous disease. The pattern of disease inheritance in DBA/2 backcrosses suggests that one, or a closely linked group of genes, may control disease penetrance. Bone marrow reconstitution experiments demonstrated that the DBA/2 susceptibility factor(s) governing disease penetrance is likely non-hematopoietic since bone marrow from disease-resistant 2C mice can adoptively transfer the full disease phenotype to non-transgenic DBA/2 animals. This model implicates fungal organisms and CD4+ T cell lymphopenia in the development of a SD-like condition and, as such, may mimic the development of SD in acquired immunodeficiency syndrome.