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Great advances have been made in the field of heritable skin disorders using next-generation sequencing (NGS) technologies (ie, whole-genome sequencing, whole-exome sequencing, whole-transcriptome sequencing, and disease-targeted multigene panels). When NGS first became available, the cost and lack of access to these technologies were limiting factors; however, with decreasing sequencing costs and the expanding knowledge base of genetic skin diseases, fundamental awareness of NGS has become prudent. The heritable ichthyoses comprise a genotypically and phenotypically heterogeneous group of monogenic keratinization disorders characterized by persistent scaling, with at least 55 distinct genes currently implicated in causing nonsyndromic and syndromic forms of the disease. By providing a simplified overview of available NGS techniques and applying them in the context of ichthyosis, one of the most common genodermatoses, we hope to encourage dermatologists to offer, when appropriate, genetic testing earlier in patients with unsolved presentations. With the aid of NGS, dermatologists can provide diagnostic certainty in cases of suspected genodermatoses and offer potentially life-changing genome-guided and targeted therapies as they become available., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023. Published by Elsevier Inc.)

Acquired ichthyosis (AI) is a relatively rare cutaneous entity characterized by transient, generalized scaling and pruritus in the absence of family history of ichthyosis or atopic disease. The hyperkeratosis in AI can range from the mild, white-to-brown scaling resembling that in ichthyosis vulgaris (IV) to the more prominent dark brown scaling phenotype, similar to that found in lamellar ichthyosis. The disease can wax and wane in relation to endogenous and/or exogenous factors. Histopathology of AI is similar to that found in IV. AI is usually of cosmetic concern to patients but can, in some cases, reflect the presence of more serious conditions, including malignancies, autoimmune diseases or metabolic disorders. In some cases, AI can be an adverse effect of a medication or the cutaneous symptom of a toxic exposure. Other conditions, such as severe xerosis or eczema, can present with clinical findings similar to AI, making diagnosis a challenge. Furthermore, cases of AI are sporadic throughout the literature and have been documented across a wide variety of medical settings distinct from dermatology, which often contribute to misdiagnosis of this disease. Definitive management requires prompt identification and treatment of the inciting factors combined with conservative therapies, which can include topical emollients, keratolytics, retinoids or corticosteroids, and in rare cases, oral retinoids., (© 2022 European Academy of Dermatology and Venereology.)

Ichthyosis follicularis (IF) manifests as generalized spiny follicular projections found in syndromic diseases secondary to SREBF1 and MBTPS2 mutations. We sought the genetic cause of IF in two distinct families from a cohort of 180 patients with ichthyosis. In Family 1, the proband (Patient 1) presented with IF, bilateral sensorineural hearing loss and punctate palmoplantar keratoderma. Using DNA from peripheral blood lymphocytes, two compound heterozygous mutations, c.526A>G and c.35delG, were discovered in GJB2. In Family 2, the proband (Patient 2) presented with a previously unreported IF phenotype in the context of keratitis-ichthyosis-deafness syndrome, and whole-exome sequencing found a de novo heterozygous mutation, c.148G>A in GJB2. Histopathology was consistent with porokeratotic eccrine ostial and dermal duct naevus (PEODDN) and IF in Patients 1 and 2, respectively. Our findings add to the clinical and histopathological spectrum of IF and emphasize the association of PEODDN-like entities with GJB2 variants., (© 2022 British Association of Dermatologists.)

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., (© 2021 European Academy of Dermatology and Venereology.)

The Mendelian disorders of cornification consist of a highly heterogeneous group of diseases, and the majority of nonsyndromic cases belong to the family of autosomal recessive congenital ichthyosis. Mutations in SDR9C7 have been associated with autosomal recessive congenital ichthyosis, and clinical manifestations include mild to moderately dry, scaly skin with or without hyperkeratosis, palmoplantar keratoderma, and erythroderma. SDR9C7, with short-chain dehydrogenase and/or reductase activity, is known as nicotinamide adenine dinucleotide‒ or nicotinamide adenine dinucleotide phosphate‒dependent oxidoreductase and has been shown to be involved in the final step of epidermal lipid barrier formation by covalent binding of acylceramide to the cornified envelope. In this study, we present the clinical and molecular description of 19 patients with autosomal recessive congenital ichthyosis in five consanguineous families with SDR9C7 mutations. We also downregulated the expression of SDR9C7 in keratinocytes using the small interfering RNA technique in three-dimensional organotypic skin constructs. Our results demonstrated morphological and histological abnormalities in these constructs ex vivo, similar to those observed in patients with ichthyosis. Moreover, the results from keratinocyte migration and epidermal dye penetration assays provided evidence for the role of SDR9C7 in the disease pathomechanism. Collectively, our results indicate that SDR9C7 deficiency by itself is sufficient to disrupt epidermal barrier function leading to ichthyotic phenotype., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Keratitis-ichthyosis-deafness (KID) syndrome is caused by mutations in the GJB2 gene encoding connexin 26, a component of transmembrane hemichannels which form gap junction channels, critical for cell-cell communication. Here, we report two patients from two distinct families with KID syndrome with the same GJB2 mutation (p.Asp50Asn); in both cases the mutation was de novo, as the parents depicted the wild-type allele only. The patients' cutaneous manifestations were strikingly different illustrating the wide spectrum of phenotype of these patients, even with the same GJB2 mutation. One of the patients was treated with acitretin with dramatic improvement in his skin findings, illustrating the role of oral acitretin in treatment of patients with KID syndrome. Collectively, these patients attest to the phenotypic spectrum of KID syndrome, with therapeutic perspective., (© 2020 Wiley Periodicals LLC.)

The heritable forms of keratinization disorders, including various forms of ichthyosis and keratodermas, comprise a phenotypically heterogeneous group of diseases which can be divided into syndromic and non-syndromic forms. In the non-syndromic forms, the clinical manifestations are limited to the cutaneous structures while the syndromic ones are associated with a spectrum of extracutaneous manifestations. The inheritance in different families can be autosomal dominant, autosomal recessive or either X-linked dominant or recessive. Currently at least 67 distinct genes have been associated with different forms of ichthyosis. These genes can be grouped on the basis of their physiological involvement, including genes encoding structural components of epidermis, those involved in epidermal lipid metabolism, or those critical for cell-cell adhesion, and keratinocyte differentiation. This overview highlights some of the recent progress made in understanding the molecular genetics of keratinization disorders, and presents selected, recently characterized cases as representative of different forms of heritable 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., (© 2019 British Association of Dermatologists.)

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell-cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2-associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2., (© 2018 Wiley Periodicals, Inc.)

Background: Mutations in the ST14 gene, encoding the serine protease matriptase, have been associated with ichthyosis-hypotrichosis syndrome (IHS), a Mendelian disorder with skin and hair manifestations which include, in addition to ichthyosis and hypotrichosis, hypohidrosis and follicular atrophoderma. However, the understanding of the specific consequences of mutations in ST14 on the development of this syndrome is incomplete., Results: Using a targeted next-generation sequencing array of 38 ichthyosis-associated genes on a large cohort of 180 ichthyosis patients from a primarily consanguineous background, a previously unreported homozygous p.Asp482Asn mutation in ST14 was identified in a patient with IHS. This mutation affects an essential site within a ligand-binding domain of matriptase. Comparison with previous reports of IHS allowed further delineation of the phenotype of IHS in correlation with mutations present in these patients. Histological and ultrastructural analysis of skin and hair identified novel features in this disorder., Conclusions: This study correlates genotypic and phenotypic features of the rare disorder, IHS, expands the spectrum of pathology associated with the disorder, and provides clinical evidence of the importance of the Asp482 amino acid, previously shown to have an essential role in matriptase activation.

There are at least 38 mutant genes known to be associated with the ichthyosis phenotypes, and autosomal recessive congenital ichthyosis (ARCI) is a specific subgroup caused by mutations in 13 different genes. Mutations in some of these genes, such as CERS3 with only two previous reports, are rare. In this study, we identified mutations in candidate genes in consanguineous families with ARCI with a next generation sequencing (NGS) array that incorporates 38 ichthyosis associated genes. We applied this sequencing array to DNA from 140 ichthyosis families with high prevalence of consanguinity. Among these patients we identified six distinct, previously unreported mutations in CERS3 in six Iranian families. These mutations in each family co-segregated with the ichthyosis phenotype. The patients demonstrated collodion membrane at birth, acrogeria, generalized scaling, and hyperlinearity of the palms and soles. The presence of a significant percentage of CERS3 mutations in our cohort depicts a marked difference between the etiology of ichthyoses in genetically poorly characterized regions and well-characterized western populations. Also, it shows that rare alleles are more prevalent in the gene pool of consanguineous populations and emphasizes the importance of these population studies for better understanding of ichthyosis pathogenesis.

Summary: Ichthyosis is a disorder in which the skin is very thick and scaly. It is usually caused by a genetic mistake (mutation). "Autosomal recessive" ichthyosis occurs when parents who are healthy carriers both pass on a mutant gene to their child, so the child inherits a double dose of the mutation and cannot make normal skin. Scientists have already discovered mutations in 13 genes that cause ichthyosis. This study looks at whether the type of mutation (genotype) tells us anything about the type of ichthyosis (phenotype). The doctors examined 146 ichthyosis patients, average age 17 years, from 124 families, recruited from 13 English hospitals. They extracted DNA from blood or saliva. They found mutations in 83% of patients; the other 17% presumably have mutations not detectable by current techniques or in different genes. There were mutations in 10 different ichthyosis genes, mostly a gene called TGM1. To some extent different genotypes corresponded to different phenotypes. TGM1 ichthyosis usually has large, brown scales while ALOX12B mutations cause fine white scaling. ABCA12 mutations cause more severe ichthyosis, including the very serious harlequin type with distorted fingers; by contrast patients with milder ichthyosis usually had TGM1 or ALOX12B mutations. Nearly half of the babies with ALOX12B mutations were born with the top of their ear folded over. Some TGM1 patients had abnormally red skin while others with exactly the same mutation did not. In conclusion, this large study provides a lot of new information about ichthyosis, but genotype only partly predicts phenotype. This is a summary of the study: Genotype–phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis Linked Article: Simpson et al. Br J Dermatol 2020; 182:729–737 [ABSTRACT FROM AUTHOR]