BACKGROUND:Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by a mutation in any one of five keratin genes (KRT6A, KRT6B, KRT6C, KRT16 or KRT17). Characteristic features of PC are painful palmoplantar keratoderma, variable nail dystrophy, cysts, follicular hyperkeratosis and often oral leukokeratosis. Although oral leukokeratosis can go unnoticed, mucosal involvement of the oral cavity and upper airways can manifest with pain during feeding, hoarseness, stridor and, occasionally, life-threatening obstruction.OBJECTIVES:To characterize patients with PC with symptomatic mucosal involvement.METHODS:We present a case series of nine children with PC with symptomatic mucosal involvement, all with heterozygous mutations in KRT6A. Seven patients complained of painful feeding problems. Four patients were diagnosed with failure to thrive, three of whom required a feeding tube. Simple feeding solutions were beneficial in most cases. Seven patients had laryngeal involvement and one patient died at 4 years of age from acute laryngeal obstruction.CONCLUSIONS:It is important for dermatologists and otolaryngologists to be aware that symptomatic mucosal involvement, and very rarely laryngeal obstruction, can occur in patients with PC. Usually simple feeding solutions may prevent complications and failure to thrive. What's already known about this topic? Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis due to a mutation in any one of five keratin genes. Symptomatic mucosal involvement is an important clinical feature of PC and appears to be more pronounced in KRT6A mutation carriers. Only leukokeratosis is frequently seen in PC and can be one of the earliest signs of disease. Laryngeal involvement is a less common feature. It might be symptomatic but usually presents as hoarseness, stridor and, occasionally, as a life-threatening respiratory distress. What does this study add? In most cases of laryngeal involvement, there is no need for any intervention. Although pain and feeding difficulties are usually attributed to the oral leukokeratosis, they can be related to a phenomenon called 'first bite syndrome' (FBS). Symptomatic mucosal involvement with feeding difficulty is important but can be managed in most cases with simple feeding solutions (e.g. softer nipple with a larger hole, thicker formula and feeding with a syringe). Linked Comment: Youssefian and Vahidnezhad. Br J Dermatol 2020; 182:536-537.

SVEP1 is a recently identified multidomain cell adhesion protein, homologous to the mouse polydom protein, which has been shown to mediate cell-cell adhesion in an integrin-dependent manner in osteogenic cells. In this study, we characterized SVEP1 function in the epidermis. SVEP1 was found by qRT-PCR to be ubiquitously expressed in human tissues, including the skin. Confocal microscopy revealed that SVEP1 is normally mostly expressed in the cytoplasm of basal and suprabasal epidermal cells. Downregulation of SVEP1 expression in primary keratinocytes resulted in decreased expression of major epidermal differentiation markers. Similarly, SVEP1 downregulation was associated with disturbed differentiation and marked epidermal acanthosis in three-dimensional skin equivalents. In contrast, the dispase assay failed to demonstrate significant differences in adhesion between keratinocytes expressing normal vs low levels of SVEP1. Homozygous Svep1 knockout mice were embryonic lethal. Thus, to assess the importance of SVEP1 for normal skin homoeostasis in vivo, we downregulated SVEP1 in zebrafish embryos with a Svep1-specific splice morpholino. Scanning electron microscopy revealed a rugged epidermis with perturbed microridge formation in the centre of the keratinocytes of morphant larvae. Transmission electron microscopy analysis demonstrated abnormal epidermal cell-cell adhesion with disadhesion between cells in Svep1-deficient morphant larvae compared to controls. In summary, our results indicate that SVEP1 plays a critical role during epidermal differentiation.

Congenital erythroderma is a rare and often life-threatening condition, which has been shown to result from mutations in several genes encoding important components of the epidermal differentiation program. Using whole exome sequencing, we identified in a child with congenital exfoliative erythroderma, hypotrichosis, severe nail dystrophy and failure to thrive, two heterozygous mutations in ABCA12 (c.2956C>T, p.R986W; c.5778+2T>C, p. G1900Mfs*16), a gene known to be associated with two forms of ichthyosis, autosomal recessive congenital ichthyosis, and harlequin ichthyosis. Because the patient displayed an atypical phenotype, including severe hair and nail manifestations, we scrutinized the exome sequencing data for additional potentially deleterious genetic variations in genes of relevance to the cornification process. Two mutations were identified in CAPN12, encoding a member of the calpain proteases: a paternal missense mutation (c.1511C>A; p.P504Q) and a maternal deletion due to activation of a cryptic splice site in exon 9 of the gene (c.1090_1129del; p.Val364Lysfs*11). The calpain 12 protein was found to be expressed in both the epidermis and hair follicle of normal skin, but its expression was dramatically reduced in the patient's skin. The downregulation of capn12 expression in zebrafish was associated with abnormal epidermal morphogenesis. Small interfering RNA knockdown of CAPN12 in three-dimensional human skin models was associated with acanthosis, disorganized epidermal architecture, and downregulation of several differentiation markers, including filaggrin. Accordingly, filaggrin expression was almost absent in the patient skin. Using ex vivo live imaging, small interfering RNA knockdown of calpain 12 in skin from K14-H2B GFP mice led to significant hair follicle catagen transformation compared with controls. In summary, our results indicate that calpain 12 plays an essential role during epidermal ontogenesis and normal hair follicle cycling and that its absence may aggravate the clinical manifestations of ABCA12 mutations.

Journal Article Increased epidermal expression and absence of mutations in CARD14 in a series of patients with sporadic pityriasis rubra pilaris Get access O. Eytan, O. Eytan Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv IsraelDepartment of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel Search for other works by this author on: Oxford Academic Google Scholar L. Qiaoli, L. Qiaoli Department of Dermatology and Cutaneous Biology Jefferson Medical College Philadelphia PA U.S.A Search for other works by this author on: Oxford Academic Google Scholar J. Nousbeck, J. Nousbeck Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv Israel Search for other works by this author on: Oxford Academic Google Scholar M.A.M. van Steensel, M.A.M. van Steensel Department of Dermatology and GROW School for Oncology and Developmental Biology Department of Clinical Genetics Maastricht University Medical Centre Maastricht The NetherlandsDepartment of Clinical Genetics Maastricht University Medical Centre Maastricht The Netherlands Search for other works by this author on: Oxford Academic Google Scholar B. Burger, B. Burger Department of Dermatology University Hospital Basel Basel SwitzerlandDepartment of Biomedicine University Hospital Basel Basel Switzerland Search for other works by this author on: Oxford Academic Google Scholar D. Hohl, D. Hohl Laboratory of Cutaneous Biology Service of Dermatology and Venereology Beaumont Hospital CHUV Lausanne Switzerland Search for other works by this author on: Oxford Academic Google Scholar A. Taïeb, A. Taïeb Department of Dermatology and National Reference Centre for Rare Skin Disorders CHU St‐André Bordeaux France Search for other works by this author on: Oxford Academic Google Scholar S. Prey, S. Prey Department of Dermatology and National Reference Centre for Rare Skin Disorders CHU St‐André Bordeaux France Search for other works by this author on: Oxford Academic Google Scholar D. Bachmann, D. Bachmann Laboratory of Cutaneous Biology Service of Dermatology and Venereology Beaumont Hospital CHUV Lausanne SwitzerlandCentre Hospitalier Universitaire Vaudois and University of Lausanne Lausanne Switzerland Search for other works by this author on: Oxford Academic Google Scholar E. Avitan‐Hersh, E. Avitan‐Hersh Department of Dermatology Rambam Medical Center Haifa Israel Search for other works by this author on: Oxford Academic Google Scholar ... Show more H. Jin Chung, H. Jin Chung Department of Dermatology and Cutaneous Biology Jefferson Medical College Philadelphia PA U.S.A Search for other works by this author on: Oxford Academic Google Scholar A. Shemer, A. Shemer Department of Dermatology Shebah Medical Center Tel Hashomer Israel Search for other works by this author on: Oxford Academic Google Scholar H. Trau, H. Trau Department of Dermatology Shebah Medical Center Tel Hashomer Israel Search for other works by this author on: Oxford Academic Google Scholar R. Bergman, R. Bergman Department of Dermatology Rambam Medical Center Haifa Israel Search for other works by this author on: Oxford Academic Google Scholar D. Fuchs‐Telem, D. Fuchs‐Telem Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv IsraelDepartment of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel Search for other works by this author on: Oxford Academic Google Scholar E. Warshauer, E. Warshauer Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv Israel Search for other works by this author on: Oxford Academic Google Scholar S. Israeli, S. Israeli Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv Israel Search for other works by this author on: Oxford Academic Google Scholar P.H. Itin, P.H. Itin Department of Dermatology University Hospital Basel Basel Switzerland Search for other works by this author on: Oxford Academic Google Scholar O. Sarig, O. Sarig Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv Israel Search for other works by this author on: Oxford Academic Google Scholar J. Uitto, J. Uitto Department of Dermatology and Cutaneous Biology Jefferson Medical College Philadelphia PA U.S.A Search for other works by this author on: Oxford Academic Google Scholar E. Sprecher E. Sprecher Department of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv IsraelDepartment of Human Molecular Genetics and Biochemistry Sackler Faculty of Medicine Tel Aviv University Ramat Aviv Israel Correspondence: Eli Sprecher. E‐mail: elisp@tasmc.health.gov.il Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 170, Issue 5, 1 May 2014, Pages 1196–1198, https://doi.org/10.1111/bjd.12799 Published: 01 May 2014

BACKGROUND:Autosomal dominant adermatoglyphia (ADG) is characterized by lack of palmoplantar epidermal ridges. Recently, ADG was found to be caused in one family by a mutation in SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily.OBJECTIVES:To investigate the genetic basis of ADG.METHODS:We used direct sequencing and global gene expression analysis.RESULTS:We identified three novel heterozygous mutations in SMARCAD1 (c.378 + 2T > C, c.378 + 5G > C and c.378 + 1G > A) in a total of six patients. Surprisingly, all four ADG-causing mutations identified to date disrupt a single conserved donor splice site adjacent to the 3' end of a noncoding exon and are predicted to result in haploinsufficiency for a skin-specific isoform of SMARCAD1. These data indicate a pivotal role for the SMARCAD1-skin specific isoform in dermatoglyph formation. In order to better understand the consequences of ADG-associated mutations, we ascertained the global transcription profiles of primary keratinocytes downregulated for SMARCAD1 and of patient-derived keratinocytes. A total of eight genes were found to be differentially expressed in both patient-derived and knocked down keratinocytes. Of interest, these differentially expressed genes have been implicated in epidermal ontogenesis and differentiation, and in psoriasis, which is characterized by abnormal finger ridge patterns.CONCLUSIONS:The present data suggest that ADG is genetically homogeneous and result from perturbed expression of epidermal differentiation-associated genes.

is a fibrosing disorder that causes significant morbidity through atrophy and fibrosis of the skin and underlying structures. The mechanism is believed to be autoimmune in nature, and it has been postulated that it is related to systemic sclerosis although the pathogenic pathways remain unknown. Linear morphea follows the lines of Blaschko, and somatic mutations have been found in several Blaschkoid disorders. We thus hypothesize that linear morphea is a mosaic condition caused by somatic alterations, perhaps in conjunction with germline factors that predispose to disease. Whole exome sequencing (WES) was performed on our discovery cohort of 3 pediatric subjects with linear morphea using DNA obtained from lesional tissue. WES was also performed on germline DNA from the proband, mother, and father. Analyses were performed according to methodologies developed for our clinical genomics lab and using CarpeNovo, our in house-de- veloped software platform. Initially, we targeted 24 genes and 32 risk alleles previously associated with systemic sclerosis. We identified variants of interest in three systemic sclerosis-associated genes (MIF, PTPN22, and NLRP1), with variants present in one or more of the lesional DNA samples. Further analysis and validation of the preliminary WES results are underway. Gene mutation underlies ichthyosis hystrix (IH) Lambert type is investigated and phenotype-geno- type relation is reviewed by comparison with other IH types. IH Lambert type and Curth–Macklin type are very rare genetic skin diseases characterized by striking hyperkeratotic verrucous lesions. They can be well recognized from IH Brocq type (the most common IH type also named as epidermolytic hyperkeratosis, erythrodermie congenitale ichthyosiforme type bulleuse) by no blister occurence clinically and perinuclear tonofilament shells formation ultrastructurally. Whether palms and/or soles are affected is a differential point between IH Curth–Macklin type and IH Lambert type. To now, there are 7 reports on IH Curth–Macklin type with 5 of them showing KRT1 gene mutation. Only 2 reports on IH Lambert type including the pedigree in this study. Exome sequencing, linkage and analysis and candidate genes sequencing were used. Three patients all carry the c.1304 T Ç C missense mutation in KRT10 gene, causing p.Leu435Pro substitution (corresponding to 2B domain of K10 protein), which was not found in five unaffected individuals through three generations in this family and 100 ethnically matched healthy controls. Our results supported that IH Lambert type and Curth–Macklin type are one entity which could be divided into two categories of palms and soles unaffected/affected (NPS/PS), with KRT10 mutations causing NPS phenotype and KRT1 mutations giving rise to PS phenotype, just like that in IH Brocq type. abnormalities including narrowing and dysgenesis of major cerebral vessels, which has been estimated to be present in more than 90% of these patients. While the natural history of PHACE is largely unknown, debilitating headaches have been anecdotally reported as a late manifestation. These headaches are often under-treated due to poor understanding of its pathogenesis and fears of using vasoactive, migraine-abortive medications such as triptans which can raise the risk for acute ischemic strokes. In this study, we seek to estimate the prevalence of headaches and its unique clinical characteristics in PHACE. Given the high prevalence of cerebral vascular anomalies in these patients, we also seek to determine possible associations between headaches and abnormalities found on Magnetic Resonance Angiogram (MRA). We created and distributed a survey designed to assess the quality of headaches, prior treatments, and associated neurologic symptoms based on the International Classification of Headache Disorders II diagnostic criteria. All participants are a part of our PHACE Syndrome International Clinical Registry and Genetic Repository which has clinical information of over 175 patients with confirmed PHACE. Preliminary analysis of a subset of participants queried show that 62% of patients older than the age of 4 report debilitating headaches. A large majority of these patients also have MRA abnormalities. Comparatively, less than 20% of the normal children complain of headaches. From our results, we infer that children with PHACE have an unusually high prevalence of headaches compared to the general pediatric population and there is a possible link between intracerebral arteriopathies and headaches. This pilot study will enrich our understanding of the prevalence of headaches in PHACE patients and allow us to better predict at risk children. we leveraged global gene expression data generated in our laboratory comparing lesional and non-lesional skin of chronic CLE (CCLE) patients. The lesional skin transcriptional signature in CCLE features prominent functional pathways that reflect an activated immune system, with enhanced inflammatory cytokine expression and activated neutrophils, as well as dysregulated apoptosis and complement cascade. We found a significant overlap of differentially expressed genes (DEGs) in CCLE with SLE gene expression data reported in the literature. Several previously reported SLE-associated susceptibility loci were also found to overlap with CCLE DEGs, including those mapping to CCLE “hot spots” that represent chromosomal regions harboring a statistically enhanced concentration of dysregulated transcripts. CCLE DEGs common with previously reported SLE-associated gene expression data and/or reported susceptibility loci highlight a central role for interferon and apoptosis in both cutaneous and systemic manifestations of the disease. Additionally, we identify chromosomal regions that may harbor distinct susceptibility loci for CCLE not previously associated with lupus. Our data indicate that both overlapping as well as distinct genetic factors underlie disease pathogenesis in systemic and cutaneous lupus. These findings have relevance to the diagnosis and clinical classification of disease and shed light on disease mechanisms. epidermal in a in and c.378+1G>A) in a total of 6 patients. Surprisingly, all four ADG-causing mutations identified to date disrupt a single conserved donor splice site adjacent to the 3’ end of a non-coding exon and result in degradation of a skin-specific isoform of SMARCAD1. These data attribute to the SMARCAD1-skin specific isoform a pivotal role in dermatoglyph formation. In order to better understand the consequences of ADG-associated mutations, we compared the global transcription profile of primary keratinocytes down-regulated for SMARCAD1 and of patient-derived keratinocytes. A total of 9 genes were found to be differentially expressed in both patient and knocked down keratinocytes. Of interest, 7 of those genes have been implicated in epidermal ontogenesis and differentiation. In addition, these genes have been found to be associated with psoriasis, which is characterized by abnormal finger ridge patterns. The present data suggest that ADG is genetically homogeneous and result from perturbed expression of epidermal differentiation-associated genes. Cole disease is a rare autosomal dominant genodermatosis featuring punctate keratoderma and patchy hypopigmentation. Using a combination of exome and direct sequencing, we showed complete co-segregation of the disease phenotype with 3 heterozygous mutations in ENPP1 in 3 unrelated families. Surprisingly, mutations in ENPP1 were previously shown to underlie a number of recessive conditions characterized by ectopic mineralization including GACI and PXE. While ectopic calcification-associated mutations are distributed across the entire gene sequence, all muta- tions causing Cole disease were found to affect cysteine residues within the somatomedin-B-like domain 2 (SMB2) of the protein. As this domain inhibits insulin signaling through binding of the IRS-1 receptor, and insulin signaling is known to regulate keratinocyte proliferation and pigmentation, we assessed the effect of ENPP1 down-regulation on insulin signaling in primary keratinocytes. We found out that ENPP1 deficiency was associated with activation of the insulin signaling pathway as evidenced by a 1.5, 1.7 and 2.7-fold increase in IRS-1, AKT and ERK phosphorylation, respectively. Conversely, ENPP1 down-regulation was associated with decreased expression of various epidermal differentiation markers (including filaggrin, TGM1, involucrin and loricrin). Collectively, these results demonstrate a role for ENPP1 during epidermal proliferation in addition to its known function in the regulation of tissue mineralization. Recent studies suggest that desmosomal proteins may, in addition to their role in adhesion, also regulate pivotal intracellular processes. We investigated 12 patients with widespread Skin dermatitis, severe Allergies and Metabolic wasting (SAM syndrome), often associated with acantholysis. Using exome sequencing, we identified an in-frame deletion and a frameshift mutation in DSG1, encoding desmoglein 1, in 4 of these patients. Both mutations resulted in lack of incorporation of DSG1 into desmosomes. We previously showed that DSG1 promotes epidermal differentiation by inhibiting ERK through Erbin, which interacts with Shoc2 and disrupts Ras-Raf scaffolding. Accordingly, Erbin localization was aberrant in the skin of the patients, while pERK staining was increased, albeit to a lesser degree in the presence of the in-frame deletion, correlating with clinical outcome. Absence of DSG1 was found by Proximity Ligation Assay to result in increased Shoc2-Ras complexing. Moreover, using qRTPCR, IHC and ELISA, we found that down-regulation of DSG1 in human kera- tinocytes is associated with overexpression of a wide array of cytokine genes (e.g. MCP-1, CCL22) and aberrant expression of all major differentiation markers. In summary, DSG1 deficiency results in: (1) acantholysis due to