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Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease characterized by pruritic erythematous scaly plaques distributed along the lines of Blaschko. Two cases of ILVEN with CARD14 mutations and one case with a GJA1 mutation have been previously reported.To elucidate the genetic cause of a cohort of patients diagnosed based on clinical and histopathological evaluation with ILVEN.We recruited patients diagnosed with ILVEN based on clinical and histopathological criteria. Exome sequencing of affected skin with or without blood/saliva was performed and germline and somatic pathogenic variants were identified.Five patients were enrolled. All had skin lesions from birth or early childhood. Two patients developed psoriasis vulgaris after the diagnosis of ILVEN. The first had a germline heterozygous CARD14 mutation and a post-zygotic hotspot mutation in KRT10. The histopathologic evaluation did not show epidermolytic hyperkeratosis. The second had a post-zygotic hotspot mutation in HRAS. Her ILVEN became itchy once psoriasis developed. One patient was re-diagnosed with linear porokeratosis based on a germline mutation in PMVK and a post-zygotic second-hit mutation. Two patients were re-diagnosed with congenital hemidysplasia with ichthyosiform nevus and limb defect nevus based on germline NSDHL mutations.ILVEN is a clinical descriptor for a heterogenous group of mosaic inflammatory disorders. Genetic analysis has the potential to more precisely categorize ILVEN and permits pathogenesis-directed therapies in some cases.

ImportanceGrover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and organ transplantation. The pathobiology of GD remains unknown.ObjectiveTo determine if damaging somatic single-nucleotide variants (SNVs) are associated with GD.Design, Setting, and ParticipantsIn this retrospective case series, we identified consecutive patients from a dermatopathology archive over a 4-year period (January 2007 to December 2011) who had 1 biopsy with a clinical diagnosis of GD confirmed via histopathologic findings and another non-GD biopsy. Participant DNA was extracted from both biopsy tissues and sequenced to high depth with a 51-gene panel to screen for SNVs in genes previously associated with acantholysis and Mendelian disorders of cornification. Analysis took place between 2021 and 2023.Main Outcomes and MeasuresComparative analysis of sequencing data from paired GD and control tissue was employed to identify SNVs predicted to affect gene function, which were exclusive to, or highly enriched in, GD tissue.ResultsOverall, 12 of 15 cases of GD (12 men and 3 women; mean [SD] age, 68.3 [10.0] years) were associated with C>T or G>A ATP2A2 SNVs in GD tissue; all were predicted to be highly damaging via combined annotation dependent depletion (CADD) scores, and 4 were previously associated with Darier disease. In 9 cases (75%), the GD-associated ATP2A2 SNV was absent from control tissue DNA, and in 3 cases (25%), ATP2A2 SNVs were enriched 4- to 22-fold in GD vs control tissue.Conclusions and RelevanceIn this case series study of 15 patients, damaging somatic ATP2A2 SNVs were associated with GD. This discovery expands the spectrum of acantholytic disorders associated with ATP2A2 SNVs and highlights the role of somatic variation in acquired disorders.

We report two cases of cutaneous mpox virus infection (formerly known as monkeypox), one of which presented with unusual clinical findings, and demonstrate their histopathological, RNA in situ hybridization (ISH) and ultrastructural characteristics. We observed in two patients with polymerase chain reaction-confirmed mpox virus infection squamous syringometaplasia of the eccrine ducts, a finding that can aid in recognizing this disease and is explained by the demonstration of viral mRNA within eccrine epithelium by ISH.

Treatment of congenital ichthyoses primarily focuses on reversing skin scaling and is not pathogenesis based. Recent studies showed Th17 immune skewing, as in psoriasis, across the spectrum of ichthyosis, suggesting that targeting this pathway might broadly reduce disease severity.To determine whether secukinumab, an IL-17A inhibitor, can improve ichthyosis across several congenital ichthyosis subtypes.Exploratory 16-week double-blind, randomized, placebo-controlled trial comparing secukinumab 300 mg every 4wks to placebo (1:1 randomization) in adults with the four major congenital ichthyosis subtypes (NCT03041038), followed by a 16-week open-label phase to evaluate response of the placebo-first group and a 20-week extension for safety. Significant differences in secukinumab- vs. placebo-treated subjects at Wk16 in the Ichthyosis Area Severity Index (IASI) score and lack of increased mucocutaneous bacterial and/or fungal infections were the co-primary efficacy and safety endpoints, respectively.Two tertiary referral centers: Northwestern University Feinberg School of Medicine, Chicago, and Mount Sinai Icahn School of Medicine, New York.Twenty subjects ≥ 18 yo with genotype-confirmed epidermolytic ichthyosis, Netherton syndrome, lamellar ichthyosis, or congenital ichthyosiform erythroderma with at least moderate erythroderma.IL-17A inhibition did not significantly reduce severity or increase mucocutaneous infections among the 18 who completed the 16-week double-blind phase. Five patients with 29-50% clinical improvement at Wk32 requested drug continuation. Th17-related biomarkers were not significantly reduced vs. baseline or placebo-treated levels.Small sample size; heterogeneous ichthyosis subsets.IL-17 inhibition with secukinumab is safe, but not efficacious across the spectrum of adult ichthyoses. CLINICALTRIALS.NCT03041038; first posted on 02/02/2017.

Topical and systemic retinoids are often used long-term in the treatment of ichthyoses and other disorders of cornification. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address the numerous clinical concerns with use of these medications in children and adolescents and to establish best practices regarding the use of retinoids. Consensus was achieved using the Delphi process with recommendations based on the best available evidence and expert opinion. An executive summary of the results is presented herein.

IMPORTANCE: A comprehensive, user-friendly system to assess global ichthyosis disease burden is imperative to improving the care of patients with ichthyosis, identifying appropriate participants for clinical trials, and quantifying treatment outcomes. To our knowledge, there is currently no validated scale to objectively and systematically measure ichthyosis severity across the entire body. OBJECTIVE: To create and evaluate a comprehensive and user-friendly instrument to measure total body ichthyosis severity in adults and children. DESIGN, SETTING, PARTICIPANTS: In this qualitative study, ichthyosis experts participated in the content development of the Ichthyosis Scoring System (ISS). The body was divided into 10 regions, and Likert scales (0-4) were created to quantify scale and erythema, with extensive descriptors and photographic standards. An 83-image teaching set was created from photographs of participants with ichthyosis. Two cohorts of dermatologists (11 total) independently scored all test photographs twice to evaluate interrater and intrarater reliabilities. Participants were enrolled worldwide from referral centers and patient advocacy groups. Participants of all ages, races, and ethnicities were included in the creation of ISS, and dermatologists with varying experience and areas of expertise participated as raters to evaluate the ISS. The study was conducted from 2019 to 2021, and the data were analyzed in 2021. MAIN OUTCOMES AND MEASURES: Intraclass correlation coefficients determined overall reliabilities. RESULTS: Across both cohorts of 11 dermatologists in total, the intraclass correlation coefficients for total, scale and erythema scores were greater than 0.90 (95% CI, 0.77-0.97), greater than 0.91 (95% CI, 0.79-0.98), and greater than 0.88 (95% CI, 0.72-0.97), respectively. Most body sites exhibited moderate to good interrater reliabilities for scale and erythema. Intrarater reliabilities were good to excellent. CONCLUSIONS AND RELEVANCE: The results of this qualitative study demonstrate reproducibility and suggest that the ISS is a reliable system to measure global ichthyosis severity in adults and children.

CARD14-associated papulosquamous eruption (CAPE) is a proposed term that encompasses features ranging from psoriasis to pityriasis rubra pilaris (PRP) in association with CARD14 mutations. The early onset of the disease, prominent facial involvement, family history of an autosomal dominant trait, and poor response to conventional treatment are characteristics of CAPE that distinguish it from classical psoriasis and PRP. We describe the clinical features, family history, and response to therapy in three unrelated children with CAPE and compare these characteristics with those of previously described pediatric patients. Testing for CARD14 mutations in children with early onset of features of psoriasis or pityriasis rubra pilaris and resistance to conventional therapy should be considered.

Pyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis manifesting as painful inflammatory plaques and ulcers, frequently associated with inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome, and acute myeloid leukemia.1 We present a case of a young woman with a novel mutation in NFkB1 who experienced common variable immunodeficiency (CVID) and severe recurrent PG episodes.

Carvajal and erythrokeratodermia cardiomyopathy syndromes (EKC) are rare, inherited cardiocutaneous disorders with potentially fatal consequences in young children. Some patients display features of congestive heart failure and rapidly deteriorate; others exhibit no evident warning signs until sudden death reveals underlying heart disease. We present two patients to illustrate the characteristic hair, skin, teeth, and nail abnormalities, which-especially when distinct from that of other family members-should prompt cardiac evaluation and genetic analysis. In this article, we discuss established treatments as well as a promising, novel therapeutic that has led to nearly complete resolution of the cutaneous and cardiac pathology in EKC syndrome.

Anomalous marginal veins of the trunk or extremities are congenitally incompetent entities found in association with phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth syndromes, such as Klippel-Trenaunay syndrome and congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal deformities (CLOVES) syndrome. When present, they can be a major source of venous hypertension-related morbidity and potentially lethal thromboembolic events. Herein, we describe a rare case of an upper extremity marginal vein in a patient with CLOVES syndrome. Through a multimodal therapeutic approach, we identified a somatic PIK3CA mutation in the excised anomalous vein. This finding questions the validity of commonly employed terminology, such as persistent embryonic vein, in reference to these anomalous entities.

Background Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA. Methods Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis. Results DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10. Conclusions Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.

Background Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy. We hypothesized that topical therapy that aims to replenish cholesterol, an essential mevalonate pathway end-product, and block the accumulation of mevalonate pathway toxic metabolites could alleviate porokeratosis. Objective To study the efficacy of topical cholesterol/lovastatin in different variants of porokeratosis. Methods We enrolled a series of 5 porokeratosis patients,1 with disseminated superficial actinic porokeratosis, 2 with porokeratosis palmaris et plantaris disseminata, and 2 with linear porokeratosis. Patients were genotyped before initiation of therapy. Patients then applied topical cholesterol/lovastatin twice daily to a unilaterally defined treatment area for up to 3 months. The response was evaluated and patients photographed at every visit. Results Three patients had MVD mutations, and 2 patients had PMVK mutations. Treatment with topical cholesterol/lovastatin (but not cholesterol alone) resulted in near complete clearance of disseminated superficial actinic porokeratosis lesions after 4 weeks of therapy and moderate improvement of porokeratosis palmaris et plantaris disseminata lesions and linear porokeratosis lesions. There were no adverse events. Limitations Case series design with a small number of patients. Conclusion Topical cholesterol/lovastatin is an effective and well-tolerated therapy for porokeratosis that underscores the utility of a pathogenesis-based therapy that replaces deficient end products and prevents accumulation of potentially toxic precursors.

Summary: The term “cavernous hemangioma” has been used to describe vascular anomalies with histology featuring dilated vascular spaces, vessel walls consisting mainly of fibrous stromal bands lined by a layer of flattened endothelial cells, and an irregular outer rim of interrupted smooth muscle cells. Hepatic hemangiomas (HHs) and cutaneous venous malformations (VMs) share this histologic pattern, and we examined lesions in both tissues to identify genetic drivers. Paired whole-exome sequencing (WES) of lesional tissue and normal liver in HH subjects revealed a recurrent GJA4 c.121G>T (p.Gly41Cys) somatic mutation in four of five unrelated individuals, and targeted sequencing in paired tissue from 9 additional HH individuals identified the same mutation in 8. In cutaneous lesions, paired targeted sequencing in 5 VMs and normal epidermis found the same GJA4 c.121G>T (p.Gly41Cys) somatic mutation in three. GJA4 encodes gap junction protein alpha 4, also called connexin 37 (Cx37), and the p.Gly41Cys mutation falls within the first transmembrane domain at a residue highly conserved among vertebrates. We interrogated the impact of the Cx37 mutant via lentiviral transduction of primary human endothelial cells. We found that the mutant induced changes in cell morphology and activated serum/glucocorticoid-regulated kinase 1 (SGK1), a serine/threonine kinase known to regulate cell proliferation and apoptosis, via non-canonical activation. Treatment with spironolactone, an inhibitor of angiogenesis, suppressed mutant SGK1 activation and reversed changes in cell morphology. These findings identify a recurrent somatic GJA4 c.121G>T mutation as a driver of hepatic and cutaneous VMs, revealing a new pathway for vascular anomalies, with spironolactone a potential pathogenesis-based therapy.

IMPORTANCE: Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more than 50 genes, clear genotype-phenotype associations have been difficult to establish. OBJECTIVE: To expand the genotypic and phenotypic spectra of ichthyosis and delineate genotype-phenotype associations. DESIGN, SETTING, AND PARTICIPANTS: This cohort study recruited an international group of individuals with ichthyosis and describes characteristic and distinguishing features of common genotypes, including genotype-phenotype associations, during a 10-year period from June 2011 to July 2021. Participants of all ages, races, and ethnicities were included and were enrolled worldwide from referral centers and patient advocacy groups. A questionnaire to assess clinical manifestations was completed by those with a genetic diagnosis. MAIN OUTCOMES AND MEASURES: Genetic analysis of saliva or blood DNA, a phenotyping questionnaire, and standardized clinical photographs. Descriptive statistics, such as frequency counts, were used to describe the cases in the cohort. Fisher exact tests identified significant genotype-phenotype associations. RESULTS: Results were reported for 1000 unrelated individuals enrolled from around the world (mean [SD] age, 50.0 [34.0] years; 524 [52.4%] were female, 427 [42.7%] were male, and 49 [4.9%] were not classified); 75% were from the US, 12% from Latin America, 4% from Canada, 3% from Europe, 3% from Asia, 2% from Africa, 1% from the Middle East, and 1% from Australia and New Zealand. A total of 266 novel disease-associated variants in 32 genes were identified among 869 kindreds. Of these, 241 (91%) pathogenic variants were found through multiplex amplicon sequencing and 25 (9%) through exome sequencing. Among the 869 participants with a genetic diagnosis, 304 participants (35%) completed the phenotyping questionnaire. Analysis of clinical manifestations in these 304 individuals revealed that pruritus, hypohydrosis, skin pain, eye problems, skin odor, and skin infections were the most prevalent self-reported features. Genotype-phenotype association analysis revealed that the presence of a collodion membrane at birth (odds ratio [OR], 6.7; 95% CI, 3.0-16.7; P

Basal cell carcinoma (BCC) is the most common human malignant neoplasm. However, there are multiple BCC subtypes that share clinical features while demanding different management. We present a case of a woman with hundreds of BCCs throughout her body that were resistant to vismodegib and without other features of basal cell nevus syndrome. Histological results of biopsies taken from various sites revealed three lesions characteristic of infundibulocystic BCCs (IBCCs) and two BCCs. Paired whole-exome sequencing performed using DNA isolated from blood and one of her IBCCs uncovered a germline heterozygous SUFU (Suppressor of Fused) mutation. The downstream location of SUFU in the hedgehog pathway explains why its mutation results in IBCCs that will not respond to any therapeutics that target upstream components of SUFU. These results capture the significance of histological and genetic analysis in directing treatment.

Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway-NOTCH1, NOTCH2, and HES1-were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.

Advances in human genetics have enabled discovery of new genes for inherited skin diseases and cutaneous malformations as well as refined categorization of genodermatoses. Careful phenotyping has been central to genetic discoveries, and it provides critical clues for clinical diagnoses, particularly when the skin disorder is not congenital. This article will review several lesser-known genodermatoses that often present after infancy with recognizable histopathologic features.

Background Infant death in keratitis-ichthyosis-deafness (KID) syndrome is recognized; its association with specific genotypes and pathophysiology is inadequately understood. Objective We sought to discover characteristics that account for poor outcomes in lethal KID syndrome. Methods We collected 4 new cases and 9 previously reported, genotyped cases of lethal KID syndrome. We performed new molecular modeling of the lethal mutants GJB2 p.A88V and GJB2 p.G45E. Results Infant death occurred in all patients with GJB2 p.G45E and p.A88V; it is unusual with other GJB2 mutations. Early death with those 2 "lethal" mutations is likely multifactorial: during life all had ≥1 serious infection; most had poor weight gain and severe respiratory difficulties; many had additional anatomic abnormalities. Structural modeling of GJB2 p.G45E identified no impact on the salt bridge previously predicted to account for abnormal central carbon dioxide sensing of GJB2 p.A88V. Limitations This clinical review was retrospective. Conclusion GJB2 p.G45E and p.A88V are the only KID syndrome mutations associated with uniform early lethality. Those electrophysiologically severe mutations in GJB2 reveal abnormalities in many organs in lethal KID syndrome. All patients with KID syndrome may have subtle abnormalities beyond the eyes, ears, and skin. Early genotyping of KID syndrome births will inform prognostic discussion.

BACKGROUND Epidermolytic acanthoma (EA) is a rare, benign acquired cutaneous keratosis displaying epidermolytic hyperkeratosis in more than 50% of its surface. Because of the sparsity of comprehensive studies, little is known on the patient demographics and clinical characteristics of this uncommon entity. We wish to comprehensively characterize the clinical and demographic features of EA and to differentiate it from its mimickers. METHODS We carried out a retrospective review of 131 cases of EA, recorded clinical and histopathologic features and performed linear regression of yearly incidence rates to assess for possible under-reporting of this entity. RESULTS EA affected both genders equally. We found 9.08 cases per 100 000 biopsy specimens per year and linear regression analysis showed significantly decreasing incidence rates. Analysis of the anatomical site distribution of EA lesions showed a more frequent genital location in men (39.1% of cases in men, as compared to 11.3% for women). Contrary to previous studies, lesions were most frequently single (91.7%) and the mean age of presentation was 57.8 years. CONCLUSION The presented largest case series to-date indicates that EA is probably an underdiagnosed entity and establishes the demographic and clinical features of EA.

Investigation of genetic determinants of Mendelian skin disorders has substantially advanced understanding of epidermal biology. Here we show that mutations in PERP, encoding a crucial component of desmosomes, cause both dominant and recessive human keratoderma. Heterozygosity for a C-terminal truncation, which produces a protein that appears to be unstably incorporated into desmosomes, causes Olmsted syndrome with severe periorificial and palmoplantar keratoderma in multiple unrelated kindreds. Homozygosity for an N-terminal truncation ablates expression and causes widespread erythrokeratoderma, with expansion of epidermal differentiation markers. Both exhibit epidermal hyperproliferation, immature desmosomes lacking a dense midline observed via electron microscopy, and impaired intercellular adhesion upon mechanical stress. Localization of other desmosomal components appears normal, which is in contrast to other conditions caused by mutations in genes encoding desmosomal proteins. These discoveries highlight the essential role of PERP in human desmosomes and epidermal homeostasis and further expand the heterogeneous spectrum of inherited keratinization disorders.

Epidermolysis bullosa (EB) is a genotypically heterogeneous group of disorders characterized by cutaneous blistering and erosions with a tremendous spectrum of severity. One of the distinct forms of EB, Kindler EB (KEB), manifests with blistering and poikiloderma; this subtype of EB is caused by mutations in the FERMT1 gene encoding kindlin-1. In this study, we investigated a patient clinically diagnosed as KEB with reduced FERMT1 gene expression and intensity of immunostaining for kindlin-1. Transmission electron microscopy showed lamina densa reduplication, frequently observed in KEB. However, no mutations were identified in FERMT1 in this patient with consanguineous parents, and this gene resided outside of genomic regions of homozygosity (ROH). Instead, whole-exome sequencing and homozygosity mapping identified a homozygous sequence variant at the +4 position of intron 2 in the USB1 gene, encoding an exoribonuclease required for processing of U6 snRNA, a critical component of spliceosomes. Examination of the patient's RNA by RNA-Seq confirmed the pathogenicity of this variant, causing aberrant splicing predicted to result in loss of function of USB1. Mutations in this gene have been reported in patients with poikiloderma and neutropenia, with a few reported cases in association with skin fragility, a condition distinct from the KEB phenotype. Transcriptome analysis revealed that several genes, expressed in the cutaneous basement membrane zone and previously associated with different subtypes of EB, were differentially downregulated at the mRNA level. EB-associated mRNA downregulation was confirmed at protein levels by skin immunofluorescence. These observations provide a novel mechanism for blistering and erosions in the skin as a result reduced presence of adhesion complexes critical for stable association of epidermis and dermis at the level of cutaneous basement membrane zone.

Topical and systemic retinoids have long been used in the treatment of ichthyoses and other disorders of cornification. Due to the need for long‐term use of retinoids for these disorders, often beginning in childhood, numerous clinical concerns must be considered. Systemic retinoids have known side effects involving bone and eye. Additionally, potential psychiatric and cardiovascular effects need to be considered. Contraceptive concerns, as well as the additive cardiovascular and bone effects of systemic retinoid use with hormonal contraception must also be deliberated for patients of childbearing potential. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address these issues and to establish best practices regarding the use of retinoids in ichthyoses based on available evidence and expert opinion.

Genodermatoses are inherited disorders presenting with cutaneous manifestations with or without the involvement of other systems. The majority of these disorders, particularly in cases that present with a cutaneous patterning, may be explained in the context of genetic mosaicism. Despite the barriers to the genetic analysis of mosaic disorders, next-generation sequencing has led to a substantial progress in understanding their pathogenesis, which has significant implications for the clinical management and genetic counseling. Advances in paired and deep sequencing technologies in particular have made the study of mosaic disorders more feasible. In this review, we provide an overview of genetic mosaicism as well as mosaic cutaneous disorders and the techniques required to study them.

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

Background Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH. Methods Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals. Results In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome. Conclusions CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related, and expand the phenotypic spectrum of ACTB mutations.

Mutations in several lipid synthetic enzymes that block fatty acid and ceramide production produce autosomal recessive congenital ichthyoses (ARCIs) and associated abnormalities in permeability barrier homeostasis. However, the basis for the phenotype in patients with NIPAL4 (ichthyin) mutations (among the most prevalent ARCIs) remains unknown. Barrier function was abnormal in an index patient and in canines with homozygous NIPAL4 mutations, attributable to extensive membrane stripping, likely from detergent effects of nonesterified free fatty acid. Cytotoxicity compromised not only lamellar body secretion but also formation of the corneocyte lipid envelope (CLE) and attenuation of the cornified envelope (CE), consistent with a previously unrecognized, scaffold function of the CLE. Together, these abnormalities result in failure to form normal lamellar bilayers, accounting for the permeability barrier abnormality and clinical phenotype in NIPA-like domain-containing 4 (NIPAL4) deficiency. Thus, NIPAL4 deficiency represents another lipid synthetic ARCI that converges on the CLE (and CE), compromising their putative scaffold function. However, the clinical phenotype only partially improved after normalization of CLE and CE structure with topical ω-O-acylceramide because of ongoing accumulation of toxic metabolites, further evidence that proximal, cytotoxic metabolites contribute to disease pathogenesis.

Histopathological interpretation of proliferative nodules occurring in association with congenital melanocytic nevi can be very challenging due to their similarities with congenital malignant melanoma and malignant melanoma arising in association with congenital nevi. We hereby report a diagnostically challenging case of congenital melanocytic nevus with proliferative nodules and ulcerations, which was originally misdiagnosed as congenital malignant melanoma. Subsequent histopathological examination in consultation by one of the authors (R.L.) and mass spectrometry imaging analysis rendered a diagnosis of congenital melanocytic nevus with proliferative nodules. In this case, mass spectrometry imaging, a novel method capable of distinguishing benign from malignant melanocytic lesions on a proteomic level, was instrumental in making the diagnosis of a benign nevus. We emphasize the importance of this method as an ancillary tool in the diagnosis of difficult melanocytic lesions.

BACKGROUND: Ichthyoses are rare, debilitating disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking, since the underlying molecular basis is poorly understood. OBJECTIVE: To characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. METHODS: We analyzed biopsies from 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) by immunohistochemistry and RT-PCR and compared them with healthy controls, and with atopic dermatitis (AD) and psoriasis patients. Clinical measures included a severity score for ichthyosis (IASI), which integrates erythema (IASI-E) and scaling (IASI-S), transepidermal water loss (TEWL), and pruritus. RESULTS: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and K16 expression) and T-cell and dendritic-cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some Th1/IFN (IFNγ) markers in ichthyosis were comparable to psoriasis or AD. TNFα levels in ichthyosis were elevated only in Netherton syndrome, but were much lower than in psoriasis and AD. Expression of Th2 cytokines (IL-13, IL-31) in ichthyoses was similar to controls. Most notable in ichthyosis was the striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNFα (IL-17A/C, IL-19, CXCL1, PI3, CCL20, IL36G; p

Tufted angioma (TA) is a rare vascular tumor characterized by histologic tufts of proliferating capillaries that occurs in infancy or early childhood, with a poorly understood pathogenesis. Though benign, TA can be associated with the Kasabach-Merritt phenomenon (KMP), a life-threatening consumptive coagulopathy and thrombocytopenia. Here, we explored the genetic mechanism underlying a case of TA associated with KMP via targeted sequencing of laser capture micro-dissected lesion and blood DNA, and identified a somatic, activating GNA14 mutation specific to the tumor. Our findings support aberrant GNA14 activation underlies the pathogenesis of TA associated with KMP.

This study assesses the association between the severity of alopecia and ichthyosis disease severity and characterizes the severity of alopecia by genotype.

We describe unrelated individuals with ichthyosis, failure to thrive, thrombocytopenia, photophobia, and progressive hearing loss. Each have bi-allelic mutations in AP1B1, the gene encoding the β subunit of heterotetrameric adaptor protein 1 (AP-1) complexes, which mediate endomembrane polarization, sorting, and transport. In affected keratinocytes the AP-1 β subunit is lost, and the γ subunit is greatly reduced, demonstrating destabilization of the AP-1 complex. Affected cells and tissue contain an abundance of abnormal vesicles and show hyperproliferation, abnormal epidermal differentiation, and derangement of intercellular junction proteins. Transduction of affected cells with wild-type AP1B1 rescues the vesicular phenotype, conclusively establishing that loss of AP1B1 function causes this disorder.

Familial and sporadic porokeratosis are associated with germline heterozygous mutations in mevalonate pathway genes. Kubo et al. show that each skin lesion of disseminated superficial actinic porokeratosis originates from a postnatal keratinocyte clone with a different second-hit genetic event in the wild-type allele of the corresponding gene. They also confirm that linear porokeratosis derives from a single prenatal clone of keratinocytes with a second-hit genetic event.

IMPORTANCE: Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. OBJECTIVE: To identify genetic mutations associated with linear porokeratosis. DESIGN, SETTING, AND PARTICIPANTS: Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. INTERVENTIONS OR EXPOSURES: Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. MAIN OUTCOMES AND MEASURES: Germline and somatic genomic characteristics of participants with linear porokeratosis. RESULTS: Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). CONCLUSIONS AND RELEVANCE: Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.