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Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder characterized by skin fragility, chronic inflammation, malnutrition, and fibrosis. Metabolomics is an emerging investigative field that helps elucidate disease pathophysiology and identify biomarkers. However, previous metabolomic studies in RDEB are limited.To investigate the plasma metabolomic profiles in RDEB patients.We recruited 10 RDEB patients and 10 age-/gender-matched healthy controls. Peripheral blood samples were collected and plasma metabolomic profiling was performed by LC-MS/MS analysis. MS data processing and compound identification were executed by MS-DIAL. Enrichment analysis was performed by MetaboAnalyst 5.0.Metabolomic analyses demonstrated that most amino acid levels were downregulated in RDEB patients, and the extent of insufficiency correlated with clinical severity. Several metabolites were dysregulated in RDEB, including glutamine and glutamate metabolism, tryptophan-to-kynurenine ratio, phenylalanine-to-tyrosine ratio, and succinate accumulation.The study was limited by small case numbers and the unrepresentativeness of a single time-point blood sample.Our study demonstrated the altered metabolomic profiles in RDEB, reflecting the disease severity, the chronic inflammatory and malnourished status, while the fibrotic signatures were not evident.

Genetic hair disorders, also known as genotrichoses, are characterized by abnormalities of hair structure, growth, or differentiation, giving rise to a spectrum of phenotypes such as hypertrichosis, hypotrichosis and atrichia. These disorders may present as isolated phenotypes or be part of more complex phenotypes including abnormalities in skin or other organs. Genetic discoveries for hair disorders have been recently augmented with the advent of next-generation sequencing (NGS) technologies. We reviewed the literature and summarised disease-gene associations for inherited hair disorders, as well as genodermatoses presenting with hair abnormalities discovered by NGS technologies. We identified 28 non-syndromic hair disorders, involving 25 individual genes and four unidentified genes. We have also discovered that approximately 30% of all genodermatoses that were identified by NGS approaches demonstrated hair abnormalities as part of their phenotype. This review underscores the huge impact of NGS technologies in disclosing the genetics of hair disorders and the potential the discoveries provide for future translational research and new therapies.

Chronic wounds present a major disease burden in people with recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering skin disorder caused by mutations in COL7A1 encoding type VII collagen, the major component of anchoring fibrils at the dermal-epidermal junction. Treatment of RDEB wounds is mostly symptomatic, and there is considerable unmet need in trying to improve and accelerate wound healing. In this study, we defined transcriptomic profiles and gene pathways in RDEB wounds and compared these to intact skin in RDEB and healthy control subjects. We then used a reverse transcriptomics approach to discover drugs or compounds, which might restore RDEB wound profiles towards intact skin. Differential expression analysis identified >2000 differences between RDEB wounds and intact skin, with RDEB wounds displaying aberrant cytokine-cytokine interactions, Toll-like receptor signalling, and JAK-STAT signalling pathways. In-silico prediction for compounds that reverse gene expression signatures highlighted methotrexate as a leading candidate. Overall, this study provides insight into the molecular profiles of RDEB wounds and underscores the possible clinical value of reverse transcriptomics data analysis in RDEB, and the potential of this approach in discovering or repurposing drugs for other diseases.

WNTs (Wingless-related integration sites) are secreted glycoproteins that are involved in signalling pathways critical to organ development and tissue regeneration. Of the 19 known WNT ligands, one member of this family, WNT10A, appears to have specific relevance to skin, its appendages and teeth. This review focuses on how variants in the WNT10A gene have been associated with various ectodermal disorders and how such changes may have clinical relevance to dermatologists and dentists. Germline mutations in WNT10A underlie several forms of autosomal recessive ectodermal dysplasia in which heterozygous carriers may also display some lesser ectodermal anomalies. Within the general population, multiple heterozygous variants in WNT10A can cause skin, hair, sweat gland or dental alterations, also known as ectodermal derivative impairments. WNT10A variants have also been implicated in hair thickness, male androgenetic alopecia, hair curl, acne vulgaris, lipodystrophy, keloids, wound healing, tooth size, tooth agenesis, hypodontia, taurodontism and oral clefting. Beyond dermatology and dentistry, WNT10A abnormalities have also been identified in kidney fibrosis, keratoconus, certain malignancies (particularly gastrointestinal) and neuropathic pain pathways. In this review, we detail how WNT10A is implicated as a key physiological and pathological contributor to syndromic and nonsyndromic disorders, as well as population variants, affecting the skin and teeth, and document all reported mutations in WNT10A with genotype-phenotype correlation.

Launch of the European Society for Dermatological Research (ESDR) in 1970 coincided with genetics also entering a new era. Arriving alongside new models of DNA structure and the discovery of restriction endonucleases, the ESDR has parallel-tracked 50 years of major developments in genomics, technological innovations, and big data. Patients with rare Mendelian genetic skin diseases have witnessed the discovery of causative genes and pathogenic variants, improved genetic counseling, and the advent of prenatal diagnosis. Translational research has also heralded early phase clinical trials of gene, cell, and protein therapies, as well as enhanced disease models, mechanism-based therapies, and impactful clinical progress.

ImportanceKeloids and hypertrophic scars (excessive scarring) are relatively understudied disfiguring chronic skin conditions with high treatment resistance.ObjectiveTo evaluate established comorbidities of excessive scarring in European individuals, with comparisons across ethnic groups, and to identify novel comorbidities via a phenome-wide association study (PheWAS).Design, Setting, and ParticipantsThis multicenter cross-sectional population-based cohort study used UK Biobank (UKB) data and fitted logistic regression models for testing associations between excessive scarring and a variety of outcomes, including previously studied comorbidities and 1518 systematically defined disease categories. Additional modeling was performed within subgroups of participants defined by self-reported ethnicity (as defined in UK Biobank). Of 502 701 UKB participants, analyses were restricted to 230078 individuals with linked primary care records.ExposuresKeloid or hypertrophic scar diagnoses.Main Outcomes and MeasuresPreviously studied disease associations (hypertension, uterine leiomyoma, vitamin D deficiency, atopic eczema) and phenotypes defined in the PheWAS Catalog.ResultsOf the 972 people with excessive scarring, there was a higher proportion of female participants compared with the 229 106 controls (65% vs 55%) and a lower proportion of White ethnicity (86% vs 95%); mean (SD) age of the total cohort was 64 (8) years. Associations were identified with hypertension and atopic eczema in models accounting for age, sex, and ethnicity, and the association with atopic eczema (odds ratio [OR], 1.68; 95% CI, 1.36-2.07; P P = .02) and with vitamin D deficiency in Asian participants (OR, 2.24; 95% CI, 1.26-3.97; P = .006). The association with uterine leiomyoma was borderline significant in Black women (OR, 1.93; 95% CI, 1.00-3.71; P = .05), whereas the association with atopic eczema was significant in White participants (OR, 1.68; 95% CI, 1.34-2.12; P P = .048) and Black participants (OR, 1.89; 95% CI, 0.83-4.28; P = .13). The PheWAS identified 110 significant associations across disease systems; of the nondermatological, musculoskeletal disease and pain symptoms were prominent.Conclusions and RelevanceThis cross-sectional study validated comorbidities of excessive scarring in UKB with comprehensive coverage of health outcomes. It also documented additional phenome-wide associations that will serve as a reference for future studies to investigate common underlying pathophysiologic mechanisms.

Background Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. Objectives To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. Methods In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. Results The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. Conclusions TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.

With recent advances in high-throughput technologies, we are now in an era where the use of large-scale datasets of biological samples and individual diseases can be analysed using omics methodologies. These include genomics, transcriptomics, proteomics, metabolomics, lipidomics and epigenomics. Omics approaches have been developed to deliver a holistic understanding of systems biology, to identify key biomarkers, and to aid in the interpretation of molecular, biochemical and environmental interactions. Navigating through the plethora of online datasets to find useful and concise information for comparison of data can be complex and overwhelming. The purpose of this article is to review the current repositories and databases, and to evaluate their application in dermatological research and their relevance to clinical practice. For this study, an extensive review of online platforms used in dermatology research was undertaken. Online resources for genetic disease information, genetic disease connection platforms for patients and researchers, clinical interpretation of variants, genome and DNA databases, and omics data repositories and resources were collected. This study provides a comprehensive overview of relevant databases that will aid clinicians and scientists using omics data in dermatology.

International audience; TKFC-encoded triokinase catalyses glyceraldehyde phosphorylation in fructose metabolism and favours lipogenesis in mice. In Tkfc knockouts or knockdowns, fructose oxidation predominates over lipogenesis. The highly prevalent human variant Ala185Thr-Triokinase/FMN cyclase (TKFC) has been reported to be 'null' for fructose metabolism, since Ala185-TKFC rescues the mouse TKFC-deficient phenotype, whereas Ala185Thr-TKFC does not. Such report implies that most humans would display a noncanonical fructose metabolism, but it ignores the well-characterized triokinase activity of Ala185Thr-TKFC. Here, earlier evidence is summarized, along with new evidence that both human variants are equally active in yeast. Therefore, future research on triokinase in the context of human fructose metabolism should consider that Ala185Thr-TKFC is not biochemically 'null'.

Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene. To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported. Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology. Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay. We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81A>C; p.Asn27Thr in MSMO1. Segregation analysis in all available family members confirmed recessive inheritance of the mutation. The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement. This study demonstrates how genomics-based diagnosis and therapy can be helpful in clinical practice.

Metabolic changes occur in all forms of disease but their impact on fibrosis is a relatively recent area of interest. This review provides an overview of the major metabolic pathways, glycolysis, amino acid metabolism and lipid metabolism, and highlights how they influence fibrosis at a cellular and tissue level, drawing on key discoveries in dermal, renal, pulmonary and hepatic fibrosis. The emerging influence of adipose tissue-derived cytokines is discussed and brings a link between fibrosis and systemic metabolism. To close, the concept of targeting metabolism for fibrotic therapy is reviewed, drawing on lessons from the more established field of cancer metabolism, with an emphasis on important considerations for clinical translation.

H syndrome is a rare autosomal recessive disorder with clinical features comprising: hyperpigmentation, hypertrichosis, hearing loss, heart anomalies, low height, hypogonadism and hepatosplenomegaly. H syndrome results from loss-of-function mutations in SLC29A3 which leads to abnormal proliferation and function of histiocytes. Herein, we discuss the considerable phenotypic heterogeneity detected in a consanguineous Egyptian family comprising of four affected siblings, two of which are monozygotic twin and the possible therapeutics. The phenotypic variability may be attributed to the role of histiocytes in the tissue response to injury. Such variable expressivity of H syndrome renders the diagnosis challenging and delays the management. The different treatment approaches used for this rare entity are reviewed.

Frontal fibrosing alopecia (FFA) is a recently described inflammatory and scarring type of hair loss affecting almost exclusively women. Despite a dramatic recent increase in incidence the aetiopathogenesis of FFA remains unknown. We undertake genome-wide association studies in females from a UK cohort, comprising 844 cases and 3,760 controls, a Spanish cohort of 172 cases and 385 controls, and perform statistical meta-analysis. We observe genome-wide significant association with FFA at four genomic loci: 2p22.2, 6p21.1, 8q24.22 and 15q2.1. Within the 6p21.1 locus, fine-mapping indicates that the association is driven by the HLA-B*07:02 allele. At 2p22.1, we implicate a putative causal missense variant in CYP1B1, encoding the homonymous xenobiotic- and hormone-processing enzyme. Transcriptomic analysis of affected scalp tissue highlights overrepresentation of transcripts encoding components of innate and adaptive immune response pathways. These findings provide insight into disease pathogenesis and characterise FFA as a genetically predisposed immuno-inflammatory disorder driven by HLA-B*07:02., Frontal fibrosing alopecia (FFA) features lichenoid cutaneous inflammation and scarring hair loss. Here, Tziotzios et al. identify four genetic loci associated with FFA by GWAS followed by Bayesian fine-mapping, co-localisation and HLA imputation which highlights HLA-B*07:02 as a risk factor.

Epidermolysis bullosa (EB) is a highly diverse group of inherited skin disorders, resulting from mutations in genes encoding proteins of the dermal-epidermal junction (DEJ). Itch (pruritus) is one of the commonest symptoms across all EB subtypes. It occurs in blistered or wounded sites, or manifests as a generalized phenomenon, thereby affecting both intact skin and healing wounds. The mechanism of pruritus in EB is unclear. It is likely that skin inflammation secondary to barrier disruption, wound healing cascades and dysregulated activation of epidermal sensory nerve endings are all involved in its pathophysiology on the molecular and cellular level. Understanding these mechanisms in depth is crucial in developing optimised treatments for people with EB and improving quality of life. This review summarises current evidence on the prevalence, mechanisms and management of itch in EB.

Sterol-C4-methyl oxidase (SC4MOL) deficiency was recently described as an autosomal recessive cholesterol biosynthesis disorder caused by mutations in the MSMO1 (sometimes also referred to as SC4MOL) gene. To date, 5 patients from 4 unrelated families with SC4MOL deficiency have been reported. Diagnosis can be challenging as the biochemical accumulation of methylsterols can affect global development and cause skin and ocular pathology. Herein, we describe 2 siblings from a consanguineous Turkish family with SC4MOL deficiency presenting with psoriasiform dermatitis, ocular abnormalities (nystagmus, optic hypoplasia, myopia, and strabismus), severe intellectual disability, and growth and motor delay. We undertook whole-exome sequencing and identified a new homozygous missense mutation c.81AC; p.Asn27Thr in MSMO1. Segregation analysis in all available family members confirmed recessive inheritance of the mutation. The siblings were treated with a combination of oral and topical statin and cholesterol which resulted in clinical improvement. This study demonstrates how genomics-based diagnosis and therapy can be helpful in clinical practice.

Background Discovering the genetic basis of inherited skin diseases is fundamental to improving diagnostic accuracy and genetic counselling. In the 1990s and 2000s, genetic linkage and candidate gene approaches led to the molecular characterization of several dozen genodermatoses, but over the past decade the advent of next-generation sequencing (NGS) technologies has accelerated diagnostic discovery and precision. Objectives This review examines the application of NGS technologies from 2009 to 2019 that have (i) led to the initial discovery of gene mutations in known or new genodermatoses and (ii) identified involvement of more than one contributing pathogenic gene in individuals with complex Mendelian skin disorder phenotypes. Methods A comprehensive review of the PubMed database and dermatology conference abstracts was undertaken between January 2009 and December 2019. The results were collated and cross-referenced with OMIM. Results We identified 166 new disease-gene associations in inherited skin diseases discovered by NGS. Of these, 131 were previously recognized, while 35 were brand new disorders. Eighty-five were autosomal dominant (with 43 of 85 mutations occurring de novo), 78 were autosomal recessive and three were X-linked. We also identified 63 cases harbouring multiple pathogenic mutations, either involving two coexisting genodermatoses (n = 13) or an inherited skin disorder in conjunction with other organ system phenotypes (n = 50). Conclusions NGS technologies have accelerated disease-gene discoveries in dermatology over the last decade. Moreover, the era of NGS has enabled clinicians to split complex Mendelian phenotypes into separate diseases. These genetic data improve diagnostic precision and make feasible accurate prenatal testing and better-targeted translational research.

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4β1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4β1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

BACKGROUND Desmosomes are intercellular cadherin-mediated adhesion complexes that anchor intermediate filaments to the cell membrane and are required for strong adhesion for tissues under mechanical stress. One specific component of desmosomes is plakophilin 1 (PKP1), which is mainly expressed in the spinous layer of the epidermis. Loss-of-function autosomal recessive mutations in PKP1 result in ectodermal dysplasia-skin fragility (EDSF) syndrome, the initial inherited Mendelian disorder of desmosomes first reported in 1997. METHODS To investigate two new cases of EDSF syndrome and to perform a literature review of pathogenic PKP1 mutations from 1997 to 2019. RESULTS Sanger sequencing of PKP1 identified two new homozygous frameshift mutations: c.409_410insAC (p.Thr137Thrfs*61) and c.1213delA (p.Arg411Glufs*22). Comprehensive analyses were performed for the 18 cases with confirmed bi-allelic PKP1 gene mutations, but not for one mosaic case or 6 additional cases that lacked gene mutation studies. All pathogenic germline mutations were loss-of-function (splice site, frameshift, nonsense) with mutations in the intron 1 consensus acceptor splice site (c.203-1>A or G>T) representing recurrent findings. Skin fragility and nail involvement were present in all affected individuals (18/18), with most cases showing palmoplantar keratoderma (16/18), alopecia/hypotrichosis (16/18) and perioral fissuring/cheilitis (12/15; not commented on in 3 cases). Further observations in some individuals included pruritus, failure to thrive with low height/weight centiles, follicular hyperkeratosis, hypohidrosis, walking difficulties, dysplastic dentition and recurrent chest infections. CONCLUSION These data expand the molecular basis of EDSF syndrome and help define the spectrum of both the prototypic and variable manifestations of this desmosomal genodermatosis.

Purpose Primary ciliary dyskinesia (PCD) is characterised by repeated upper and lower respiratory tract infections, neutrophilic airway inflammation and obstructive airway disease. Different ultrastructural ciliary defects may affect lung function decline to different degrees. Lung clearance index (LCI) is a marker of ventilation inhomogeneity that is raised in some but not all patients with PCD. We hypothesised that PCD patients with microtubular defects would have worse (higher) LCI than other PCD patients. Methods Spirometry and LCI were measured in 69 stable patients with PCD. Age at testing, age at diagnosis, ethnicity, ciliary ultrastructure, genetic screening result and any growth of Pseudomonas aeruginosa was recorded. Results Lung clearance index was more abnormal in PCD patients with microtubular defects (median 10.24) than those with dynein arm defects (median 8.3, p = 0.004) or normal ultrastructure (median 7.63, p = 0.0004). Age is correlated with LCI, with older patients having worse LCI values (p = 0.03, r = 0.3). Conclusion This study shows that cilia microtubular defects are associated with worse LCI in PCD than dynein arm defects or normal ultrastructure. The patient’s age at testing is also associated with a higher LCI. Patients at greater risk of obstructive lung disease should be considered for more aggressive management. Differences between patient groups may potentially open avenues for novel treatments. Electronic supplementary material The online version of this article (10.1007/s00408-018-0086-x) contains supplementary material, which is available to authorized users.

Background Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder due to a lack of type VII collagen. At present, treatment is mainly supportive. Objectives To determine whether intravenous allogeneic bone marrow–derived mesenchymal stromal/stem cells (BM-MSCs) are safe in RDEB adults and if the cells improve wound healing and quality of life. Methods We conducted a prospective, phase I/II, open-label study recruiting 10 RDEB adults to receive 2 intravenous infusions of BM-MSCs (on day 0 and day 14; each dose 2-4 × 106 cells/kg). Results BM-MSCs were well tolerated with no serious adverse events to 12 months. Regarding efficacy, there was a transient reduction in disease activity scores (8/10 subjects) and a significant reduction in itch. One individual showed a transient increase in type VII collagen. Limitations Open-label trial with no placebo. Conclusions MSC infusion is safe in RDEB adults and can have clinical benefits for at least 2 months.

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.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe form of skin fragility disorder due to mutations in COL7A1 encoding basement membrane type VII collagen (C7), the main constituent of anchoring fibrils (AFs) in skin. We developed a self-inactivating lentiviral platform encoding a codon-optimized COL7A1 cDNA under the control of a human phosphoglycerate kinase promoter for phase I evaluation. METHODS: In this single-center, open-label phase I trial, 4 adults with RDEB each received 3 intradermal injections (~1 × 10(6) cells/cm(2) of intact skin) of COL7A1-modified autologous fibroblasts and were followed up for 12 months. The primary outcome was safety, including autoimmune reactions against recombinant C7. Secondary outcomes included C7 expression, AF morphology, and presence of transgene in the injected skin. RESULTS: Gene-modified fibroblasts were well tolerated, without serious adverse reactions or autoimmune reactions against recombinant C7. Regarding efficacy, there was a significant (P < 0.05) 1.26-fold to 26.10-fold increase in C7 mean fluorescence intensity in the injected skin compared with noninjected skin in 3 of 4 subjects, with a sustained increase up to 12 months in 2 of 4 subjects. The presence of transgene (codon-optimized COL7A1 cDNA) was demonstrated in the injected skin at month 12 in 1 subject, but no new mature AFs were detected. CONCLUSION: To our knowledge, this is the first human study demonstrating safety and potential efficacy of lentiviral fibroblast gene therapy with the presence of COL7A1 transgene and subsequent C7 restoration in vivo in treated skin at 1 year after gene therapy. These data provide a rationale for phase II studies for further clinical evaluation. TRIAL REGISTRATION: ClincalTrials.gov NCT02493816. FUNDING: Cure EB, Dystrophic Epidermolysis Bullosa Research Association (UK), UK NIHR Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, and Fondation René Touraine Short-Exchange Award.

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype–phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.