Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genodermatosis characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. RDEB is caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils which form attachment structures stabilizing the cutaneous basement membrane zone. Most of the previously reported COL7A1 mutations are located in the coding or intronic regions. We describe 6 patients with localized or intermediate RDEB for whom one recessive pathogenic variant in the coding region and a second variant in the COL7A1 promoter were identified. These substitutions, three of which are novel, are localized in two Sp1 binding sites of the promoter region. DNA pull-down assay showed a drastic reduction of Sp1 binding consistent with a dramatic decrease in COL7A1 transcript and almost undetectable C7 protein levels. Our results reveal that mutations in the COL7A1 promoter on the background of a null allele can underlie localized or intermediate RDEB. They further emphasize the functional importance of Sp1 motifs in the proximal COL7A1 promoter which should be carefully investigated for regulatory mutations in the case of RDEB with only one pathogenic variant identified in the coding or intronic regions.

Hidradenitis suppurativa (HS) is a chronic dermatosis characterized by nodules and abscesses in apocrine gland–bearing sites. Mutations in three GSC genes have been identified in autosomal dominant forms of HS (Frew et al., 2017) (Supplementary Tables S1 and S2). NCSTN, PSEN1, and PSENEN mutations have been reported in 41 patients with unrelated HS, one Chinese family with HS, and 21 patients with unrelated HS with or without Dowling-Degos disease, respectively (Frew et al., 2017). The functional consequences of these mutations are yet to be elucidated.

Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway-inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.

Importance:Olmsted syndrome is a rare and disabling genodermatosis for which no successful treatment is currently available.Objective:To evaluate the clinical response to the mammalian target of rapamycin (mTOR) inhibitor sirolimus and/or the epidermal growth factor receptor (EGFR) inhibitor erlotinib among patients with Olmsted syndrome.Design, Setting, and Participants:This case series focused on 4 children with treatment-refractory Olmsted syndrome. These children received treatments (initiated in 2017 and 2018) at the outpatient dermatology clinic at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin; Children's National Hospital in Washington, DC; and Hospital Infantil Pequeno Príncipe, Curitiba in Paraná, Brazil.Exposures:Immunohistochemical analyses for mTOR and EGFR activation were performed on skin biopsy specimens from 2 patients. Oral sirolimus was administered to these 2 patients at a dosage of 0.8 mg/m2 twice daily, titrated to a goal trough whole-blood concentration of 10 to 15 ng/mL. Erlotinib was administered to all 4 patients at a dosage of 2 mg/kg/d.Main Outcomes and Measures:Clinical responses were assessed with visual analog scales for pruritus and pain and/or the Children's Dermatology Life Quality Index. Adverse effects were monitored throughout treatment.Results:Four patients (mean [SD] age, 7 [6] years; 2 boys and 2 girls) were analyzed. Lesional skin immunostaining showed increased phosphorylated ribosomal protein S6 (RPS6) and phosphorylated EGFR staining in the epidermis, indicating enhanced mTOR and EGFR signaling activation. Patients 1 and 2 were initially treated with sirolimus, displaying substantial clinical improvement in erythema and periorificial hyperkeratosis afterward. When switched to erlotinib, these patients showed substantial palmoplantar keratoderma (PPK) improvement. Patients 3 and 4 were treated with erlotinib only and later showed rapid and near complete resolution of PPK and substantial improvement in Children's Dermatology Life Quality Index scores. All 4 patients had sustained improvements in pruritus and pain. No severe adverse effects were reported.Conclusions and Relevance:This study's findings suggest that the EGFR-mTOR cascade may play a substantial role in the pathophysiological process of Olmsted syndrome and may serve as a major therapeutic target. Oral sirolimus and erlotinib may be a promising, life-altering treatment for pediatric patients with Olmsted syndrome.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the skin associated with specific lesional dysbiotic features. We studied the microbiome of clinically unaffected typical HS sites (armpits, inguinal folds, and gluteal clefts) in 60 patients with HS and 17 healthy controls. A total of 192 samples obtained by swabbing were analyzed by bacterial cultures. Of these, 116 randomly selected samples were studied by 16S rRNA gene amplicon sequencing. Patients and controls showed similar characteristics, except for smoking (87% vs. 6%, respectively). HS skinfolds were characterized by an increased abundance of anaerobes, predominantly Prevotella, but also Actinomyces, Campylobacter ureolyticus, and Mobiluncus, contrasting with a lower abundance of skin commensals such as Staphylococcus epidermidis, a major component of the skin microbiome; Kocuria; and Micrococcus luteus. The following three independent factors were associated with an abundance of high anaerobes by multivariate analysis: samples originating from patients with HS patients (P = 2.1 x 10(-4)); body mass index (P = 5 x 10(-5)); and the sampling site, the gluteal cleft being the most anaerobic area, followed by inguinal folds and axilla (P = 3 x 10(-6)). The microbiome of clinically unaffected HS skinfolds is reminiscent, albeit to a minor extent, of the microbiome of chronic suppurative HS lesions and may fuel inflammation at a preclinical stage of the disease.

L’étiologie de l’hidradénite suppurée reste mal connue. Des mutations dans le gène de la g-sécretase ont été décelées, mais ne concernent que 5 % des patients. Les cultures prolongées ainsi que la métagénomique bactérienne ont identifié une flore commensale lésionnelle opportuniste et des traitements antibiotiques ciblés contre cette flore couplés à la chirurgie permettent d’obtenir une rémission. Ces données suggèrent une dysrégulation de l’immunité cutanée innée vis-à-vis du microbiome, responsable d’une réponse inflammatoire anormalement prolongée, inefficace à éliminer cette prolifération bactérienne dermique. Pour identifier d’éventuelles altérations métaboliques sous-jacentes pouvant faire le lien entre génétique et microbiologie, nous avons réalisé la première étude métabolomique de lésions d’hidradénite suppurée et de peaux contrôles. Sur des biopsies en peau lésionnelle (L-HS) et péri-lésionnelle (PL-HS) chez 19 patients atteints d’hidrosadénite suppurée (HS) de stade 1 de Hurley sans maladie inflammatoire associée et chez 20 contrôles sains (CS), ont été réalisées des analyses métabolomiques, transcriptomiques et histologiques. L’étude métabolomique a révélé des altérations significatives du métabolisme du tryptophane (trp) dans les biopsies L-HS, marquées par une réduction du niveau local de cet acide aminé essentiel et l’accumulation de 2 produits de dégradation, le quinolinate et la kynurénine (kyn), en comparaison aux biopsies PL-HS et CS. Ces anomalies étaient corrélées avec une augmentation de l’expression dans les fibroblastes dermiques d’IDO, enzyme limitante du catabolisme du tryptophane stimulée par l’IFN-g, et avec une infiltration de cellules immunes productrices d’IFN-g. Contrairement au psoriasis et à la dermatite atopique, où ces métabolites sont peu ou pas modulés, kyn et quinolinate étaient significativement augmentés dans les lésions d’HS, suggérant une anomalie distinctive du catabolisme du trp. Outre la voie kyn, principalement utilisée par les cellules humaines, le trp peut être dégradé en indoles par les bactéries ou transformé en sérotonine dans le cerveau. Dans la maladie de Crohn, le dérèglement des 2 voies métaboliques kyn et indole serait impliqué dans l’inflammation et la dysbiose intestinales. Le trp aurait également un rôle clé dans le syndrome métabolique et la spondylarthrite, souvent associées à l’HS. Enfin, le quinolinate est une neurotoxine associée aux douleurs chroniques et à la dépression, souvent présentes dans l’HS. En conclusion, cette étude, financée par la SFD, suggère l’implication de la voie du trp dans la physiopathologie de l’HS de stade I de Hurley. Des études sur de plus grandes séries et d’autres stades de sévérité sont nécessaires pour confirmer ces résultats, mieux comprendre ces dérèglements immuno-métaboliques et découvrir de nouvelles cibles thérapeutiques.

diseases according to the Global Burden of Disease (GBD) and the current portfolio of CS reviews. 5 Diseases were grouped as to whether or not they were in the 'top 15', and whether or not previous work had identified a low representation within the CS portfolio.The final list of grouped titles was then reviewed by the CS clinical editors with respect to current titles and potential number of reviews that could be supported.The rankings were combined to generate an overall priority list.New titles were advertised for competitive application from suitably qualified and resourced author teams; priority titles currently in progress were supported with extra editorial resources.If an author team did not make adequate progress, extra support was offered from CS, or titles were readvertised for review by a new qualified and resourced team.For these priority titles, CS aims to produce high-quality systematic reviews within 18 months of title registration.Going forward, CS will continue to support our existing portfolio of reviews and protocols and consider author suggestions for new review titles on an annual basis in relation to editorial capacity at CS and ranking of related titles in the most recent prioritization exercise.Potential disadvantages include limited GBD data in some global regions that may skew title priority.CS will have an increasing focus on supporting high-priority, potentially high-impact systematic review titles generated by a formal prioritization process.This is consistent with the Cochrane Collaboration Strategy 2020, which aims to produce timely, high-priority reviews of evidence to guide health decision-making. 6CS will repeat the 2017 prioritization process every 2-3 years to ensure our portfolio continues to include important and timely systematic review titles.This methodological shift in the production of CS systematic reviews is necessary to ensure that Cochrane authors and editorial resources continue to be utilized in areas where evidence synthesis is needed.Routine updates of existing reviews, redundant reviews, and incongruent methodologies can dilute the quality and relevance of systematic reviews.The implementation of a prioritization system allows Cochrane to commit their resources to high-impact reviews that are produced in a timely manner.Embracing newer methodologies such as network meta-analysis allows Cochrane to ensure that our in-house methodological expertise is used to its fullest extent.CS will no longer aim to maintain an up-to-date portfolio covering all skin diseases but will focus on the rapid delivery of a smaller number of high-priority, potentially practice-changing reviews.Using cutting-edge review methodologies, CS will ensure that information gaps are addressed and will facilitate the timely support of relevant clinical guidelines.

This study aims to pre-select patients with recessive dystrophic epidermolysis bullosa (RDEB) for the GENEGRAFT clinical trial – a phase I/II ex vivo gene therapy trial designed for a safe and efficient therapy using autologous skin equivalents genetically corrected with a self-inactivating retroviral vector encoding COL7A1 (Orphan drug: EU/3/09/630). Patients with moderate to severe RDEB were identified from France and the UK based on eligibility criteria for optimal safety and feasibility. One potential safety issue is the development of autoimmune EB acquisita caused by IgG autoantibodies against type VII collagen (C7). This is of particular concern for RDEB patients with null C7 expression. Optimal patients were therefore further defined as those who express "minimal" C7 with negative indirect immunofluorescence (IIF), indicating the absence of neutralizing circulating C7 antibodies. Both B- and T- cell mediated responses to normal C7 were also assessed by ELISA and ELISPOT. Thirty patients (21 from France, 9 from the UK) were identified, age range 20-53 years. RDEB subtypes included generalized intermediate (n=16), generalized severe (n=10) and inversa (n=4). Patients with chronic wounds unsuitable for grafting and those who developed squamous cell carcinoma were excluded. Six patients had positive ELISA and five had positive ELISPOT but all had negative IIF. Consequently, six suitable patients were identified, with three defined as optimal candidates. All six patients express low levels of C7 of apparent normal molecular weight as a result of their specific COL7A1 mutations. The GENEGRAFT trial is currently undergoing clinical trial applications and approvals.

TP63 mutations are the primary source of several autosomal dominant ectodermal dysplasias, which are characterized by various combinations of limb, ectodermal, and orofacial abnormalities (Rinne et al., 2007). We describe a family with prominent alopecia and mild ectodermal dysplasias features, which co-segregate with a TP63 mutation.

Acne fulminans (AF) and hidradenitis suppurativa (HS) are 2 severe conditions with no consensus on medical treatment and no clear pathophysiology.1,2 We report the remission of long-lasting and severe AF with HS that was unresponsive to many previous treatments.

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.

Inherited epidermolysis bullosa (EB) comprises rare heterogeneous disorders characterized by cutaneous and mucosal fragility. Most of the 20 proteins affected have structural functions. Recently, a previously undescribed type of EB simplex (EBS), caused by gain-of-function mutations in KLHL24, encoding KLHL24 has been identified (He et al., 2016He Y. Maier K. Leppert J. Hausser I. Schwieger-Briel A. Weibel L. et al.Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.Am J Hum Genet. 2016; 99: 1395-1404Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, Lin et al., 2016Lin Z. Li S. Feng C. Yang S. Wang H. Ma D. et al.Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility.Nat Genet. 2016; 48: 1508-1516Crossref PubMed Scopus (82) Google Scholar). This protein seems to be involved in protein ubiquitination. Patients carrying monoallelic mutations in the translation initiation codon of KLHL24 have a characteristic clinical phenotype, showing skin defects and blistering at birth and unusual stellate scarring, skin fragility, and whorled or macular hyperpigmentation or hypopigmentation in childhood (Figure 1a–e ). Although skin fragility improves by adulthood, nail dystrophy, anetoderma, and hair loss may occur (Figure 1f–h). Given that KLHL24 is widely expressed, we investigated extracutaneous features in a cohort comprising families from Chile, Germany, Italy, Switzerland, and the United States (see Supplementary Material online). Institutional approval for investigations and written informed consent were obtained, and patients gave permission to have their photographs and medical information published. Eighteen patients with EBS-KLHL24 from nine families (nine males, nine females) were examined (Table 1). The mean patient age was 21.7 years, with nine children (2–13 years old) and nine adults (24–46 years old). Patients 1–10 have previously been described (He et al., 2016He Y. Maier K. Leppert J. Hausser I. Schwieger-Briel A. Weibel L. et al.Monoallelic mutations in the translation initiation codon of KLHL24 cause skin fragility.Am J Hum Genet. 2016; 99: 1395-1404Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar), and patients 11–18 are newly reported. Two additional individuals (patients 19 and 20) belong to family 9; they had skin fragility and died of dilated cardiomyopathy (DCM) at the ages of 39 and 54 years. In all examined patients, pathogenic variants in the translation initiation codon of KLHL24 were found (Table 1). Whole-exome sequencing and multigene panel data showed no pathogenic variants in genes known to be associated with DCM (Burke et al., 2016Burke M.A. Cook S.A. Seidman J.G. Seidman C.E. Clinical and mechanistic insights into the genetics of cardiomyopathy.J Am Coll Cardiol. 2016; 68: 2871-2886Crossref PubMed Scopus (176) Google Scholar).Table 1Patient descriptions with genetic, clinical, and laboratory findings1Values in bold exceed reference values.Patient NumberFamily NumberAge in Years (Sex)Country of OriginMutation KLHL24Cardiac Symptoms/Clinical FeaturesCK in U/L (Normal Value)CKMB in ng/ml (Normal Value)Pro-BNP in pg/ml (Normal Value)ECG/Echocardiogram/MRIOther Clinical Features/Symptoms1134 (M)Switzerland-Italyc.[1A>G]None/BP = 105/80 mm Hg237 (<168)32 (<25)1,221 (<120)ECG: Nonspecific changesEcho: Severe biventricular DCM, EF = 27%MRI: Transmural fibrosis, corresponding to the thinned inferior and inferolateral wall of the LVNontransmural mid-wall fibrosis in the septum; the lateral, anterior and septal segments of the LV show nontransmural fibrosisDiffuse fibrosis in the RV.Chronic proteinuria and hematuriaXerosis cutis, palmoplantar keratoderma, nail dystrophy216 (F)Switzerland-Italyc.[1A>G]None121 (<147)2.3 (<6)333 (<390)ECG: n/dEcho: Normal resultsDiffuse alopecia, nail dystrophy, xerosis cutisSpeech delay319 (F)Switzerland-Italyc.[1A>G]None526 (<147)23.7 (<6)874 (<390)ECG: n/dEcho: Normal resultsMild diffuse alopecia, xerosis cutis, palmoplantar keratoderma, nail dystrophy426 (M)Switzerland-Germanyc.[2T>C]Tachycardia, extrasystoles182 (<168)7.7 (<6)82 (<390)ECG: Normal resultsEcho: Normal resultsDevelopmental and fine motor skill delay5346 (F)Germanyc.[1A>G]None66 (<170)15 (<25)695.7 (<169)ECG: Nonspecific changesEcho: Mild systolic dysfunction with dilatation of left ventricleComplete scalp and body hair loss636 (F)Germanyc.[1A>G]None95 (<149)64.9 (<24)60.1 (<40)ECG: n/dEcho: n/d7436 (F)Germanyc.[1A>G]None74 (<168)19 (<25)170 (<125)ECG: n/dEcho: n/dComplete scalp and body hair loss.8512 (M)Germanyc.[1A>G]None74 (<152)30 (<25, 40.5% of CK)186.7 (<186)ECG: n/dEcho: n/d9639 (M)Italyc.[1A>G]Occasional chest pain at night (2014), improved with medicationn/dn/dn/dECG: Mean = 50 b.p.m. (bradycardia), sporadic ventricular extrasystolesEcho 2014: LV dilatation, EF = 43%.Echo 2018: EF = 43% by Simpson method, global hypokinesia10613 (M)Italyc.[1A>G]None209 (≤200)5.0 (≤5)125.6 (<125)ECG: Normal resultsEcho: Normal results11735 (F)United Statesc.[1A>G]None, but episode with loss of consciousnessn/dn/dn/dECG: Normal resultsEcho: Normal resultsHair thinning in early adulthood, progressive hair lossSeizure disorder of unknown origin12828 (F)Chilec.[1A>G]None Normal6014 (<25)43 (<125)ECG: Normal resultsEcho: Normal resultsModerate alopecia since 11 years of ageFine and dry hair1394 (M)Chilec.[2T>G]None/Normal129 (<308)31 (<25)89 (<125)ECG: n/dEcho: Normal resultsFine and dry hairMild follicular atrophoderma on arms14933 (M)Chilec.[2T>G]Heart murmur (I/IV)75 (<308)11 (<25)926 (<125)ECG: Electric axis diverted to the left. Normal headsets, ventricular complexes and AV conductionIntraventricular conduction altered by anterior left hemiblock.Echo: Severe DCM, diagnosed 2016LV severely dilated in systole (83ml/m2) and diastole (112ml/m2), diffuse hypokinesia and severely depressed systolic function (LVEF = 26%)Mild alopecia, dry hairModerate follicular atrophoderma on cheeks, arms and thighs15925 (M)Chilec.[2T>G]Heart murmur (II/IV), extrasystoles85 (<308)13 (<25)638 (<125)ECG: Isolated ventricular extrasystolesNonspecific alteration of ventricular repolarizationEcho: LV severely dilated, moderate to severe systolic dysfunction (LVEF 30%), mild to moderate functional mitral insufficiency, Carpentier IIIMild alopeciaFine and dry hairMild follicular atrophoderma on thighs16933 (F)Chilec.[2T>G]Heart murmur (I/VI)104 (<308)10 (<25)258 (<125)ECG: NormalEcho: Mild systolic dysfunction of LV, LVEF = 40% normal left atrium and right chambersModerate alopeciaFine and dry hairModerate follicular atrophoderma on thighs and armsHip dysplasia and scoliosis17924 (F)Chilec.[2T>G]None/normal101 (<308)9 (<25)152 (<125)ECG: n/dEcho: Normal with normal/low systolic functionDry hair and moderate alopecia since 13 years of ageMild follicular atrophoderma on arms and thighs1892 (M)Chilec.[2T>G]None141 (<308)40 (<25)210 (<125)ECG: n/dEcho: NormalMild alopecia, dry hair199Death at age 39 (M)Chilec.[2T>G]Cardiac death———DCM from history only—209Death at age 54 (F)Chilec.[2T>G]Cardiac death———DCM from history only—Abbreviations: AV, atrioventricular; BP, blood pressure; CK, creatine kinase; CKMB, CK muscle band; DCM, dilated cardiomyopathy; ECG, electrocardiography; Echo, echocardiography; EF, ejection fraction; F, female; LV, left ventricle; LVEF, left ventricular ejection fraction; M, male; MRI, magnetic resonance imaging; n/d, not done; RV, right ventricle.1 Values in bold exceed reference values. Open table in a new tab Abbreviations: AV, atrioventricular; BP, blood pressure; CK, creatine kinase; CKMB, CK muscle band; DCM, dilated cardiomyopathy; ECG, electrocardiography; Echo, echocardiography; EF, ejection fraction; F, female; LV, left ventricle; LVEF, left ventricular ejection fraction; M, male; MRI, magnetic resonance imaging; n/d, not done; RV, right ventricle. Two examined patients had been diagnosed with DCM before our study (patients 9 and 14). The latter had a positive family history with cardiac death of a brother and mother, both of whom also had skin fragility (patients 19 and 20). Three unrelated patients had neurological involvement: patient 4 with delay of cognitive and motor development, patient 2 with speech delay, and patient 11 with seizures of unknown origin (Table 1). Because missense and pathologic in frame mutations of KLHL24 were recently linked to neurological disease (Anazi et al., 2017Anazi S. Maddirevula S. Salpietro V. Asi Y.T. Alsahli S. Alhashem A. et al.Expanding the genetic heterogeneity of intellectual disability.Hum Genet. 2017; 136: 1419-1429Crossref PubMed Scopus (87) Google Scholar) and because KLHL24 is involved in the regulation of the function of kainate receptors (Laezza et al., 2008Laezza F. Wilding T.J. Sequeira S. Craig A.M. Huettner J.E. The BTB/kelch protein, KRIP6, modulates the interaction of PICK1 with GluR6 kainate receptors.Neuropharmacology. 2008; 55: 1131-1139Crossref PubMed Scopus (18) Google Scholar), these results might also be of significance. This is supported by a recent case report (Yenamandra et al., 2018Yenamandra V.K. van den Akker P.C. Lemmink H.H. Jan S.Z. Diercks G.F.H. Vermeer M. et al.Cardiomyopathy in epidermolysis bullosa simplex patients with mutations in the KLHL24 gene [epub ahead of print].Br J Dermatol. 2018; 179: 1181-1183Crossref PubMed Scopus (19) Google Scholar). Laboratory examinations showed normal values for kidney, liver, pancreas, and thyroid parameters. In 12 of 16 tested patients, NT-pro-BNP, a specific and prognostic biomarker for heart disease (Zile et al., 2016Zile M.R. Claggett B.L. Prescott M.F. McMurray J.J.V. Packer M. Rouleau J.L. et al.Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure.J Am Coll Cardiol. 2016; 68: 2425-2436Crossref PubMed Scopus (213) Google Scholar). was increased. All adult patients with more than 2-fold elevated NT-pro-BNP levels (n = 5) had significant dysfunction on echocardiography and/or cardiac magnetic resonance imaging (Figure 1i–l). Creatine kinase muscle band was elevated in 7 of the 16 patients. Fifteen patients were evaluated by cardiology, of whom six were diagnosed with DCM (40%); the youngest was 25 years old (patient 15). None of the newly diagnosed patients (patients 1, 5, 15, and 16) had reported cardiac symptoms (Table 1). Taken together, in this cohort of 20 patients with EBS-KLHL24, 17 (85%) had evidence of cardiac involvement with either elevated cardiac biomarkers or documented DCM (8/20 patients [40%]), leading to death at an early age in two of them. DCM is defined as ventricular dilatation with impaired ventricular systolic function (left ventricular ejection fraction < 50%) in the absence of features of different phenotypes of cardiomyopathy or evidence of acquired heart disease (e.g., coronary artery disease). Early, even presymptomatic intervention improves outcome (Burke et al., 2016Burke M.A. Cook S.A. Seidman J.G. Seidman C.E. Clinical and mechanistic insights into the genetics of cardiomyopathy.J Am Coll Cardiol. 2016; 68: 2871-2886Crossref PubMed Scopus (176) Google Scholar). DCM occurs as a familial disease in 20%–35% of cases with more than 30 genes identified. Onset of familial DCM tends to be earlier in life than average. There is significant variability explained by modifying genetic and acquired risk factors (Burke et al., 2016Burke M.A. Cook S.A. Seidman J.G. Seidman C.E. Clinical and mechanistic insights into the genetics of cardiomyopathy.J Am Coll Cardiol. 2016; 68: 2871-2886Crossref PubMed Scopus (176) Google Scholar). DCM in EB may occur as a primary feature when due to PLEC, JUP, or DSP mutations (Fine et al., 2014Fine J.-D. Bruckner-Tuderman L. Eady R.A.J. Bauer E.A. Bauer J.W. Has C. et al.Inherited epidermolysis bullosa: updated recommendations on diagnosis and classification.J Am Acad Dermatol. 2014; 70: 1103-1126Abstract Full Text Full Text PDF PubMed Scopus (625) Google Scholar) or as a secondary complication in severe dystrophic and junctional EB (Lara-Corrales et al., 2010Lara-Corrales I. Mellerio J.E. Martinez A.E. Green A. Lucky A.W. Azizkhan R.G. et al.Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study.Pediatr Dermatol. 2010; 27: 238-243Crossref PubMed Scopus (28) Google Scholar). KLHL24 is expressed at similar levels in keratinocytes and cardiomyocytes (see Supplementary Figure S1 online). As in the skin, cardiac KLHL24 may regulate the degradation of structural cytoskeletal proteins involved in mechanical resilience. KLHL24 was also identified as interacting with components of the COP9 signalosome, a critical regulator of the cullin-RING family of ubiquitin ligases activity (Bennett et al., 2010Bennett E.J. Rush J. Gygi S.P. Harper J.W. Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.Cell. 2010; 143: 951-965Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, Sowa et al., 2009Sowa M.E. Bennett E.J. Gygi S.P. Harper J.W. Defining the human deubiquitinating enzyme interaction landscape.Cell. 2009; 138: 389-403Abstract Full Text Full Text PDF PubMed Scopus (1179) Google Scholar). The dysfunction of the COP9 signalosome has been associated with DCM in mice (Su et al., 2011Su H. Li J. Menon S. Liu J. Kumarapeli A.R. Wei N. et al.Perturbation of cullin deneddylation via conditional Csn8 ablation impairs the ubiquitin-proteasome system and causes cardiomyocyte necrosis and dilated cardiomyopathy in mice.Circ Res. 2011; 108: 40-50Crossref PubMed Scopus (81) Google Scholar, Su et al., 2013Su H. Li J. Osinska H. Li F. Robbins J. Liu J. et al.The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice.Circ Heart Fail. 2013; 6: 1049-1057Crossref PubMed Scopus (46) Google Scholar). Here, we provide evidence that patients with EBS-KLHL24 display potentially life-threatening DCM in early adulthood. Although dilated cardiomyopathy may be a final common pathway of a variety of acquired and inherited cardiac conditions, none of our patients with DCM showed a different cardiac phenotype (e.g., hypertrophic cardiomyopathy or restrictive cardiomyopathy) or heart disease (e.g., coronary artery disease, cardiac arrhythmias). Our data are supported by two other reports. Recently, severe cardiomyopathy was reported in a single case of EBS-KLHL24 (Yenamandra et al., 2018Yenamandra V.K. van den Akker P.C. Lemmink H.H. Jan S.Z. Diercks G.F.H. Vermeer M. et al.Cardiomyopathy in epidermolysis bullosa simplex patients with mutations in the KLHL24 gene [epub ahead of print].Br J Dermatol. 2018; 179: 1181-1183Crossref PubMed Scopus (19) Google Scholar), and homozygous KLHL24 loss-of-function mutations were found in two siblings with hypertrophic cardiomyopathy with glycogen accumulation in cardiomyocytes (Hedberg-Oldfors et al., 2016Hedberg-Oldfors C. Danielsson O. Hübbert L. Nennesmo I. Abramsson A. Banite R. et al.Hypertrophic cardiomyopathy and abnormal glycogen storage in heart and skeletal muscle associated with inactivation of KLHL24.Neuromuscula Disord. 2016; 26: S152Abstract Full Text Full Text PDF Google Scholar). DCM in EBS-KLHL24 may be missed because skin fragility and blistering improve with age, leading to infrequent follow-up evaluations. Moreover, because of reduced physical activity because of skin fragility and slow development of DCM, patients may not experience early cardiac symptoms. Thus, regular screening for cardiac involvement to identify presymptomatic DCM is required. Given its high sensitivity, serial measurements of NT-pro-BNP levels along with careful history taking may be the optimal screening tool (Zile et al., 2016Zile M.R. Claggett B.L. Prescott M.F. McMurray J.J.V. Packer M. Rouleau J.L. et al.Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure.J Am Coll Cardiol. 2016; 68: 2425-2436Crossref PubMed Scopus (213) Google Scholar). In the case of cardiomyopathy, timely implementation of preventive measures, such as heart failure medication or device therapy, may likely improve outcomes. This study was likely crucial for the survival of patient 1, who initially refused echocardiogram for lack of clinical symptoms. His ejection fraction turned out to be 27%. If EBS-KLHL24 is clinically suspected, genetic testing and cardiac monitoring are mandatory. The authors state no conflict of interest. We thank the patients and their families for participation in this study. Gabriele Grüninger is acknowledged for expert technical assistance. Most of this study was supported by Debra International (HAS 1 CH) and the Chilean whole-exome sequencing data analysis by the CONICYT FONDEQUIP EQM150093 and EQM140157. Download .pdf (.11 MB) Help with pdf files Supplementary Material and Supplementary Figure S1 KLHL24: Beyond Skin FragilityJournal of Investigative DermatologyVol. 139Issue 1PreviewKLHL24 mutations have recently been associated with epidermolysis bullosa simplex. Initial studies focused on skin fragility. However, the picture of KLHL24 mutations causing extracutaneous human disease is emerging, with dilated cardiomyopathy as a strong association. In addition, neurological disease is suspected as well. Careful clinical follow-up and functional studies of (mutated) KLHL24 in these tissues are needed. Full-Text PDF Open Archive

Journal of the European Academy of Dermatology and VenereologyVolume 32, Issue 12 p. e440-e442 Letter to the Editor A new nonsense mutation in the POGLUT1 gene in two sisters with Dowling–Degos disease S. Duchatelet, S. Duchatelet INSERM, UMR 1163, Imagine Institute, Université Paris Descartes - Sorbonne Paris Cité, Paris, FranceSabine Duchatelet, Héloïse Clerc and Thibault Kervarrec equally contributed to the article.Search for more papers by this authorH. Clerc, H. Clerc Department of Dermatology, CHRU de Tours, Tours, FranceSabine Duchatelet, Héloïse Clerc and Thibault Kervarrec equally contributed to the article.Search for more papers by this authorL. Machet, L. Machet Department of Dermatology, CHRU de Tours, Tours, France Inserm U1253, University of Tours, Tours, FranceSearch for more papers by this authorP. Gaboriaud, P. Gaboriaud UMR INRA ISP 1282, University of Tours, Tours, FranceSearch for more papers by this authorS. Miskinyte, S. Miskinyte INSERM, UMR 1163, Imagine Institute, Université Paris Descartes - Sorbonne Paris Cité, Paris, FranceSearch for more papers by this authorT. Kervarrec, Corresponding Author T. Kervarrec thibaultkervarrec@yahoo.fr UMR INRA ISP 1282, University of Tours, Tours, France Department of Pathology, CHRU de Tours, Tours, France Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, GermanySabine Duchatelet, Héloïse Clerc and Thibault Kervarrec equally contributed to the article.Correspondence: T. Kervarrec. Email: thibaultkervarrec@yahoo.frSearch for more papers by this authorA. Hovnanian, A. Hovnanian INSERM, UMR 1163, Imagine Institute, Université Paris Descartes - Sorbonne Paris Cité, Paris, France Department of Genetics, APHP Necker Hospital for Sick Children, Paris, FranceSearch for more papers by this author S. Duchatelet, S. Duchatelet INSERM, UMR 1163, Imagine Institute, Université Paris Descartes - Sorbonne Paris Cité, Paris, FranceSabine Duchatelet, Héloïse Clerc and Thibault Kervarrec equally contributed to the article.Search for more papers by this authorH. Clerc, H. Clerc Department of Dermatology, CHRU de Tours, Tours, FranceSabine Duchatelet, Héloïse Clerc and Thibault Kervarrec equally contributed to the article.Search for more papers by this authorL. Machet, L. Machet Department of Dermatology, CHRU de Tours, Tours, France Inserm U1253, University of Tours, Tours, FranceSearch for more papers by this authorP. Gaboriaud, P. Gaboriaud UMR INRA ISP 1282, University of Tours, Tours, FranceSearch for more papers by this authorS. Miskinyte, S. Miskinyte INSERM, UMR 1163, Imagine Institute, Université Paris Descartes - Sorbonne Paris Cité, Paris, FranceSearch for more papers by this authorT. Kervarrec, Corresponding Author T. Kervarrec thibaultkervarrec@yahoo.fr UMR INRA ISP 1282, University of Tours, Tours, France Department of Pathology, CHRU de Tours, Tours, France Department of Dermatology, Venereology and Allergology, University Hospital Würzburg, Würzburg, GermanySabine Duchatelet, Héloïse Clerc and Thibault Kervarrec equally contributed to the article.Correspondence: T. Kervarrec. Email: thibaultkervarrec@yahoo.frSearch for more papers by this authorA. Hovnanian, A. Hovnanian INSERM, UMR 1163, Imagine Institute, Université Paris Descartes - Sorbonne Paris Cité, Paris, France Department of Genetics, APHP Necker Hospital for Sick Children, Paris, FranceSearch for more papers by this author First published: 23 March 2018 https://doi.org/10.1111/jdv.14958Citations: 4 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume32, Issue12December 2018Pages e440-e442 RelatedInformation

Background. Hidradenitis suppurativa (HS) is a frequent and severe disease of the skin, characterized by recurrent or chronic skinfold suppurative lesions with a high impact on quality of life. Although considered inflammatory, antimicrobial treatments can improve or lead to clinical remission of HS, suggesting triggering microbial factors. Indeed, mixed anaerobic microbiota are associated with a majority of HS lesions. Our aim in this study was to characterize the landscape of anaerobic infections in HS using high-throughput sequencing.Methods. We sampled and cultured 149 lesions and 175 unaffected control skinfold areas from 65 adult HS patients. The microbiome of 80 anaerobic lesions was compared to that of 88 control samples by 454 high-throughput sequencing after construction of 16S ribosomal RNA gene libraries.Results. Bacterial cultures detected anaerobes in 83% of lesions vs 53% of control samples, combined with milleri group streptococci and actinomycetes in 33% and 26% of cases, respectively. High-throughput sequencing identified 43 taxa associated with HS lesions. Two gram-negative anaerobic rod taxa, Prevotella and Porphyromonas, predominated, contrasting with a reduced abundance of aerobic commensals. These rare taxa of normal skinfold microbiota were associated with lesions independently of gender, duration and familial history of HS, body mass index, and location. Two main additional taxa, Fusobacterium and Parvimonas, correlated with the clinical severity of HS.Conclusions. In this study we reveal the high prevalence and particular landscape of mixed anaerobic infection in HS, paving the way for rationale targeted antimicrobial treatments.

PASH syndrome is a clinical entity associating pyoderma gangrenosum (PG), severe acne and hidradenitis suppurativa (HS)1. Absence of pyogenic sterile arthritis (PA) distinguishes PASH syndrome from PAPASH and PAPA syndromes which associate PA in combination with PG, severe acne with or without HS, respectively2,3. Mutations in PSTPIP1 (proline-serine-threonine-phosphatase interacting protein 1) gene were identified in patients with PAPA and PAPASH syndromes, although genetic heterogeneity was observed in PAPA syndrome2,3. Loss-of-function mutations in the y-secretase genes, Nicastrin (NCSTN), Presenilin Enhancer-2 (PSENEN), and Presenilin-1 (PSEN1), have been reported in a small proportion of HS patients4,5. This article is protected by copyright. All rights reserved.

La maladie de Dowling-Degos (MDD) ou pigmentation réticulée des plis a été décrite en association à l’hidradénite suppurée (HS) chez 30 patients, dont 8 cas porteurs d’une mutation de PSENEN. Nous rapportons l’étude génétique réalisée chez 2 cas associant MDD + HS. Deux patients porteurs de MDD + HS ont fait l’objet d’une recherche de mutation dans les gènes de la gamma-secrétase (GS) par séquençage de nouvelle génération ciblé. Cas no 1 : Une patiente suisse de 34 ans consultait pour une HS de stade 1 de Hurley multiple des aisselles, seins et pli anal, ayant débuté à 24 ans, associée à une pigmentation des plis. L’histologie confirmait la MDD. L’interrogatoire trouvait une HS + MDD chez sa mère et sa grand-mère maternelle. L’HS était mise en rémission sous linézolide (lzl) en un mois, après échec de l’association pristinamycine (psn) + métronidazole (mtn). Sous cotrimoxazole (cmx), les rechutes survenant uniquement dans les cicatrices des aisselles ont justifié leur exérèse, qui a stabilisé l’HS, avec arrêt du cmx et traitement à la demande 1–2 fois/an avec psn ± mtn pendant 3 semaines. Cas no 2 : Un patient espagnol de 56 ans, porteur d’une déficience mentale néonatale et d’un diabète depuis 23 ans, présentait une pigmentation en mottes des plis associée à une HS depuis l’âge de 38 ans, de stade 2 de Hurley, en poussée continuelle des plis de l’aine et du pli anal malgré 4 exérèses larges. L’histologie confirmait la MDD. L’épilepsie contre-indiquait la rifampicine. Un traitement par mtn initié par son médecin depuis 6 semaines imposait l’arrêt pour éviter une neuropathie. Sous ertapénème instauré après pose de cathéter veineux central de type PICC®, en parallèle avec l’équilibration du diabète, à 6 semaines, l’évolutivité persistante justifiait l’addition de lzl pour 4 semaines, qui obtenait la rémission. Mais 2 rechutes dans les mêmes cicatrices justifiaient l’exérèse à froid de celles-ci, ce qui permettait une rémission prolongée sous cyclines. L’étude génétique mettait en évidence une mutation de PSENEN à l’état hétérozygote chez ces 2 patients : c.168T > G p.Tyr56* pour la patiente 1 (mutation également retrouvée chez sa mère) et c.304T > A p.*102Argext*50 pour le patient 2. La MDD isolée est classiquement associée à une mutation de KRT5, POFUT1 ou POGLUT1. Cependant, 3 publications récentes ont rapporté une mutation de PSENEN chez 10 patients non apparentés (4 chinois, 3 allemands, 1 indien, 1 thaïlandais et 1 français) porteurs de MDD avec (8 patients) ou sans HS (2 patients). L’identification d’une mutation de PSENEN chez nos patients confirme l’implication de ce gène dans l’association de MDD et HS. Ces 2 nouveaux cas confirment l’implication de PSENEN dans la genèse de l’association MDD + HS.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in COL7A1 encoding type VII collagen forming anchoring fibrils. DEB can be inherited in an autosomal dominant or recessive pattern. We report four unrelated patients (age range 19-49 years) presenting with generalized DEB who are compound heterozygotes for a dominant and a recessive COL7A1 mutation. In the first family, the mother and two of her children had a mild phenotype with nail dystrophy and minor skin blistering. They were heterozygous for the c.8109+4A>G splicing mutation. Four siblings presented with a more severe phenotype with finger contractures and esophageal stenosis. They had an additional recessive mutation (p.Ser2447Aspfs*17). In the second family, the mother had a multigenerational history of very mild blistering and nail dystrophy. Her daughter had a more severe phenotype with finger contractures and esophageal stenosis. Both had a p.Gly2009Val dominant mutation but the daughter had also inherited a p.Arg2791Trp recessive mutation from her unaffected father. The two other patients were sporadic cases from unaffected parents. The third patient had skin blistering predominant on his legs without finger contractures and no esophageal stenosis. He had inherited a p.Arg1538His COL7A1 recessive mutation from his unaffected mother, and carried a de novo dominant mutation p.Gly2079Arg. The fourth patient had intertriginous lesions, finger contractures and esophageal stricture resembling RDEB inversa. Mutation analysis revealed a dominant p.Gly2003Arg mutation and a recessive p.Arg578* mutation. Her parents have not yet been investigated. This report emphasizes the importance of searching for a second COL7A1 recessive mutation in case of a patient with unexpected severity in multigenerational dominant DEB families. It also points to the phenotypic variability resulting from the combination of a dominant and recessive COL7A1 mutation.

Des formes familiales de psoriasis monogénique et de pityriasis rubra pilaire (PRP) sont dues à des mutations de CARD14. Nous rapportons en rapportons une fratrie (3 cas) traitée avec succès par ustékinumab. Un homme (33 ans) et ses sœurs (23 et 30 ans) issus de 2 parents sains, cousins germains, d'origine tunisienne étaient suivis pour une dermatose érythémato-squameuse non congénitale, mais très précoce. Les 3 patients avaient une kératodermie palmoplantaire jaunâtre, un érythème du visage, des plaques érythémato-squameuses bien limitées et des intervalles de peau saine. La benjamine était plus atteinte avec des poussées érythrodermiques subintrantes alors que la cadette avait une atteinte plus localisée (4 membres) et le frère un phénotype intermédiaire. La clinique était évocatrice d'un PRP par son aspect figuré et l'aspect orangé des paumes et des plantes. L'histologie était psoriasiforme. L'étude génétique familiale montrait que les 3 patients étaient homozygotes pour la mutation c.349G > A (p.Gly117Ser) de CARD14. Après échec de plusieurs lignes de traitement (acitrétine et méthotrexate chez les 3, cyclosporine et anti-TNFα chez la plus jeune), l'ustékinumab était débuté pour les 3 (45, puis 90 mg M0-M1-M3, puis trimestriel permettant une amélioration spectaculaire : PASI 19,5 à 1,4 ; DLQI : 20 à 0 pour le frère aîné, PASI de 5 à 1 pour la cadette en 3 mois et blanchiment quasi complet pour la benjamine (Fig. 1 et 2). CARD14 est une protéine jouant un rôle dans le recrutement des caspases liées à l'inflammation. Des mutations de type gain-de-fonction de CARD14, de transmission autosomique dominante (AD), ont été identifiées dans des psoriasis monogéniques, pustuleux et des PRP. La mutation CARD14 identifiée dans cette famille a déjà été rapportée dans des formes de psoriasis en plaque, pustuleux et rhumatismaux de transmission AD, de pénétrance incomplète et d'expressivité clinique intra et interfamiliale variable (âge de début, sévérité, forme de psoriasis). In vitro CARD14 entraîne une augmentation de l'activation de la voie de signalisation NFκB et plusieurs anomalies d'épissage, qui en association avec d'autres facteurs génétiques, épigénétiques et/ou environnementaux participent à l'expression clinique de la maladie. Notre observation confirme qu'il est parfois difficile de distinguer un psoriasis d'un PRP. Les formes familiales mutées CARD14 font probablement partie du même spectre et relèvent des mêmes traitements du fait de leur physiopathologie commune. L'ustékinumab, Ac humanisé monoclonal dirigé contre la sous-unité p40 commune aux IL12/23 qui augmentent l'activité transcriptionnelle intracellulaire de NFKB comme CARD 14, a été utilisé avec succès dans des PRP mutés CARD14. L'ustékinumab peut représenter une option thérapeutique intéressante pour le traitement de formes familiales de psoriasis ou de PRP mutés CARD14.