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Annular lipoatrophy of the ankle is a rare and unique acquired lipoatrophic panniculitis that mainly affects children. There is no consensus on treatment, and the long-term course is not well known. We present four new pediatric cases that contribute to the understanding of this rare disease.

Background Topical calcineurin inhibitors are used off label in the treatment of vitiligo, and there is a lack of placebo-controlled, blinded studies to support their use. Objective This study aimed to compare the efficacy of tacrolimus 0.1% ointment with that of the vehicle for repigmentation in adult patients with facial vitiligo. Design This study was a 24-week multicenter randomized parallel double-blind study with a 24-week post-treatment follow-up extension. Population Participants included were adult patients with recent facial vitiligo target lesions ( Intervention Patients received either tacrolimus 0.1% ointment or vehicle twice daily. Main Outcomes and Measures The primary outcome was a therapeutic success, defined as a change ≥75% in the repigmentation of the target lesion between baseline and week 24, measured by ImageJ software. Secondary outcome measures were a variation of the physicians’ global assessment scores and patients’ satisfaction scores, safety data, and the rate of relapse at week 48. Results A total of 42 patients were included. Therapeutic success was achieved in 65% of tacrolimus-treated patients versus 0% of vehicle-treated patients at week 24 (P Conclusions and Relevance Twice-daily tacrolimus 0.1% ointment showed superior efficacy to that of the vehicle through the 24 weeks of intervention and 24 weeks of follow-up in adult patients with facial vitiligo. Trial Registration This study was registered at ClinicalTrials.gov (identifier: NCT02466997 ).

Human skin melanin pigmentation is regulated by systemic and local factors. According to the type of melanin produced by melanocytes, the transfer and degradation of melanosomes differ, thus accounting for most variations between ethnicities. We made the surprising observation that in a drastically changed environment, white and black phenotypes are reversible since Caucasian skin grafted onto nude mice can become black with all black phenotypic characteristics. Black xenografts differed essentially from other grafts by the levels of epidermal FGF-2 and keratin 5. In vitro analysis confirmed that FGF-2 directly regulates keratin 5. Interestingly, this phenomenon may be involved in human pathology. Keratin 5 mutations in Dowling-Degos Disease (DDD) have already been associated with the pheomelanosome-eumelanosome transition. In a DDD patient, keratin 5 was expressed in the basal and spinous layers, as observed in black xenografts. Furthermore, in a common age-related hyperpigmentation disorder like senile lentigo (SL), keratin 5 distribution is also altered. In conclusion, modulation of keratin 5 expression and distribution either due to mutations or factors may account for the development of pigmentary disorders.

Albinism is a worldwide genetic disorder caused by mutations in at least 20 genes, identified to date, that affect melanin production or transport in the skin, hair and eyes. Patients present with variable degrees of diffuse muco-cutaneous and adnexal hypopigmentation, as well as ocular features including nystagmus, misrouting of optic nerves and foveal hypoplasia. Less often, albinism is associated with blood, immunological, pulmonary, digestive and/or neurological anomalies. Clinical and molecular characterizations are essential in preventing potential complications. Disease-causing mutations remain unknown for about 25% of patients with albinism. These guidelines have been developed for the diagnosis and management of syndromic and non-syndromic forms of albinism, based on a systematic review of the scientific literature. These guidelines comprise clinical and molecular characterization, diagnosis, therapeutic approach and management.

This study assessed the effectiveness and safety of secukinumab in patients with moderate-severe psoriasis vulgaris in a real-world setting. A total of 120 patients (35.8% women; mean age 49.8 years) were enrolled. Mean PASI significantly decreased from 12.0 ± 6.6 at baseline to 4.7 ± 3.2 and 2.3 ± 4.0 at 3 and 12 months, respectively (P < .001). Patients with two or more lines of prior biological therapies had poorer persistence to therapy at 12 months (71%) vs those who were bio-naive (93%) or patients with only one prior failure with a biological agent (88%) (log-rank = 9.33; P = .009). Multivariate regression analysis showed that patients beyond the second line of treatment had an increased risk of discontinuing secukinumab (HR: 3.6; 95% CI 1.3-10.2), while those without comorbidities had a lower risk (HR: 0.31; 95% CI 0.1-0.8). Our study confirms the effectiveness and safety of secukinumab in a real-life setting for psoriatic disease.

Loss of melanocytes is the pathological hallmark of vitiligo, a chronic inflammatory skin depigmenting disorder induced by exaggerated immune response, including autoreactive CD8 T cells producing high levels of type 1 cytokines. However, the interplay between this inflammatory response and melanocyte disappearance remains to be fully characterized. Here, we demonstrate that vitiligo skin contains a significant proportion of suprabasal melanocytes, associated with disruption of E-cadherin expression, a major protein involved in melanocyte adhesion. This phenomenon is also observed in lesional psoriatic skin. Importantly, apoptotic melanocytes were mainly observed once cells were detached from the basal layer of the epidermis, suggesting that additional mechanism(s) could be involved in melanocyte loss. The type 1 cytokines IFN-γ and TNF-α induce melanocyte detachment through E-cadherin disruption and the release of its soluble form, partly due to MMP-9. The levels of MMP-9 are increased in the skin and sera of patients with vitiligo, and MMP-9 is produced by keratinocytes in response to IFN-γ and TNF-α. Inhibition of MMP-9 or the JAK/STAT signaling pathway prevents melanocyte detachment in vitro and in vivo. Therefore, stabilization of melanocytes in the basal layer of the epidermis by preventing E-cadherin disruption appears promising for the prevention of depigmentation occurring in vitiligo and during chronic skin inflammation.

Atopic dermatitis comorbidities extend well beyond the march to allergic conditions (food allergy, asthma, allergic rhinitis, allergic conjunctivitis, and eosinophilic esophagitis), suggesting both cutaneous and systemic immune activation. In reviewing atopic dermatitis comorbidities, Councilors of the International Eczema Council found a strong pattern of immune activation in peripheral blood and the propensity to both skin and systemic infections. Associations with cardiovascular, neuropsychiatric, and malignant diseases were increasingly reported, but confirmation of their link with atopic dermatitis requires longitudinal studies. Given the possibility of atopic dermatitis-related systemic immune activation, future investigations of new interventions should concurrently examine the impact on these comorbidities.

Based on the VGICC classification, vitiligo/NSV, a consensus umbrella term for all forms of generalized vitiligo, is meant to describe different clinical subtypes of vitiligo that are all clearly distinct from SV including acrofacial, generalized, mucosal (multifocal), and universal. According to the VETF definition, generalized vitiligo is characterized by asymptomatic well-circumscribed milky-white macules involving both sides of the body with usually a symmetrical pattern. In acrofacial vitiligo (AFV), the involved sites are by definition limited to the face, head, hands, and feet with typically depigmentation of the distal fingers and facial orifices. Vitiligo universalisis a rapidly progressive form of the disease, which needs a more in-depth investigation especially for associated autoimmunity.

> Some mechanisms of melanocyte loss have been pooe In Viro > Pathomechanisms should be envisioned within an enlarged dermal—epidermal melanin unit (including nerve endings) > Melanocyte Stemnes, innate immunity Somatic Mosaicism (for SV), Membrane Lipids are newamas in the puzzle of utiligo pathophy-siology

Introduction La dysplasie muco-epitheliale hereditaire (HMD ; MIM 158310) est une affection dermatologique rare de transmission autosomique dominante, caracterisee par des lesions mucoepitheliales chroniques impliquant la peau, les phaneres et les muqueuses. Le diagnostic est evoque cliniquement devant la triade clinique : alopecie, erytheme bien limite de la muqueuse buccale et eruption psoriasiforme perineale. Une anomalie des proteines des jonctions intercellulaires et un defaut d’adhesion epithelial ou muqueux a l’origine de l’affection avait ete suggere en raison des anomalies cliniques et histologiques obervees chez les patients. Materiel et methodes Un sequencage d’exome etait realise initialement en trio chez une patiente porteuse de dysplasie mucoepitheliale et ses parents sains, puis chez differents sujets atteints issus d’une meme famille et deux autres patients presentant une forme sporadique de l’affection. Ces patients avaient ete examines dans le service de Dermatologie pediatrique et le diagnostic etait confirme cliniquement. Resultats Des variations faux-sens a l’etat heterozygote de survenue de novo ou herite segregeant avec la pathologie dans le gene SREBF1 etaient mis en evidence chez les patients issus de ces 4 familles. Deux variants faux-sens differents etaient trouves, impliquant tous deux l’arginine 557 : p.Arg557Cys et p.Arg557His. Ces variants etaient absents de la base de donnees GnomAD, et predits deleteres par de multiples logiciels de prediction. Le residu Arg557 etait tres conserve au sein des especes. Discussion Le gene SREBF1 code un facteur de transcription (SREBP1) implique dans le controle de l’homeostasie des lipides en activant la transcription de genes regules par les sterols. SREBP1 est implique dans la regulation de l’inflammation en modulant la production d’acides gras insatures anti-inflammatoires par les macrophages. SREBP1 est clive et active par MBTPS2, responsable de l’association ichtyose folliculaire, atrichie et photophobie (syndrome IFAP), qui partage des similarites avec l’HMD sur le plan clinique. Il a ete montre que le residu Arginine557 mute chez nos patients etait essentiel pour le processus de clivage de SREBP1 et ainsi de son activation. L’accumulation d’une proteine non clivee peut egalement entrainer des modifications de la reponse inflammatoire. Ces resultats suggerent qu’un hot-spot mutationnel au residu Arg557 de SREBP1 est responsable de l’HMD, via une absence de clivage et d’activation de la proteine. Ce mecanisme physiopathologique permet de relier l’HMD et le syndrome IFAP avec lequel il partage des caracteristiques cliniques communes. Des etudes fonctionnelles complementaires sont necessaires afin de mieux comprendre le developpement des manifestations associees a l’HMD et ainsi d’ameliorer la prise en charge des patients.

Introduction Le syringocystadenocarcinome papillifere (SCACP) est une tumeur maligne rare des glandes sudorales, developpee aux depens d’un syringocystadenome papillifere (SCAP) ou d’un hamartome sebace. Observations Une femme de 74 ans presentait un volumineux SCACP temporal gauche, developpe progressivement a partir d’un hamartome sebace congenital. La biopsie confirmait le diagnostic de SCACP developpe sur un SCAP. La tumeur n’etant pas resecable, une polychimiotherapie suivie d’une radio-chimiotherapie (sels de platine et 5-fluoro-uracile) permettait d’obtenir une reponse complete clinique et scanographique a 9 mois. Cinq ans plus tard, la patiente consultait pour l’apparition d’une tumefaction bourgeonnante et indolore de la paupiere et de la conjonctive gauches, associees a un symblepharon. La biopsie conjonctivale confirmait le diagnostic de SCACP. Un bilan d’extension par scanner et IRM ne montrait pas de localisation a distance. La meme polychimiotherapie etait reprise, associee a un traitement local par collyre de mitomycine, permettant la regression de la tumefaction et le maintien des capacites fonctionnelles de l’œil. L’analyse moleculaire a identifie une mutation HRAS G13R ainsi qu’une mutation BRAF K601N avec des frequences alleliques similaires dans les tumeurs du scalp et de la conjonctive (75 % pour la mutation HRAS et 25–30 % pour la mutation BRAF) plus en faveur d’une recidive conjonctivale homolaterale du SCACP temporal gauche que d’une 2e localisation. Discussion Les localisations oculaires de SCACP sont rares avec seulement 2 cas rapportes dans la litterature. Le potentiel metastatique serait faible et associe dans ces rares cas a un pronostic sombre. Le traitement n’est pas standardise mais la chirurgie est souvent privilegiee. Le syndrome de Schimmelpenning–Feuerstein–Mims (SFM) est defini par l’association d’un hamartome sebace a des anomalies extra-cutanees et des mutations en mosaique. L’hamartome sebace et le syndrome SFM sont associes a des mutations post-zygotiques activatrices de HRAS, NRAS et KRAS. HRAS est implique dans plus de 90 % des hamartomes sebaces primaires et dans l’ensemble des tumeurs secondaires associees. Le SCAP est egalement associe a des mutations post-zygotiques de BRAF. Dans notre cas, la patiente presentait un hamartome sebace congenital identifie sur une biopsie a l’âge adulte, avec la presence de la mutation HRAS G13R (frequence allelique 21 %). La transformation maligne de l’hamartome a pu etre induite par l’acquisition d’une seconde mutation activatrice de BRAF, rendant cette tumeur plus agressive expliquant la recidive au niveau conjonctival. Il s’agit d’un cas original de SCACP associe a un syndrome de Schimmelpenning avec une recidive conjonctivale, dont le traitement par polychimiotherapie a permis une conservation fonctionnelle de l’œil.

Vitiligo is an autoimmune disease in which depigmented skin results from destruction of\ud skin melanocytes, with strong epidemiologic association with several other autoimmune\ud diseases. In previous linkage and genome-wide association studies (GWAS1, GWAS2),\ud we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We\ud carried out a third GWAS (GWAS3) of vitiligo in EUR subjects, with augmentation of\ud GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three\ud vitiligo GWAS, followed by an independent replication study. The combined analyses,\ud with 4,680 vitiligo cases and 39,586 controls, identified 23 novel replicated loci, as well as\ud 7 new suggestive loci, most encoding immune regulators, apoptotic regulators, and\ud melanocyte regulators, several of which are also associated with other autoimmune\ud diseases. Functional analyses indicate a predominance of causal regulatory variation, in\ud some cases corresponding to eQTL at these loci. Together, the identified genes provide\ud a framework for vitiligo genetic architecture and pathobiology, highlight genetic\ud relationships to other autoimmune diseases and melanoma, and offer potential targets\ud for vitiligo treatment.

Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease combining inflammatory, vasculopathic and fibrotic manifestations. Skin features, which give their name to the disease and are considered as diagnostic as well as prognostic markers, have not been thoroughly investigated in terms of therapeutic targets. CCN proteins (CYR61/CCN1, CTGF/CCN2, NOV/CCN3 and WISP1-2-3 as CCN4-5-6) are a family of secreted matricellular proteins implicated in major cellular processes such as cell growth, migration, differentiation. They have already been implicated in key pathophysiological processes of SSc, namely fibrosis, vasculopathy and inflammation. In this review, we discuss the possible implication of CCN proteins in SSc pathogenesis, with a special focus on skin features, and identify the potential actionable CCN targets.

Folliculitis decalvans (FD) is a chronic inflammatory disease leading to scarring alopecia with poorly defined pathogenesis. The aim of this study was to investigate the expression of markers associated with the activation of innate immune signals, such as inflammasome (NALP1 and NALP3), interleukin (IL)-1β and IL-8 and type I interferon (MxA). A retrospective monocentric study was conducted and included 17 patients with FD with available biopsies. Disease activity (stable vs. active) was defined clinically and histologically. Immunostaining was performed using antibodies directed against NALP1, NALP3, IL-1β, IL-8, and MxA on FD skin biopsies. Results were compared with normal controls and lichen planopilaris. Eleven patients had active disease and 6 had stable disease. NALP1, NALP3, and IL-1β expression were significantly increased in hair follicles in FD compared with controls and lichen planopilaris. This study highlights the predominant immune signal associated with inflammasome activation in FD, suggesting the use of IL-1β blockade in FD.

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Introduction Le dupilumab est un anticorps monoclonal ciblant la sous-unite alpha du recepteur de l’interleukine IL-4 commune a deux cytokines IL-4 et IL-13 dont l’efficacite est desormais clairement demontree pour le traitement de la dermatite atopique (DA) moderee a severe. La DA est classiquement associee a d’autres pathologies auto-immunes comme la pelade, une maladie encore orpheline de therapeutique efficace. Ainsi nous rapportons de facon surprenante l’efficacite du dupilumab sur les deux conditions, notamment une repousse complete du cuir chevelu. Observation Un homme de 28 ans nous etait adresse pour la prise en charge d’une DA severe ayant debutee dans l’enfance, associee a un asthme. Depuis un an et demi, il presentait egalement une pelade universelle. Pour sa DA, le patient avait recu successivement de la ciclosporine et du methotrexate, avec un controle seulement partiel. Ces deux traitements n’avaient eu aucun effet sur l’evolution de sa pelade. Ainsi etait debute en relais le dupilumab (1 injection sous-cutanee initiale de 600 mg, puis 300 mg tous les 15 jours). A 6 mois, les scores d’activite de la DA etaient significativement ameliores (Δ total SCORAD : −22 ; Δ score EASI : −8,4). Par ailleurs, il etait constate une repousse spectaculaire des cheveux, des cils et des sourcils, debutant des 3 mois, quasi-complete a 6 mois (Δ score SALT : −80,4). La tolerance du dupilumab etait excellente, sans conjonctivite ( Fig. 1 ). Discussion Alors que son efficacite dans la DA moderee a severe est desormais bien demontree, l’action spectaculaire du dupilumab sur la pelade confirme les avancees recentes dans la comprehension de cette pathologie. Jusque-la, les etudes sur sa physiopathologie etaient majoritairement conduites sur des modeles murins et s’attachaient a decrire le role de la reponse immune Th1 et de l’IFNg, amenant a l’utilisation recente des inhibiteurs de JAK. Il a ete ainsi montre chez l’homme des polymorphismes des genes codant pour l’IL-4 et l’IL-13 associes a un risque accru de pelade. Chez des patients atteints de pelade, des etudes transcriptomiques sur tissu cutane ont revele une augmentation de l’expression des genes associes a la reponse Th2, ainsi qu’une augmentation des taux d’IL-13 dans le serum. Enfin, des donnees recentes suggerent que le blocage des cytokines impliquees dans la voie Th2 pourrait induire un passage des follicules pileux en phase anagene. L’ensemble de ces resultats suggere que le blocage de cette voie pourrait etre une therapeutique efficace, au moins dans le sous-groupe de patients touches par ces deux comorbidites : DA et pelade. Conclusion Nous rapportons ainsi le premier cas d’efficacite du dupilumab dans la pelade chez un patient atteint egalement de DA. Cette efficacite semble etre supportee par des donnees montrant l’implication de la voie Th2 au cours de la pelade et justifie des essais cliniques pilotes afin de preciser son efficacite reelle.

Introduction La maladie de Darier (MD) est une maladie familiale autosomique dominante liee a une mutation du gene ATP2A2, se manifestant par une dermatose acantholytique secondaire a une anomalie de canaux calciques aboutissant a une perte de la cohesion interkeratinocytaire et a des anomalies de la differenciation des keratinocytes. Dans les formes severes, peu d’alternatives therapeutiques sont proposees en cas d’echec des retinoides oraux. Observations Nous rapportons le cas d’un homme de 54 ans, suivi pour une MD evoluant depuis l’enfance, sans antecedents familiaux, associee a une ichtyose vulgaire et une dermatite atopique (DA). Pendant plusieurs annees, il a recu des traitements locaux par dermocorticoides, 5-fluoro-uracile, bien conduits. En raison de poussees invalidantes, parfois erythrodermiques, il a ete mis sous acitretine a la dose de 0,3 mg/kg/jour, arretee precocement apres 2 mois de traitement pour mauvaise efficacite. En relais, il a ete decide d’initier un traitement par immunoglobulines intraveineuses (IgIV) a dose immunosubstitutive de 0,4 g/kg toutes les 3 semaines. Apres 4 perfusions soit 3 mois de traitement, le patient etait significativement ameliore : les lesions de MD avaient cicatrise et l’ichtyose avait nettement diminue ( Fig. 1 ). Discussion Les IgIV ont des indications variees, notamment en dermatologie, pour leur action sur le systeme immunitaire a plusieurs niveaux : modulation des cytokines, des cellules dendritiques et des recepteurs Fc, interaction avec le complement et controle de l’activation lymphocytaire B et T. Cependant, son role direct sur la restauration de la barriere epidermique est meconnu mais a ete suggere par son efficacite dans quelques cas rapportes de syndrome de Netherton, maladie hereditaire responsable d’une erythrodermie ichtyosiforme liee a une mutation entrainant une anomalie de l’inhibiteur de la protease a serine LEKT1, responsable d’une alteration majeure de la couche cornee. Ces observations nous ont ainsi conduits a tester cette therapeutique dans une autre maladie atteignant la barriere epidermique comme la MD avec une efficacite surprenante. A notre connaissance, il s’agit du premier cas de MD traite efficacement par IgIV, suggerant un role potentiel direct de ce traitement sur la restauration de la barriere cutanee, confirme chez notre patient par l’amelioration concomitante de l’ichtyose vulgaire et de la DA. Conclusion Outre leur role bien connu sur la modulation de la reponse inflammatoire, ces resultats suggerent ainsi l’effet benefique des IgIV sur le controle de la barriere epidermique, justifiant son essai dans des dermatoses chroniques epidermiques comme la maladie de Darier, dermatose rare, orpheline de therapeutique efficace.

Introduction L’acanthosis nigricans naevoide ou « Round And Velvety Epidermal Naevus » (RAVEN) est une forme rare d’Acanthosis nigricans qui peut se manifester a tout âge ou avant la puberte. Cette entite n’est pas associee a d’autres causes comme des endocrinopathies, des causes medicamenteuses, un syndrome genetique ou a des tumeurs. Observations Une femme de 43 ans presentait une lesion pigmentee localisee depuis 2 ans. Aucun membre de sa famille n’avait les memes lesions. Elle n’avait pas de surpoids, ni de diabete ou autre probleme endocrinologique. La lesion avait debute par une lesion papuleuse pigmentee dans la region pre-sternale avec une extension sous mammaire lineaire. La surface etait legerement en relief avec un aspect papillomateux. Un homme de 22 ans, sans antecedent, presentait peu apres la puberte une lesion pigmentee de distribution lineaire au niveau thoracique avec une surface en relief, papillomateuse. Les deux patients n’avaient pas d’autre atteinte cutanee ou muqueuse. Le reste de l’examen clinique etait normal. L’histologie montrait dans les deux cas une hyperplasie epidermique papillomateuse, hyperkeratosique avec une pigmentation de l’assise basale. Une mutation de FGFR2 etait identifiee au niveau du naevus chez la premiere patiente et une mutation non decrite de FGFR3 chez le second patient. La recherche de la mutation au niveau sanguin etait negative chez les deux patients. Une seance de laser CO2 continu (9 Watts) etait realisee chez les deux patients, avec un aspect cicatriciel d’evolution satisfaisante ( Fig. 1 et 2 ). Discussion FGFR3 et FGFR2 sont des recepteurs tyrosine kinase. Les mutations constitutionnelles du gene FGFR3 sont responsables d’osteodysplasie, de syndrome de Crouzon ou de syndrome associant craniostenose et acanthosis nigricans. Des cas familiaux d’acanthosis nigricans sans anomalies osseuses sont rapportes. Les mutations constitutionnelles de FGFR2 sont associees au syndrome d’Apert. Des mutations activatrices somatiques de FGFR3 sont identifiees dans les keratoses seborrheiques et dans les naevi epidermiques. Des mutations post-zygotiques de FGFR2 sont responsables d’hamartome comedonien et plus recemment d’un hamartome sebace pedicule chez un fœtus. Des mutations de genes de FGFR peuvent ainsi etre associees a des manifestations cliniques variables selon l’effet de la mutation, le moment ou elle survient et dans quel type cellulaire. De nombreux traitements sont proposes, retinoides, calcipotriol, cryotherapie, dermabrasion, exerese chirurgicale (si lesion de petite taille) et laser alexandrite, avec des resultats variables. Le laser CO2 a ete realise dans 2 cas avec de bons resultats. Conclusion A notre connaissance ; ce sont les premiers cas de RAVEN associes a des mutations post-zygotiques FGFR3 et FGFR2. Cela confirme comme suspecte que l’acanthosis nigricans naevoide est lie a des mutations tyrosine kinase en mosaique. Le laser CO2 semble etre une bonne alternative therapeutique.

Introduction Les dysplasies ectodermiques constituent un groupe d’affections hereditaires secondaires a une anomalie du developpement des annexes pendant la morphogenese. Les dysplasies ectodermiques touchant uniquement les ongles et les cheveux sont rares. Observations Deux sœurs, nees en 1980 et 1987, etaient adressees dans l’enfance pour un tableau de dysplasie pilaire. L’histoire familiale n’etait pas informative. Les parents etaient non apparentes. Le frere aine ne presentait aucun symptome. A la naissance, elles presentaient une alopecie irreguliere puis totale, avec repousse complete. Elles evoluaient avec une dysplasie pilaire comportant des cheveux dystrophiques, courts, cassants et un cuir chevelu spinulosique. Des episodes d’alopecie etaient decrits lors des episodes febriles, ainsi que sur les zones de frottements. A l’adolescence, la qualite des cheveux s’ameliorait pour l’ainee, alors que la cadette gardait une hypotrichose marquee. Une hypoplasie ungueale se developpait par ailleurs. L’histologie du cuir chevelu etait peu contributive et le trichogramme non interpretable car tous les cheveux preleves etaient casses. Resultats L’analyse d’un panel de genes impliques dans les hypotrichoses etait realisee mettant en evidence 2 mutations heterozygotes composites du gene KRT85, codant pour une keratine de type II. Les parents des deux sœurs etaient chacun porteurs de l’un des alleles mutes. La sœur ainee presentait les memes mutations mais avec un phenotype moins severe, en faveur d’une expressivite variable ( Fig. 1 et 2 ). Discussion Les mutations du gene KRT85 sont associees a une forme rare de dysplasie ectodermique touchant uniquement les ongles et les cheveux. Les patients decrits dans la litterature sont issus de 3 familles consanguines pakistanaises et presentent des mutations homozygotes de KRT85. Deux autres genes sont impliques dans des tableaux cliniques superposables, HOXC 13 (4 cas), gene regulant l’activite de transcription des keratines situe sur le chromosome 12 et KRT74 (1 famille cas), qui code donc pour une exokeratine de type II. La keratine KRT85 est specifique de la fibre capillaire, exprimee dans les cellules matricielles du follicule pilaire et dans la cuticule. Les mutations des genes de keratines ont generalement un effet dominant negatif et les keratines mutees interferent avec l’assemblage des filaments intermediaires. Les mutations de KRT85 a l’etat heterozygote ne sont pas associees a des manifestations cliniques. L’absence totale de KRT85 fonctionnelle perturberait l’assemblage des filaments intermediaires a l’origine de la dysplasie pilaire. Conclusion Nous rapportons le premier cas d’heterozygotie composite de KRT85 chez deux sœurs presentant une forme recessive de dysplasie ectodermique avec une atteinte uniquement phanerienne. Ces donnees soulignent le role majeur de KRT85 dans la keratinisation des ongles et des cheveux.

Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16 INK4a expression, β-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc -/- mice than in young Xpc +/+ ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc -/- was as low as in control aged Xpc +/+ animals. Furthermore, the metabolic profile in young Xpc -/- mice resembled that found in aged Xpc +/+ mice. Furthermore, premature skin aging features in young Xpc -/- mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology.

The risk of relapse after successful repigmentation in vitiligo is estimated to 40% within the first year. It has been shown in atopic dermatitis that continuous low-level use of topical corticosteroids and calcineurin inhibitors in previously affected skin can prevent new flares. We hypothesized that a twice-weekly application of 0.1% tacrolimus ointment might be effective for maintaining repigmentation in therapeutically repigmented lesions of vitiligo patients. After randomization, sixteen patients with 31 patches were assigned to the placebo group and 19 patients with 41 patches were assigned to the tacrolimus group. In the intention-to-treat analysis, 48.4% of lesions showed depigmentation in the placebo group, whereas 26.8% did in the tacrolimus group (P=0.059). The intention-to-treat results did not remain significant after adjustment for within-patient clustering, odds ratio (OR) 2.55; 95% confidence interval (CI; 0.65–9.97); P=0.1765. The per-protocol analysis (n=56) showed that 40% of lesions had some depigmentation in the placebo group, whereas only 9.7% did in the tacrolimus group (P=0.0075). The per-protocol results remained significant after adjustment for within-patient clustering: OR 6.22; 95% CI (1.48–26.12); P=0.0299. Our study shows that twice-weekly application of 0.1% tacrolimus ointment is effective in preventing the depigmentation of vitiligo patches that have been previously successfully repigmented.

Nucleotide excision repair (NER) is an important DNA repair pathway involved in the removal of a wide array of DNA lesions. The absence or dysfunction of NER results in the following distinct disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, UV-sensitive syndrome (UVSS), trichothiodystrophy (TTD), or combined syndromes including XP/CS, XP/TTD, CS/TTD, and COFS/TTD. In addition to their well-characterized role in the NER signaling pathway, NER factors also seem to be important in biological processes that are not directly associated with DNA damage responses, including mitochondrial function and redox homeostasis. The potential causative role of these factors in the large clinical spectrum seen in NER diseases is discussed in this review.

Although emollients are recommended in the management of atopic dermatitis (AD), regimens for emollient maintenance therapy are awaiting validation. We conducted an international, multicenter, open-label trial to assess the effects of a 3-month maintenance treatment regimen with a sterile, preservative-free emollient cream containing oat plantlets in children (ages 6 mos-6 yrs) with moderate AD. After a 14-day run-in stabilization phase using a topical corticosteroid (TCS) treatment of medium potency, 108 children with a SCORing Atopic Dermatitis (SCORAD) index of 20 or less were included in the study. Emollient was applied twice daily for 3 months. Rescue TCS treatment was used only in cases of flare-ups. The SCORAD index, Patient-Oriented SCORAD (PO-SCORAD) index, number of flares, TCS use, and tolerance were assessed at months 1, 2, and 3 (M1, M2, M3). AD severity improved, with a highly significant decrease in the SCORAD and PO-SCORAD indexes at M2 and M3 (p < 0.001). Changes from baseline to M3 were 48.6 ± 73.6% for SCORAD and 29.6 ± 125.3% for PO-SCORAD. The number of flares and TCS use significantly decreased by M3 (both p < 0.001). Very good tolerance was recorded in 100% of children at M2 and M3. Notwithstanding the limitations inherent in open-label trials, twice daily application of the oat-based sterile emollient cream led to a significant improvement of clinical symptoms, evidenced by parallel changes in the SCORAD and PO-SCORAD indexes and fewer flare-ups. Clinical benefit and less TCS use were maintained at M3. Tolerance was very good.

Background Interleukin (IL)-13 plays a key role in type 2 inflammation and is an emerging pathogenic mediator in atopic dermatitis (AD). Objective We investigated the efficacy and safety of lebrikizumab, an IL-13 monoclonal antibody, as an add-on to topical corticosteroid (TCS) treatment. Methods A randomized, placebo-controlled, double-blind, phase 2 study. Adults with moderate-to-severe AD were required to use TCS twice daily and then randomized (1:1:1:1) to lebrikizumab 125 mg single dose, lebrikizumab 250 mg single dose, lebrikizumab 125 mg every 4 weeks for 12 weeks, or placebo every 4 weeks for 12 weeks, after a 2-week TCS run-in. The primary endpoint was percentage of patients achieving Eczema Area and Severity Index (EASI)-50 at week 12. Results In total, 209 patients received the study drug. At week 12, significantly more patients achieved EASI-50 with lebrikizumab 125 mg every 4 weeks (82.4%; P = .026) than placebo every 4 weeks (62.3%); patients receiving a single dose of lebrikizumab showed no statistically significant improvements in EASI-50 compared with placebo. Adverse events were similar between groups (66.7% all lebrikizumab vs 66.0% placebo) and mostly mild or moderate. Limitations Protocol-mandated twice daily TCS treatment limits our understanding of the efficacy of lebrikizumab as a monotherapy. The short study duration did not enable long-term efficacy or safety evaluations. Conclusion When combined with TCS, lebrikizumab 125 mg taken every 4 weeks led to a significant improvement and was well tolerated in patients with moderate-to-severe AD.

Skin protects the body from dehydration, pathogens, and external mutagens. NADPH oxidases are central components for regulating the cellular redox balance. There is increasing evidence indicating that reactive oxygen species (ROS) generated by members of this enzyme family play important roles in the physiology and pathophysiology of the skin. Recent Advances: NADPH oxidases are active producers of ROS such as superoxide and hydrogen peroxide. Different isoforms are found in virtually all tissues. They play pivotal roles in normal cell homeostasis and in the cellular responses to various stressors. In particular, these enzymes are integral parts of redox-sensitive prosurvival and proapoptotic signaling pathways, in which they act both as effectors and as modulators. However, continuous (re)activation of NADPH oxidases can disturb the redox balance of cells, in the worst-case scenario in a permanent manner. Abnormal NADPH oxidase activity has been associated with a wide spectrum of diseases, as well as with aging and carcinogenesis.Sunlight with its beneficial and deleterious effects induces the activation of NADPH oxidases in the skin. Evidence for the important roles of this enzyme family in skin cancer and skin aging, as well as in many chronic skin diseases, is now emerging.Understanding the precise roles of NADPH oxidases in normal skin homeostasis, in the cellular responses to solar radiation, and during carcinogenesis will pave the way for their validation as therapeutic targets not only for the prevention and treatment of skin cancers but also for many other skin-related disorders. Antioxid. Redox Signal. 28, 1238-1261.

International audience; Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway(1). Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupre-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern(2). We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs)(3-5) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.

International audience

Psoriasiform eruptions are a classical adverse skin reaction of tumour necrosis factor (TNF)-α inhibitors. The aim of this study was to identify the association between the severity or pattern of psoriasiform reactions and the underlying disease. A retrospective study was conducted between January 2012 and May 2015. Adult patients who developed psoriasiform eruptions whilst being treated with TNFα inhibitors were included. For each patient, 3 independent blinded dermatologists graded twice the severity of the lesions according to 6 clinical psoriasiform eruption types. Inter- and intra-individual kappa tests were performed to evaluate the robustness of the scoring system. The association between severity score levels or the pattern of reactions and the underlying disease was assessed. The severity scoring system showed good inter- and intra-observer reproducibility. Women patients treated with TNFα inhibitors for inflammatory bowel diseases showed a higher risk of developing severe reactions with scalp and skin-fold involvement.