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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.

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OBJECTIVES Hidradenitis suppurativa (HS) is an inflammatory skin disease typically localized in the axillae and inguinal and perineal areas. In the absence of standardized medical treatment, severe HS patients present chronic suppurative lesions with polymicrobial anaerobic abscesses. Wide surgery is the cornerstone treatment of severe HS, but surgical indications are limited by the extent of lesions. Intravenous broad-spectrum antibiotics may help control HS, but their efficacy is not documented. This study was designed to assess the efficacy of a 6 week course of ertapenem (1 g daily) and of antibiotic consolidation treatments for 6 months (M6) in severe HS. PATIENTS AND METHODS Thirty consecutive patients with severe HS were retrospectively included in this study. The clinical severity of HS was assessed using the Sartorius score, which takes into account the number and severity of lesions. RESULTS The median (IQR) Sartorius score dropped from 49.5 (28-62) at baseline to 19.0 (12-28) after ertapenem (P < 10(-4)). Five patients were lost to follow-up thereafter. At M6 the Sartorius score further decreased for the 16 patients who received continuous consolidation treatments, since 59% of HS areas reached clinical remission at M6 (i.e. absence of any inflammatory symptoms, P < 10(-4)). Nine patients interrupted or received intermittent consolidation treatments due to poor observance or irregular follow-up. Their Sartorius score stopped improving or returned to baseline. No major adverse event occurred. CONCLUSIONS Ertapenem can dramatically improve severe HS. Consolidation treatments are needed to further improve HS and are mandatory to prevent relapses. Combined with surgery, optimized antibiotic treatments may be promising in severe HS.

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., 2016, Lin et al., 2016). 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).

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Erythrokeratodermia variabilis et progressiva (EKVP) is a genodermatosis with clinical and genetic heterogeneity, most often transmitted in an autosomal dominant manner, caused by mutations in GJB3 and GJB4 genes encoding connexins (Cx)31 and 30.3, respectively. In this issue, Boyden et al. (2015) report for the first time de novo dominant mutations in GJA1 encoding the ubiquitous Cx43 in patients with EKVP. These results expand the genetic heterogeneity of EKVP and the human disease phenotypes associated with GJA1 mutations. They disclose that EKVP is allelic to oculo-dento-digital dysplasia, a rare syndrome previously known to be caused by dominant GJA1 mutations.

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.

Introduction La maladie de Dowling-Degos (MDD) ou pigmentation reticulee des plis a ete decrite en association a l’hidradenite suppuree (HS) chez 30 patients, dont 8 cas porteurs d’une mutation de PSENEN. Nous rapportons l’etude genetique realisee chez 2 cas associant MDD + HS. Materiel et methodes Deux patients porteurs de MDD + HS ont fait l’objet d’une recherche de mutation dans les genes de la gamma-secretase (GS) par sequencage de nouvelle generation cible. Observations 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 debute a 24 ans, associee a une pigmentation des plis. L’histologie confirmait la MDD. L’interrogatoire trouvait une HS + MDD chez sa mere et sa grand-mere maternelle. L’HS etait mise en remission sous linezolide (lzl) en un mois, apres echec de l’association pristinamycine (psn) + metronidazole (mtn). Sous cotrimoxazole (cmx), les rechutes survenant uniquement dans les cicatrices des aisselles ont justifie leur exerese, qui a stabilise l’HS, avec arret du cmx et traitement a la demande 1–2 fois/an avec psn ± mtn pendant 3 semaines. Cas no 2 : Un patient espagnol de 56 ans, porteur d’une deficience mentale neonatale et d’un diabete depuis 23 ans, presentait une pigmentation en mottes des plis associee a une HS depuis l’âge de 38 ans, de stade 2 de Hurley, en poussee continuelle des plis de l’aine et du pli anal malgre 4 exereses larges. L’histologie confirmait la MDD. L’epilepsie contre-indiquait la rifampicine. Un traitement par mtn initie par son medecin depuis 6 semaines imposait l’arret pour eviter une neuropathie. Sous ertapeneme instaure apres pose de catheter veineux central de type PICC®, en parallele avec l’equilibration du diabete, a 6 semaines, l’evolutivite persistante justifiait l’addition de lzl pour 4 semaines, qui obtenait la remission. Mais 2 rechutes dans les memes cicatrices justifiaient l’exerese a froid de celles-ci, ce qui permettait une remission prolongee sous cyclines. L’etude genetique mettait en evidence une mutation de PSENEN a l’etat heterozygote chez ces 2 patients : c.168T > G p.Tyr56* pour la patiente 1 (mutation egalement retrouvee chez sa mere) et c.304T > A p.*102Argext*50 pour le patient 2. Discussion La MDD isolee est classiquement associee a une mutation de KRT5, POFUT1 ou POGLUT1. Cependant, 3 publications recentes ont rapporte une mutation de PSENEN chez 10 patients non apparentes (4 chinois, 3 allemands, 1 indien, 1 thailandais et 1 francais) 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 gene dans l’association de MDD et HS. Conclusion Ces 2 nouveaux cas confirment l’implication de PSENEN dans la genese de l’association MDD + HS.

Introduction Des formes familiales de psoriasis monogenique et de pityriasis rubra pilaire (PRP) sont dues a des mutations de CARD14. Nous rapportons en rapportons une fratrie (3 cas) traitee avec succes par ustekinumab. Observations Un homme (33 ans) et ses sœurs (23 et 30 ans) issus de 2 parents sains, cousins germains, d’origine tunisienne etaient suivis pour une dermatose erythemato-squameuse non congenitale, mais tres precoce. Les 3 patients avaient une keratodermie palmoplantaire jaunâtre, un erytheme du visage, des plaques erythemato-squameuses bien limitees et des intervalles de peau saine. La benjamine etait plus atteinte avec des poussees erythrodermiques subintrantes alors que la cadette avait une atteinte plus localisee (4 membres) et le frere un phenotype intermediaire. La clinique etait evocatrice d’un PRP par son aspect figure et l’aspect orange des paumes et des plantes. L’histologie etait psoriasiforme. L’etude genetique familiale montrait que les 3 patients etaient homozygotes pour la mutation c.349G > A (p.Gly117Ser) de CARD14. Apres echec de plusieurs lignes de traitement (acitretine et methotrexate chez les 3, cyclosporine et anti-TNFα chez la plus jeune), l’ustekinumab etait debute pour les 3 (45, puis 90 mg M0-M1-M3, puis trimestriel permettant une amelioration spectaculaire : PASI 19,5 a 1,4 ; DLQI : 20 a 0 pour le frere aine, PASI de 5 a 1 pour la cadette en 3 mois et blanchiment quasi complet pour la benjamine ( Fig. 1 et 2 ). Discussion CARD14 est une proteine jouant un role dans le recrutement des caspases liees a l’inflammation. Des mutations de type gain-de-fonction de CARD14, de transmission autosomique dominante (AD), ont ete identifiees dans des psoriasis monogeniques, pustuleux et des PRP. La mutation CARD14 identifiee dans cette famille a deja ete rapportee dans des formes de psoriasis en plaque, pustuleux et rhumatismaux de transmission AD, de penetrance incomplete et d’expressivite clinique intra et interfamiliale variable (âge de debut, severite, forme de psoriasis). In vitro CARD14 entraine une augmentation de l’activation de la voie de signalisation NFκB et plusieurs anomalies d’epissage, qui en association avec d’autres facteurs genetiques, epigenetiques et/ou environnementaux participent a l’expression clinique de la maladie. Notre observation confirme qu’il est parfois difficile de distinguer un psoriasis d’un PRP. Les formes familiales mutees CARD14 font probablement partie du meme spectre et relevent des memes traitements du fait de leur physiopathologie commune. L’ustekinumab, Ac humanise monoclonal dirige contre la sous-unite p40 commune aux IL12/23 qui augmentent l’activite transcriptionnelle intracellulaire de NFKB comme CARD 14, a ete utilise avec succes dans des PRP mutes CARD14. Conclusion L’ustekinumab peut representer une option therapeutique interessante pour le traitement de formes familiales de psoriasis ou de PRP mutes CARD14.

Early onset retinal degeneration associated with obesity can present a diagnostic challenge in paediatric ophthalmology practice. Clinical overlap between Bardet-Biedl syndrome (BBS) and Alström syndrome has been described, although the two entities are genetically distinct. To date, 16 genes are known to be associated with BBS (BBS1-16) and only one gene has been identified for Alström syndrome (ALMS1).In collaboration with the French National Center for Sequencing (CNS, Evry), all coding exons and flanking introns were sequenced for 27 ciliopathy genes (BBS1-12, MGC1203, TTC21b, AHI1, NPHP2-8 (NPHP6=BBS14), MKS1(BBS13), MKS3, C2ORF86, SDCCAG8, ALMS1) in 96 patients referred with a clinical diagnosis of BBS. ALMS1 gene analysis included sequencing of all coding exons.BBS known gene mutations were found in 44 patients (36 with two mutations and 8 heterozygous). ALMS1 mutations were found in four cases. The rate of ALMS1 mutations among patients suspected of having BBS was 4.2%.Clinically, all four patients presented early-onset severe retinal degeneration with congenital nystagmus associated with obesity. The difficult early differential diagnosis between the two syndromes is outlined. One mutation had already been reported (c.11310delAGAG/p.R3770fsX) and three were novel (c.2293CT/p.Q765X, c.6823insA/p.R2275fsX, c.9046delA/p.N3016fsX).Ciliopathy genes sequencing can be very helpful in providing a timely diagnosis in this group of patients, hence appropriate genetic counselling for families and adequate medical follow-up for affected children.

Keywords: anaerobes; hidradenitis suppurativa; inflammatory disease; microbiology; soft tissue and skin infections

Pyoderma gangrenosum, severe acne, and suppurative hidradenitis (PASH) syndrome can prove refractory to treatment and is characterized by relapses and recurrences. The combination of antibiotic therapy and surgery can produce success in the management of the syndrome. Acute treatment is required, but maintenance therapy is also necessary to prevent disease relapse. The response to antibiotic therapy is hypothesis generating, raising the issue of a modified host response. To date, anecdotal reports support the use of surgery and medical therapy, but controlled investigations with extended follow-up are necessary to substantiate preliminary data observed with individual cases.

Introduction Nous rapportons la coexistence d’une acne fulminante (AF) et d’une hidrosadenite suppuree (HS) chez 8 patients au sein d’une cohorte de 800 patients porteurs d’HS. Etant donnee la rarete de l’AF, nous posons la question d’une association non fortuite constituant un sous-groupe phenotypique particulier d’HS. Observations Au sein de notre cohorte de 800 HS, 8 hommes ont presente une acne fulminante dont 2 sont porteurs d’un syndrome PASH. Nous decrivons ces 6 cas d’AF + HS ainsi que les 2 cas de PASH syndrome. Le sequencage des genes PSTPIP1 et de la Nicastrine , impliques respectivement dans le PASH syndrome et l’HS, n’a pas permis d’identifier de mutation chez ces 8 patients. Discussion Contrairement a la prevalence de l’HS, estimee a 1 %, l’AF est tres rare, nous en avons recense 188 cas dans la litterature a ce jour. La prevalence de l’AF dans notre cohorte est de 1 % soit une valeur nettement superieure au chiffre attendu dans la population generale. Des acnes severes ont egalement ete decrites chez des patients HS porteurs d’une mutation de la Nicastrine. De plus, le syndrome PASH recemment decrit associe pyoderma gangrenosum (PG), acne severe et HS. Pour toutes ces raisons, la coexistence d’AF et d’HS ne nous parait pas fortuite. La presence d’un syndrome PASH chez 2 freres d’une meme famille au sein de notre cohorte evoque une transmission genetique de ce syndrome. La coexistence d’une acne fulminante et d’HS chez nos 6 patients non porteurs de PASH pose la question de savoir si ces patients, actuellement non porteurs d’un PG, sont porteurs de la meme anomalie genetique que nos 2 patients PASH mais n’ont pas encore exprime le PG ou s’il s’agirait d’une anomalie genetique differente responsable de l’association AF et HS uniquement, sans PG. Chez les 2 patients PASH, le PG a debute a 15 et 18 ans, soit un an apres le debut de l’AF, et l’HS a debute un an avant l’apparition de l’AF pour l’un et un an apres pour l’autre. L’âge actuel de nos 6 patients porteurs d’AF + HS se situe entre 21 et 32 ans, sans developpement de PG a ce jour, ce qui serait en faveur d’une entite clinique separee du PASH. Les 8 patients ont des antecedents familiaux d’acne severe et 6/8 des antecedents familiaux d’HS. Conclusion L’association AF + HS ne nous parait pas fortuite et pourrait soit etre une forme clinique de syndrome PASH incomplet, soit etre une entite differente sous-tendue par une autre anomalie genetique. Le sequencage des genes PSTPIP1 et de la Nicastrine n’a pas permis d’identifier de mutation chez les 8 patients. Nous proposons l’acronyme ASH pour cette entite dans laquelle pourraient etre egalement incluses des acnes severes constituant peut-etre un sous-groupe phenotypique. Cette entite pose la question d’un mecanisme d’action commun a l’AF et a l’HS.

Introduction L’hidrosadenite suppuree (HS) de Stade III de la classification de Hurley est la forme la plus severe de la maladie. Il n’existe pas de traitement medical consensuel chez ces patients. Nous rapportons retrospectivement la duree de prise en charge, les effets secondaires et l’evolution de 12 patients severes porteurs d’HS, pour lesquels une remission clinique a pu etre obtenue grâce a des traitements antibiotiques a large spectre (ALS) prolonges. Observations L’histoire clinique de ces 12 patients de stade III inoperables a ete analysee retrospectivement. La strategie de traitement, developpee dans notre centre a titre compassionnel, dans le cadre d’une prise en charge multidisciplinaire incluant des infectiologues, des microbiologistes et des chirurgiens etait : ertapeneme 1 g/j (6 semaines), puis rifampicine-moxifloxacine-metronidazole (6 semaines), puis rifampicine-moxifloxacine (6 semaines). En cas de persistance de lesions inoperables, un deuxieme cycle d’antibiotiques etait prescrit apres analyse microbiologique. Apres remission (disparition de tout signe inflammatoire et suppuration) obtenue medicalement et eventuellement apres chirurgie, un traitement preventif par cotrimoxazole 400 mg/j etait prescrit. Les resultats sont exprimes en mediane [IQR]. Resultats Les 12 patients (9 hommes et 3 femmes, âge median de 45 ans) avaient en mediane 6 sites actifs [5 ;8], une symptomatologie permanente depuis 4 ans [3 ;11] et 8 interventions chirurgicales prealables [6 ;18]. Sous ALS, le delai median de remission clinique de l’HS etait 11,5 mois [8 ;17], avec intervention chirurgicale associee dans 5 cas. Apres remission, la mediane de suivi etait de 16,5 mois [14 ;31], avec 1 a 2 rechutes mineures par an traitees medicalement. Les effets secondaires notables etaient des troubles digestifs, des candidoses muqueuses, des douleurs tendineuses (moxifloxacine), une asthenie. Discussion Le traitement actuel recommande de l’HS severe repose sur la chirurgie etendue ou les biotherapies dont l’efficacite est variable et permet au mieux d’obtenir une amelioration des scores cliniques. Nous avons montre qu’une flore anaerobie pathogene est associee aux lesions d’HS. Cette serie demontre qu’une antibiotherapie adaptee et prolongee peut permettre d’obtenir une remission de l’HS chez ces patients, limite le nombre et la taille des sites a operer, et que son benefice est maintenu par la suite, les rechutes etant mineures. Pour une maladie aussi handicapante, cette strategie de traitement nous semble donc une option therapeutique envisageable a comparer aux biotherapies. Conclusion Une antibiotherapie a large spectre, possiblement associee a une chirurgie limitee, peut obtenir une remission prolongee de patients atteints d’HS severe inoperable. Ces resultats devront etre confirmes par une etude prospective controlee.

or Africans. 4 The prevalence of FLG mutations is similar in Europeans and Asians. In contrast, FLG mutations seem to be less common in African populations, although they have been less extensively studied, with the consequent possibility of underestimating the frequency of distinct FLG mutations. The strongest associations have been reported between FLG mutations and the risk of early-onset, persistent, and severe AD. 4

Importance Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis. Observations Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3 , p.Leu673Phe, predicted to be damaging. Conclusions and Relevance This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome.

Background The SCN5A gene encodes for the alpha-subunit of the cardiac sodium channel. The cardiac sodium current I Na is essential for generation and transmission of the action potential, and I Na dysfunction is responsible for multiple arrhythmias. Here, we characterized a distal truncating SCN5A mutation, R1860GfsX12, which was identified in a family with mixed clinical phenotypes of sick sinus syndrome, atrial fibrillation, atrial flutter, and AV block. Methods and Results Patch-clamp analysis performed in HEK 293 cells expressing the mutant channel showed a 70% reduction in I Na density compared to cells expressing the wild-type (WT) channels, consistent with western blot analysis showing a partial degradation of the mutant. In addition, the R1860Gfs12X mutation drastically altered the steady-state inactivation leading to a –25-mV shift, delayed the fast and slow inactivation, and increased the persistent current. Moreover, when mimicking the heterozygous state of the patients by coexpressing WT with R1860GfsX12, the biophysical properties were still altered. Loss of I Na density and alteration of the inactivation properties of this mutant channel are associated with a mix of atrial phenotype and AV block within the family. The variety of clinical phenotype seen in this family for the same mutation and the absence of a ventricular phenotype led us to investigate I Na density in HEK cells at membrane potentials mimicking a ventricular vs an atrial resting membrane potential (–86 and –83 mV, respectively). Surprisingly, despite an only 3-mV hyperpolarizing difference in the resting membrane potential of atria, we observed a further decrease in I Na density by 40% at the atrial resting membrane potential compared to the resting membrane potential of the ventricles. Conclusions Multiple mechanisms underlie functional consequences of SCN5A mutations. Here, we demonstrated that one mutation may have different clinical consequences in the atria or the ventricles due to their difference in resting membrane potential based on its biophysical defects. These results could explain how this mutation led to different atrial arrhythmias and conduction defect phenotype within the same family but to the absence of a Brugada phenotype.