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We describe a patient exhibiting clinical features of PRAAS due to a homozygous mutation in PSMB10. This gene encodes the only immunoproteasome subunit in which mutations have not yet been associated with PRAAS.

International audience; A girl, born with a posterior lumbosacral giant congenital nevus, developed a central nodule that expanded over a period of 14 months into a 10-cm pedunculated mass. Histological analysis of the mass revealed melanoma of myxoid, small round-cell type with areas of rhabdomyosarcomatous transformation confirmed by immunohistochemistry. RNA sequencing identified an in-frame SASS6(e14)-RAF1(e8) fusion in both components and the nevus. A RAF1 FISH break-apart test found a balanced rearrangement pattern in the nevus and an unbalanced pattern in the malignant areas. Wild-type status of NRAS and BRAF was confirmed by NGS techniques. The array-CGH profile displayed copy number alterations commonly found in rhabdomyosarcomas. Despite intensive treatment, widespread metastatic evolution of the melanomatous component was observed.

Background There is limited information regarding early development of soft-tissue and/or bone hypertrophy with facial port-wine stains (PWS). Objective We sought to characterize patients with hypertrophic PWS presenting during childhood. Methods Patients with a facial PWS and underlying hypertrophy that developed before the age of 18 years were included in a multicenter retrospective study. Age at onset of the hypertrophy, its location, association with odontologic problems, presence of other associated complications, and response to laser treatment were recorded. Results A total of 98 patients were included. The mean age at onset of hypertrophy, retrieved for 77 of 98 patients, was 5.6 years. The hypertrophy was congenital in 26%. Odontologic problems were noted in 39.8% of cases. Other complications, including cataract, asymmetric development of the maxillary bone, and speech delay/disorders, were reported in 18.4%. In all, 67 patients received laser treatment. Only 3% achieved complete or nearly complete clearance of the PWS. Limitations As only cases of PWS with early-onset hypertrophy were included, we were unable to calculate the prevalence of this manifestation. Conclusion PWS with early-onset hypertrophy are associated with a high rate of complications and a poor response to laser treatment. Periodic monitoring is recommended for early detection and treatment of complications.

Gezdirici, Alper/0000-0002-2432-9279; Gezdirici, Alper/0000-0002-2432-9279; vasse, marc/0000-0002-8784-7209; Beyens, Aude/0000-0003-0231-6861 WOS: 000493185700008 PubMed: 29952037 In ATP6V0A2-related cutis laxa, the skin phenotype varies from a wrinkly skin to prominent cutis laxa and typically associates with skeletal and neurological manifestations. The phenotype remains incompletely characterized, especially in adult patients. Glycosylation defects and reduced acidification of secretory vesicles contribute to the pathogenesis, but the consequences at the clinical level remain to be determined. Moreover, the morphology of the elastic fibres has not been studied in ATP6V0A2-related cutis laxa, nor its relation with potential clinical risks. We report on the extreme variability in ATP6V0A2-related cutis laxa in 10 novel patients, expand the phenotype with emphysema and von Willebrand disease and hypothesize on the pathogenesis that might link both with deficiency of glycosylation and with elastic fibre anomalies. Our data will affect clinical management of patients with ATP6V0A2-related cutis laxa. Special Research Fund of Ghent UniversityGhent University [01N04516]; Scientific Research Fund - Flanders

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal-dominant disorder, caused by heterozygous RASA1 mutations, and manifesting multifocal CMs and high risk for fast-flow lesions. A limited number of patients have been reported, raising the question of the phenotypic borders. We identified new patients with a clinical diagnosis of CM-AVM, and patients with overlapping phenotypes. RASA1 was screened in 261 index patients with: CM-AVM (n=100), common CM(s) (port-wine stain; n=100), Sturge-Weber syndrome (n=37), or isolated AVM(s) (n=24). Fifty-eight distinct RASA1 mutations (43 novel) were identified in 68 index patients with CM-AVM and none in patients with other phenotypes. A novel clinical feature was identified: cutaneous zones of numerous small white pale halos with a central red spot. An additional question addressed in this study was the second-hit hypothesis as a pathophysiological mechanism for CM-AVM. One tissue from a patient with a germline RASA1 mutation was available. The analysis of the tissue showed loss of the wild-type RASA1 allele. In conclusion, mutations in RASA1 underscore the specific CM-AVM phenotype and the clinical diagnosis is based on identifying the characteristic CMs. The high incidence of fast-flow lesions warrants careful clinical and radiologic examination, and regular follow-up. (C) 2013 Wiley Periodicals, Inc.

Background: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. Results: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1 -related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1 -encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

Autosomal recessive cutis laxa type I (ARCL type I) is characterized by generalized cutis laxa with pulmonary emphysema and/or vascular complications. Rarely, mutations can be identified in FBLN4 or FBLN5. Recently, LTBP4 mutations have been implicated in a similar phenotype. Studying FBLN4, FBLN5, and LTBP4 in 12 families with ARCL type I, we found bi-allelic FBLN5 mutations in two probands, whereas nine probands harbored biallelic mutations in LTBP4. FBLN5 and LTBP4 mutations cause a very similar phenotype associated with severe pulmonary emphysema, in the absence of vascular tortuosity or aneurysms. Gastrointestinal and genitourinary tract involvement seems to be more severe in patients with LTBP4 mutations. Functional studies showed that most premature termination mutations in LTBP4 result in severely reduced mRNA and protein levels. This correlated with increased transforming growth factor-beta (TGFβ) activity. However, one mutation, c.4127dupC, escaped nonsense-mediated decay. The corresponding mutant protein (p.Arg1377Alafs(*) 27) showed reduced colocalization with fibronectin, leading to an abnormal morphology of microfibrils in fibroblast cultures, while retaining normal TGFβ activity. We conclude that LTBP4 mutations cause disease through both loss of function and gain of function mechanisms.

Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype. MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in sterol control of transcription and ER stress response. Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids. These functions were impaired in five mutations as detected in unrelated patients. The degree of diminished activity correlated with clinical severity as noted in male patients. Our findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress.

PurposeThe purpose of this paper is to review systematically the available literature relating to the implementation of peer education to promote health and healthy behaviour in prisons.Design/methodology/approachThe authors undertook a narrative systematic review of Medline, EMBASE, CINAHL, Psychinfo, Web of Science and Cochrane databases. Relevant journals and reference lists were hand searched for relevant articles to be included in the review. Of the abstracts found, full‐text papers were retrieved for those papers deemed as possibly fulfilling the inclusion criteria of the review.FindingsA total of 3,033 abstracts were identified leading to 46 full‐text articles being retrieved, of which ten were included in the review. Peer education in prisons can have an impact on attitudes, knowledge, and behaviour intention regarding HIV risk behaviour. The research findings were inconclusive for the impact of peer education upon illicit drug use and injecting practice. There was a paucity of research evaluating the impact of peer education upon mental ill health, obesity, diet, smoking, or self‐management of chronic physical diseases.Originality/valuePeer education is effective in reducing risk of HIV transmission. It is possible that peer education for mental health issues is stigmatising, presenting an opportunity for further research activity. The impact of peer education upon illicit drug use practice, obesity, diet, smoking, and self‐management of chronic physical diseases also presents further research opportunities. Research evaluating models of active peer educator involvement in health service delivery and organisation is also lacking.

L’une des pathologies courantes en dermatologie pédiatrique est l’hémangiome, de diagnostic évident mais pas toujours posé. L’évolution qui est d’habitude bénigne peut être émaillée de complications redoutables nécessitant parfois un traitement curatif, qui a connu de grands progrès essentiellement les bétabloquants topiques, ces derniers ont fait preuve d’efficacité et de bonne tolérance. Nous rapportons le cas d’une fille âgée de 1 an qui présentait un hémangiome vulvaire non diagnostiqué et compliqué de surinfection, entrainant des vulvites répétées et résistantes aux antibiotiques usuels. L’utilisation de béta- bloquants topiques après la stérilisation de la lésion a permis une régression importante de l’hémangiome, ainsi qu’une amélioration de la qualité de vie de la patiente et de ses parents, sans aucun effet secondaire. L’hémangiome vulvaire reste fréquent et bénin mais parfois grave, Il faut y penser pour mieux traiter.

Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome is an X-linked genodermatosis with congenital atrichia being the most prominent feature. Recently, we have shown that functional deficiency of MBTPS2 (membrane-bound transcription factor protease site 2) - a zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response - causes the disease. Here, we present results obtained by analysing two intronic MBTPS2 mutations, c.671-9T>G and c.225-6T>A, using in silico and cell-based splicing assays. Accordingly, the c.225-6T>A transversion generated a new splice acceptor site, which caused extension of exon 3 by four bases and subsequently introduced a premature stop codon. Both, minigene experiments and RT-PCR analysis with patient-derived mRNA, demonstrated that the c.671-9T>G mutation resulted in skipping of exon 6, most likely because of disruption of the polypyrimidin tract or a putative intronic splicing enhancer (ISE). Our combined biocomputational and experimental analysis strongly suggested that both intronic alterations are disease-causing mutations.

Introduction Certains angiomes plans comportent une hypertrophie tissulaire precoce differente de l’hypertrophie cutanee des « angiomes plans vieillis ». Leur profil evolutif et la reponse therapeutique semblent specifiques. L’objectif de cette etude etait d’evaluer les caracteristiques cliniques des angiomes plans precocement hypertrophiques du visage ainsi que leur reponse au traitement laser. Materiel et methodes Etude retrospective dans 12 centres dermatologiques. Les donnees etaient recueillies a l’aide d’un questionnaire standardise. Etaient recueillis : le sexe, l’âge au debut de l’hypertrophie et au moment de la consultation, la localisation de l’angiome et de l’hypertrophie, les complications associees, les eventuels traitements realises et l’âge au debut du traitement, le type de laser, le nombre de seances, la duree totale du traitement et la reponse therapeutique. Resultats Quatre-vingt cas d’angiomes plans precocement hypertrophiques ont ete recueillis. Le sex-ratio H/F etait de 0,5. L’âge de debut de l’hypertrophie etait connu dans 57 cas. Il etait en moyenne de 6,5 ans (0–15). L’hypertrophie etait congenitale dans 11 cas sur 57(19,3 %). Les troubles odontologiques etaient frequents (38,8 %). Seize autres cas (20 %) avaient d’autres complications associees (cataracte, comitialite, asymetrie de developpement des maxillaires et troubles orthophoniques). Cinquante-sept ont ete traites par laser (laser a colorant pulse dans la majorite des cas) avec une moyenne de 14 seances (1–60) sur une periode moyenne de 8,2 ans (1–22). L’âge median de debut du traitement etait de 8 ans avec des extremes de 1 mois a 58 ans. Une amelioration 90 %). Discussion A notre connaissance, une seule etude s’est interessee aux angiomes plans hypertrophiques. Sur 335 patients âges de 0 a 81 ans, une hypertrophie etait observee chez 68 patients. Cependant, il s’agissait d’hypertrophies le plus souvent tardives survenant en moyenne apres l’âge de 31 ans. Seulement 6 patients avaient une hypertrophie avant 20 ans et aucune donnee specifique n’etait rapportee pour cette population. Notre serie confirme que les patients ayant un angiome plan du visage precocement hypertrophique ont un profil particulier avec un taux eleve de complications et des taux de reponse au traitement laser largement inferieurs a ce qui est habituellement observe dans les angiomes plans non precocement hypertrophiques. Conclusion Les enfants ayant un angiome plan precocement hypertrophique doivent faire l’objet d’une surveillance particuliere en raison de la frequence des complications associees. Le traitement par laser de ces formes parait tres decevant et les patients et leurs familles doivent en etre prevenus. Des etudes genetiques apparaissent importantes afin de determiner si ce phenotype clinique est associe a une ou plusieurs mutations particulieres.

mented and hypertrichotic skin lesion with unilateral arrangement. This disorder that is today called Becker’s nevus is characterized by the presence of a light or dark brown macule with a sharply outlined but irregular border that resolves into small spots reminiscent of an archipelago. In male patients, the lesion shows increased hairiness after puberty. It tends to be arranged in a checkerboard pattern. 2 Becker’s nevus is fairly common 3 but often overlooked or misdiagnosed. The disorder may become obvious in late childhood or adolescence but for obvious reasons we think that it is always congenital. An association of Becker’s nevus with other developmental anomalies has sometimes been reported. Happle and Koopman 4 reviewed 23 cases and proposed the new term ‘‘Becker’s nevus syndrome’’ for a simultaneous occurrence of Becker’s nevus and unilateral breast hypoplasia or other cutaneous, muscular, or skeletal defects. All of these anomalies tend to show a regional correspondence to the nevus and are mostly ipsilateral. To assess the clinical spectrum of this syndrome in more detail, we present an overview of 55 cases as reported in the literature 3,5-40 and in some personal communications.

The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 is generally implicated in familial cylindromatosis, whereas a gene region for multiple familial trichoepithelioma has been assigned to 9p21. Markers from both chromosome intervals were subjected to linkage analysis in a large family with multiple hereditary trichoepithelioma (TE) from Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a candidate. Mutation analysis identified a single bp germ-line deletion expected to result in truncation or absence of the encoded protein, which segregated with the multiple TE phenotype. In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial TE indistinguishable from the phenotype assigned to 9p21.