Publications by authors named "Emmanuelle Bourrat"

53 Publications

Porokeratosis Plantaris, Palmaris et Disseminata Caused by Con- genital Pathogenic Variants in the MVD Gene and Loss of Hetero-zygosity in Affected Skin.

Acta Derm Venereol 2021 Feb 16;101(2):adv00397. Epub 2021 Feb 16.

Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, DE-79106 Freiburg, Germany.

Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. However, the molecular mechanism leading to development of porokeratosis plantaris, palmaris et disseminata is not known. This study analysed a cohort of 4 patients with linear porokeratosis and 3 patients with porokeratosis plantaris, palmaris et disseminata, and performed mutation analyses of DNA extracted from blood samples and skin biopsies. All of the study patients carried the heterozygous germline variant c.70+5G>A in the MVD gene. Loss of heterozygosity due to a second hit mutation was found in affected skin of 3 patients with linear porokeratosis and 2 patients with porokeratosis plantaris, palmaris et disseminata. These results suggest that porokeratosis plantaris, palmaris et disseminata shares the same pathogenetic mechanism as other porokeratosis subtypes and belongs to the phenotypic spectrum of MVD-associated porokeratosis.
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http://dx.doi.org/10.2340/00015555-3753DOI Listing
February 2021

Meta-Analysis of Mutations in or Identified in a Large Cohort of 224 Patients.

Genes (Basel) 2021 Jan 9;12(1). Epub 2021 Jan 9.

Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: , , , , , , , , , and . The main focus of this report is the mutational spectrum of the genes and , which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in and 27 pathogenic mutations in have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in and 25 novel mutations in . We investigated the spectrum of mutations in and in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.
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http://dx.doi.org/10.3390/genes12010080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826849PMC
January 2021

Chronic Ulceration of the Scalp Associated with Genetically Different Types of Congenital Ichthyosis: A Series of Four Cases.

Acta Derm Venereol 2020 Dec 14. Epub 2020 Dec 14.

Dermatology Department, Reference Center for Rare Skin Diseases, CHU Larrey, Université Paul Sabatier, FR-31000 Toulouse, France. E-mail:

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http://dx.doi.org/10.2340/00015555-3720DOI Listing
December 2020

Duality of Netherton syndrome manifestations and response to ixekizumab.

J Am Acad Dermatol 2020 Jul 18. Epub 2020 Jul 18.

Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France; University of Paris, Paris, France; Department of Genetics, Necker Hospital for Sick Children (Assistance Publique - Hôpitaux de Paris), Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.07.054DOI Listing
July 2020

Cutaneous lipomas and macrocephaly as early signs of PTEN hamartoma tumor syndrome.

Pediatr Dermatol 2020 Sep 13;37(5):839-843. Epub 2020 Jul 13.

CRMRPM-Sud, Service de Dermatologie, CHU Nice, Nice, France.

Background: The diagnosis of PTEN hamartoma tumor syndrome (PHTS) is difficult in children because they usually do not meet diagnostic criteria. The objective of our study was to characterize lipoma as an early presentation of PHTS.

Methods: We performed a retrospective review of children with PHTS diagnosed in French academic hospitals from 2000 to 2019. We included patients presenting at least one lipoma and PTEN-related disorder confirmed genetically.

Results: Thirteen children were included (mean age 5.5 years [range 2.5-16]). All children had solitary (n = 5) or multiple (n = 8) lipomas, all located on the trunk. Clinical examination revealed macrocephaly in all patients. Genital lentiginosis was found in all patients in whom genitalia were examined (n = 6).

Conclusions: In addition to the classical presentation of PHTS with neurological disorders and macrocephaly, some patients, especially the youngest ones, have an initial dermatologic presentation with multiple lipomas. Search for penile freckling and macrocephaly in these patients allows for the diagnosis of PHTS. Lipomatosis should be a major diagnostic criterion in children.
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http://dx.doi.org/10.1111/pde.14265DOI Listing
September 2020

Novel CLDN1 Deletion Associated with Ichthyosis, Sclerosing Cholangitis and Acquired Alopecia.

Acta Derm Venereol 2020 Jun 11;100(13):adv00173. Epub 2020 Jun 11.

Department of Dermatology, Necker Hospital, Paris, France.

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http://dx.doi.org/10.2340/00015555-3522DOI Listing
June 2020

Clinical Characteristics of Acne Fulminans Associated With Chronic Nonbacterial Osteomyelitis in Pediatric Patients.

J Rheumatol 2020 12 1;47(12):1793-1799. Epub 2020 Apr 1.

A. Faye, MD, PhD, Department of General Pediatrics, Pediatric Infectious Diseases and Pediatric Rheumatology, Hôpital Robert Debré, AP-HP, National Reference Centre for Rare Pediatric Inflammatory Rheumatisms and Systemic Auto-immune diseases (RAISE), and Biology and Genetics of Bacterial Cell Wall Unit, Institut Pasteur, Paris.

Objective: Acne fulminans (AF) is a rare, explosive systemic form of acne. Chronic nonbacterial osteomyelitis (CNO) or chronic recurrent multifocal osteomyelitis (CRMO) is a primarily pediatric autoinflammatory disorder characterized by sterile osteolytic bone lesions. Concomitant occurrence of CNO/CRMO and AF is very rare, and little is known about the epidemiological and clinical particularities of this association. The aim of this retrospective observational study was to describe the characteristics of pediatric patients with CNO/CRMO associated to AF.

Methods: Electronic mailing lists of French medical societies were used to call for patients with CNO/CRMO and AF. A search for published patients with CNO/CRMO and AF was performed by screening PubMed.

Results: We identified 5 original patients and 10 patients from the literature. All patients were adolescent boys. Mean age at disease onset was 14.8 years. Nine of 15 patients had received isotretinoin before the sudden onset of AF. Osteoarticular symptoms appeared within < 1-3 months after the onset of AF. The mean numbers of clinical and radiological bone lesions were 3.6 and 5.6, respectively. The percentages of patients with involvement of vertebrae, pelvis, chest, and cranial were 40%, 40%, 33.3%, and 6.6%, respectively. Arthritis was observed in 69.2% of patients and sacroiliac arthritis in 46.2%.

Conclusion: CNO/CRMO associated to AF occurs predominantly in male adolescents and is characterized by frequent involvement of the axial skeleton and arthritis. Epidemiological and clinical features of these patients differ from general CNO/CRMO cohorts. Clinical management requires careful handling of isotretinoin doses.
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http://dx.doi.org/10.3899/jrheum.191232DOI Listing
December 2020

Genetics of Inherited Ichthyoses and Related Diseases.

Acta Derm Venereol 2020 Mar 25;100(7):adv00096. Epub 2020 Mar 25.

Institute of Human Genetics, Medical Center, Faculty of Medicine, University of Freiburg, DE-79106 Freiburg, Germany.

Inherited ichthyoses are classified as Mendelian disorders of cornification (MEDOC), which are defined on the basis of clinical and genetic features and are mainly divided into non-syndromic and syndromic ichthyoses. Numerous genes, which encode for corresponding proteins, are involved in the normal differentiation of keratinocytes (cornification) and participate in the formation of a functional epidermal barrier. To date, mutations in more than 50 genes are known to result in various types of ichthyoses. Thanks to modern genetic diagnostic methods based on targeted next generation sequencing (NGS), approximately 80-90% of cases can be resolved at present. Further sequencing methods covering the whole exome (WES) or whole genome (WGS) will obviously elucidate another portion of the remaining unknown ichthyoses in the future.
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http://dx.doi.org/10.2340/00015555-3432DOI Listing
March 2020

Camptodactlyly in Pediatric Practice: Blau Syndrome.

J Pediatr 2020 06 26;221:257-259. Epub 2020 Feb 26.

Department of General Pediatrics, Paediatric Internal Medicine, Rheumatology and Infectious Diseases, National Reference Centre for Rare Paediatric Inflammatory Rheumatisms and Systemic Auto-immune diseases RAISE, Robert Debré University Hospital, Assistance Publique-Hôpitaux de Paris; Université Paris Diderot-Sorbonne Paris-Cité, INSERM, UMR1149; Biology and Genetics of Bacterial Cell Wall Unit, Pasteur Institute, Paris, France.

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http://dx.doi.org/10.1016/j.jpeds.2020.01.057DOI Listing
June 2020

Efficacy of Dupilumab for Controlling Severe Atopic Dermatitis in a Patient with Hyper-IgE Syndrome.

J Clin Immunol 2020 02 28;40(2):418-420. Epub 2020 Jan 28.

Université de Paris, Imagine Institute, 75015, Paris, France.

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http://dx.doi.org/10.1007/s10875-020-00751-4DOI Listing
February 2020

NLRP3-associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations.

J Allergy Clin Immunol 2020 04 6;145(4):1254-1261. Epub 2019 Dec 6.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), "Childhood genetic disorders", Paris, France; Département de Génétique Médicale, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

Background: NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations.

Objective: To identify mosaic- versus germline-specific NLRP3 mutations' characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of 3 novel patients.

Methods: The pathogenicity of all reported mosaic/germline mutations was reassessed according to international recommendations and their location on the NLRP3 3-dimensional structure. Deep-targeted sequencing and NLRP3-inflammasome-activation assays were used to identify the disease-causing mutation in 3 patients.

Results: We identified, in 3 patients, mosaic mutations affecting the same NLRP3 amino acid (Glu569). This residue belongs to 1 of the 2 mosaic mutational hot spots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hot spots account for 68.5% of patients (37 of 54) with mosaic mutations. Glu569 is affected in 22% of the patients (12 of 54) with mosaic mutations and in 0.4% of patients (1 of 223) with germline mutations. Only 8 of 90 mutations were found in mosaic and germinal states. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the 5 most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state.

Conclusions: The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.
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http://dx.doi.org/10.1016/j.jaci.2019.11.035DOI Listing
April 2020

Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling.

Rheumatology (Oxford) 2020 08;59(8):1927-1937

Paediatric Hematology-Immunology and Rheumatology Department, Reference center for Rheumatic, AutoImmune and Systemic diseases in children (RAISE), Hôpital Necker-Enfants Malades, AP-HP, Paris.

Objectives: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2).

Methods: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes.

Results: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported.

Conclusion: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.
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http://dx.doi.org/10.1093/rheumatology/kez525DOI Listing
August 2020

Reverse Phenotyping in Patients with Skin Capillary Malformations and Mosaic GNAQ or GNA11 Mutations Defines a Clinical Spectrum with Genotype-Phenotype Correlation.

J Invest Dermatol 2020 05 11;140(5):1106-1110.e2. Epub 2019 Nov 11.

Dermatology Department, Dijon Burgundy University Hospital, Dijon, France; INSERM UMR1231, Team Genetics of Development Anomalies, Bourgogne-Franche-Comté University, Dijon, France; Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC)-Mosaic, Burgundy University Hospital, Dijon, France.

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http://dx.doi.org/10.1016/j.jid.2019.08.455DOI Listing
May 2020

Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4.

Hum Mutat 2019 12 6;40(12):2318-2333. Epub 2019 Sep 6.

Institute of Human Genetics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations.
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http://dx.doi.org/10.1002/humu.23883DOI Listing
December 2019

Genotype/phenotype correlations of childhood-onset congenital sideroblastic anaemia in a European cohort.

Br J Haematol 2019 11 23;187(4):530-542. Epub 2019 Jul 23.

CHU de Bordeaux, Hôpital Pellegrin, Bordeaux, France.

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23·3%) and SLC25A38 (n = 8; 18·6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited B-cell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.
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http://dx.doi.org/10.1111/bjh.16100DOI Listing
November 2019

Evaluation of Children with Psoriasis from the BiPe Cohort: Are Patients Using Biotherapies in Real Life Eligible for Phase III Clinical Studies?

Paediatr Drugs 2019 Jun;21(3):169-175

Service de Dermatologie, Hôpital Victor Dupouy, 69 rue du Lieutenant-Colonel Prud'hon, 95100, Argenteuil, France.

Background: Phase III clinical trials of biotherapies for childhood psoriasis are designed for a selected population, which can differ from real-life patients.

Objective: Our objective was to assess the proportion of children with psoriasis that received biotherapy in the biological treatments for pediatric psoriasis (BiPe) cohort that would be excluded from phase III clinical trials of these treatments.

Methods: Data concerning initiation of the first biotherapy from all patients included in the BiPe cohort were analyzed. Ineligibility was assessed after applying the exclusion criteria used in the principal phase III trials of etanercept, adalimumab, and ustekinumab for childhood psoriasis.

Results: Of the 134 patients included, 73 (54.5%) were ineligible for at least one randomized controlled trial based on one or more exclusion criteria. Amongst the 63 children treated with etanercept, 35 (55.5%) were ineligible: 22 because of the type of psoriasis, 12 because of concomitant treatment, and six because of psoriasis severity based on psoriasis assessment severity index (PASI) and physician global assessment (PGA) scores (PASI < 12 and PGA < 3). Amongst the 44 children treated with adalimumab, 32 (72.7%) were ineligible: 17 because of the clinical type of psoriasis, 12 because of psoriasis severity (PASI < 20 and PGA < 4), and seven because of concomitant treatment. Amongst the 27 children patients treated with ustekinumab, 12 (44.4%) were ineligible: eight because of psoriasis severity (PASI < 12 and PGA < 3), five because of the clinical type of psoriasis, and one because of concomitant treatment. Drug survival and the frequency of serious adverse events did not differ between eligible and ineligible patients.

Conclusion: The majority of children treated with biotherapies in real-life practice differ from those in phase III trials, most commonly because of the clinical type of their psoriasis, the disease severity being lower than required and the use of prior or concomitant psoriasis treatment. Efficacy and safety results from phase III clinical trials in selected populations may not sufficiently reflect what is seen in real life, thus results from real-life cohort studies are necessary.
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http://dx.doi.org/10.1007/s40272-019-00335-9DOI Listing
June 2019

Infliximab Paradoxical Psoriasis in a Cohort of Children With Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2019 08;69(2):189-193

Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré.

Objectives: In adult inflammatory bowel disease (IBD) treated by anti-TNF antibodies, paradoxical psoriasis has an estimated prevalence of 1.6 to 22%, especially in infliximab (IFX)-treated patients. Little is known in the pediatric IBD (PIBD) populations.

Methods: All patients ages from 2 to 18 years with Crohn disease (CD) or ulcerative colitis (UC) and treated for the first time by IFX between January 2002 and March 2014, were considered for inclusion in this retrospective study performed in a tertiary PIBD centre. Paradoxical psoriasis events together with clinical and biological data were collected in all patients. Comparisons between psoriasis and control groups were performed using univariate statistical analyses.

Results: One hundred and twenty-three CD patients and 24 UC patients were treated with IFX. Twenty patients (13.6%) experienced a paradoxical psoriasis. All of them were affected by CD. Perianal CD was more frequent in the psoriasis group (P = 0.033). Fourteen patients (70%) were in remission when skin lesions occurred. Paradoxical psoriasis was diagnosed 355 days (median, interquartile range [IQR] 239; 532) after the initiation of IFX corresponding to the eighth injection (median, IQR: 6; 15). Psoriasis lesions were controlled by local steroids in all cases and no patients discontinued IFX therapy.

Conclusions: 13.6% of our IBD patients treated with IFX developed psoriasis during a median follow-up of 23.9 months (IQR: 11.6; 36.5). Crohn disease patients with perianal disease were at a higher risk to develop this common side effect.
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http://dx.doi.org/10.1097/MPG.0000000000002349DOI Listing
August 2019

Clinical Profile of Methotrexate-resistant Juvenile Localised Scleroderma.

Acta Derm Venereol 2019 May;99(6):539-543

Reference Centre of Rare Skin Diseases, Larrey Hospital, Paul Sabatier University, 31400 Toulouse, France.

Methotrexate has demonstrated its efficiency for the treatment of juvenile localized scleroderma but some patients may be resistant. The aim of our study was to define the profile of such patients. We performed an observational retrospective multicenter study between 2007 and 2016 and included all children seen in the French Paediatric Dermatology and Rheumatology departments with active localized scleroderma treated by methotrexate for a minimum of 4 months. Metho-trexate efficacy was assessed clinically and/or by imaging between the fourth to twelfth months of treatment. A total of 57 patients were included. Metho-trexate dosage ranged from 7 to 15 mg/m2/week. Only 4 patients were resistant. No common features could be identified between these 4 patients. Children with localized scleroderma are rarely resistant to metho-trexate and we did not identify a clinical profile for those resistant patients.
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http://dx.doi.org/10.2340/00015555-3155DOI Listing
May 2019

Acanthosis nigricans, hypochondroplasia, and FGFR3 mutations: Findings with five new patients, and a review of the literature.

Pediatr Dermatol 2019 Mar 14;36(2):242-246. Epub 2019 Feb 14.

Department of Dermatology, CHU Nantes, Nantes, France.

Early development of extensive acanthosis nigricans (AN) is a key feature in some patients who have hypochondroplasia (HCH) in association with FGFR3 mutations. We here report regarding five new patients with HCH who exhibited AN, and we compare their characteristics to the eight patients previously described in the literature. In these patients, the AN lesions began in childhood, and they were extensive. These lesions were located on the torso, the abdomen, and the face, in addition to the typical skin fold sites. Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.
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http://dx.doi.org/10.1111/pde.13748DOI Listing
March 2019

Scabies outbreaks in care homes for the elderly.

Lancet Infect Dis 2018 12;18(12):1310

Department of Dermatology, CHU Rennes, Rennes, France.

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http://dx.doi.org/10.1016/S1473-3099(18)30665-0DOI Listing
December 2018

Mutation update for CYP4F22 variants associated with autosomal recessive congenital ichthyosis.

Hum Mutat 2018 10 7;39(10):1305-1313. Epub 2018 Aug 7.

Faculty of Medicine, Institute of Human Genetics, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare disorders of keratinization characterized by generalized abnormal scaling of the skin. Ten genes are currently known to be associated with ARCI: TGM1, ALOXE3, ALOX12B, NIPAL4 (ICHTHYIN), ABCA12, CYP4F22, PNPLA1, CERS3, SDR9C7, and SULT2B1. Over a period of 22 years, we have studied a large patient cohort from 770 families with a clinical diagnosis of ARCI. Since the first report that mutations in the gene CYP4F22 are causative for ARCI in 2006, we have identified 54 families with pathogenic mutations in CYP4F22 including 23 previously unreported mutations. In this report, we provide an up-to-date overview of all published and novel CYP4F22 mutations and point out possible mutation hot spots. We discuss the molecular and clinical findings, the genotype-phenotype correlations and consequences on genetic testing.
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http://dx.doi.org/10.1002/humu.23594DOI Listing
October 2018

Childhood pilomatricomas: Associated anomalies.

Pediatr Dermatol 2018 Sep 1;35(5):548-551. Epub 2018 Jul 1.

Larrey Hospital, Paul Sabatier University, Toulouse, France.

Pilomatricoma is a common benign tumor in children. We present a review of the literature with the aim of helping clinicians manage these patients. A detailed review of the literature was performed in the PubMed database using an exhaustive list of Medical Subject Heading words. One thousand four hundred fifty-eight children were described in retrospective series and case reports. An associated disease was found in 32 children (2.2%), most of whom had several pilomatricomas (n = 23); 9 had a single lesion. Based on this literature review, we recommend reassuring the family and then conducting a detailed interview regarding past medical and family history and a thorough clinical examination for signs of Turner syndrome, constitutional mismatch repair deficiency, Kabuki syndrome, Steiner's myotonic dystrophy, or Gardner syndrome. Regular long-term clinical follow-up is recommended. Specific paraclinical examinations should be performed only in cases of other clinical anomalies or a positive family history. Pilomatricoma requires management because it may be associated with other potentially serious diseases, especially when multiple lesions are present.
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http://dx.doi.org/10.1111/pde.13564DOI Listing
September 2018

Alitretinoin reduces erythema in inherited ichthyosis.

Orphanet J Rare Dis 2018 04 4;13(1):46. Epub 2018 Apr 4.

Reference Centre for Rare Skin Diseases, Dermatology Department, CHU Larrey, Paul Sabatier University, 24, Chemin de Pouvourville, 31400, Toulouse, Cedex 09, France.

Background: Acitretin is the main retinoid used to treat severe inherited ichthyosis. Alternatives may be considered if it results ineffective or there are side-effects, or for women of childbearing age. Our objective is evaluation of the effects and tolerance of alitretinoin. An observational retrospective multicentric study was designed to analyse patients with inherited ichthyosis treated by alitretinoin.

Results: A total of 13 patients were included, 11 of whom were receiving acitretin at inclusion. The main reason for switching to alitretinoin was a desire for pregnancy, but also because of side-effects or unsatisfactory efficacy. Starting dose was 10 mg/day, increased to 20 or 30 mg/day. Alitretinoin seemed to be more effective than acitretin at reducing erythema, but was less effective at reducing scaling or hyperkeratosis. Global efficacy was considered low for two patients, moderate for nine, and high for two. Treatment was well-tolerated, except for one patient who presented with benign intracranial hypertension leading to discontinuation of treatment.

Conclusions: Alitretinoin may be suitable for hereditary ichthyosis with prominent erythema, especially for women of childbearing age.
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http://dx.doi.org/10.1186/s13023-018-0783-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885373PMC
April 2018

Clinical and Therapeutic Aspects of Linear Psoriasis: A Study of 30 Cases.

Am J Clin Dermatol 2018 Aug;19(4):609-615

Service de Dermatologie, Hôpital Victor Dupouy, 69 rue du Lieutenant-Colonel Prud'hon, 95100, Argenteuil, France.

Background: Psoriasis affects 2-4% of the population, with the most common clinical type being plaque psoriasis. The linear form of psoriasis is very rare. The literature on linear psoriasis (LP) consists of only case reports, and data are few.

Objective: This study aimed to better understand LP in a large-scale study.

Patients And Methods: We retrospectively retrieved the medical records from 14 French medical centers of patients newly diagnosed clinically with LP, with or without the support of histology, between 1 February and 31 July 2015. For each case, we assessed the clinical features, treatments and treatment efficacy.

Results: In total, 30 cases of LP (mean age 26.8 years, 13 males) were reported. Mean age at onset of LP was 20.0 years, with 18 developing LP in childhood. Ten patients had a family history of psoriasis, and two had psoriatic arthritis. A total of 19 cases were linear at onset, with concomitant classical psoriasis; these were termed "superimposed" LP. The remaining 11 cases were not associated with classical psoriasis and were termed "isolated" LP. In four of the superimposed cases, LP developed when the patient was receiving systemic treatment: methotrexate (n = 2), etanercept (n = 1) or infliximab (n = 1). Topical steroids were effective in 76% of cases in which they were used, and systemic treatment was effective in < 66%. Treatments were less effective in LP than in classical psoriasis.

Discussion: We identified a wide range of LP, with two profiles: isolated LP and superimposed LP. Topical treatment usually evoked clinical response, with relative resistance to systemic therapy. Methotrexate and anti-tumor necrosis factor (TNF)-α therapies can possibly unmask LP.
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http://dx.doi.org/10.1007/s40257-018-0354-9DOI Listing
August 2018

Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: Not a panacea.

PLoS Negl Trop Dis 2017 Nov 20;11(11):e0006094. Epub 2017 Nov 20.

INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Centre d'Infectiologie Necker-Pasteur, Institut Pasteur, Paris, France.

Background: Complex cutaneous and muco-cutaneous leishmaniasis (CL and MCL) often requires systemic therapy. Liposomal amphotericin B (L-AmB) has a strong potential for a solid clinical benefit in this indication.

Methods: We conducted a retrospective analysis of data from a French centralized referral treatment program and from the "LeishMan" European consortium database. All patients with parasitologically proven CL or MCL who received at least one dose of L-AmB were included. Positive outcome was based on ulcer closure as per recent WHO workshop guidelines.

Results: From 2008 through 2016, 43 travelers returning from 18 countries (Old World n = 28; New World n = 15) were analyzed with a median follow-up duration of 79 days [range 28-803]. Main clinical forms were: localized CL with one or multiple lesions (n = 32; 74%) and MCL (n = 8; 19%). As per published criteria 19 of 41 patients (46%) were cured 90 days after one course of L-AmB. When the following items -improvement before day 90 but no subsequent follow-up, delayed healing (>3 months) and healing after a second course of L-AmB- were included in the definition of cure, 27 of 43 patients (63%) had a positive outcome. Five patients (MCL = 1; CL = 4) experienced a relapse after a median duration of 6 months [range 3-27] post treatment and 53% of patients (23/43) experienced at least one adverse event including severe hypokalaemia and acute cardiac failure (one patient each). In multivariate analysis, tegumentary infection with L. infantum was associated with complete healing after L-AmB therapy (OR 5.8 IC 95% [1.03-32]) while infection with other species had no impact on outcome.

Conclusion: In conditions close to current medical practice, the therapeutic window of L-AmB was narrow in travellers with CL or MCL, with the possible exception of those infected with L. infantum. Strict follow-up is warranted when using L-AmB in patients with mild disease.
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http://dx.doi.org/10.1371/journal.pntd.0006094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714383PMC
November 2017

Pain and quality of life evaluation in patients with localized epidermolysis bullosa simplex.

Orphanet J Rare Dis 2017 06 28;12(1):119. Epub 2017 Jun 28.

Reference Centre for Inherited Epidermolysis Bullosa, Archet 2 Hospital, University of Nice Sophia Antipolis, Nice, France.

Background: A localized form of epidermolysis bullosa simplex (EBS-l) is considered one of the mildest forms of epidermolysis bullosa (EB), with blisters limited to the palms and soles. However, these lesions can be very painful. The aim of the study was to characterize pain in patients with EBS-l and evaluate its impact on quality of life (QoL). Patients were contacted via the Research Group of the French Society of Pediatric Dermatology and the association of EB patients (DEBRA France). One investigator used a standardized questionnaire that included validated scales for pain and QoL for a telephone interview.

Results: We included 57 patients (27 children). All patients had pain: the mean pain on a 10-mm visual analog scale was >5 for most adults (90%) and children ≥8 years old (94%) when blisters were present and for most adults (73%) and about half of the children ≥ age 8 (53%) during dressing changes. Similar results were found for younger patients. Overall, 75% of patients had neuropathic pain; for 55% of children and 73% of adults, the pain had a moderate to severe impact on QOL. Only seven patients used premedication before changing dressings and seven regularly used oral treatment for chronic pain. A total of 21% and 23% of patients used non-steroidal anti-inflammatory drugs and grade 2 analgesics, respectively. These treatments were not effective for neuropathic pain. Six patients tried 5% lidocaine plasters on their feet, with good efficacy.

Conclusions: EBS-l patients have frequent and severe pain with neuropathic characteristics. This pain is undertreated and affects QoL.
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http://dx.doi.org/10.1186/s13023-017-0666-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490235PMC
June 2017

Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome.

Exp Dermatol 2019 10 26;28(10):1114-1117. Epub 2017 Oct 26.

Sorbonne Paris Cité, IMAGINE Institute, Necker Hospital, Enfants-Malades, UMR 1163, Paris-Descartes University, Paris, France.

The identification of loss-of-function mutations of the IL36RN gene encoding the interleukin-36 receptor antagonist (IL-36Ra) in generalized pustular psoriasis (GPP) emphasized the key role of this pathway in skin innate immunity and systemic inflammation. It has been previously shown in vitro that removal of the N-terminal amino acid IL36Ra (M1) is critical to its biological activity, but the in vivo contribution of this processing remains unknown. We report herein a new homozygous (c4G>T, pV2F) missense IL36RN mutation segregating in a family with three GPP-affected patients. The V2F mutation does not alter IL-36Ra protein expression but was devoid of any antagonist activity. Mass spectrometry showed that the V2F IL-36Ra mutant retains its first N-terminal methionine. These results provide the first in vivo demonstration that removal of N-terminal methionine of native IL-36Ra is a mandatory step to reach optimal antagonist activity and to prevent sustained skin and systemic inflammation in humans.
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http://dx.doi.org/10.1111/exd.13387DOI Listing
October 2019

Continuous increase of Trichophyton tonsurans as a cause of tinea capitis in the urban area of Paris, France: a 5-year-long study.

Med Mycol 2017 Jul;55(5):476-484

Laboratoire de Parasitologie-Mycologie; AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal.

Tinea capitis (TC) is a highly contagious fungal infection of the scalp due to dermatophytes in children. To obtain information on the epidemiology of TC in the urban area of Paris, we analysed the microbiological results of 3090 patients seen with suspected TC from October 2010 to September 2015 at Saint Louis hospital, Paris, France. A peak of TC was observed in 3-6 year-old children, followed by a progressive decrease until 16 years of age. Of the 1311 positive cultures, 95% (1246) yielded one of the three anthropophilic species [Trichophyton tonsurans (33.5%), Trichophyton soudanense (38.3%), or Microsporum audouinii (28.2%)]. When considering one TC case per family, we observed a significant increase of T. tonsurans (P = .018) during these 5 years. The increase was more pronounced (P = .0047) in patients of West-African descent (n = 666), and was at the expense of M. audouinii and T. soudanense. On the other hand, the Caribbean patients (n = 85) remained predominantly (72.9%) infected by T. tonsurans. Our results show a better virulence of T. tonsurans over other species as already reported. Since T. tonsurans has not been reported in Africa, the infection of patients of West-African descent probably took place in the Paris area by exchanges with Caribbean patients. This increase of TC due to T. tonsurans was observed in the context of griseofulvin being the only licensed paediatric treatment for TC in France, which should deserve reappraisal because terbinafine may be more efficacious.
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http://dx.doi.org/10.1093/mmy/myw107DOI Listing
July 2017

The scalp hair collar and tuft signs: A retrospective multicenter study of 78 patients with a systematic review of the literature.

J Am Acad Dermatol 2017 Mar 11;76(3):478-487. Epub 2016 Oct 11.

Department of Pediatric Dermatology, National Center for Rare Skin Disorders-Institut National de la Santé et de la Recherche Médicale (INSERM) U1035, Bordeaux, France.

Background: Hair collar sign (HCS) and hair tuft of the scalp (HTS) are cutaneous signs of an underlying neuroectodermal defect, but most available data are based on case reports.

Objective: We sought to define the clinical spectrum of HCS and HTS, clarify the risk for underlying neurovascular anomalies, and provide imaging recommendations.

Methods: A 10-year multicenter retrospective and prospective analysis of clinical, radiologic, and histopathologic features of HCS and HTS in pediatric patients was performed.

Results: Of the 78 patients included in the study, 56 underwent cranial and brain imaging. Twenty-three of the 56 patients (41%) had abnormal findings, including the following: (1) cranial/bone defect (30.4%), with direct communication with the central nervous system in 28.6%; (2) venous malformations (25%); or (3) central nervous system abnormalities (12.5%). Meningeal heterotopia in 34.6% (9/26) was the most common neuroectodermal association. Sinus pericranii, paraganglioma, and combined nevus were also identified.

Limitations: The partial retrospective design and predominant recruitment from the dermatology department are limitations of this study.

Conclusions: Infants with HCS or HTS are at high risk for underlying neurovascular anomalies. Magnetic resonance imaging scans should be performed in order to refer the infant to the appropriate specialist for management.
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http://dx.doi.org/10.1016/j.jaad.2016.08.046DOI Listing
March 2017

IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular Diseases.

J Invest Dermatol 2016 09 21;136(9):1811-1819. Epub 2016 May 21.

INSERM unit U1163, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France. Electronic address:

Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36-dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.
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http://dx.doi.org/10.1016/j.jid.2016.04.038DOI Listing
September 2016