Publications by authors named "Stéphanie Leclerc-Mercier"

35 Publications

Histological Patterns of Skin Lesions in Tuberous Sclerosis Complex: A Panorama.

Dermatopathology (Basel) 2021 Jul 4;8(3):236-252. Epub 2021 Jul 4.

Reference Center for Genodermatoses (MAGEC Center), Department of Pathology, Necker-Enfants Malades Hospital, Paris Centre University, 75015 Paris, France.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disease characterized by cutaneous and extracutaneous hamartomas. The diagnosis is based on the association of major and minor criteria, defined by a consensus conference updated in 2012. The clinical examination of the skin is crucial because seven diagnostic criteria are dermatological: four major (hypomelanotic macules, angiofibroma or fibrous cephalic plaques, ungual fibromas, shagreen patches) and three minor criteria (confetti skin lesions, dental enamel pits, intraoral fibromas). Skin biopsy is commonly performed to assert the diagnosis of TSC when the clinical aspect is atypical. Histopathology of TSC cutaneous lesions have been poorly reported until now. In this article, we review the histologic features described in the literature and share our experience of TSC skin biopsies in our pediatric hospital specialized in genetic disorders. Both hypomelanotic lesions and cutaneous hamartomas (angiofibroma/fibrous cephalic plaques, ungual fibromas, shagreen patches) are discussed, including the recent entity called folliculocystic and collagen hamartoma, with a special emphasis on helpful clues for TSC in such lesions.
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http://dx.doi.org/10.3390/dermatopathology8030029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293214PMC
July 2021

Hand surgery in recessive dystrophic epidermolysis bullosa: Our experience with dermal substitutes.

J Plast Reconstr Aesthet Surg 2021 Jun 15. Epub 2021 Jun 15.

Institut de la Main, 22 rue Georges Bizet, 75116 Paris; Pediatric Orthopaedic department, Hôpital Necker Enfants Malades, Université Paris Descartes, 149 rue de Sevres, 75015 Paris. Electronic address:

Background: Deformities of the hands occur in most patients with recessive dystrophic epidermolysis bullosa. All structures of the hand may be involved. To restore hand function, it is necessary to identify the proper method of treatment.

Patients And Methods: We conducted a retrospective review of 18 patients for a total of 30 surgically treated hands. The data were collected between 1998 and 2016 at Hôpital Necker Enfants Malades (Paris, France) and Institut de la Main (Paris, France). The postoperative follow-up period ranged between 22 months and 168 months, with an average duration of 76 months. The procedure performed on all of these patients involved a first web release for the thumb and pseudosyndactyly release for the remaining digits. A full thickness skin graft was used at the level of the first commissure and palm of the hand, while acellular dermal substitutes (Integra® or Matriderm®) were used to cover the remaining commissures, digits, and the remainder of the hand, followed by a split thickness skin graft. Postoperative rehabilitation ensued.

Results: Long-term results are encouraging, demonstrating maintenance of function greater than 3 years in 57% of cases, and greater than 5 years in 33% of cases.

Conclusion: We believe that good surgical technique followed by good rehabilitation, combined with an interdisciplinary overall management of these patients, allowed us to succeed in maintaining a very satisfactory, esthetic, and functional result exceeding 5 years for one-third of patients. The resultant psychological benefit is very important.
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http://dx.doi.org/10.1016/j.bjps.2021.05.056DOI Listing
June 2021

How to Deal with Skin Biopsy in an Infant with Blisters?

Dermatopathology (Basel) 2021 Jun 4;8(2):159-175. Epub 2021 Jun 4.

Reference Center for Genodermatoses (MAGEC Center), Department of Pathology, Necker-Enfants Malades Hospital, Paris Centre University, 75015 Paris, France.

The onset of blisters in a neonate or an infant is often a source of great concern for both parents and physicians. A blistering rash can reveal a wide range of diseases with various backgrounds (infectious, genetic, autoimmune, drug-related, traumatic, etc.), so the challenge for the dermatologist and the pediatrician is to quickly determine the etiology, between benign causes and life-threatening disorders, for a better management of the patient. Clinical presentation can provide orientation for the diagnosis, but skin biopsy is often necessary in determining the cause of blister formations. In this article, we will provide information on the skin biopsy technique and discuss the clinical orientation in the case of a neonate or infant with a blistering eruption, with a focus on the histology for each etiology.
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http://dx.doi.org/10.3390/dermatopathology8020022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293140PMC
June 2021

Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation.

Biochem Biophys Res Commun 2020 09 30;530(3):520-526. Epub 2020 Jun 30.

INSERM, LNC UMR1231 Team HSP-pathies, University of Burgundy and Franche-Comté, F-21000, Dijon, France. Electronic address:

PIK3CA-related overgrowth spectrum is caused by mosaicism mutations in the PIK3CA gene. These mutations, which are also observed in various types of cancer, lead to a constitutive activation of the PI3K/AKT/mTOR pathway, increasing cell proliferation. Heat shock transcription factor 1 (HSF1) is the major stress-responsive transcription factor. Recent findings indicate that AKT phosphorylates and activates HSF1 independently of heat-shock in breast cancer cells. Here, we aimed to investigate the role of HSF1 in PIK3CA-related overgrowth spectrum. We observed a higher rate of proliferation and increased phosphorylation of AKT and p70S6K in mutant fibroblasts than in control cells. We also found elevated phosphorylation and activation of HSF1, which is directly correlated to AKT activation. Specific AKT inhibitors inhibit HSF1 phosphorylation as well as HSF1-dependent gene transcription. Finally, we demonstrated that targeting HSF1 with specific inhibitors reduced the proliferation of mutant cells. As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.
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http://dx.doi.org/10.1016/j.bbrc.2020.04.146DOI Listing
September 2020

An unsual case of palmoplantar keratoderma.

Pediatr Dermatol 2020 Jan;37(1):e17-e19

Department of Dermatology, Reference Centre for Genodermatoses and Rare Skin Disease (MAGEC), Hopital Universitaire Necker-Enfants Malades, APHP, Paris, France.

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http://dx.doi.org/10.1111/pde.14038DOI Listing
January 2020

Use of Epidermal Growth Factor Receptor Inhibitor Erlotinib to Treat Palmoplantar Keratoderma in Patients With Olmsted Syndrome Caused by TRPV3 Mutations.

JAMA Dermatol 2020 02;156(2):191-195

Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Hôpital Necker-Enfants Malades, APHP, Paris, France.

Importance: Olmsted syndrome is a genodermatosis characterized by painful and mutilating palmoplantar keratoderma (PPK) that progresses from infancy onward and lacks an effective treatment. It is most often caused by mutations in the transient receptor potential vanilloid 3 (TRPV3) gene. In animal models and keratinocyte cell lines, TRPV3 signaling leads to epidermal growth factor receptor (EGFR) transactivation.

Objective: To examine the possibility of blocking EGFR transactivation with the inhibitor erlotinib hydrochloride to treat PPK in patients with Olmsted syndrome due to TRPV3 mutations.

Design, Setting, And Participants: In this case series, 3 patients from 2 unrelated families who had TRPV3-mutation-associated PPK were treated with erlotinib from May 5, 2018, through May 13, 2019.

Main Outcomes And Measures: Clinical follow-up included evaluation of PPK progression, pain and interventions for pain, as well as erlotinib dose adjustment based on treatment effect, plasma levels, and tolerance.

Results: The 3 patients (2 brothers aged 15 and 17 years and a 13-year-old girl) had severe palmoplantar hyperkeratosis, intolerable pain with erythromelalgia, severe growth delay, anorexia, and insomnia, which had been progressing since infancy despite numerous therapies. Two patients were confined to wheelchairs owing to intense pain and joint restrictions because of hyperkeratosis. All patients experienced depression and did not engage in social activities. Within 3 months of initiating therapy with erlotinib, hyperkeratosis and pain disappeared. All patients were able to touch the ground with their feet, wear shoes, and walk. Anorexia and insomnia remitted and paralleled improved growth. In addition, the patients resumed social activities. These improvements were sustained across 12 months of treatment and follow-up. The doses of erlotinib used were lower than those used in oncology, and only mild to moderate adverse effects were noted.

Conclusions And Relevance: The findings of this study report improvement of PPK in patients with Olmsted syndrome caused by TRPV3 mutations when treated with erlotinib. Targeting EGFR transactivation with erlotinib therapy may result in clinical remission in an orphan disease that lacks an effective intervention.
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http://dx.doi.org/10.1001/jamadermatol.2019.4126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990711PMC
February 2020

Pityriasis Lichenoides: A Large Histopathological Case Series With a Focus on Adnexotropism.

Am J Dermatopathol 2020 Jan;42(1):1-10

Department of Dermatology, Hôpital Necker-Enfants Malades, Paris, France.

Introduction: Pityriasis lichenoides (PL) is an infrequent skin disorder. The clinical manifestations are usually specific enough for a reliable diagnosis, although the histopathological assessment of a biopsy is sometimes needed to differentiate between PL and a range of other diseases. The objectives of this study were to review cases of PL managed in our hospital, confirm the classical histopathological features of PL, and identify signs that may be of value in the diagnosis of PL.

Materials And Methods: All cases of PL assessed in our pathology department between January 2007 and December 2017 were retrieved, and all slides were reviewed. Cases were selected only if a diagnosis of PL was initially suggested by a dermatologist and then confirmed by the histopathological assessment.

Results: Seventy-one cases met the study criteria. The following features were almost always present: vacuolar changes or necrotic keratinocytes (100%), both superficial and deep lymphocytic infiltrates (99%), and the infiltration of lymphocytes into the adnexal epithelium (97%). The inflammatory cells were always small- to medium-sized lymphocytes. There were no eosinophilic infiltrates. Superficial perivascular and/or intraepidermal red blood cells were observed in 83% of cases.

Discussion: We highlighted the presence of a deep dermal lymphocytic infiltrate, with a "T-shaped" periadnexal arrangement along the full length of the follicular and sudoral epithelia. This might be a feature that enables the differentiation of PL from other diseases. Our findings also prompted a number of physiopathological hypotheses for PL.

Conclusions: Our present results confirmed the classical histological aspects of PL and provided some useful new diagnostic features.
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http://dx.doi.org/10.1097/DAD.0000000000001448DOI Listing
January 2020

Clinical variability and probable founder effect in oculocutaneous albinism type 7.

Clin Genet 2020 03 6;97(3):527-528. Epub 2019 Nov 6.

Reference Centre for Genodermatoses and Rare Skin Disease (MAGEC) and Department of Dermatology, Filière Maladies Rares Dermatologiques (FIMARAD), ERN-Skin Hôpital Necker-Enfants Malades, Université de Paris-Centre, Paris, France.

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http://dx.doi.org/10.1111/cge.13655DOI Listing
March 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

The Case | Posttransplant upper limb inflammatory nodules.

Kidney Int 2019 03;95(3):721-722

Department of Kidney Transplantation, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, RTRS "Centaure," Paris, France.

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http://dx.doi.org/10.1016/j.kint.2018.10.012DOI Listing
March 2019

Langerhans Cell Histiocytoma: A Benign Histiocytic Neoplasm of Diverse Lines of Terminal Differentiation.

Am J Dermatopathol 2019 Jan;41(1):29-36

Pathology Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Langerhans cell (LC) histiocytoma is a neonatal tumor that often consists of a single, ulcerated nodule. Systemic involvement is rare, and LC histiocytoma is considered to be a variant of congenital, self-healing LC histiocytosis (also referred to as Hashimoto-Pritzker disease). In view of its low prevalence, LC histiocytoma is not always diagnosed in a clinical examination and requires histological confirmation. Furthermore, the histological and molecular features of LC histiocytoma have not been well characterized. Here, we report on 6 cases of this rare disease and review the corresponding literature. LC histiocytoma differs from classical self-healing LC histiocytosis with regard to the pathological features; we found that LC histiocytoma was associated with massive infiltration by histiocytes of various sizes and shapes (although often large) throughout the dermis and the superficial subcutis. Epidermotropism was rare, mitotic figures were not inconspicuous, and necrotic or calcified areas were often present. Immunohistochemical assessment revealed a mixture of different types of histiocytes (with CD1a CD207, CD1a CD207, and CD1a CD207 CD163 cells). Genetic testing was performed in 5 cases; it revealed a BRAF mutation (p.V600E and p.485_490delinsF) in 2 cases, a HRAS mutation (p.T58I) in 1 case, a combination of 2 PTEN mutations in another case (p.I224M and p. R234W), and no mutations in the fifth case. All the lesions regressed spontaneously, and none recurred during follow-up.
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http://dx.doi.org/10.1097/DAD.0000000000001255DOI Listing
January 2019

New splicing pathogenic variant in EBP causing extreme familial variability of Conradi-Hünermann-Happle Syndrome.

Eur J Hum Genet 2018 12 22;26(12):1784-1790. Epub 2018 Aug 22.

Service de génétique, CHU de Poitiers, Poitiers, France.

X-linked dominant chondrodysplasia punctata (CDPX2 or Conradi-Hünermann-Happle syndrome, MIM #302960) is caused by mutations in the EBP gene. Affected female patients present with Blaschkolinear ichthyosis, coarse hair or alopecia, short stature, and normal psychomotor development. The disease is usually lethal in boys. Nevertheless, few male patients have been reported; they carry a somatic mosaicism in EBP or present with Klinefelter syndrome. Here, we report CDPX2 patients belonging to a three-generation family, carrying the splice variant c.301 + 5 G > C in intron 2 of EBP. The grandfather carries the variant as mosaic state and presents with short stature and mild ichthyosis. The mother also presents with short stature and mild ichthyosis and the female fetus with severe limb and vertebrae abnormalities and no skin lesions, with random X inactivation in both. This further characterizes the phenotypical spectrum of CDPX2, as well as intrafamilial variability, and raises the question of differential EBP mRNA splicing between the different target tissues.
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http://dx.doi.org/10.1038/s41431-018-0217-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244079PMC
December 2018

Epithelial barrier dysfunction in desmoglein-1 deficiency.

J Allergy Clin Immunol 2018 08 27;142(2):702-706.e7. Epub 2018 Apr 27.

Laboratory of Genetics of Monogenic Auto-inflammatory Diseases, Necker Branch, U1163, Necker-Enfants Malades Hospital (AP-HP), Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078820PMC
August 2018

Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder.

J Hepatol 2017 12 30;67(6):1334-1339. Epub 2017 Aug 30.

Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Institut National de la Santé et de la Recherche Médicale Unité 1163, Centre National de la Recherche Scientifique, Equipes de Recherche Labellisées 8254, Institut Imagine, Paris, France; Assistance Publique-Hopitaux de Paris (AP-HP), Hôpital Necker - Enfants Malades, Haematology Service, Paris, France.

Background & Aim: Several types of unexplained extra-hepatic manifestations, including haematological disorders, have been reported in the context of hepatitis E virus (HEV) infection. However, the underlying mechanism(s) of these manifestations are unknown. We provide evidence that HEV has an extra-hepatic endothelial tropism that can engage cutaneous T cells towards clonality.

Methods: A patient with a CD30(+) cutaneous T cell lymphoproliferative disorder (T-LPD) and biopsy-proven chronic HEV infection received three rounds of oral ribavirin treatment, administered either without or with interferon, and eventually achieved a sustained virologic response (SVR). Pathologic, virologic and immunologic investigations were carried out on biopsied skin lesion, and peripheral blood mononuclear cells between the 2nd and 3rd round of antiviral treatment and biopsied liver.

Results: Remission of T-LPD was observed upon antiviral treatment, and the patient remained in complete remission after achieving SVR. The T cell analysis showed large CD30(+) lymphocytes surrounding the blood vessels within the CD8(+) T cell infiltrate. HEV was detected within dermal microvascular endothelial cells using immunofluorescence staining, in situ hybridisation and electron microscopy. Infiltrating T cells mostly comprised memory CD8(+) T cells with a tissue-resident memory T cell phenotype. Overall, 98% of extracted T cells were CD8(+) T cells with aVβ signature skewed towards Vβ4 and with an oligoclonal profile. T cell clones from T-LPD were more like T cells in the liver than T cells in the blood [odds ratio=4.55, (3.70-5.60), p<0.0001]. No somatic mutations were found in the T-LPD exomes.

Conclusion: HEV has an extra-hepatic tissue tropism in humans, including dermal endothelium, and can induce CD30(+) T-LPD that is sensitive to antivirals.

Lay Summary: Hepatitis E virus (HEV) has an extra-hepatic tissue tropism and should be added to the list of viruses associated with lymphoproliferative disorders. As such, HEV should be part of the laboratory workup of any lymphoproliferation, particularly those of the T cell phenotype that involve the skin. In the context of HEV-associated cutaneous T cell lymphoproliferative disorders, antiviral treatment could be considered a first-line treatment instead of chemotherapy.
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http://dx.doi.org/10.1016/j.jhep.2017.08.011DOI Listing
December 2017

Multiplex epithelium dysfunction due to CLDN10 mutation: the HELIX syndrome.

Genet Med 2018 02 3;20(2):190-201. Epub 2017 Aug 3.

Qatar Biomedical Research Institute, Hamad Ben Khalifa University, Doha, Qatar.

PurposeWe aimed to identify the genetic cause to a clinical syndrome encompassing hypohidrosis, electrolyte imbalance, lacrimal gland dysfunction, ichthyosis, and xerostomia (HELIX syndrome), and to comprehensively delineate the phenotype.MethodsWe performed homozygosity mapping, whole-genome sequencing, gene sequencing, expression studies, functional tests, protein bioinformatics, and histological characterization in two unrelated families with HELIX syndrome.ResultsWe identified biallelic missense mutations (c.386C>T, p.S131L and c.2T>C, p.M1T) in CLDN10B in six patients from two unrelated families. CLDN10B encodes Claudin-10b, an integral tight junction (TJ) membrane-spanning protein expressed in the kidney, skin, and salivary glands. All patients had hypohidrosis, renal loss of NaCl with secondary hyperaldosteronism and hypokalemia, as well as hypolacrymia, ichthyosis, xerostomia, and severe enamel wear. Functional testing revealed that patients had a decreased NaCl absorption in the thick ascending limb of the loop of Henle and a severely decreased secretion of saliva. Both mutations resulted in reduced or absent Claudin-10 at the plasma membrane of epithelial cells.ConclusionCLDN10 mutations cause a dysfunction in TJs in several tissues and, subsequently, abnormalities in renal ion transport, ectodermal gland homeostasis, and epidermal integrity.
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http://dx.doi.org/10.1038/gim.2017.71DOI Listing
February 2018

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

APN/CD13 is over-expressed by Psoriatic fibroblasts and is modulated by CGRP and IL-4 but not by retinoic acid treatment.

J Cell Physiol 2018 Feb 23;233(2):958-967. Epub 2017 May 23.

Laboratory of Cellular and Molecular Basis of Normal Hematopoiesis and Hematological Disorders, INSERM UMR 1163, Paris, France.

Psoriasis vulgaris is a common skin inflammatory disease characterized by recurrent flare episodes associated with scaly well-demarcated skin plaques. Skin biopsies from psoriatic patients with high PASI score (22.67 ± 8.67) and from HD were used to study APN/CD13. APN/CD13 is over-expressed in LP and nLP compare to HD skins and fibroblasts. This over-expression is positively correlated with specific enzymatic activity enhancement. However, discrepancies between APN/CD13 expression in LP and nLP prompt us to focus our study on APN/CD13 modulation. Calcitonin Gene Related Peptide (CGRP), a neuropeptide, positively modulated expression and activity of APN/CD13. CGRP consistently induced IL4 secretion, which is also involved in the increase of APN/CD13 expression and activity, which is significantly reversed using IL-4 blocking antibody. Surprisingly, retinoic acid altered the APN/CD13 enzymatic activity only in nLP fibroblasts without modification of APN/CD13 expression. APN/CD13 is over-expressed on psoriatic fibroblasts and exerted high level of activity compare to HD fibroblasts. Taken together, several factors such as CGRP and IL-4 acted on positive regulation of APN/CD13 expression and activity. This study highlighted the interest of APN/CD13 as a new potential target, which should be investigated in psoriasis.
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http://dx.doi.org/10.1002/jcp.25941DOI Listing
February 2018

Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation.

Autophagy 2017 May 15;13(5):854-867. Epub 2017 Feb 15.

a Signalling Programme , The Babraham Institute , Babraham , UK.

The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting lysosome function, while others were developed to activate the pathway. Here, we report the surprising finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes. Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together, our data raise important issues regarding the interpretation of LC3 lipidation data and the use of autophagy modulators, and highlight the need for a greater understanding of the functional consequences of noncanonical autophagy.
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http://dx.doi.org/10.1080/15548627.2017.1287653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446083PMC
May 2017

Eosinophilic esophagitis and colonic mucosal eosinophilia in Netherton syndrome.

J Allergy Clin Immunol 2017 06 23;139(6):2003-2005.e1. Epub 2016 Dec 23.

Descartes-Sorbonne Paris Cité University, Paris, France; Department of Dermatology, Referral Center for Genodermatoses (MAGEC), Imagine Institute, Necker-Enfants Malades Hospital (AP-HP), Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.10.045DOI Listing
June 2017

Cutaneous and Visceral Chronic Granulomatous Disease Triggered by a Rubella Virus Vaccine Strain in Children With Primary Immunodeficiencies.

Clin Infect Dis 2017 Jan 6;64(1):83-86. Epub 2016 Oct 6.

Biology of Infection Unit, Laboratory of Pathogen Discovery, Inserm U1117.

Persistence of rubella live vaccine has been associated with chronic skin granuloma in 3 children with primary immunodeficiency. We describe 6 additional children with these findings, including 1 with visceral extension to the spleen.
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http://dx.doi.org/10.1093/cid/ciw675DOI Listing
January 2017

New regulations for oral contraceptive prescription in France in 2013: what is the impact on adult female acne?

Eur J Dermatol 2016 Aug;26(4):345-9

Department of Dermatology, University of Nantes, France.

In 2012, a young French woman lodged a complaint against a pharmaceutical company having suffered a cerebral stroke. The French health authority recommended all prescribers of hormonal contraception (HCP) to favour second-generation HCP. To evaluate the consequences of these recommendations on female acne. A prospective multicentre study using a standardised questionnaire completed by 1,724 women. The mean age was 26.57 years; 58.7% of the women had changed their HCP during the last 12 months. The initial ratio of first or second/third or fourth-generation drugs was 5.5%/82.9% which changed after the recommendations to 70.6%/29.4%. Among the patients who switched from third or fourth to first or second-generation drugs, 83.9% considered that their acne had worsened (p<0.0001). In those patients who received a local acne treatment, 72.1% had additional systemic treatment. This study confirms the important rise in prescriptions of first or second-generation HCP. This switch has resulted in a significant increase in acne, requiring treatment for the large majority of patients, thus confirming the role of a hormonal factor in female acne.
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http://dx.doi.org/10.1684/ejd.2016.2773DOI Listing
August 2016

Skin Biopsy in Netherton Syndrome: A Histological Review of a Large Series and New Findings.

Am J Dermatopathol 2016 Feb;38(2):83-91

*Dermatopathologist and Dermatologist, Department of Pathology, Hôpital Necker-Enfants Malades, APHP, Paris, France; Reference Center for Rare Cutaneous Diseases MAGEC, Hôpital Necker-Enfants Malades, APHP, Paris, France; Department of Dermatology, Hôpital Necker-Enfants Malades, APHP, Paris, France; †Head of the Department of Dermatology, Department of Pathology, Hôpital Necker-Enfants Malades, APHP, Paris, France; Reference Center for Rare Cutaneous Diseases MAGEC, Hôpital Necker-Enfants Malades, APHP, Paris, France; University Paris Descartes-Sorbonne Paris Cité, Paris, France; ‡Researcher, University Paris Descartes-Sorbonne Paris Cité, Paris, France; INSERM UMR 1163, Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France; §Senior Consultant in Dermatology, Department of Pathology, Hôpital Necker-Enfants Malades, APHP, Paris, France; Reference Center for Rare Cutaneous Diseases MAGEC, Hôpital Necker-Enfants Malades, APHP, Paris, France; University Paris Descartes-Sorbonne Paris Cité, Paris, France; ¶Dermatologist, Department of Pathology, Hôpital Necker-Enfants Malades, APHP, Paris, France; Reference Center for Rare Cutaneous Diseases MAGEC, Hôpital Necker-Enfants Malades, APHP, Paris, France; ‖Head of the Department of Pediatric Dermatology, University Children's Hospital Zürich and University Hospital Zürich, Zürich, Switzerland; **Senior Dermatologist, Department of Dermatology, Hôpital Fournier, Nancy, France; ††Medical Doctor, Department of Dermatology, MAGEC, Hôpital Saint Louis, APHP, Paris, France; ‡‡Assistant Professor, Department of Pathology, Hôpital Henri Mondor, APHP, Paris, France; §§Head of the Department of Pathology, Hôpital Necker-Enfants Malades, APHP, Paris, France; University Paris Descartes-Sorbonne Paris Cité, Paris, France; ¶¶Professor of Genetics, University Paris Descartes-Sorbonne Paris Cité, Paris, France; Director of Genetic Skin Disease Laboratory, INSERM UMR 1163, Laboratory o

Netherton syndrome (NS) is a severe genetic skin disorder, with often delayed or misleading clinical signs. The histological features of skin biopsies, usually described as a psoriasiform hyperplasia, have only been reported in isolated case reports or small case series. The aim of this study is to define, for the first time, the precise histological pattern of cutaneous lesions, in a large cohort of skin biopsies from confirmed NS patients. The study included 80 consecutive skin biopsies from 67 patients taken between January 1995 and June 2014. All were from confirmed NS patients with either a negative lympho-epithelial Kazal-type-related inhibitor (LEKTI) immunohistochemistry and/or molecular confirmation by identified mutation in SPINK5. In this cohort, the most frequent histological finding was also psoriasiform hyperplasia, but there were additional, less common, or previously unreported findings, including compact parakeratosis with large nuclei, subcorneum or intracorneum splitting, presence of clear cells in the upper epidermis or stratum corneum, dyskeratosis, dermal infiltrate with neutrophils and/or eosinophils, and dilated blood vessels in the superficial dermis. An early confirmation of the diagnosis of NS is essential for improved patient management. Thus, in the situation of a patient with an unknown skin disorder and non specific clinical presentation, the dermatopathologist may now be able to suggest the diagnosis of NS based on these newly reported characteristics. However, LEKTI immunohistochemistry remains the essential diagnostic investigation in cases with misleading or nonspecific histological features and is mandatory for the definitive diagnosis of NS in all patients.
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http://dx.doi.org/10.1097/DAD.0000000000000425DOI Listing
February 2016

Melanoma in xeroderma pigmentosum type C children: Overrepresentation of desmoplastic type?

J Am Acad Dermatol 2015 Jun;72(6):e173-6

Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Dermatology, Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2015.02.1124DOI Listing
June 2015

Assessment and effective targeting of Interleukin-1 in multicentric reticulohistyocytosis.

Joint Bone Spine 2015 Jul 13;82(4):280-3. Epub 2015 Mar 13.

Department of Internal Medicine, université Paris VI, hôpital Tenon, département hospitalo-universitaire I2B, Assistance Publique-Hôpitaux de Paris, 75020 Paris, France.

Multicentric reticulohistyocytosis (MRH) is a rare multisystemic non-Langerhans histiocytosis characterized by cutaneous nodules and severe destructive polyarthritis, sometimes associated with constitutional symptoms and various organ involvements. Its treatment remains empirical and challenging. We first report herein, the successful treatment of a multicentric reticulohistiocytosis patient with anakinra based on cutaneous biopsy immunostaining and serum cytokines features. A first-line treatment associating methotrexate, cortisone and hydoxychloroquine showed none improvement. Therefore, while further tests were performed to rule out an associated malignancy, auto-immune disease or mycobacterial infection, a treatment with anakinra was chosen instead of anti-TNF-alpha drugs. As soon as the 5th day, anakinra allowed control of fever, then rapid improvement of constitutional symptoms, arthritis, cutaneous lesions, and normalization of C-reactive protein, IL-6, and especially IL-1β levels. Then methotrexate was added, while anakinra was removed at the 12th month, with persistent and complete remission over the two-year follow up. Further assessment of IL-1 pathogenic role and blockade on larger cohorts of patient could open new therapeutic perspectives for refractory/relapsing MRH, considering the good tolerance profile of specific targeting drugs.
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http://dx.doi.org/10.1016/j.jbspin.2015.02.003DOI Listing
July 2015

Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin.

J Invest Dermatol 2015 Jul 10;135(7):1781-1789. Epub 2015 Feb 10.

Université Pierre et Marie Curie, Paris, France; UMR 1138, INSERM, Centre de Recherche des Cordeliers, Paris, France.

A major deleterious side effect of glucocorticoids is skin atrophy. Glucocorticoids activate the glucocorticoid and the mineralocorticoid (MR) receptor, both present in the epidermis. We hypothesized that glucocorticoid-induced epidermal atrophy may be related to inappropriate occupancy of MR by glucocorticoids. We evaluated whether epidermal atrophy induced by the topical glucocorticoid clobetasol could be limited by coadministration of MR antagonist. In cultured human skin explants, the epidermal atrophy induced by clobetasol was significantly limited by MR antagonism (canrenoate and eplerenone). Blockade of the epithelial sodium channel ENaC by phenamil was also efficient, identifying a role of MR-ENaC cascade in keratinocytes, acting through restoration of clobetasol-induced impairment of keratinocyte proliferation. In the SPIREPI randomized double-blind controlled trial, gels containing clobetasol, the MR antagonist spironolactone, both agents, or placebo were applied on four zones of the forearms of 23 healthy volunteers for 28 days. Primary outcome was histological thickness of the epidermis with clobetasol alone or clobetasol+spironolactone. Spironolactone alone did not affect the epidermal thickness but coapplication of clobetasol and spironolactone significantly limited clobetasol-induced atrophy and was well tolerated. Altogether, these findings identify MR as a factor regulating epidermal homeostasis and suggest that topical MR blockade could limit glucocorticoid-induced epidermal atrophy.
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http://dx.doi.org/10.1038/jid.2015.44DOI Listing
July 2015

Multicentre consensus recommendations for skin care in inherited epidermolysis bullosa.

Orphanet J Rare Dis 2014 May 20;9:76. Epub 2014 May 20.

Dermatology Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza S, Onofrio, 4, 00165 Rome, Italy.

Background: Inherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by fragility and blistering of skin and mucous membranes. Clinical features combined with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy allow to define the EB type and subtype. Molecular diagnosis is nowadays feasible in all EB subtypes and required for prenatal diagnosis. The extent of skin and mucosal lesions varies greatly depending on EB subtype and patient age. In the more severe EB subtypes lifelong generalized blistering, chronic ulcerations and scarring sequelae lead to multiorgan involvement, major morbidity and life-threatening complications. In the absence of a cure, patient management remains based on preventive measures, together with symptomatic treatment of cutaneous and extracutaneous manifestations and complications. The rarity and complexity of EB challenge its appropriate care. Thus, the aim of the present study has been to generate multicentre, multidisciplinary recommendations on global skin care addressed to physicians, nurses and other health professionals dealing with EB, both in centres of expertise and primary care setting.

Methods: Almost no controlled trials for EB treatment have been performed to date. For this reason, recommendations were prepared by a multidisciplinary team of experts from different European EB centres based on available literature and expert opinion. They have been subsequently revised by a panel of external experts, using an online-modified Delphi method to generate consensus.

Results: Recommendations are reported according to the age of the patients. The major topics treated comprise the multidisciplinary approach to EB patients, global skin care including wound care, management of itching and pain, and early diagnosis of squamous cell carcinoma. Aspects of therapeutic patient education, care of disease burden and continuity of care are also developed.

Conclusion: The recommendations are expected to be useful for daily global care of EB patients, in particular in the community setting. An optimal management of patients is also a prerequisite to allow them to benefit from the specific molecular and cell-based treatments currently under development.
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http://dx.doi.org/10.1186/1750-1172-9-76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110526PMC
May 2014

Congenital erosive and vesicular dermatosis: a new case and review of the literature.

Pediatr Dermatol 2012 Nov-Dec;29(6):756-8. Epub 2011 Dec 30.

Service de Dermatologie, Hôpital Necker-Enfants Malades, Université Paris V-Descartes, Paris, France.

Congenital erosive and vesicular dermatosis is a rare syndrome first described by Cohen et al in 1985. Most of the 18 cases published have been reported in premature newborns. Affected babies typically present with erosions and vesicles that tend to heal shortly after birth with reticulated scaring. We report an additional case, followed up for 5 years, in which we excluded a pathogenic mutation in the TP63 gene.
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http://dx.doi.org/10.1111/j.1525-1470.2011.01663.xDOI Listing
September 2013
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