Publications by authors named "Christine Bodemer"

200 Publications

Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa.

Front Genet 2021 1;12:705019. Epub 2021 Sep 1.

Holostem Terapie Avanzate, s.r.l, Modena, Italy.

Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene has been the first genetic skin disease successfully tackled by gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of -related JEB. Autologous clonogenic keratinocytes will be isolated from patients' skin biopsies, genetically corrected with a gamma-retroviral vector (γRV) carrying the full-length human cDNA and plated onto a fibrin support (144cm). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses. Clinical Trial Registration: EudraCT Number: 2018-000261-36.
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http://dx.doi.org/10.3389/fgene.2021.705019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440932PMC
September 2021

Therapeutic plasma exchange for life-threatening pediatric disorders.

J Clin Apher 2021 Sep 1. Epub 2021 Sep 1.

Hôpital Necker Enfants Malades, Paris, France.

Introduction: Therapeutic plasma exchange (TPE) is acknowledged to be an effective treatment in life-threatening pediatric disorders. Apheresis for pediatric diseases has been poorly investigated, and most studies to date featured small numbers of patients and lacked control groups. The objective of the present study was to evaluate the tolerance of TPE in pediatric patients.

Materials And Methods: A retrospective cohort study via a web-based electronic case report form including pediatric patients referred for TPE between January 2005 and December 2014.

Results: A total of 78 patients (median [range] age: 9.8 [0.53-17.93]) and 731 TPE procedures were analyzed. The indications were antibody-mediated rejection (n = 33; 42%) and desensitization therapy (n = 5; 6%) after solid organ or hematopoietic stem cell transplantation, thrombotic microangiopathy (n = 17; 22%), pediatric inflammatory diseases (n = 16; 21%), kidney diseases (n = 6; 8%), and hyperviscosity syndrome (n = 1; 1%). On average, each patient underwent six procedures during the first session [range: 1-19]. In the 2 weeks following the start of a session, 72 patients (92%) presented a total of 311 adverse events (AEs) potentially related to TPE. The risk of AEs was not related to the indication for TPE, the intensity of care, venous access, plasma substitute use, or body weight. None of the deaths was related to the TPE.

Conclusion: We studied one of the largest retrospective pediatric cohorts described to date. Our experience of TPE children's TPE feasibility concerned specific, life-threatening conditions and otherwise treatment-refractory diseases.
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http://dx.doi.org/10.1002/jca.21934DOI Listing
September 2021

The association of Greig syndrome and mastocytosis reveals the involvement of hedgehog pathway in advanced mastocytosis.

Blood 2021 Aug 23. Epub 2021 Aug 23.

IMAGINE Institute- INSERM UMR 1163, Paris, France.

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in one or several organs. Although a somatic KIT D816V mutation is detected in ~85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From three children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, MIM#175700) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and overactive in neoplastic MCs. We show that GLI3 and KIT mutations have a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, we show that Hh inhibitors suppress neoplastic MC proliferation in vitro and extend the survival time of aggressive systemic mastocytosis (ASM) mice. This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in ASM, leading to the identification of new promising therapeutic targets.
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http://dx.doi.org/10.1182/blood.2020010207DOI Listing
August 2021

Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A.

J Exp Med 2021 Oct 13;218(10). Epub 2021 Aug 13.

Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, Institut National de la Santé et de la Recherche Médicale, Unité mixte de recherche 1163, Paris, France.

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
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http://dx.doi.org/10.1084/jem.20201560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374862PMC
October 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

The Burden of Autosomal Recessive Congenital Ichthyoses on Patients and their Families: An Italian Multicentre Study.

Acta Derm Venereol 2021 Jun 22;101(6):adv00477. Epub 2021 Jun 22.

IDI-IRCCS (Istituto Dermopatico dell'Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico, Dermatological Research Hospital), Via Monti di Creta 104, IT-00167 Rome, Italy.

Autosomal recessive congenital ichthyoses (ARCI) are characterized by generalized skin scaling, hyperkeratosis, erythroderma, and disabling features affecting the skin (palmoplantar keratoderma, fissures, pain, itch), eyes, ears, and joints. Disease severity and chronicity, patient disfigurement, and time and costs required for care impose a major burden on quality of life. This multicentre cross-sectional study investigated the impact of ARCI on quality of life of patients and families, using the Dermatology Life Quality Index (DLQI), the Children DLQI (CDLQI) and Family Burden of Ichthyosis (FBI) questionnaires. Disease severity was assessed by a dermatologist. A total of 94 patients were recruited, of whom 52 (55.3%) children. Mean age was 20.1 (median 13.5) years. The mean CDLQI/DLQI score was 7.8, and 21 patients scored >10, indicating a major impairment in quality of life: symptoms, feelings and treatment problems were the most affected domains of quality of life. FBI showed a major repercussion on psychological factors and work. The results of this study highlight the impact of ARCI on specific aspects of patient and family life, underlining the need for psychological support.
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http://dx.doi.org/10.2340/00015555-3822DOI Listing
June 2021

Interferon-β Therapy in a Patient with Incontinentia Pigmenti and Autoantibodies against Type I IFNs Infected with SARS-CoV-2.

J Clin Immunol 2021 07 25;41(5):931-933. Epub 2021 Mar 25.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, EU, France.

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http://dx.doi.org/10.1007/s10875-021-01023-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990897PMC
July 2021

JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study.

Rheumatology (Oxford) 2021 Feb 12. Epub 2021 Feb 12.

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

Objective: To evaluate the efficacy and safety of JAK inhibitors (JAKi) in juvenile dermatomyositis (JDM).

Methods: We conducted a single-center retrospective study of patients with JDM treated by JAKi with a follow-up of at least 6 months. Proportion of clinically inactive disease (CID) within six months of JAKi initiation was evaluated using PRINTO criteria and skin Disease Activity Score. Serum IFN-α concentration was measured by SIMOA assay.

Results: Nine refractory and one new-onset patients with JDM treated with ruxolitinib (n = 7) or baricitinib (n = 3) were included. The main indications for treatment were refractory muscle involvement (n = 8) and ulcerative skin disease (n = 2). CID was achieved in 5/10 patients (2/2 anti-MDA5, 3/4 anti-NXP2, 0/3 anti-TIF1γ positive patients) within six months of JAKi introduction. All responders could withdraw plasmatic exchange, immunoadsorption and other immunosuppressive drugs. The mean daily steroid dose decreased from 1.1 mg/Kg (range 0.35-2 mg/Kg/d) to 0.1 (range, 0-0.3, p= 0.008) in patients achieving CID, and was stopped in two. Serum IFN-α concentrations were elevated in all patients at the time of treatment initiation and normalized in both responder and non-responder. A muscle biopsy repeated in one patient 26 months after the initiation of JAKi, showed a complete restoration of muscle endomysial microvascular bed. Herpes zoster and skin abscesses developed in three and two patients, respectively.

Conclusion: JAKis resulted in a CID in a subset of new-onset or refractory patients with JDM and may dramatically reverse severe muscle vasculopathy. Overall tolerance was good except for a high rate of herpes zoster infection.
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http://dx.doi.org/10.1093/rheumatology/keab116DOI Listing
February 2021

Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies.

J Clin Immunol 2021 04 7;41(3):603-609. Epub 2021 Jan 7.

General Paediatrics- Infectious Diseases and Internal Medicine Department, Robert-Debré Hospital, AP-HP, Nord - Université de Paris, Paris, France.

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
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http://dx.doi.org/10.1007/s10875-020-00952-xDOI Listing
April 2021

Criteria for the Regression of Pediatric Mastocytosis: A Long-Term Follow-Up.

J Allergy Clin Immunol Pract 2021 04 15;9(4):1695-1704.e5. Epub 2020 Dec 15.

Department of Dermatology, Reference Center for Genodermatoses (MAGEC), Necker-Enfants Malades Hospital (AP-HP5), Paris-Centre University, Imagine Institute, INSERM U1163, Paris, France. Electronic address:

Background: Mastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in 1 or more organ. Adults tend to have persistent, systemic mastocytosis, whereas MC infiltration in children is usually limited to the skin and typically regresses after several years. Both adults and children could display mast cell activation symptoms (MCASs) due to MC mediator release. In more than 85% of both adult and pediatric cases, KIT mutations are present, with the KIT D816V mutation being present in most affected adults but in only half the affected children.

Objective: To identify the clinical, biological, and molecular factors associated with the regression of cutaneous mastocytosis (CM) in children, and to assess the correlation between MCASs and CM regression.

Methods: Patients having suffered from pediatric-onset mastocytosis for at least 8 years were included in a longitudinal cohort study. Clinical data, the baseline serum tryptase level, the KIT sequence, and the progression of MCASs and CM were recorded.

Results: CM regressed in 210 of the 272 included patients (77.2%; mean time to regression, 6.10 years). The rare cases of aggressive systemic mastocytosis were symptomatic from the outset. Congenital mastocytosis and the KIT D816V mutation were associated with CM regression (odds ratio, 0.48, P = .031, and 0.173, P = .031, respectively). Aggravation of MCASs over time was correlated with the persistence of skin lesions. However, the MCASs became more intense in 19% of the patients with MCASs at baseline and CM regression, justifying long-term follow-up in this setting.

Conclusions: Our results open up new hypotheses with regard to the spontaneous regression of CM in pediatric patients.
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http://dx.doi.org/10.1016/j.jaip.2020.12.019DOI Listing
April 2021

From Diagnosis to Prognosis: Revisiting the Meaning of Muscle ISG15 Overexpression in Juvenile Inflammatory Myopathies.

Arthritis Rheumatol 2021 06 26;73(6):1044-1052. Epub 2021 Apr 26.

Institut Mondor de Recherche Biomédicale, Université Paris-Est Créteil, INSERM, Centre de Reference pour les Maladies Neuromusculaires, Hôpital Necker-Enfants Malades, AP-HP, FILNEMUS, Paris, France.

Objective: Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology.

Methods: The study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real-time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed.

Results: ISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up-regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation-associated gene 5 (MDA-5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing.

Conclusion: Muscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG-15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA-5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement.
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http://dx.doi.org/10.1002/art.41625DOI Listing
June 2021

Major response to imatinib and chemotherapy in a newborn patient prenatally diagnosed with generalized infantile myofibromatosis.

Pediatr Blood Cancer 2021 01 8;68(1):e28576. Epub 2020 Sep 8.

SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut Curie, PSL University, Paris, France.

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http://dx.doi.org/10.1002/pbc.28576DOI Listing
January 2021

Early management of sight threatening retinopathy in incontinentia pigmenti.

Orphanet J Rare Dis 2020 08 27;15(1):223. Epub 2020 Aug 27.

Ophthalmology Department and Rare Eye Disease Reference Center OPHTARA, Necker-Enfants malades University Hospital, AP-HP, Paris, France.

Background: Early blindness secondary to incurable retinal detachment is one of the main complications of incontinentia pigmenti (IP). The efficiency of ophthalmological management for preventing such evolution has not been proven. The objective of this retrospective study was to report a screening and treatment strategy of the vascular retinopathy in newborns and infants with IP.

Results: All files of patients diagnosed with IP within the two first months of life in a single tertiary referral center, between 2010 and 2015, were retrospectively included. The minimum follow-up duration was three years. Patients had undergone systematic indirect ophthalmoscopy examination, looking for signs of peripheric retinal vasculopathy, according to a standardized schedule: at diagnosis, at age 1, 2, 3, 6, 9, 12, 18 and 24 months, and then once a year. Urgent laser therapy was performed under anesthesia in case of signs of retinal ischemia. Nineteen children files (17 girls) were studied. Median age at IP diagnosis was 1 day [0-44]; median age at first retinal evaluation was 25 days. Retinal manifestations occurred in 7 patients (n = 10/38 eyes, 26.3%); they were diagnosed at median age 19 days [3-59]. These patients underwent one or two ablative session per eye (mean 1.7, median 2), under general anaesthesia. No retinal detachment or fold occurred during the follow-up (median 6 years [3-9.8]).

Conclusion: Ocular screening should be performed in all cases of IP as soon as possible after diagnosis. A strict ophthalmological monitoring and prophylactic treatment of retinal vasculopathy can efficiently prevent the early blinding complications of the disease.
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http://dx.doi.org/10.1186/s13023-020-01509-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450972PMC
August 2020

Wound closure in epidermolysis bullosa: data from the vehicle arm of the phase 3 ESSENCE Study.

Orphanet J Rare Dis 2020 07 21;15(1):190. Epub 2020 Jul 21.

Amicus Therapeutics, Inc., Cranbury, NJ, USA.

Background: Chronic wounds are a fundamental issue for patients with epidermolysis bullosa (EB). Herein, we assess the natural history of wound closure in patients with EB who were randomly assigned to the vehicle-control arm of the multicenter, randomized, double-blind, phase 3 ESSENCE (NCT02384460) trial.

Methods: ESSENCE was designed to assess the efficacy and safety of a topical cream formulation of 6% allantoin (SD-101 6%) vs vehicle (SD-101 0%) in patients ≥1 month old who had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10-50 cm present for ≥21 days. Time to complete target wound closure and the proportion of patients with target wound closure over time were analyzed overall and by parameters including patient age and baseline body surface area index (BSAi) of total wound burden (< 5% and ≥ 5%). Changes in BSAi of lesional skin, pain, and itching were also assessed.

Results: The vehicle-control arm included 87 patients. Mean (standard deviation [SD]) time to target wound closure within 3 months was 53.6 (28.6) days, with a range of 14 to 142 days. The proportion of patients with target wound closure increased over time from 7.1% at day 14 to 53.6% at month 3. Mean (SD) changes from baseline in BSAi of total wound burden and BSAi of lesional skin at month 3 were -2.3% (6.3) and -5.0% (13.5) of total body coverage, respectively. Reductions in pain and itching were observed at day 7 and maintained for 3 months. Faster healing times and a greater proportion of patients with wound closure were observed in patients aged 1 month to < 2 years; those with wounds < 30 days old, and in those with BSAi of total body wound burden < 5%.

Conclusions: Treatment response observed in the vehicle-control arm of the ESSENCE study was unexpectedly high and may have been due to unforeseen benefits of vehicle or enhanced wound care provided by the clinical trial staff. These observations will help inform the study design of future trials in patients with EB.

Trial Registration: ClinicalTrials.gov , NCT02384460 ; Date of registration: February 13, 2015; First participant enrollment: March 11, 2015.
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http://dx.doi.org/10.1186/s13023-020-01435-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374851PMC
July 2020

Efficacy and tolerability of the investigational topical cream SD-101 (6% allantoin) in patients with epidermolysis bullosa: a phase 3, randomized, double-blind, vehicle-controlled trial (ESSENCE study).

Orphanet J Rare Dis 2020 06 23;15(1):158. Epub 2020 Jun 23.

Amicus Therapeutics, Inc, Cranbury, NJ, USA.

Background: Epidermolysis bullosa (EB) is a rare genetic disorder that manifests as blistering and/or skin erosion. There is no approved treatment for EB; current standard of care consists of wound and pain management. SD-101 6% is a topical cream containing 6% allantoin that was developed for treating skin lesions in patients with EB. The aim of this phase 3, multicenter, randomized, double-blind, vehicle-controlled study was to assess the efficacy and safety of SD-101 6% cream versus vehicle (0% allantoin) on lesions in patients with EB.

Methods: Eligible patients were ≥1 month old, had a diagnosis of EB (simplex, recessive dystrophic, or intermediate junctional) and a target wound 10-50 cm in size that was present for ≥21 days. Patients were randomly assigned to SD-101 6% cream or vehicle, which was applied topically once a day to the entire body for 3 months. Primary efficacy endpoints were time to complete target wound closure within 3 months and the proportion of patients who experienced complete target wound closure within 3 months. Post hoc subgroup analyses were conducted by patient age and in those with body surface area index of total body wound burden ≥5% at baseline.

Results: In total, 169 patients were enrolled and randomly assigned to SD-101 6% (n = 82) or vehicle (n = 87). Baseline demographics and disease characteristics were similar between treatment groups. There were no statistically significant differences between treatment groups in time to target wound closure (hazard ratio, 1.004; 95% confidence interval [CI] 0.651, 1.549; P = 0.985) or proportion of patients with complete target wound closure within 3 months (odds ratio [95% CI], 0.733 [0.365, 1.474]; nominal P = 0.390). A positive trend toward faster wound closure with SD-101 6% versus vehicle was observed in patients aged 2 to <12 years and those with total body wound burden ≥5% at baseline. SD-101 6% cream was well tolerated.

Conclusions: SD-101 6% cream for treatment of EB-associated lesions was not more effective than vehicle in shortening the time to complete target wound closure or achieving complete target wound closure within 3 months.

Trial Registration: ClinicalTrials.gov, NCT02384460; Date of trial registration, February 13, 2015; First participant enrolled, March 11, 2015.
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http://dx.doi.org/10.1186/s13023-020-01419-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310548PMC
June 2020

Emergency management in epidermolysis bullosa: consensus clinical recommendations from the European reference network for rare skin diseases.

Orphanet J Rare Dis 2020 06 6;15(1):142. Epub 2020 Jun 6.

Dermatology Department, reference Centre MAGEC, Necker- Enfants Malades Hospital, Paris-Centre University, Paris, France.

Epidermolysis bullosa (EB) comprises a group of genetic disorders with the hallmark of fragility of the skin and mucosal surfaces. The severity of different types of EB varies markedly as does the occurrence of extra-cutaneous involvement and complications. A number of emergency situations may occur in the context of EB including obstruction to oral intake from oral or esophageal blisters or scarring, acute airway obstruction, acute urinary retention, sepsis and corneal erosions. Whilst general management principles apply in each of these settings, specific considerations are essential in managing EB to avoid undue trauma or damage to delicate tissues. These recommendations have been developed from a literature review and consensus from experts of the European Network for Rare Skin Disorders (ERN-Skin) to aid decision-making and optimize clinical care by non-EB expert health professionals encountering emergency situations in babies, children and adults with EB.
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http://dx.doi.org/10.1186/s13023-020-01403-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276067PMC
June 2020

The histopathology of congenital haemangioma and its clinical correlations: a long-term follow-up study of 55 cases.

Histopathology 2020 Aug 26;77(2):275-283. Epub 2020 Jul 26.

Paris Descartes University, Sorbonne Paris Cité, Paris, France.

Aims: Congenital haemangiomas (CHs) can be subdivided into different subtypes [rapidly involuting CHs (RICHs), non-involuting CHs (NICHs), and partially involuting CHs (PICHs)]. During the first few days of life, RICHs may be associated with transient but sometimes marked thrombocytopenia. We sought to assess the histological aspects and clinicopathological correlations of the three subtypes.

Methods And Results: We assessed the histopathological features of 10 RICHs, 25 NICHs, and 20 PICHs, described the patients' long-term clinical outcomes, and assessed clinicopathological correlations. All CHs were located in the dermis and hypodermis, and comprised both capillary lobules (with three distinct histopathological patterns) and extralobular large vessels. Most of the extralobular vessels were abnormal veins and abnormal lymphatic vessels. We did not observe significant correlations between the CH subtype, the histopathological pattern, and the time of the histopathological assessment. Interestingly, unexpected intralobular expression of podoplanin was found in neonatal biopsies of five RICHs and PICHs. Four of these five patients had concomitant thrombocytopenia. The podoplanin staining intensity decreased over time as the thrombocytopenia resolved and the tumour shrank.

Conclusion: The histopathological features were similar in all three subtypes of CH, and were related to the time since disease onset; we consider that RICH, PICH and NICH form a single entity and differ only in their involuting potential. Along with the transient expression of intralobular podoplanin observed in some specimens from the newborn, the lobular architecture might lead to misdiagnosis of tufted haemangioma or kaposiform haemangioendothelioma.
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http://dx.doi.org/10.1111/his.14114DOI Listing
August 2020

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects.

Br J Clin Pharmacol 2020 10 24;86(10):2063-2069. Epub 2020 Apr 24.

Center for Ectodermal Dysplasias, University Hospital Erlangen, Germany.

In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.
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http://dx.doi.org/10.1111/bcp.14301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495278PMC
October 2020

Correction to: Italian translation, cultural adaptation, and pilot testing of a questionnaire to assess family burden in inherited ichthyoses.

Ital J Pediatr 2020 03 11;46(1):30. Epub 2020 Mar 11.

Department of Dermatology, Necker-Enfants Malades Hospital, Centre de Référence National pour les Maladies Génétiques à Expression Cutanée (MAGEC), APHP, Paris, France.

The original article contains a misspelling of co-author, Christine Bodemer's name which is presented correctly in this Correction article.
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http://dx.doi.org/10.1186/s13052-020-0791-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065451PMC
March 2020

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome.

Pediatr Dermatol 2020 May 10;37(3):541-544. Epub 2020 Mar 10.

Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), APHP, Institut Imagine, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France.

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.
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http://dx.doi.org/10.1111/pde.14139DOI Listing
May 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

Severe Abdominal Manifestations in Juvenile Dermatomyositis.

J Pediatr Gastroenterol Nutr 2020 02;70(2):247-251

Laboratoire d'Immunogénétique des maladies auto-immunes de l'enfant, Institut Imagine, INSERM U 1163.

Juvenile dermatomyositis (JDM) is a rare and heterogeneous pediatric-onset idiopathic inflammatory myopathy. Gastrointestinal (GI) involvement occurs in 22% to 37% of JDM patients but has only been described in case reports. In this retrospective, single-center, observational study, we aimed to assess the causes and management of severe GI manifestations in JDM patients. We studied a cohort of 9 patients among 110 JDM patients followed during the study period (8.3%). The GI complications were related to JDM in most cases (17/19), with digestive tract involvement (n = 10), acute pancreatitis (n = 4), and hepatitis (n = 3). Three patients died from refractory JDM 2.9 years (2-3.6) after the JDM diagnosis. We highlight the need to consider pancreatitis as a main diagnostic factor in JDM patients with severe GI manifestations and the requirement of early aggressive treatment for these patients.
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http://dx.doi.org/10.1097/MPG.0000000000002575DOI Listing
February 2020

Improvement of epidermal covering on AEC patients with severe skin erosions by PRIMA-1/APR-246.

Cell Death Dis 2020 01 16;11(1):30. Epub 2020 Jan 16.

Department of Dermatology and Reference center for Genodermatoses and Rare Skin Diseases (MAGEC), Paris, F-75006, France.

P63 is a major transcription factor regulating skin development and homeostasis. It controls many genes involved in cell proliferation, adhesion, and early differentiation. P63 is mutated in several rare syndromes called p63-related ectodermal dysplasia syndromes (ED). The main forms are EEC and AEC syndromes due to p63 missense mutations on the DBD and SAM domains, respectively. ED patients display many developmental defects, including ectrodactyly, clef/lip palate, and ectodermal dysplasia, while AEC patients suffer from severe skin erosions that not always heal. We have previously showed that ED-derived iPSC display altered epidermal commitment. P63 belongs to the p53 gene family sharing similar structural domains. We found that ED-iPSC epidermal commitment can be rescued by a p53-reactivating compounds called PRIMA-1, also named APR-246 and currently used in anticancer clinical trials. Here, we established primary epidermal culture from two AEC children (S.F. and Y.M.) suffering from persistent skin erosions at age of 9 and 15, respectively. These patients carry missense mutations on the SAM domain (I576T and I537T). We found that primary keratinocytes (KCs) isolated from these AEC patients underwent altered epidermal differentiation that was rescued by PRIMA-1 treatment. It prompted us to formulate the compound onto a cream that was topically applied on the right hand of one patient and on the scalp of the second patient. In both cases, the daily treatment allowed re-epithelialization of the eroded skin and a drastic loss of pain after few weeks, improving quality of life. Normally, mutant p63 exerts a dominant-negative effect, mainly through the formation of aggregate with WT p63 and p73. PRIMA-1 did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1 targets cell differentiation and not p63 activity directly. In conclusion, we propose that repurposing of the antitumoral PRIMA-1 compound could become a general treatment of AEC skin erosions.
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http://dx.doi.org/10.1038/s41419-020-2223-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965199PMC
January 2020

Devastating Gynecological Infections in Women with STAT3 Deficiency.

Clin Infect Dis 2020 10;71(7):e186-e190

Paris University, Necker-Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, University Hospital Institute (IHU)  Imagine, Paris, France.

We provide the first description of a series of 9 severe gynecological infections (mastitis and pelvic cellulitis) occurring in the French national cohort of women with STAT3 deficiency. Each episode had unique features in terms of clinical presentation, microbial documentation, location, treatment duration, and related persistent esthetic damage.
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http://dx.doi.org/10.1093/cid/ciaa020DOI Listing
October 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
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