Publications by authors named "Juliette Mazereeuw-Hautier"

85 Publications

Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial.

JAMA Dermatol 2021 Sep 15. Epub 2021 Sep 15.

University of Tours, Centre Hospitalier Régional Universitaire Tours, Department of Pediatric Radiology, Tours, France.

Importance: Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking.

Objective: To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment.

Design, Setting And Participants: This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020.

Interventions: Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient.

Main Outcomes And Measures: The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety.

Results: Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]).

Conclusions And Relevance: This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.

Trial Registration: ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamadermatol.2021.3459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444064PMC
September 2021

Annular lipoatrophy of the ankle: Four new pediatric cases and a review of the literature.

Pediatr Dermatol 2021 Aug 21. Epub 2021 Aug 21.

University Hospital, Larrey Hospital, Dermatology Department, Paul Sabatier University, Reference Centre for Rare Skin Diseases Toulouse, Toulouse, France.

Annular lipoatrophy of the ankle is a rare and unique acquired lipoatrophic panniculitis that mainly affects children. There is no consensus on treatment, and the long-term course is not well known. We present four new pediatric cases that contribute to the understanding of this rare disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pde.14670DOI Listing
August 2021

Health care transition for patients with vascular malformations: a French multicenter cross-sectional study.

Orphanet J Rare Dis 2021 08 6;16(1):352. Epub 2021 Aug 6.

Department of Dermatology and Reference Center for Rare Diseases and Vascular Malformations (MAGEC), CHRU Tours, Avenue de La République, 37044, Tours Cedex 9, France.

Background: Health care transition (i.e., transition from pediatric to adult care) is challenging in chronic conditions but has been poorly studied in rare chronic skin diseases. We investigated the proportion of lost to follow-up among patients with superficial vascular malformations after health care transition. We also collected patients' opinions. This prospective, multicenter, cross-sectional study was performed at 7 French hospitals. We included patients aged 19-25 years, who were followed for a superficial vascular malformation before age 16, and who had completed the transition period in 2020. Data were collected from medical records and a questionnaire was sent to included patients asking about the health care transition.

Results: Among the 90 patients included, 41 (46%) were lost to follow-up after health care transition period. The age at diagnosis was significantly higher for lost to follow-up than non- lost to follow-up patients. The lost to follow-up proportion was similar between patients who changed and did not change hospitals during the transition. Responses to the questionnaire were obtained for 47 of 90 patients (52.2% response rate); most were satisfied with their care (n = 31/36, 86.1%); however, a lack of psychological support was reported.

Conclusions: Health care transition is associated to a high rate of lost to follow-up. Early management seems associated to less lost to follow-up. Further studies are needed to better understand risk factors for a failed health care transition and its consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01970-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349005PMC
August 2021

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Series of 49 French Pediatric Cases.

J Allergy Clin Immunol Pract 2021 Jul 29. Epub 2021 Jul 29.

Service de Dermatologie, Hôtel Dieu, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and potentially fatal adverse reaction. It can be difficult to diagnose, even more so among children, because symptoms may mimic other commonly encountered pediatric conditions.

Objective: To describe clinical and laboratory features of DRESS syndrome in the pediatric population (age ≤18 years) and establish causative agents and treatment modalities.

Methods: This was a multicenter retrospective study of probable and definite DRESS cases (Registry of Sever Cutaneous Adverse Reaction score ≥ 4) in children hospitalized in 15 French university hospitals between 2000 and 2020.

Results: We included 49 cases. All children had fever and rash, 69.4% had lymphadenopathy, and 65.3% had facial edema. The most common organ affected was the liver (83.7%). Treatment consisted of topical corticosteroid in only 30.6% and systemic corticosteroid in 55.1%; 12.2% received intravenous immunoglobulin. Among probable and likely culprit drugs, 65% were antibiotics and 27.5% were antiepileptics, median time to DRESS symptom onset after initiation of 15 days (13 days with antibiotics and 21 days with antiepileptics). Twenty-seven children had allergy assessment for causative agents, 65.4% of whom had positive tests.

Conclusions: Culprit drugs are frequently antibiotics and antiepileptic drugs, and onset is often less than 2 weeks after treatment starts, especially with antibiotics. Treatment with topical corticosteroids appears to be sufficient in the least severe cases. Treatment by systemic corticosteroid therapy remains the reference treatment in case of severe organ damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2021.07.025DOI Listing
July 2021

Severe Phenotype in Patients with Large Deletions of .

Cancers (Basel) 2021 Jun 13;13(12). Epub 2021 Jun 13.

Lille University, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France.

Complete deletion of the gene is identified in 5-10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. -deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed an NF1 reference population. A deletion of the gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of -deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described "classic" NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the -deleted group. We described the largest -deleted cohort to date and clarified the more severe phenotype observed in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13122963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231977PMC
June 2021

Botulinum toxin injections as an effective treatment for patients with intertriginous Hailey-Hailey or Darier disease: an open-label 6-month pilot interventional study.

Orphanet J Rare Dis 2021 02 18;16(1):93. Epub 2021 Feb 18.

Reference Centre for Rare Skin Diseases, Dermatology Department (CRMRP), Larrey University Hospital, 24, Chemin de Pouvourville TSA 30030, 31059, Toulouse, France.

Background: Patients with Hailey-Hailey and Darier diseases present with disabling inflammatory lesions located in large skin folds, which are often exacerbated or induced by sweating. Quality of life is highly impaired because of pain and recurrent skin infections. An improvement in skin lesions after botulinum toxin A injections has previously been reported in some patients but no prospective interventional studies are available. The aim of this open-label, 6-month, interventional pilot study (NCT02782702) was to evaluate the effectiveness and safety of botulinum toxin A for patients with moderate to very severe skin lesions located in folds.

Results: Thirty patients (26 Hailey-Hailey/4 Darier) were included. Botulinum toxin A proved effective within the first month in two-thirds of patients, taking all study parameters (itchiness, cutaneous pain, sweating and odour, infections, psychosocial impairment and quality of life) into account and persisted during the 6-month follow-up period. No patient was classed as a BtxA non-responder, but 11 (37%) Hailey-Hailey patients (the most severe ones), experienced a relapse during the study. No serious side effects were reported. Mild transient clear fluid discharge at the site of the injections was reported for 27% of patients.

Conclusions: Botulinic toxin seems to be an effective and safe treatment for Hailey-Hailey and Darier diseases. Nevertheless, it may prove insufficient for the severest of Hailey-Hailey cases and could be considered as supplementary to other conventional treatments. Further studies are required to confirm our results on larger Darier cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01710-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893874PMC
February 2021

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

Genes (Basel) 2021 01 9;12(1). Epub 2021 Jan 9.

Department of Medical Sciences/Dermatology, Uppsala University, SE-751 85 Uppsala, Sweden.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12010080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826849PMC
January 2021

Clinical and neuroimaging findings in 33 patients with MCAP syndrome: A survey to evaluate relevant endpoints for future clinical trials.

Clin Genet 2021 05 20;99(5):650-661. Epub 2021 Jan 20.

Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, Dijon, France.

Megalencephaly-CApillary malformation-Polymicrogyria (MCAP) syndrome results from somatic mosaic gain-of-function variants in PIK3CA. Main features are macrocephaly, somatic overgrowth, cutaneous vascular malformations, connective tissue dysplasia, neurodevelopmental delay, and brain anomalies. The objectives of this study were to describe the clinical and radiological features of MCAP, to suggest relevant clinical endpoints applicable in future trials of targeted drug therapy. Based on a French collaboration, we collected clinical features of 33 patients (21 females, 12 males, median age of 9.9 years) with MCAP carrying mosaic PIK3CA pathogenic variants. MRI images were reviewed for 21 patients. The main clinical features reported were macrocephaly at birth (20/31), postnatal macrocephaly (31/32), body/facial asymmetry (21/33), cutaneous capillary malformations (naevus flammeus 28/33, cutis marmorata 17/33). Intellectual disability was present in 15 patients. Among the MRI images reviewed, the neuroimaging findings were megalencephaly (20/21), thickening of corpus callosum (16/21), Chiari malformation (12/21), ventriculomegaly/hydrocephaly (10/21), cerebral asymmetry (6/21) and polymicrogyria (2/21). This study confirms the main known clinical features that defines MCAP syndrome. Taking into account the phenotypic heterogeneity in MCAP patients, in the context of emerging clinical trials, we suggest that patients should be evaluated based on the main neurocognitive expression on each patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13918DOI Listing
May 2021

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

Acta Derm Venereol 2021 Mar 9;101(3):adv00408. Epub 2021 Mar 9.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3720DOI Listing
March 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pde.14265DOI Listing
September 2020

532 nm Q-switched laser for the treatment of hyperpigmentation induced by topical tacrolimus.

J Cosmet Laser Ther 2020 Feb 21;22(2):90-92. Epub 2020 Mar 21.

Department of Dermatology, Paul Sabatier University, Toulouse University Hospital, Toulouse, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14764172.2020.1740273DOI Listing
February 2020

Inflammatory Vegetative Lesions of the Perineum: A Rare and Severe Clinical Presentation of Netherton Syndrome.

Acta Derm Venereol 2020 Apr 23;100(8):adv00123. Epub 2020 Apr 23.

Department of Dermatology, Reference Center for Rare and undiagnosed Skin Diseases, Larrey Hospital, 24, Chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex 9, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3446DOI Listing
April 2020

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial.

Trials 2019 Dec 17;20(1):739. Epub 2019 Dec 17.

INSERM U1246 -SPHERE « MethodS in Patients-centered outcomes and HEalth REsearch », University of Nantes, University of Tours, 37000, Tours, France.

Background: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.

Methods: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm.

Discussion: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.

Trial Registration: ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-019-3767-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918625PMC
December 2019

Why is it so difficult for GPs to effectively manage patients with rare skin diseases?

Presse Med 2019 Dec 19;48(12):e382-e388. Epub 2019 Nov 19.

Toulouse University Hospital, Referral Centre for Rare Skin Diseases, Department of Dermatology, 31059 Toulouse cedex 09, France.

Background: Rare diseases are defined by a prevalence of less than one out of 2000 persons. In clinical practice, their management is difficult, due to their diversity, their complexity and a lack of adapted physician training.

Objective: The aims of this study were to identify rare skin diseases in a reference center, to describe the difficulties encountered by general practitioners (GPs) in management of these uncommon cases, and to pinpoint the characteristics of the GPs having the most problems.

Methods: A survey conducted from March to June 2017 involving GPs at least one of whose rare skin disease patients was being monitored in a reference center.

Results: All in all, 96/195 (49.2%) of the GPs contacted completed the questionnaire, and virtually all of them (95%) reported five main categories of difficulties: giving a diagnosis, monitoring treatment, coordinating care, providing support, and ensuring management of intercurrent pathologies. The most widely reported difficulties were related to diagnosis (88.5%) and care coordination (76%). The GPs most in need of assistance were those practicing in rural areas (11 times more likely to experience difficulties), those with over 10 years of experience (up to 9.8 times more risk) and those not considering their role in the management of patients with rare diseases as instrumental (2.28 times more risk).

Conclusions: This study brought to light the difficulties encountered by GPs in management of patients with rare skin diseases. We identified those the most in need of assistance, who are to be targeted for actions aimed at improving the care and treatment of patients suffering from rare skin diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lpm.2019.09.061DOI Listing
December 2019

Identification of Mutations in SDR9C7 in Three Patients with Autosomal Recessive Congenital Ichthyosis.

Acta Derm Venereol 2020 02 5;100(4). Epub 2020 Feb 5.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3359DOI Listing
February 2020

Segmental schwannomatosis: characteristics in 12 patients.

Orphanet J Rare Dis 2019 08 22;14(1):207. Epub 2019 Aug 22.

Service de Dermatologie, Hôpital Larrey, CHU de Toulouse, Toulouse, France.

Background: Segmental schwannomatosis is characterized by multiple schwannomas affecting one-limb or less than 5 contiguous segments of spine. Its characteristics are not well described in the literature. Our objective was to better describe the demographic and clinical characteristics of this condition.

Methods: This was a retrospective, bi-center study conducted in two French expert centers for neurofibromatosis and schwannomatosis. The clinical, radiographic, pathological and molecular aspects were extracted from patients' clinical records.

Results: Twelve patients with segmental schwannomatosis were identified. Eight were female and 4 were male. The median age at initial symptom was 29 years (range: 6-60 years) and the median age at diagnosis was 34.5 years (range: 13-65 years). Pain was the initial symptom for the majority of patients (7 of 12). The number of tumors was variable with six patients having more than 10 tumors. Peripheral distribution was seen in all patients. Quality of life could be impaired (median Dermatology Life Quality Index score was 4.5 (range: 2-13). The median duration of follow up was 3 years (range: 1-26). Chronic pain was the main complication (9 of 12 patients). Surgical intervention to control chronic pain was performed for 9 patients of whom 5 experienced recurrence of tumors. Molecular investigations revealed heterozygous LZTR1 variants in 3 of 9 patients.

Conclusion: Segmental schwannomatosis is a rare condition that may start early in life and often remains undiagnosed for many years. Pain is the main symptom and consequently could impair the quality of life. Surgery seems to be effective, but recurrences are frequent. Some patients carried heterozygous LZTR1 variants. Further studies are needed to better understand this rare condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1176-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704629PMC
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40272-019-00335-9DOI Listing
June 2019

Keratitis-Ichthyosis-Deafness Syndrome: Early Death Caused by the GJB2 Mutation p.Gly12Arg.

Acta Derm Venereol 2019 09;99(10):921-922

Dermatology Department, Reference Center for Rare Skin Diseases, CHU Larrey, Université Paul Sabatier, 31000 Toulouse, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3218DOI Listing
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pde.13748DOI Listing
March 2019

Effect of Topical Rapamycin 1% on Multiple Trichoepitheliomas.

Acta Derm Venereol 2019 Apr;99(4):454-455

Department of Dermatology, Reference Centre for Rare Skin Diseases, Paul Sabatier University, FR- 31400 Toulouse, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3116DOI Listing
April 2019

Compounded topical preparations in plaque psoriasis: Still a place for it in 2018?

Dermatol Ther 2019 01 28;32(1):e12780. Epub 2018 Nov 28.

Dermatologie, Université Paul Sabatier, CHU Toulouse, Toulouse, France.

Compounded topical preparations (CTP) were used to treat psoriasis until the last century and have disappeared from guidelines. The present authors report two severe psoriasis patients who were treated with CTP. A man had psoriasis with a PASI of 23 and a body surface area (BSA) of 43%. He had been using daily for several weeks a CTP including minoxidil, clobetasol propionate and hydroxyprogesterone formulated in an alcohol based vehicle. A woman suffered from psoriasis with an annular inflammatory pattern and a central healing. The PASI was 20 and the BSA was 30%. She had been using a CTP daily for 4 months including resorcinol, salicylic acid, 0.05% tretinoin cream, bethamethasone dipropionate cream. Until the 1970s, the dermatological textbooks recommended to treat severe psoriasis with CTP. Nowadays, CTP are considered outdated because of the large therapeutic armamentarium. The stability and benefit risks of the CTP used here were not documented. The use of CTP in psoriasis should be regulated and must be evidence based. Strict protocol and stability evaluation for preparations must be confirmed prior to compounding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dth.12780DOI Listing
January 2019

Severe gynaecological involvement in Proteus Syndrome.

Eur J Med Genet 2019 Apr 10;62(4):270-272. Epub 2018 Aug 10.

Department of Dermatology, Reference Centre for Rare Skin Diseases, CHU Larrey, Paul Sabatier University, Toulouse, France.

Proteus Syndrome is a rare complex overgrowth syndrome. We report a young female patient with Proteus Syndrome due to AKT1 mutation c.49G > A (p.Glu17Lys), presenting with a severe gynaecological involvement which necessitated a complete hysterectomy and a left adnexectomy. Cases of gynecological involvements in Proteus Syndrome are rare, not well known by physicians while they can be potentially severe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2018.08.003DOI Listing
April 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pde.13564DOI Listing
September 2018

Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design.

Trials 2018 Jun 27;19(1):340. Epub 2018 Jun 27.

University of Tours, University of Nantes, INSERM, SPHERE U1246, Tours, France.

Background: Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes.

Objective: The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs.

Methods/design: This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor).

Discussion: The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study).

Trial Registration: ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13063-018-2725-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020321PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-018-0783-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885373PMC
April 2018

Massive hemorrhage: A rare complication of rapidly involuting congenital hemangioma.

Pediatr Dermatol 2018 May 23;35(3):e159-e160. Epub 2018 Mar 23.

Department of Dermatology, Paul Sabatier University and Toulouse University Hospital, Toulouse, France.

Rapidly involuting congenital hemangioma is a subtype of congenital hemangioma. Ulceration and bleeding are rarely reported in rapidly involuting congenital hemangioma, with only four cases reported in the literature to our knowledge. We describe a case of a newborn girl who presented with rapidly involuting congenital hemangioma complicated by ulceration and severe bleeding and discuss treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pde.13474DOI Listing
May 2018

Transcriptomic Analysis of Two Cdsn-Deficient Mice Shows Gene Signatures Biologically Relevant for Peeling Skin Disease.

J Invest Dermatol 2018 06 23;138(6):1431-1435. Epub 2017 Dec 23.

Unité Différenciation Epithéliale et Autoimmunité Rhumatoïde, UMR 1056 Inserm-Université de Toulouse, Place du Dr Baylac, Hôpital Purpan, Toulouse, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jid.2017.12.020DOI Listing
June 2018

Search for RASA1 Variants in Capillary Malformations of the Legs in 113 Children: Results from the French National Paediatric Cohort CONAPE.

Acta Derm Venereol 2018 Feb;98(2):251-255

Department of Dermatology, CHRU Tours, Hospital Trousseau, Avenue de la République, FR-37044, Tours Cedex 9, France.

Patients with an inherited autosomal-dominant disorder, capillary malformation-arteriovenous malformation (CM-AVM), frequently have mutations in Ras P21 protein activator 1 (RASA1). The aims of this study were to determine the prevalence of germline RASA1 variants in a French multicentre national cohort of children, age range 2-12 years, with sporadic occurrence of capillary malformation (CM) of the legs, whatever the associated abnormalities, and to identify genotype-phenotype correlates. DNA was extracted from leukocytes in blood samples, purified and amplified, and all exons of the RASA1 gene were analysed. Among 113 children analysed, 7 had heterozygous variants (6.1%). Four different variants were identified; 2 were new. In children with RASA1 variants, CMs were more frequently bilateral and multifocal. In conclusion, RASA1 variants are rarely found in children with sporadic CM of lower limbs without CM-AVM syndrome. CMs in this study were heterogeneous, and no disease-causing relationship could be proven.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-2835DOI Listing
February 2018

Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas.

Nat Med 2017 Oct 4;23(10):1226-1233. Epub 2017 Sep 4.

Genoscope (CEA), CNRS UMR 8030, University of Evry, Evry, France.

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as Bazex-Dupré-Christol syndrome (BDCS)-a cancer-prone genodermatosis with an X-linked, dominant inheritance pattern. We have identified mutations in the ACTRT1 gene, which encodes actin-related protein T1 (ARP-T1), in two of the six families with BDCS that were examined in this study. High-throughput sequencing in the four remaining families identified germline mutations in noncoding sequences surrounding ACTRT1. These mutations were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression. ARP-T1 was found to directly bind to the GLI1 promoter, thus inhibiting GLI1 expression, and loss of ARP-T1 led to activation of the Hedgehog pathway in individuals with BDCS. Moreover, exogenous expression of ACTRT1 reduced the in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway. In summary, our study identifies a disease mechanism in BCC involving mutations in regulatory noncoding elements and uncovers the tumor-suppressor properties of ACTRT1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.4368DOI Listing
October 2017
-->