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1.
J Clin Immunol ; 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33411153

RESUMO

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.

3.
Arthritis Rheumatol ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33314705

RESUMO

OBJECTIVES: Juvenile idiopathic inflammatory/immune myopathies (JIIM) constitute a highly heterogeneous group with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) were first recognized as reliable tools for patient sub-stratification. Considering the key role of type 1 interferon (IFN-I) up-regulation in JIIM, we investigated whether the IFN-stimulated gene 15 (ISG15) could be reliable biomarker for stratification and diagnosis while shedding light on its role in JIIM pathophysiology. METHODS: We included 56 patients, 24 Juvenile Dermatomyositis (JDM), 12 Juvenile Overlap Myositis (JOM), 10 patients with Duchenne Muscular Dystrophy (DMD) and 10 patients with Congenital Myopathies (CM). Muscle biopsies have been studied using immunohistochemistry, immunoblotting, and real-time quantitative PCR. The negative (ISG15, USP18) and positive regulators (DDX58, and IFIH1) of IFN-I were analyzed. RESULTS: ISG15 expression discriminated JIIM from non-immune myopathies, and among JIIM, JDM from JOM. Among JDM patients, IFN-I positive upregulation (DDX58, IFIH1) was similar whatever MSAs. In contrast, the highest level of ISG15, which is a negative regulator of IFN-I was observed in MDA5(+) patients compared to others. Finally, ISG15 level was inversely correlated with the severity of muscle histological injuries, and was positively correlated with motor performance (CMAS, MMT). CONCLUSIONS: Muscle ISG15 expression is strongly associated with diagnosis of JDM. Patients present a different muscle signature of ISG15 according to their MSAs class. JDM MDA5(+) patients have a higher expression of ISG15 (gene and protein) compared to the other subgroups. Moreover, our data showed that the IFN-I negative regulation correlates with milder muscle involvement.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33338682

RESUMO

BACKGROUND: Mastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in one or more organs. Adults tend to have persistent, systemic mastocytosis (SM), whereas MC infiltration in children is usually limited to the skin and typically regresses after several years. Both adults and children could display MC activation symptoms (MCAs) due to MC mediator release. In more than 85% of both adult and pediatric cases, KIT mutations are present, the KIT D816V mutation being present in most affected adults but in only half of 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 MCAs 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 MCAs 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 SM were symptomatic from the outset. Congenital mastocytosis and the KIT D816V mutation were associated with CM regression [odds ratio=0.48 (p=0.031) and 0.173 (p=0.031), respectively]. Aggravation of MCAs over time was correlated with the persistence of skin lesions. However, the MCAs became more intense in 19% of the patients with MCAs at baseline and CM regression - justifying long-term follow-up in this setting. CONCLUSION: Our results open up new hypotheses with regard to the spontaneous regression of CM in pediatric patients.

5.
Orphanet J Rare Dis ; 15(1): 223, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32854719

RESUMO

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.

6.
Orphanet J Rare Dis ; 15(1): 190, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32693833

RESUMO

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 cm2 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.

7.
J Am Acad Dermatol ; 83(4): 1222-1224, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32682031
8.
Orphanet J Rare Dis ; 15(1): 158, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576219

RESUMO

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 cm2 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.

9.
Orphanet J Rare Dis ; 15(1): 142, 2020 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-32505191

RESUMO

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.

11.
Histopathology ; 77(2): 275-283, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32281140

RESUMO

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.

12.
Br J Clin Pharmacol ; 86(10): 2063-2069, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32250462

RESUMO

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.

13.
Ital J Pediatr ; 46(1): 30, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32160898

RESUMO

The original article contains a misspelling of co-author, Christine Bodemer's name which is presented correctly in this Correction article.

14.
Pediatr Dermatol ; 37(3): 541-544, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32157705

RESUMO

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.

15.
Blood ; 135(13): 1058-1061, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32005988
17.
JAMA Dermatol ; 156(2): 191-195, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31895432

RESUMO

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.


Assuntos
Cloridrato de Erlotinib/administração & dosagem , Ceratodermia Palmar e Plantar/tratamento farmacológico , Canais de Cátion TRPV/genética , Adolescente , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Cloridrato de Erlotinib/farmacologia , Feminino , Seguimentos , Humanos , Ceratodermia Palmar e Plantar/genética , Masculino , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Síndrome
18.
Cell Death Dis ; 11(1): 30, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949132

RESUMO

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-1MET, 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-1MET 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-1MET did not reduce protein aggregation while enhancing cell differentiation, suggesting that PRIMA-1MET targets cell differentiation and not p63 activity directly. In conclusion, we propose that repurposing of the antitumoral PRIMA-1MET compound could become a general treatment of AEC skin erosions.

19.
Clin Infect Dis ; 71(7): e186-e190, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31916572

RESUMO

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.

20.
J Pediatr Gastroenterol Nutr ; 70(2): 247-251, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31978027

RESUMO

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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