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1.
Acta Derm Venereol ; 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33205825

RESUMO

Management of congenital melanocytic naevi in childhood may vary depending on the habits and experience of the treating clinician. The aim of this study was to assess current practice and determinants of surgical excision decision-making among French physicians. A national survey was conducted among dermatologists, paediatricians and surgeons, using clinical vignettes illustrating 29 scenarios. The primary outcome was the decision to perform surgical excision in each vignette. Of the 11,310 decisions made by the 390 participants (257 dermatologists, 35 surgeons, and 98 paediatricians) surgical excision was chosen in 33% of cases. The stated motivations for performing surgical excision were: melanoma risk, aesthetic/psychosocial risk, or both, in 39%, 34% and 27% of cases, respectively. Physicians with a higher level of experience in oncodermatology were more likely to opt for surgical excision. The age of the child, the size of the congenital melanocytic naevi, and the visibility of the lesion had no influence on the decision to perform surgical excision.

2.
Arthritis Res Ther ; 22(1): 272, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208192

RESUMO

OBJECTIVE: To report on the characteristics and long-term course of rheumatic manifestations in Schnitzler syndrome (SchS). METHODS: A retrospective cohort study of patients with SchS followed between 2000 and 2020. Inclusion criteria included a diagnosis of SchS (Strasbourg criteria). All available bone scans were reviewed and scored according to the intensity and number of pathological sites. The scintigraphic score was compared with the clinical activity score, CRP level, and treatments. RESULTS: Twenty-five patients were included. Median age at diagnosis was 68 years. Eighty patients (72%) had SchS-related rheumatic pain. Most patients had a long-standing isolated rash before constitutional and/or rheumatic symptoms appeared. The monoclonal component level was usually very low (IgMκ in 22/25). Rheumatic pain predominated around the knees. Bone scans revealed abnormal tracer uptake in 15/18 (85%). The scintigraphic score correlated with clinical activity (r = 0.4, p < 0.02) and CRP level (r = 0.47, p < 0.01). The scintigraphic score was lower in patients receiving corticosteroids or IL1Ra (interleukin 1 receptor antagonist) than in untreated patients (median scores:2, 0, and 13, respectively; p < 0.05). Two patients developed Waldenström macroglobulinemia. Of the 22 surviving patients, median age at follow-up was 76 years. IL1Ra was used in 13 patients, with dramatic efficacy on both symptoms and bone scan features. CONCLUSIONS: Rheumatic manifestations are very prevalent in SchS. However, bone pain can be misleading and contribute to misdiagnosis. Bone scan abnormalities are very prevalent and correlate with disease activity and treatments. IL1-Ra has a dramatic and durable efficacy but may not be required in every patient early on.

5.
Blood ; 135(14): 1101-1110, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32027747

RESUMO

Scleromyxedema is a rare skin and systemic mucinosis that is usually associated with monoclonal gammopathy (MG). In this French multicenter retrospective study of 33 patients, we investigated the clinical and therapeutic features of MG-associated scleromyxedema. Skin molecular signatures were analyzed using a transcriptomic approach. Skin symptoms included papular eruptions (100%), sclerodermoid features (91%), and leonine facies (39%). MG involved an immunoglobulin G isotype in all patients, with a predominant λ light chain (73%). Associated hematologic malignancies were diagnosed in 4 of 33 patients (12%) (smoldering myeloma, n = 2; chronic lymphoid leukemia, n = 1; and refractory cytopenia with multilineage dysplasia, n = 1). Carpal tunnel syndrome (33%), arthralgia (25%), and dermato-neuro syndrome (DNS) (18%) were the most common systemic complications. One patient with mucinous cardiopathy died of acute heart failure. High-dose IV immunoglobulin (HDIVig), alone or in combination with steroids, appeared to be quite effective in nonsevere cases (clinical complete response achieved in 13/31 patients). Plasma cell-directed therapies using lenalidomide and/or bortezomib with dexamethasone and HDIVig led to a significant improvement in severe cases (HDIVig refractory or cases with central nervous system or cardiac involvement). The emergency treatment of DNS with combined plasmapheresis, HDIVig, and high-dose corticosteroids induced the complete remission of neurological symptoms in 4 of 5 patients. Quantitative reverse-transcriptase polymerase chain reaction analysis of 6 scleromyxedema skin samples showed significantly higher profibrotic pathway levels (transforming growth factor ß and collagen-1) than in healthy skin. Prospective studies targeting plasma cell clones and/or fibrotic pathways are warranted for long-term scleromyxedema management.


Assuntos
Paraproteinemias/complicações , Paraproteinemias/terapia , Plasmócitos/patologia , Escleromixedema/complicações , Escleromixedema/terapia , Adulto , Idoso , Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lenalidomida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Paraproteinemias/genética , Paraproteinemias/patologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Plasmaferese , Estudos Retrospectivos , Escleromixedema/genética , Escleromixedema/patologia , Pele/metabolismo , Pele/patologia , Transcriptoma
6.
Artigo em Inglês | MEDLINE | ID: mdl-32006346

RESUMO

INTRODUCTION: Atopic dermatitis (AD) is an incurable, inflammatory skin disease characterized by skin barrier disruption and immune dysregulation. Although AD is considered a childhood disease, adult onset is possible, presenting with daily sleep disturbance and functional impairment associated with itch, neuropsychiatric issues (anxiety and depression), and reduced health-related quality of life. Although such aspects of adult AD disease burden have been measured through standardized assessments and based on population-level data, the understanding of the disease experienced at the patient level remains poor. This text-mining study assessed the impact of AD on the lives of adult patients as described from an experiential perspective. METHODS: Natural language processing (NLP) was applied to qualitative patient response data from two large-scale international cross-sectional surveys conducted in the USA and countries outside of the USA (non-USA; Canada, France, Germany, Italy, Spain, and the UK). Descriptive analysis was conducted on patient responses to an open-ended question on how they felt about their AD and how the disease affected their life. Character length, word count, and stop word (common words) count were evaluated; centrality analysis identified concepts that were most strongly interlinked. RESULTS: Patients with AD in all countries were most frequently impacted by itch, pain, and embarrassment across all levels of disease severity. Patients with moderate-to-severe AD were more likely than patients with mild AD to describe sleep disturbances, fatigue, and feelings of depression, anxiety, and a lack of hope that were directly associated with AD. Centrality analysis revealed sleep disturbance was strongly linked with itch. Collectively, these concepts revealed that patients with AD are impacted by both physical and emotional burdens that are intricately connected. CONCLUSIONS: Qualitative data from NLP, being more patient-centric than data from clinical standardized measures, provide a more comprehensive view of the burden of AD to inform disease management.

9.
Trials ; 20(1): 739, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847908

RESUMO

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 cm2. 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.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Linfangiectasia/tratamento farmacológico , Sirolimo/administração & dosagem , Dermatopatias/tratamento farmacológico , Administração Cutânea , Adolescente , Adulto , Criança , Ensaios Clínicos Fase II como Assunto , Método Duplo-Cego , França , Humanos , Linfangiectasia/patologia , Anormalidades Linfáticas/tratamento farmacológico , Anormalidades Linfáticas/patologia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Dermatopatias/patologia , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Adulto Jovem
11.
Nutrients ; 11(8)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398959

RESUMO

Allergic diseases now affect over 30% of individuals in many communities, particularly young children, underscoring the need for effective prevention strategies in early life. These allergic conditions have been linked to environmental and lifestyle changes driving the dysfunction of three interdependent biological systems: microbiota, epithelial barrier and immune system. While this is multifactorial, dietary changes are of particular interest in the altered establishment and maturation of the microbiome, including the associated profile of metabolites that modulate immune development and barrier function. Prebiotics are non-digestible food ingredients that beneficially influence the health of the host by 1) acting as a fermentable substrate for some specific commensal host bacteria leading to the release of short-chain fatty acids in the gut intestinal tract influencing many molecular and cellular processes; 2) acting directly on several compartments and specifically on different patterns of cells (epithelial and immune cells). Nutrients with prebiotic properties are therefore of central interest in allergy prevention for their potential to promote a more tolerogenic environment through these multiple pathways. Both observational studies and experimental models lend further credence to this hypothesis. In this review, we describe both the mechanisms and the therapeutic evidence from preclinical and clinical studies exploring the role of prebiotics in allergy prevention.


Assuntos
Hipersensibilidade/microbiologia , Hipersensibilidade/prevenção & controle , Sistema Imunitário/microbiologia , Microbiota/imunologia , Prebióticos/microbiologia , Ácidos Graxos Voláteis/metabolismo , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Humanos
12.
J Dermatolog Treat ; : 1-9, 2019 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-31179791

RESUMO

Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized. Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL. Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness. Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p < .05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p < .0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p < .0001). Limitations: Cultural differences of translated PROs. Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.

13.
Paediatr Drugs ; 21(3): 169-175, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155692

RESUMO

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.


Assuntos
Terapia Biológica/métodos , Psoríase/tratamento farmacológico , Adolescente , Feminino , Humanos , Masculino , Resultado do Tratamento
15.
BMJ Open ; 9(4): e024974, 2019 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-31005913

RESUMO

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory disease affecting 10%-15% of children in Europe. There is a need for new primary preventive therapeutic strategies in at-risk populations. Recent research has indicated that atopic diseases are associated with a disrupted gut microbial 'balance' in early life raising the possibility that interventions which yield optimal patterns of microflora could improve host's health. Prebiotics, sugars with immunomodulatory properties that stimulate the diversity of the digestive microbiota, are ideal candidates for such research. So far, most clinical trials have focused on improving infant gut colonisation postnatally. However, prenatal life is a crucial period during which different tolerance mechanisms are put in place. We aim to determine whether antenatal prebiotics supplementation prevents AD in high-risk children. METHODS AND ANALYSIS: This is a randomised, multicentre, double-blind, trial to evaluate the effectiveness of antenatal prebiotic maternal supplementation (galacto-oligosaccharide/inulin) in pregnant women versus placebo on the occurrence of AD at 1 year of age in at-risk children (defined as having a maternal history of atopic disease). Participating women will be randomised to daily ingestion of a prebiotics or placebo (maltodextrin) from 20 weeks' gestation until delivery. The primary outcome is the prevalence of AD at 1 year of age, using the version of the UK Working Party Diagnostic Criteria optimised for preventive studies. Key secondary endpoints are AD severity, quality of life and prebiotics tolerance. The target sample size is 376 women (188 patients per group) which will provide 80% power to detect a 33% reduction of the risk of AD in the verum group (α=0.05). The primary analysis will be based on the intention-to-treat principle. ETHICS AND DISSEMINATION: Results will be presented in peer-reviewed journals and at international conferences. Ethics approval for the study was obtained from the institutional ethical review board of 'Comité de Protection des Personnes Sud Ouest-Outre-Mer III' of the University Hospital Centre of Bordeaux (2017/13). TRIAL REGISTRATION NUMBER: NCT03183440; Pre-results.


Assuntos
Dermatite Atópica/prevenção & controle , Estudos Multicêntricos como Assunto , Prebióticos/administração & dosagem , Gestantes , Ensaios Clínicos Controlados Aleatórios como Assunto , Dermatite Atópica/dietoterapia , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Cuidado Pré-Natal , Resultado do Tratamento
16.
J Am Acad Dermatol ; 81(1): 143-151, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30825533

RESUMO

BACKGROUND: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. OBJECTIVE: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort. METHODS: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up. RESULTS: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10-9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10-9, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm3) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10-6). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs. LIMITATIONS: No control group, missing data. CONCLUSION: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Conjuntivite/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Eosinofilia/induzido quimicamente , Segurança do Paciente/estatística & dados numéricos , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Estudos de Coortes , Conjuntivite/epidemiologia , Dermatite Atópica/diagnóstico , Relação Dose-Resposta a Droga , Esquema de Medicação , Eosinofilia/epidemiologia , Feminino , França , Humanos , Injeções Subcutâneas , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença
17.
Trials ; 20(1): 184, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30909923

RESUMO

BACKGROUND: Atopic dermatitis is a highly prevalent, chronic, relapsing disease in both adults and children. On the severity spectrum, lower-end patients benefit from small amounts of topical anti-inflammatory treatments (TAT), whereas higher-end patients need systemic immunosuppressants; in-between patients are treated with TAT and phototherapy. The major therapeutic challenge in this population is the long-term control of disease activity, and the current TAT-based pro-active strategy does not meet all their needs. Immunosuppressants are used as long-term control add-on treatments, but they are restricted to the most severely affected patients because of safety concerns. In addition, neither immunosuppressants nor other strategies have been properly evaluated in the long term despite long-term control having been acknowledged as one of the most important core outcome domains to be targeted in atopic dermatitis trials. Safe add-on therapies, rigorously evaluated for long-term control of the disease, are therefore needed. Phototherapy and vitamin D supplementation are both good candidates. METHODS: This is a multicenter, national, randomized, superiority, crossover trial testing add-on phototherapy (one winter under spaced sessions of phototherapy and one winter under observation) among subjects receiving standard care (i.e., TAT). On the same population, we will test the long-term control provided by oral supplementation of vitamin D versus placebo in a randomized, superiority, double-blind, parallel-group trial. The primary outcomes are (1) repeat measures of the PO-SCORAD severity score over 1 year and (2) cumulate consumption of TAT (number of tubes) during the winter. They will be tested following a hierarchical testing procedure. The secondary outcomes will be measures repeated over 2 years of investigator-based severity scores, patient-reported severity and quality of life scores, serum vitamin D levels, weeks during which the disease is well-controlled, inter-visit cumulate consumption of TAT, and synthetic patient-reported satisfaction at the end of each winter. DISCUSSION: This study includes two separate 2-year pragmatic trials designed to evaluate the efficacy of vitamin D supplementation and pro-active phototherapy for primary care atopic dermatitis patients receiving TAT on long-term control of disease activity. The experimental design enables the study of both interventions and exploration of the interaction between vitamin D and phototherapy. A pragmatic trial is particularly suited to the assessment of long-term control. This study explores the possibility of new and safe therapeutic strategies for the control of long-term atopic dermatitis, and is an example of efficacy research that is unlikely to be sponsored by industrialists. A potentially effective low-cost therapeutic strategy for long-term control is essential for patients and public health. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02537509 , first received: 1 September 2015.


Assuntos
Anti-Inflamatórios/administração & dosagem , Colecalciferol/administração & dosagem , Dermatite Atópica/terapia , Suplementos Nutricionais , Estações do Ano , Terapia Ultravioleta/métodos , Administração Cutânea , Administração Oral , Anti-Inflamatórios/efeitos adversos , Colecalciferol/efeitos adversos , Terapia Combinada , Estudos Cross-Over , Dermatite Atópica/diagnóstico , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , França , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Pragmáticos como Assunto , Fatores de Tempo , Resultado do Tratamento , Terapia Ultravioleta/efeitos adversos
18.
Acta Derm Venereol ; 99(6): 539-543, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30810215

RESUMO

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.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Resistência a Medicamentos , Metotrexato/uso terapêutico , Esclerodermia Localizada/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
19.
Genet Med ; 21(9): 2025-2035, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30723320

RESUMO

PURPOSE: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features. METHODS: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay. RESULTS: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance. CONCLUSION: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.


Assuntos
Alopecia/genética , Colesterol/metabolismo , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transferases Intramoleculares/genética , Idade de Início , Alopecia/complicações , Alopecia/patologia , Criança , Pré-Escolar , Colesterol/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/patologia , Epilepsia/complicações , Epilepsia/genética , Epilepsia/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Lanosterol/genética , Lanosterol/metabolismo , Masculino , Mutação , Linhagem , Fenótipo , Esqualeno/análogos & derivados , Esqualeno/metabolismo , Sequenciamento Completo do Exoma
20.
Pediatr Dermatol ; 36(2): 242-246, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30762251

RESUMO

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.


Assuntos
Acantose Nigricans/genética , Osso e Ossos/anormalidades , Nanismo/genética , Deformidades Congênitas dos Membros/genética , Lordose/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acantose Nigricans/complicações , Adulto , Criança , Nanismo/complicações , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Deformidades Congênitas dos Membros/complicações , Lordose/complicações , Masculino , Mutação , Fenótipo , Pele/patologia , Adulto Jovem
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