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3.
Curr Opin Pharmacol ; 54: 51-58, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32947075

RESUMO

Moderate to severe inflammatory bowel disease patients can fail to respond to conventional therapy and/or to biologic treatment. In the era of TNFα antagonists and other non-anti-TNF biologic drugs, it is important to review the literature on biologic treatment failure, which could be defined as primary non-response, secondary loss of response and intolerance. Therapeutic drug monitoring (TDM), that is, drug trough level and antidrug antibodies, should enable to determine the mechanisms of treatment failure and to optimize drug efficacy. There is a consensus on reactive TDM at the time of loss of response. Proactive TDM could be of interest during induction and/or maintenance, but randomized controlled trials are required.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32740538

RESUMO

OBJECTIVES: Crohn disease (CD) can affect patient's quality of life (QOL) with physical, social, and psychological impacts. This study aimed to investigate the QOL of children with CD and its relationship with patient and disease characteristics. METHODS: Children ages from 10 to 17 years with diagnosed CD for more than 6 months were eligible to this cross-sectional study conducted in 35 French pediatric centers. QOL was assessed by the IMPACT-III questionnaire. Patient and disease characteristics were collected. RESULTS: A total of 218 children (42% of girls) were included at a median age of 14 years (interquartile range [IQR]: 13--16). Median duration of CD was 3.2 years (IQR: 1.7-5.1) and 63% of children were in clinical remission assessed by wPCDAI. Total IMPACT-III score was 62.8 (±11.0). The lowest score was in "emotional functioning" subdomain (mean: 42.8 ±â€Š11.2). Clinical remission was the main independent factor associated with QOL of children with CD (5.74 points higher compared with those "with active disease", 95% confidence interval [CI] 2.77--8.70, P < 0.001). Age of patient at the evaluation was found negatively correlated with QOL (-0.76 per year, 95% CI: -1.47 to -0.06, P = 0.009). Presence of psychological disorders was associated with a lower QOL (-9.6 points lower to those without, 95% CI: -13.34 to -5.86, P < 0.0001). Total IMPACT-III and its subdomains scores were not related to sex, disease duration, or treatments. CONCLUSIONS: These results not only confirm that clinical remission is a major issue for the QOL of patients, but also highlights the importance of psychological care.

6.
J Pediatr ; 211: 120-125.e1, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31072651

RESUMO

OBJECTIVE: To identify predictors of and factors associated with the performance of antireflux surgery during the first year of life in children born with esophageal atresia. STUDY DESIGN: All patients were included in a French registry for esophageal atresia. All 38 multidisciplinary French centers completed questionnaires about perinatal characteristics and one-year outcome for children born with esophageal atresia. RESULTS: Of 835 infants with esophageal atresia born in France from 2010 to 2014, 682 patients, excluding those with long-gap esophageal atresia, were included. Three patients had type I, 669 had type III, and 10 had type IV esophageal atresia. Fifty-three children (7.8%) received fundoplication during the first year of life. The median age at the time of the end-to-end esophageal anastomosis was 1.1 day (range 0-15). Multivariate analysis identified three perioperative factors that predicted the need for early antireflux surgery: anastomotic tension (P = .004), associated malformations (P = .019), and low birth weight (P = .018). Six other factors, measured during the first year of life, were associated with the need for antireflux surgery: gastroesophageal reflux (P < .001), anastomotic stricture (P < .001), gastrostomy (P < .001), acute life-threatening event (P = .002), respiratory complications (P = .045), and poor nutritional status (P < .001). CONCLUSIONS: Gastroesophageal reflux disease, low birth weight, poor nutrition, and surgical anastomosis difficulties predicted the performance of antireflux surgery in the first year of life in infants with esophageal atresia.


Assuntos
Atresia Esofágica/cirurgia , Fundoplicatura , Anastomose Cirúrgica/efeitos adversos , Constrição Patológica , Atresia Esofágica/classificação , Feminino , França , Refluxo Gastroesofágico/cirurgia , Gastrostomia , Humanos , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Análise Multivariada , Estado Nutricional , Sistema de Registros
7.
J Crohns Colitis ; 12(9): 1104-1112, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-29788237

RESUMO

BACKGROUND AND AIMS: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. METHODS: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. RESULTS: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. CONCLUSIONS: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/etiologia , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Doenças Inflamatórias Intestinais/terapia , Masculino , Valor Preditivo dos Testes
8.
BMC Ophthalmol ; 17(1): 227, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29195497

RESUMO

BACKGROUND: Nivolumab is a fully human antibody which is routinely used at first therapy for metastatic melanoma. Usually, side effects are immune-related adverse events. We report a case of a man who developed bilateral anterior uveitis and macular serous retinal detachment during nivolumab treatment for metastatic melanoma. CASE PRESENTATION: A man on nivolumab treatment for a leg melanoma with duodenal and lymph nodes metastases developed a sudden bilateral visual acuity impairment and bilateral non-painfull redness eyes several days after the third infusion. The clinical examination showed a significant decreased of the visual acuity. Slit lamp examination revealed the presence of bilateral granulomatous keratic precipitates, anterior chamber cells +++, bilateral synechiae, bilateral papilledema and macular edema associated with serous retinal detachment in the left eye. The anti-Programmed cells Death-1 was stopped and a topical corticosteroid treatment was administrated. After 8 days of topical corticosteroid treatment visual acuity was worsening with similar optical coherence tomography examination. An oral corticosteroid treatment was started. Evolution was favorable with a decrease of ocular inflammation and a complete visual acuity recovery after 3 weeks. Nivolumab was re-initiated. CONCLUSIONS: This is the second clinical report of bilateral anterior uveitis associated with macular serous retinal detachment related to anti-PD-1 treatment, and the first with nivolumab. Cases of uveitis were reported several times. Although rare, ophthalmologic manifestations that are rapidly recognized and adequately managed can be treated.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos/efeitos adversos , Edema Macular/induzido quimicamente , Uveíte/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe
9.
J Immunother Cancer ; 5(1): 57, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28716106

RESUMO

BACKGROUND: The anti-Programmed Death receptor 1 (anti-PD-1) antibodies nivolumab and pembrolizumab are new treatments in metastatic melanoma. Immunotherapies are best known to be responsible for thrombotic microangiopathy. However, immune interstitial nephritis has been described in a patient treated by nivolumab and ipilimumab concomitantly, and three cases of granulomatous interstitial nephritis have been reported with ipilimumab monotherapy. We report herein a case of acute interstitial immune nephritis in a patient treated with nivolumab after ipilimumab for pulmonary metastatic melanoma. CASE PRESENTATION: Interstitial nephritis was diagnosed after acute kidney injury following three cycles and was confirmed by kidney biopsy. Kidney injury responded rapidly to prednisolone, which was then gradually reduced. As a follow-up computed tomography scan indicated mixed response, with minimal size progression of a pulmonary nodule, but a significant reduction in the size of the other nodules, nivolumab was reintroduced after renal function improvement. Low-dose corticosteroids were first maintained during nivolumab treatment and subsequently discontinued. Only one month after prednisolone discontinuation, creatinine levels increased. A second kidney biopsy confirmed relapse of acute interstitial nephritis. CONCLUSIONS: To our knowledge, this is the first case of nivolumab-induced acute interstitial immune nephritis. This case highlights that anti-PD-1 immunotherapy may be continued when renal function is adequate, and this requires close interaction between dermatologists and nephrologists. This adverse effect should be made known to prescribers as nivolumab is associated with significant improvement of survival in metastatic melanoma and may be used in many different types of cancer.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias do Ânus/tratamento farmacológico , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológico , Nefrite Intersticial/induzido quimicamente , Doença Aguda , Lesão Renal Aguda/induzido quimicamente , Idoso , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Substituição de Medicamentos , Feminino , Humanos , Infusões Intravenosas , Ipilimumab/administração & dosagem , Neoplasias Pulmonares/secundário , Melanoma/secundário , Nódulos Pulmonares Múltiplos/secundário , Recidiva Local de Neoplasia/etiologia , Nivolumabe , Recidiva
12.
Ann Surg ; 264(6): 1004-1008, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26720426

RESUMO

OBJECTIVE: To study the prevalence of Barrett esophagus (BE) (gastric and/or intestinal metaplasia) in adolescents treated for esophageal atresia (EA). SUMMARY OF BACKGROUND DATA: EA patients are at high risk of BE. METHODS: This multicenter prospective study included EA patients aged 15 to 19 years. All eligible patients were proposed an upper endoscopy with multistaged esophageal biopsies under general anesthesia. Histological suspicion of metaplasia was confirmed centrally. RESULTS: One hundred twenty patients [mean age, 16.5 years (±1.4)] were included; 70% had been treated for gastroesophageal reflux disease (GERD) during infancy. At evaluation, 8% were undernourished, 41% had received antireflux surgery, and 41% presented with GERD symptoms, although only 28% were receiving medical treatment. Esophagitis was found at endoscopy in 34% and confirmed at histology in 67%. BE was suspected after endoscopy in 37% and was confirmed by histology for 43% of patients (50 gastric and 1 intestinal metaplasia). No endoscopic or histological anomalies were found at the anastomosis site. BE was not significantly related to clinical symptoms. In multivariate analysis, BE was associated with EA without fistula (P = 0.03), previous multiple antireflux surgery (P = 0.04), esophageal dilation (P = 0.04), suspicion of BE at endoscopy (P < 0.001), and histological esophagitis (P = 0.02). CONCLUSIONS: Patients with EA are at high risk of persistent GERD and BE. The development of BE is related to GERD history. Long-term systematic follow-up of the esophageal mucosa including multistaged biopsies is required, even in asymptomatic patients. (NCT02495051).


Assuntos
Esôfago de Barrett/epidemiologia , Atresia Esofágica/cirurgia , Adolescente , Biópsia , Esofagite/complicações , Esofagoscopia , Feminino , França/epidemiologia , Refluxo Gastroesofágico/complicações , Humanos , Masculino , Prevalência , Estudos Prospectivos , Adulto Jovem
13.
Orphanet J Rare Dis ; 9: 206, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25496976

RESUMO

BACKGROUND: The aim of the present national prospective population-based study was to assess the early morbidity of esophageal atresia (EA). METHODS: All 38 multidisciplinary French centers that care for patients with EA returned a specific questionnaire about the 1-year outcome for each patient. This information was centralized, checked, and entered into a database. RESULTS: From the total population of 307 EA patients born in 2008 and 2009, data about the 1-year outcome were obtained from 301 (98%) patients, of whom 4% were lost to follow-up and 5% died. Medical complications occurred in 34% of the patients: anastomotic leaks (8%), recurrent tracheoesophageal fistula (4%), and anastomotic stenosis (22%); all of the latter group needed dilation (median, 2 dilations/patient). A new hospitalization was required for 59% of patients (2.5 hospitalizations/patient) for digestive (52%) or respiratory (48%) reasons. Twelve percent of patients required antireflux surgery at a median age of 164 days (range, 33-398 days), and 1% underwent an aortopexy for severe tracheomalacia. The weight/age Z-score was -0.8 (range, -5.5 to 3.7 months) at 12 months. Fifteen percent of patients were undernourished at 12 months of age, whereas 37% presented with respiratory symptoms and 15% had dysphagia at the last follow-up. Significant independent factors associated with medical complications were anastomotic esophageal tension (p = .0009) and presence of a gastrostomy (p = .0002); exclusive oral feeding at discharge was associated with a decreased risk of complications (p = .007). CONCLUSIONS: Digestive and respiratory morbidities remain frequent during the first year of life and are associated with difficult anastomosis and lack of full oral feeding.


Assuntos
Atresia Esofágica/diagnóstico , Atresia Esofágica/epidemiologia , Vigilância da População , Sistema de Registros , Atresia Esofágica/terapia , Feminino , Seguimentos , França/epidemiologia , Hospitalização/tendências , Humanos , Lactente , Recém-Nascido , Masculino , Vigilância da População/métodos , Fatores de Tempo , Resultado do Tratamento
14.
J Am Chem Soc ; 136(31): 10949-55, 2014 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-25003533

RESUMO

The enormous synthetic efforts on novel solar cell materials require a reliable and fast technique for the rapid screening of novel donor/acceptor combinations in order to quickly and reliably estimate their optimized parameters. Here, we report the applicability of such a versatile and fast evaluation technique for bulk heterojunction (BHJ) organic photovoltaics (OPV) by utilizing a steady-state photoluminescence (PL) method confirmed by electroluminescence (EL) measurements. A strong relation has been observed between the residual singlet emission and the charge transfer state emission in the blend. Using this relation, a figure of merit (FOM) is defined from photoluminescence and also electroluminescence measurements for qualitative analysis and shown to precisely anticipate the optimized blend parameters of bulk heterojunction films. Photoluminescence allows contactless evaluation of the photoactive layer and can be used to predict the optimized conditions for the best polymer-fullerene combination. Most interestingly, the contactless, PL-based FOM method has the potential to be integrated as a fast and reliable inline tool for quality control and material optimization.

16.
Arch Dis Child ; 99(1): 35-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24108068

RESUMO

OBJECTIVES: Syndromic diarrhoea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital syndrome. The main features are intractable diarrhoea of infancy, hair abnormalities, facial dysmorphism, intrauterine growth restriction and immune system abnormalities. It has been linked to abnormalities in two components of the putative human ski complex: SKIV2L and TTC37. The long-term outcome of this syndrome is still unknown. We aim to describe the long-term outcome, in the French cohort of patients born since 1992. DESIGN: Review of the clinical and biological features of the 15 patients with SD/THE, followed in France and born between 1992 and 2010. RESULTS: All patients presented typical SD/THE syndrome features, of intractable diarrhoea in infancy requiring parenteral nutrition, a facial dysmorphism with hair abnormalities, and immunological disorders. Half of them also had liver and skin abnormalities. Five children died, among which 3 died due to infections. Probabilities of survival according to the Kaplan-Meier method were 93.3%, 86.7%, 74.3 and 61.9%, respectively at 1 year, 5 years, 10 years and 15 years of age. 3/15 were weaned from parenteral nutrition (PN) with likelihood of weaning being 10% at 5 years and 40% at 10 years. At birth 80% were small for gestational age and the short stature persisted in 60%. Haemophagocytic syndrome was noted in 60% and mild mental retardation was present in 60%. CONCLUSIONS: SD/THE is a rare disease with high morbidity and mortality. Management should be focused on nutrition and immunological defects.


Assuntos
Proteínas de Transporte/genética , DNA Helicases/genética , Diarreia Infantil/epidemiologia , Diarreia/genética , Retardo do Crescimento Fetal/epidemiologia , Doenças do Cabelo/epidemiologia , Nutrição Parenteral/estatística & dados numéricos , Distribuição por Idade , Estudos de Coortes , Diarreia Infantil/genética , Diarreia Infantil/imunologia , Facies , Feminino , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/imunologia , França/epidemiologia , Doenças do Cabelo/genética , Doenças do Cabelo/imunologia , Humanos , Lactente , Estimativa de Kaplan-Meier , Fígado/anormalidades , Masculino , Síndrome
17.
Orphanet J Rare Dis ; 8: 186, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24289834

RESUMO

BACKGROUND: Congenital esophageal stenosis (CES) is a rare condition frequently associated with esophageal atresia (EA). There are limited data from small series about the presentation, treatment, and outcomes of CES. METHODS: Medical records of all patients with CES included in the French Network on Esophageal Malformations and Congenital Diseases were reviewed retrospectively with regard to diagnosis, treatment, and outcome. RESULTS: Over 18 years, 61 patients (30 boys) had CES, and 29 (47%) of these patients also had EA. The mean age at diagnosis was 24 months (1 day to 14 years) and was younger in patients with CES and EA than in those with isolated CES (7 vs. 126 months, p < 0.05). Twenty-one of the 61 patients with CES had no clinical symptoms: in three patients, the findings were incidental, and in 18 of the 29 patients with associated EA, CES was diagnosed at the time of surgical repair of EA or during a postoperative systematic esophageal barium study. In the 40 other patients, at diagnosis, 50% presented with dysphasia, 40% with vomiting, 50% with food impaction, and 42% with respiratory symptoms. Diagnosis of CES was confirmed by esophageal barium study (56/61) and/or esophageal endoscopy (50/61). Sixteen patients had tracheobronchial remnants (TBR), 40 had fibromuscular stenosis (FMS), and five had membrane stenosis (MS). Thirty-four patients (56%) were treated by dilation only (13/34 remained asymptomatic at follow-up); 15 patients were treated by dilation but required later surgery because of failure (4/15 remained asymptomatic at follow-up); and nine patients had a primary surgical intervention (4/9 were asymptomatic at follow-up). Dilation was complicated by esophageal perforation in two patients (3.4%). At follow-up, dysphagia remained in 36% (21/58) of patients, but the incidence did not differ between the EA and the isolated CS groups (10/29 vs. 7/32, p = 0.27). CONCLUSIONS: CS diagnosis can be delayed when associated with EA. Dilation may be effective for treating patients with FMS and MS, but surgical repair is often required for those with TBR. Our results show clearly that, regardless of the therapeutic option, dysphagia occurs frequently, and patients with CES should be followed over the long term.


Assuntos
Estenose Esofágica/diagnóstico , Adolescente , Criança , Pré-Escolar , Atresia Esofágica/diagnóstico , Atresia Esofágica/cirurgia , Atresia Esofágica/terapia , Estenose Esofágica/cirurgia , Estenose Esofágica/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
18.
J Pediatr Surg ; 48(8): 1664-9, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23932604

RESUMO

PURPOSE: A prospective national register was established in 2008 to record all new cases of live-birth newborns with esophageal atresia (EA). This epidemiological survey was recommended as part of a national rare diseases plan. METHODS: All 38 national centers treating EA participated by completing for each patient at first discharge a questionnaire validated by a national committee of experts. Data were centralized by the national reference center for esophageal anomalies. Quantitative and qualitative analyses were performed, with P-values of less than 0.05 considered statistically significant. Results of the 2008-2009 data collection are presented in this report. RESULTS: Three hundred seven new living cases of EA were recorded between January 1, 2008, and December 31, 2009. The male/female sex ratio was 1.3, and the live-birth prevalence of EA was 1.8 per 10,000 births. Major characteristics were comparable to those reported in the literature. Survival was 95%, and no correlation with caseload was noted. CONCLUSIONS: Epidemiologic surveys of congenital anomalies such as EA, which is a rare disease, provide valuable data for public health authorities and fulfill one important mission of reference centers. When compared with previous epidemiological data, this national population-based registry suggests that the incidence of EA remains stable.


Assuntos
Atresia Esofágica/epidemiologia , Doenças do Prematuro/epidemiologia , Anormalidades Múltiplas/epidemiologia , Adolescente , Adulto , Peso ao Nascer , Estudos de Coortes , Terapia Combinada , Atresia Esofágica/diagnóstico , Atresia Esofágica/tratamento farmacológico , Atresia Esofágica/cirurgia , Feminino , França/epidemiologia , Idade Gestacional , Humanos , Incidência , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/cirurgia , Masculino , Idade Materna , Pessoa de Meia-Idade , Poli-Hidrâmnios/epidemiologia , Vigilância da População , Gravidez , Diagnóstico Pré-Natal , Prevalência , Estudos Prospectivos , Sistema de Registros/estatística & dados numéricos , Inquéritos e Questionários , Taxa de Sobrevida , Carga de Trabalho , Adulto Jovem
19.
Retrovirology ; 8: 58, 2011 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-21767373

RESUMO

BACKGROUND: Maternofetal transmission (MFT) of HIV-1 is relatively rare during the first trimester of pregnancy despite the permissivity of placental cells for cell-to-cell HIV-1 infection. Invasive placental cells interact directly with decidual cells of the uterine mucosa during the first months of pregnancy, but the role of the decidua in the control of HIV-1 transmission is unknown. RESULTS: We found that decidual mononuclear cells naturally produce low levels of IL-10, IL-12, IL-15, TNF-α, IFN-α, IFN-γ and CXCL-12 (SDF-1), and large amounts of CCL-2 (MCP1), CCL-3 (MIP-1α), CCL-4 (MIP-1ß), CCL-5 (Rantes), CXCL-10 (IP-10), IL-6 and IL-8. CCL-3 and CCL-4 levels were significantly upregulated by in vitro infection with R5 HIV-1 but not X4. Decidual CD14+ antigen presenting cells were the main CCL-3 and CCL-4 producers among decidual leukocytes. R5 and X4 HIV-1 infection was inhibited by decidual cell culture supernatants in vitro. Using HIV-1 pseudotypes, we found that inhibition of the HIV-1 entry step was inhibited by decidual soluble factors. CONCLUSION: Our findings show that decidual innate immunity (soluble factors) is involved in the control of HIV-1 infection at the maternofetal interface. The decidua could thus serve as a mucosal model for identifying correlates of protection against HIV-1 infection.


Assuntos
Citocinas/imunologia , Decídua/imunologia , Infecções por HIV/transmissão , HIV-1/fisiologia , Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez/imunologia , Citocinas/genética , Decídua/virologia , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Gravidez , Complicações Infecciosas na Gravidez/virologia
20.
Hum Mutat ; 32(3): 277-81, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21120949

RESUMO

The Tricho-Hepato-Enteric (THE) syndrome is an autosomal recessive condition marked by early and intractable diarrhea, hair abnormalities, and immune defects. Mutations in TTC37, which encodes the putative protein Thespin, have recently been associated with THE syndrome. In this article, we extend the pattern of TTC37 mutations by the description of 11 novel mutations in 9 patients with a typical THE syndrome. The mutations were spread along the gene sequence, none of themrecurrent. Different types of mutation were observed: frameshift mutations, splice-site altering mutations, or missense mutations, most of them leading to the creation of a premature stop codon. Concurrently, we investigated the pattern of TTC37 expression in a panel of normal human tissues and showed that this gene is widely expressed, with high levels in vascular tissues, lymph node, pituitary, lung, and intestine. In contrast, TTC37 is not expressed in the liver, an organ that is not consistently affected in THE syndrome. Last, we suggested a model for the putative structure of the unknown Thespin protein.


Assuntos
Proteínas de Transporte/genética , Diarreia/genética , Doenças Genéticas Inatas/genética , Criança , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Perfilação da Expressão Gênica , Cabelo/anormalidades , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Mutação de Sentido Incorreto , Fenótipo , Isoformas de Proteínas/genética , Síndrome
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