Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations.

Aims/Hypothesis: Caused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. Methods: Clinical records were analyzed and described in detail. The functional impact of two RFX6R181W and RFX6V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. Results: All four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6V506G and RFX6R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/Interpretation: Multidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.

Growth hormone treatment in Prader-Willi syndrome patients: systematic review and meta-analysis.

BACKGROUND: Growth hormone (GH) treatment is currently recommended in Prader-Willi syndrome (PWS) patients. OBJECTIVES: To evaluate the impact (efficacy and safety) of the use of recombinant human GH (rhGH) as a treatment for PWS. METHOD: We performed a systematic review and, where possible, meta-analysis for the following outcomes: growth, body mass index, body composition, cognitive function, quality of life, head circumference, motor development/strength, behaviour and adverse effects. We included all PWS patients, with all types of genetic defects and with or without GH deficiency, who participated in rhGH studies performed in infancy, childhood and adolescence, that were either randomised controlled trials (RCTs) (double-blinded or not) or non-randomised controlled trials (NRCTs) (cohort and before and after studies). The databases used were MEDLINE, Embase and Cochrane Central. RESULTS: In 16 RCTs and 20 NRCTs selected, the treated group had an improvement in height (1.67 SD scores (SDS); 1.54 to 1.81); body mass index z-scores (-0.67 SDS; -0.87 to -0.47) and fat mass proportion (-6.5% SDS; -8.46 to -4.54) compared with the control group. Data about cognition could not be aggregated. Conclusion Based on high quality evidence, rhGH treatment favoured an improvement of stature, body composition and body mass index, modifying the disease's natural history; rhGH treatment may also be implicated in improved cognition and motor development in PWS patients at a young age. ETHICS AND DISSEMINATION: The current review was approved by the ethical committee of our institution. The results will be disseminated through conference presentations and publications in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019140295.

Translation and validation of Pediatric Quality of Life InventoryTM 3 0 Diabetes Module (PedsQLTM 3 0 Diabetes Module) in Brazil-Portuguese language / Tradução e validação do Pediatric Quality of Life InventoryTM 3 0 Diabetes Module (PedsQLTM 3 0 Diabetes Module) para a língua portuguesa do Brasil

Abstract Objective: The aim of the present study was to create a translated version of the Pediatric Quality of Life InventoryTM 3.0 Diabetes Module (PedsQLTM 3.0 Diabetes Module) in Brazilian Portuguese that was conceptually equivalent to the original American English version and to linguistically validate it in a Brazilian pediatric population with type 1 diabetes mellitus and their parents or caregivers. Methods: The instrument was translated, back-translated, and then administered to 83 children/adolescents (5-18 years) with type 1 diabetes mellitus and their family members and to 25 parents/caregivers of patients aged between 2 and 4 years. The final translated version was tested for reliability by analyzing internal consistency, intraobserver (test-retest) reliability, and concurrent validity. Results: Cronbach's alpha coefficient for the total score of the questionnaires of children/adolescents (α = 0.85) and their parents (α = 0.82) was above the recommended minimum of 0.70 for group comparisons. Intraobserver reliability and concurrent validity exhibited a significant positive correlation (p < 0.001), indicating the reliability of the translated instrument. A moderate but significant positive correlation (r = 0.40; p < 0.001) was demonstrated between the total scores of patient self-report and parent proxy-report scales. There was no significant correlation between glycated hemoglobin (HbA1c) levels and the respective scores in the questionnaires answered by patients and their parents/caregivers. Conclusion: The analysis of the translated version of the PedsQLTM 3.0 Diabetes Module revealed adequate psychometric characteristics with respect to reliability and validity following administration to a sample of Brazilian children/adolescents with type 1 diabetes mellitus and their caregivers.

Resumo Objetivo: Produzir uma versão do questionário Pediatric Quality of Life InventoryTM 3.0 Diabetes Module (PedsQLTM 3.0 Diabetes Module) para a língua portuguesa do Brasil, que fosse conceitualmente equivalente à versão original em inglês, e proceder à sua validação linguística numa população pediátrica brasileira portadora de diabetes mellitus tipo 1 (DM1) e seus pais ou cuidadores. Métodos: A tradução do instrumento foi feita pela metodologia de tradução-tradução reversa, foi aplicado a 83 crianças/adolescentes (5-18 anos) portadores de diabetes mellitus tipo 1 com seus parentes e a 25 pais/cuidadores de pacientes entre 2 e 4 anos de idade. A confiabilidade da versão traduzida foi avaliada pelas seguintes análises: consistência interna, confiabilidade teste-reteste e validade concorrente. Resultados: O coeficiente alfa de Cronbach para a pontuação total do questionário das crianças/adolescentes (α = 0,85) e seus pais (α = 0,82) excedeu o mínimo recomendado 0,70 para comparação entre grupos. Na confiabilidade intraobservador e validade concorrente observou-se correlação positiva e estatisticamente significativa (p < 0,001), indicou a fidedignidade do instrumento traduzido. Na comparação entre os escores totais obtidos por pais/cuidadores e crianças/adolescentes, houve uma correlação positiva, pequena, mas significativa (r = 0,40; p < 0,001). Não houve correlações estatisticamente significativas entre os níveis de hemoglobina glicada e os escores obtidos nos questionários respondidos pelos pacientes e seus pais/cuidadores. Conclusão: As análises do instrumento PedsQLTM 3.0 Módulo Diabetes demonstraram propriedades psicométricas adequadas em termos de confiabilidade e validade quando aplicado nessa amostra de crianças/adolescentes brasileiros portadores de DM tipo 1 e seus cuidadores.

Translation and validation of Pediatric Quality of Life Inventory™ 3.0 Diabetes Module (PedsQL™ 3.0 Diabetes Module) in Brazil-Portuguese language.

OBJECTIVE: The aim of the present study was to create a translated version of the Pediatric Quality of Life Inventory™ 3.0 Diabetes Module (PedsQL™ 3.0 Diabetes Module) in Brazilian Portuguese that was conceptually equivalent to the original American English version and to linguistically validate it in a Brazilian pediatric population with type 1 diabetes mellitus and their parents or caregivers. METHODS: The instrument was translated, back-translated, and then administered to 83 children/adolescents (5-18 years) with type 1 diabetes mellitus and their family members and to 25 parents/caregivers of patients aged between 2 and 4 years. The final translated version was tested for reliability by analyzing internal consistency, intraobserver (test-retest) reliability, and concurrent validity. RESULTS: Cronbach's alpha coefficient for the total score of the questionnaires of children/adolescents (α=0.85) and their parents (α=0.82) was above the recommended minimum of 0.70 for group comparisons. Intraobserver reliability and concurrent validity exhibited a significant positive correlation (p<0.001), indicating the reliability of the translated instrument. A moderate but significant positive correlation (r=0.40; p<0.001) was demonstrated between the total scores of patient self-report and parent proxy-report scales. There was no significant correlation between glycated hemoglobin (HbA1c) levels and the respective scores in the questionnaires answered by patients and their parents/caregivers. CONCLUSION: The analysis of the translated version of the PedsQL™ 3.0 Diabetes Module revealed adequate psychometric characteristics with respect to reliability and validity following administration to a sample of Brazilian children/adolescents with type 1 diabetes mellitus and their caregivers.

Tuberculose na infância na forma de pseudotumor torácico / Tuberculosis in childhood in form of chest pseudotumor

Objetivo: Descrever um caso de pseudotumor tuberculoso do parênquima pulmonar em criança erever a literatura sobre o tema. Relato do Caso: ANF, 2 anos e 2 meses, sexo feminino, procurou o HU-USP por pneumonia lobar, que não estavarespondendo ao tratamento. Havia recebido 10 dias de amoxacilina e 5 dias de penicilina procaína, masmantinha tosse, febre e imagem radiológica inalterada. Internada em nosso serviço para tratamentocom cefuroxima, posteriormente associada claritromicina, com manutenção da febre e imagemradiológica. Tomografia de tórax mostrou opacificação heterogênea com 5 cm de diâmetro em ápice esquerdo com realce periférico. Indicada toracotomia, que mostrou massa aderida ao parênquima e à histopatologia granuloma epitelioide, com necrose caseosa e bacilo álcool ácido resistente (BAAR), comcritério diagnóstico para pseudotumor tuberculoso do parênquima pulmonar. Evoluiu com remissão dafebre após o sexto dia de tratamento com esquema tríplice. Discussão: Esta forma de tuberculose apresenta 27 casos relatados na literatura, sendoapenas dois em crianças. A maioria dos pacientes apresenta-se com tosse não produtiva e sintomas constitucionais são paucibacilíferos, imunocompetentes,com PPD positivo e o diagnóstico é feitopor meio de biopsia por broncoscopia ou toracotomia. A paciente apresentava, como critério diagnóstico para tuberculose, pontuação de 45, segundo Clemax; e para pseudotumor, massa maior de 3 cm associada à histopatologia de granuloma epitelioidecom presença de BAAR positivo e resposta efetiva ao tratamento. O caso se apresentou semelhante à literatura e ressaltamos que é necessário levantar a suspeita diagnóstica de tuberculose em pneumonias de evolução atípica, com critérios clínicos e exames diagnósticos.

Objective: To describe a child’s case of parenchymal pseudotumoral tuberculosis and review theliterature about this disease. Case Report: ANF, 2 years-old, female, looked for HU-USP because of alobar pneumonia that was not responding to the treatment.The child was given amoxicillin for 10 days and procaine penicillin for another five days without showing any improvement. Admitted to our hospitalfor treatment with cefuroxime and clarithromycin which however, without response in fever and radiologicalimaging. Chest tomography showed heterogeneous opacification with 5 cm diameter in the left apex with peripheral enhancement. Thoracotomy was prescribed, which showed a mass attached to the parenchyma andin histopathology an epithelioid granuloma with caseous necrosis and acid alcohol resistant bacilli (AFB), withdiagnostic criteria for Tuberculous pseudotumor of the lung parenchyma. Evolved with remission from fever 237after the sixth day of anti-tubercular therapy. Discussion: This type of tuberculosis was reported in 27 casesin the English literature, of which only two were children. Most patients presented nonproductive cough and constitutional symptoms. They were paucibacillary, immunocompetent, positive on tuberculin testing andthe diagnosis is made through a biopsy by bronchoscopy or thoracotomy. For diagnostic criterion of tuberculosis, this patient presented 45 in Clemax score; and for pseudotumor a mass larger than 3 cm associated withthe histopathology of epithelioid granuloma with the presence of AFB positive and effective response to treatment. This case was considered similar to those reported in literature and emphasizes the need to raise the diagnosis of tuberculosis in the evolution of atypical pneumonia, with clinical criterion and diagnostic tests.