Puberty in girls with Prader-Willi syndrome: cohort evaluation and clinical recommendations in a Latin American tertiary center

IntroductionPrader-Willi syndrome (PWS) is a genetic disorder characterized by hypothalamic-pituitary deficiencies including hypogonadism. In girls with PWS, hypogonadism can present early in childhood, leading to genital hypoplasia, delayed puberty, incomplete pubertal development, and infertility. In contrast, girls can present with premature activation of the adrenal axis leading to early pubarche and advanced bone age. We aim to evaluate the progression of puberty and adrenarche signals in girls with PWS.MethodologyA longitudinal retrospective cohort study included girls with PWS followed at a Pediatric Endocrinology Outpatient Clinic in a Tertiary University Hospital in Sao Paulo, Brazil from 2002 to 2022. Data collected via chart review included clinical information on birth history, breast and pubic hair Tanner stages, presence of genital hypoplasia, age at menarche, regularity of menstrual cycles, body mass index (BMI) z-score, final height, age of initiation of estrogen replacement and growth hormone replacement, as well as results for PWS genetic subtype; biochemical investigation (LH, FSH, estradiol, DHEA-S); radiographic bone age and pelvic ultrasound.ResultsA total of 69 girls were included in the study and the mean age of puberty onset was 10.2 years in those who started puberty after the age of 8 years. Breast Tanner stage IV was reached by 29.1% girls at a mean age of 14.9 years. Spontaneous menarche was present in 13.8% and only one patient had regular menstrual cycles. Early adrenarche was seen in 40.4% of cases.ConclusionOur study demonstrated in a large sample that girls with PWS often present with delayed onset of puberty despite frequent premature adrenarche. Based on our results, we suggest an estrogen replacement protocol for girls with PWS to be started at the chronological age or bone age of 12–13 years, taking into consideration the uterus size. Further prospective studies are needed

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

Aims/HypothesisCaused 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. MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6(R181W) and RFX6(V506G) 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. ResultsAll 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 RFX6(V506G) and RFX6(R181W) 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/InterpretationMultidisciplinary 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.Peer reviewe

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

Introdução: O tratamento com hormônio do crescimento recombinante (rhGH) é atualmente recomendado em pacientes com síndrome de Prader-Willi (SPW). Objetivos: Avaliar o impacto do uso de rhGH como tratamento para a SPW. Método: Foi realizada uma revisão sistemática e, quando possível, meta-análise para os seguintes resultados: crescimento, índice de massa corpórea, composição corporal, função cognitiva, qualidade de vida, desenvolvimento motor / força, comportamento e efeitos adversos. Foram incluídos todos os pacientes com SPW, com todos os tipos de defeitos genéticos; com ou sem deficiência de hormônio de crescimento; que participaram de estudos de rhGH realizados na infância e adolescência. As bases de dados utilizadas foram MEDLINE, Embase e Cochrane Central. Resultados: Em 16 estudos randomizados controlados, o grupo tratado teve uma melhora na altura (ZE- Estatura 1,67 DP; 1,54-1,81); Z-IMC (- 0,67 DP; -0,87- -0,47) ; massa magra de 2,03DP (IC95% -1,34- 2,71) e proporção de massa gorda (-6,5%DP; -8,46- -4,54) em comparação ao grupo controle. Dentre os estudos não randomizados o grupo tratado teve uma melhora de altura de 1,52 DP (IC95% - 0,86;2,16) e uma redução significativa na porcentagem de massa gorda (-8,39%; IC95% -14,53; -2,25). Os dados sobre cognição não puderam ser agregados, mas a maioria dos estudos mostrou dados favoráveis. Conclusão: Com base em evidências de alta qualidade, o tratamento com rhGH favoreceu a melhora da estatura, composição corporal e IMC, modificando a história natural da doença; O tratamento com rhGH também pode estar implicado na melhora da cognição e do desenvolvimento motor sobretudo em pacientes abaixo de 2 anos portadores de SPWBackground: Growth hormone (rhGH) treatment is currently recommended in Prader- Willi syndrome (PWS) patients. Objectives: To evaluate the impact of the use of 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 randomized clinical trials (double- blinded or not) or non-randomized controlled studies (cohort and before and after studies). The databases used were MEDLINE, Embase and Cochrane Central. Results: In 16 RCTs, the treated group had an improvement in height (1.67 SDS; 1.54-1.81); Z-BMI (- 0.67 SDS; -0.87- -0.47) and fat mass proportion (-6.5%; -8.46- -4.54) compared to 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 BMI, modifying the diseases natural history; rhGH treatment may also be implicated in improved cognition and motor development in PWS patients at a young ag

Translation and validation of Diabetes Self-Management Profile (DSMP) into Brazilian Portuguese language: first instrument to access type 1 diabetes self-management in a pediatric population

Objetivo: Traduzir e validar o instrumento Diabetes Self-Management Profile (DSMP)-Regime Convencional e Flexível para a língua portuguesa do Brasil, numa população pediátrica portadora de diabetes mellitus tipo 1 (DM1) e seus cuidadores, para avaliar a qualidade do autocuidado desta população. Método: O DSMP é uma entrevista semiestruturada composta de 25 questões, dividida em 5 subscalas (exercício, hipoglicemia, alimentação, monitorização glicêmica e insulinoterapia). Foi administrado para pacientes com DM1 entre 6 e 18 anos (n=102) e seus cuidadores. Crianças menores de 11 anos foram entrevistadas com os pais e as maiores separadamente. Os pacientes foram entrevistados duas vezes no intervalo de 3 meses pelo mesmo pesquisador, e estas entrevistas foram gravadas e avaliadas por um segundo pesquisador. A análise estatística para confiabilidade e validade incluiu a associação do escore com a Hb1Ac e um questionário de percepção medica. Resultados: O escore do DSMP total mostrou adequada consistência interna (Cronbach=0,79) e adequada confiabilidade inter (r=0,38,p < 000,1) e intraobservador (0,43, p < 000,1). O escore total do DSMP e subscalas tiveram correlação negativa com a HbA1c (r = -0.53, p < 0.001) e positiva com a percepção médica do autocuidado (r=0.67, p < 0.001). Conclusões: A versão traduzida do DSMP demonstrou que este é um instrumento confiável e válido para avaliar o autocuidado do DM1. O escore do DSMP foi correlacionado com HbA1c em nossa população brasileira, sendo agora é o primeiro instrumento de autocuidado validado em nossa língua para avaliar pacientes pediátricosObjective: To translate and validate the instrument DSMP-Conventional and Flexible Regimens into Brazilian Portuguese language in order to evaluate the quality of diabetes self-management in children and adolescents with type 1 diabetes and their caregivers. Method: DSMP was translated into Brazilian Portuguese language by forward and back translation method and validated in a group of 102 type 1 diabetes youths between 6 and 18 years (n=102) and their families by the analysis of its internal consistency, intra and interobserver reliability and concurrent correlation with HbA1c and physician perception. Results: DSMP total scores demonstrated adequate internal consistency (Cronbach\'s 0.79), 3-month test-retest reliability (r=0.43), inter-interviewer agreement (r=0.38). DSMP total scores and all subscales were significantly correlated to HbA1c (r= -0.53, p < 0,001), as well as physician perception (r=0.67, p < 0,001). Conclusion: DSMP-translated version into Brazilian Portuguese language is a reliable and valid tool to assess diabetes self-managemen

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. Resumo: Objetivo: Produzir uma versão do questionário Pediatric Quality of Life Inventory™ 3.0 Diabetes Module (PedsQL™ 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 PedsQL™ 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. Keywords: Validation studies, Quality of life, Type 1 diabetes mellitus, Child, Adolescent, Palavras‐chave: Estudos de validação, Qualidade de vida, Diabetes mellitus tipo 1, Criança, Adolescent

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.ConclusionBased 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 CRD4201914029

Supplementary data for: Growth hormone treatment for adults with Prader-Willi syndrome - a meta-analysis

CONTEXT: Features of Prader-Willi syndrome (PWS) overlap with features of growth hormone (GH) deficiency, like small hands and feet, short stature, increased body fat, and low muscle mass and strength. In children with PWS, GH treatment (GHt) improves physical health and cognition. GHt has become the standard of care in PWS children, but in adults this is not yet the case. OBJECTIVE: This work aims to provide an overview of the current knowledge on GHt in PWS adults. METHODS: Medline, Embase, and the Cochrane Central Register of Controlled Trials databases were searched. Study selection included randomized clinical trials (RCTs) and nonrandomized (un)controlled trials (NRCTs) that reported data for adults with PWS, who received GHt for at least 6 months. Data on body composition, body mass index (BMI), cardiovascular end points, bone, cognitive function, quality of life, and safety were extracted. RESULTS: Nine RCTs and 20 NRCTs were included. Body composition improved during 12 months of GHt with an increase in mean (95% CI) lean body mass of 1.95 kg (0.04 to 3.87 kg) and a reduction of mean (95% CI) fat mass of –2.23% (–4.10% to –0.36%). BMI, low-density lipoprotein cholesterol levels, fasting glucose levels, and bone mineral density did not change during GHt. There were no major safety issues. CONCLUSION: GHt appears to be safe and improves body composition in adults with PWS. Because poor body composition is closely linked to the observed high incidence of cardiovascular morbidity in adults with PWS, improving body composition might reduce cardiovascular complications in this vulnerable patient group