SIN3A Defects Associated with Syndromic Congenital Hypogonadotropic Hypogonadism: An Overlap with Witteveen-Kolk Syndrome.

INTRODUCTION: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. More than 40 genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. Mutations involving the same gene (e.g., FGFR1, PROK2/PROKR2, CHD7) were found to cause normosmic CHH and Kallmann syndrome (KS), with and without associated phenotypes, illustrating the coexistence of CHH with signs of other complex syndromes. The Witteveen-Kolk syndrome (WITKOS), caused by defects of the SIN3A gene, is a heterogeneous disorder characterized by distinctive facial features, microcephaly, short stature, delayed cognitive, and motor development. Although micropenis and cryptorchidism have been reported in this syndrome, WITKOS has not been formally associated with CHH so far. PATIENTS AND METHODS: A man with KS associated with mild syndromic features (S1) and a boy with global developmental delay, syndromic short stature, micropenis and cryptorchidism (S2), in whom common genetic defects associated with CHH and short stature had been previously excluded, were studied by either chromosomal microarray analysis or whole exome sequencing. RESULTS: Rare SIN3A pathogenic variants were identified in these 2 unrelated patients with CHH phenotypic features. A 550 kb deletion at 15q24.1, including the whole SIN3A gene, was identified in S1, and a SIN3A nonsense rare variant (p.Arg471*) was detected in S2. CONCLUSION: These findings lead us to propose a link between SIN3A defects and CHH, especially in syndromic cases, based on these 2 patients with overlapping phenotypes of WITKOS and CHH.

Development of a questionnaire and screening model for lipedema.

BACKGROUND: Lipedema is greatly underdiagnosed and there is a lack of low-cost tools to facilitate diagnostic. We created a lipedema screening questionnaire based on a questionnaire for assessing symptoms. OBJECTIVES: The study objectives were to identify relevant clinical questions, develop a screening questionnaire, and construct a model for predicting lipedema. METHOD: A simplified questionnaire was constructed and administered to a sample of patients with and without lipedema and then the probability of correct diagnosis was analyzed. RESULTS: All 109 patients who answered the questionnaire were female and all of them understood the questions. A predictive model using individual question scores achieved an excellent probability of correct diagnosis, at 91.2%, and a predictive model based on total score also achieved a good probability of correct diagnosis, at 86.15%. CONCLUSIONS: The lipedema screening questionnaire is a practical instrument that is quick and easy to administer and can be used with our population for identification of possible lipedema patients, raising the level of suspicion when taking a patient's history and conducting a physical examination.

Criação de questionário e modelo de rastreamento de lipedema / Development of a questionnaire and screening model for lipedema

Resumo Contexto O lipedema é muito subdiagnosticado e faltam ferramentas auxiliares diagnósticas de baixo custo. Baseado em um questionário de avaliação sintomática, criamos e validamos um questionário de rastreamento do lipedema. Objetivos Os objetivos do trabalho foram a identificação de perguntas clínicas relevantes, a elaboração de questionário de rastreamento e a criação de modelo de predição do lipedema. Métodos Um questionário simplificado foi criado e aplicado em um grupo de pacientes com e sem lipedema, sendo avaliada a probabilidade de acerto no diagnóstico. Resultados Os 109 pacientes que responderam ao questionário eram do sexo feminino e as questões foram compreendidas. O modelo preditivo com perguntas individuais mostrou excelente probabilidade de acerto, de 91,2%, e o modelo preditivo com somatória de pontos também teve boa probabilidade de acerto, de 86,15%. Conclusões O questionário de rastreamento do lipedema é um instrumento prático, de fácil e rápida aplicação, que pode ser utilizado em nossa população para a identificação de possíveis pacientes com lipedema, aumentando o nível de suspeição no momento da anamnese e exame físico.

Abstract Background Lipedema is greatly underdiagnosed and there is a lack of low-cost tools to facilitate diagnostic. We created a lipedema screening questionnaire based on a questionnaire for assessing symptoms. Objectives The study objectives were to identify relevant clinical questions, develop a screening questionnaire, and construct a model for predicting lipedema. Method A simplified questionnaire was constructed and administered to a sample of patients with and without lipedema and then the probability of correct diagnosis was analyzed. Results All 109 patients who answered the questionnaire were female and all of them understood the questions. A predictive model using individual question scores achieved an excellent probability of correct diagnosis, at 91.2%, and a predictive model based on total score also achieved a good probability of correct diagnosis, at 86.15%. Conclusions The lipedema screening questionnaire is a practical instrument that is quick and easy to administer and can be used with our population for identification of possible lipedema patients, raising the level of suspicion when taking a patient's history and conducting a physical examination.

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism.

CONTEXT: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. OBJECTIVE: Genetic characterization of a large cohort of Brazilian CHH patients. DESIGN AND PATIENTS: A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. RESULTS: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. CONCLUSIONS: This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.