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      Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort

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          Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50–75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood. Objective: To characterize the clinical and genetic features of a CDGP cohort. Methods: Fifty-nine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development. Results: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 ± 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP ­cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes ( IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A,and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group. Conclusions: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.

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          Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.

          Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
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            Clinical practice. Delayed puberty.

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              Is Open Access

              Encuesta Salud, Bienestar y Envejecimiento (SABE): metodología de la encuesta y perfil de la población estudiada

              El presente documento reseña la metodología de la encuesta SABE y los desafíos que impone a la sociedad en general y a los servicios de salud en particular el rápido envejecimiento de la población en América Latina y el Caribe. La Región esta envejeciendo a un ritmo que no se ha observado en el mundo desarrollado, y la evaluación de problemas de salud y discapacidad indica que los adultos mayores están envejeciendo con más limitaciones funcionales y peor salud que sus semejantes en países desarrollados. Además, las redes familiares están cambiando rápidamente y tienen menos capacidad de suplir la falta de protección social institucional. El estudio multicéntrico SABE se creó con el objetivo de evaluar el estado de salud de las personas adultas mayores de siete ciudades de América Latina y el Caribe: Buenos Aires, Argentina; Bridgetown, Barbados; La Habana, Cuba; Montevideo, Uruguay; Santiago, Chile; México, D.F., México y São Paulo, Brasil. La encuesta SABE establece el punto de partida para la investigación sistemática del envejecimiento en zonas urbanas de la Región de América Latina y el Caribe. Se recomienda que estudios de estas características y con este ánimo comparativo se extiendan a otros países, zonas y regiones, para enriquecer el conocimiento sobre las personas adultas mayores.

                Author and article information

                S. Karger AG
                October 2020
                15 November 2019
                : 110
                : 11-12
                : 959-966
                aUnidade do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Divisão de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
                bUnidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil
                cDivision of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
                dDepartamento de Clínica Médica, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
                Author notes
                *Ana Claudia Latronico, MD, PhD, Divisão de Endocrinologia e Metabologia, 7° andar, sala 7037, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar, 255, São Paulo, SP 05403-900 (Brazil), E-Mail anacl@usp.br
                504783 Neuroendocrinology 2020;110:959–966
                © 2019 S. Karger AG, Basel

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                Page count
                Tables: 4, Pages: 8
                Research Article


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