Dataset Information

The Genetic Basis of Delayed Puberty.

ABSTRACT: Delayed pubertal onset has many etiologies, but on average two-thirds of patients presenting with late puberty have self-limited (or constitutional) delayed puberty. Self-limited delayed puberty often has a strong familial basis. Segregation analyses from previous studies show complex models of inheritance, most commonly autosomal dominant, but also including autosomal recessive, bilineal, and X-linked. Sporadic cases are also observed. Despite this, the neuroendocrine mechanisms and genetic regulation remain unclear in the majority of patients with self-limited delayed puberty. Only rarely have mutations in genes known to cause aberrations of the hypothalamic-pituitary-gonadal axis been identified in cases of delayed puberty, and the majority of these are in relatives of patients with congenital hypogonadotropic hypogonadism (CHH), for example in the FGFR1 and GNRHR genes. Using next generation sequencing in a large family with isolated self-limited delayed puberty, a pathogenic mutation in the CHH gene HS6ST1 was found as the likely cause for this phenotype. Additionally, a study comparing the frequency of mutations in genes that cause GnRH deficiency between probands with CHH and probands with isolated self-limited delayed puberty identified that a significantly higher proportion of mutations with a greater degree of oligogenicity were seen in the CHH group. Mutations in the gene IGSF10 have been implicated in the pathogenesis of familial late puberty in a large Finnish cohort. IGSF10 disruption represents a fetal origin of delayed puberty, with dysregulation of GnRH neuronal migration during embryonic development presenting for the first time in adolescence as late puberty. Some patients with self-limited delayed puberty have distinct constitutional features of growth and puberty. Deleterious variants in FTO have been found in families with delayed puberty with extremely low BMI and maturational delay in growth in early childhood. Recent exciting evidence highlights the importance of epigenetic up-regulation of GnRH transcription by a network of miRNAs and transcription factors, including EAP1, during puberty. Whilst a fascinating heterogeneity of genetic defects have been shown to result in delayed and disordered puberty, and many are yet to be discovered, genetic testing may become a realistic diagnostic tool for the differentiation of conditions of delayed puberty.

SUBMITTER: Howard SR

PROVIDER: S-EPMC6606719 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Genetic Basis of Delayed Puberty.

Howard Sasha R SR

Frontiers in endocrinology 20190626

Delayed pubertal onset has many etiologies, but on average two-thirds of patients presenting with late puberty have self-limited (or constitutional) delayed puberty. Self-limited delayed puberty often has a strong familial basis. Segregation analyses from previous studies show complex models of inheritance, most commonly autosomal dominant, but also including autosomal recessive, bilineal, and X-linked. Sporadic cases are also observed. Despite this, the neuroendocrine mechanisms and genetic reg ...[more]

PMID: 31293522

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Project description:BACKGROUND:The neuropeptide kisspeptin stimulates luteinizing hormone (LH) secretion in healthy adults but not in adults with idiopathic hypogonadotropic hypogonadism. We hypothesized that, in children presenting with delayed or stalled puberty, kisspeptin would elicit LH secretion in those children found on detailed nighttime neuroendocrine profiling to have evidence of emerging reproductive endocrine function. METHODS:Eleven boys and four girls were admitted overnight to assess LH secretion at baseline, after a single intravenous bolus of kisspeptin, and after a single intravenous bolus of gonadotropin-releasing hormone (GnRH). Subjects then received exogenous pulsatile GnRH for 6 days and returned for a second visit to measure responses to kisspeptin and GnRH after this pituitary "priming." Responses to kisspeptin and GnRH were also measured in 5 healthy men. RESULTS:Of the 15 children with delayed/stalled puberty, 6 exhibited at least one spontaneous LH pulse overnight; all of these subjects had clear responses to kisspeptin, as did one additional subject. Seven subjects had no response to kisspeptin, and one subject exhibited an intermediate response. In the children who responded to kisspeptin, the responses had features comparable to those of adult men. CONCLUSION:In this first report of kisspeptin administration to pediatric subjects to our knowledge, children with delayed/stalled puberty showed a wide range of responses, with some showing a robust response and others showing little to no response. Further follow-up will determine whether responses to kisspeptin predict future pubertal entry for children with delayed puberty. TRIAL REGISTRATION:ClinicalTrials.gov NCT01438034 and NCT01952782. FUNDING:NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD043341, R01 HD090071, P50 HD028138), NIH National Center for Advancing Translational (UL1 TR001102), NIH National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007028), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery, Harvard Catalyst, Doris Duke Charitable Foundation (award 2013110), Charles H. Hood Foundation, Robert and Laura Reynolds MGH Research Scholar Program, and Harvard University. These funding sources had no role in the design of this study and did not have any role in conducting the study, analyses, interpretation of the data, or the decision to submit results.

Dataset Information

The Genetic Basis of Delayed Puberty.

Publications

The Genetic Basis of Delayed Puberty.

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