The Genetic Basis of Delayed Puberty

Abstract

The genetic control of puberty remains an important but mostly unanswered question. Late pubertal timing affects over 2% of adolescents and is associated with adverse health outcomes including short stature, reduced bone mineral density, and compromised psychosocial health. Self-limited delayed puberty (DP) is a highly heritable trait, which often segregates in an autosomal dominant pattern; however, its neuroendocrine pathophysiology and genetic regulation remain unclear. Some insights into the genetic mutations that lead to familial DP have come from sequencing genes known to cause gonadotropin-releasing hormone (GnRH) deficiency, most recently via next-generation sequencing, and others from large-scale genome-wide association studies in the general population. Investigation of the genetic control of DP is complicated by the fact that this trait is not rare and that the phenotype is likely to represent a final common pathway, with a variety of different pathogenic mechanisms affecting the release of the puberty “brake.” These include abnormalities of GnRH neuronal development and function, GnRH receptor and luteinizing hormone/follicle-stimulating hormone abnormalities, metabolic and energy homeostatic derangements, and transcriptional regulation of the hypothalamic-pituitary-gonadal axis. Thus, genetic control of pubertal timing can range from early fetal life via development of the GnRH network to those factors directly influencing the puberty brake during mid-childhood.

Complex genetics of female fertility

“… 23 – 28 At the other end of the distribution, delayed puberty is associated with short stature and lower bone mineral density. 29 …”

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

“…Interestingly, the p.Val-1995Ile variant was recurrent (families 2 and 3) and it segregated with the CDGP phenotype in affected members of family 2. According to Howard et al [15,36], IGSF10 variants appear to cause a dysregulation of GnRH neuronal migration during embryonic development resulting in reduced numbers or mistimed arrival of GnRH neurons at the hypothalamus, producing a functional defect in the GnRH neuroendocrine network.…”

Pesquisa de novos fatores genéticos no atraso constitucional do crescimento e desenvolvimento humano

“…O ACCD apresenta padrões complexos de herança, incluindo autossômica dominante, autossômica recessiva, bilineal (ambos os pais afetados ou um dos pais é afetado e o outro possui um parente de primeiro grau afetado) e ligada ao X, embora também sejam observados casos esporádicos (16,37,38) . A maioria das famílias exibe um padrão autossômico dominante de herança (com ou sem penetrância completa) (16,36,38) .…”

“…O ACCD apresenta uma forte base genética visto que 50 a 75% dos indivíduos possuem história familiar de puberdade atrasada (17,36) . A maioria das famílias exibe um padrão autossômico dominante de herança (com ou sem penetrância completa) (16,36,38) .…”

“…3) e segregou com o fenótipo de ACCD em membros afetados da Família 2. De acordo com Howard et al (16,34) , variantes no gene IGSF10 causam uma desregulação da migração neuronal de GnRH durante o desenvolvimento embrionário, resultando em números reduzidos ou na chegada errônea dos neurônios de GnRH ao hipotálamo, produzindo um defeito funcional na rede neuroendócrina de GnRH.…”