Delayed Puberty-Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries

Abstract

This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present both diagnostic and prognostic challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but it remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity, and epigenetic modulation. Moreover, much has been learned from comprehension of monogenic and digenic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligogenic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.

Figure 1.

Flowchart for the evaluation of a patient with delayed puberty. CDGP, constitutional delay of growth and puberty; DP, delayed puberty; FT4, free T4; GHD, GH deficiency; PRL, prolactin; TFT, thyroid function test.

Figure 2.

Possible roles in the HPG axis of several of the implicated genes from GWAS and biological mechanisms for menarche timing [adapted from Perry et al. (158)].

Figure 3.

Established genetic basis of common genetic variants of pubertal timing, conditions of CHH (IHH and KS), precocious puberty, and delayed puberty and their overlap. Activating and inactivating mutations in Kiss1 and Kiss1R cause the opposite phenotypes, that is, precocious puberty and CHH, respectively. IHH, idiopathic HH.

Figure 4.

Mutations in single genes at many levels of the HPG axis can cause HH. [Copyright © 2012 Beate K, Joseph N, Nicolas de R, Wolfram K. Genetics of isolated hypogonadotropic hypogonadism: role of GnRH receptor and other genes. Int J Endocrinol. 2012;2012:147893. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.]

Figure 5.

Factors that affect the migration of GnRH neurons through the three compartments. The illustration shows the movement of GnRH neurons from their origin in the nasal placode (NP), through the nasal compartment (NC), and their deflection at the level of the nasal–forebrain junction (NFJ) as they progress toward the basal forebrain (BF). Their migration terminates in the hypothalamus (H) from where they project to the median eminence (ME). Factors that have been shown to affect GnRH neurons at different stages of their journey are shown below. CCK, cholecystokinin; CXCR4, CXC chemokine receptor type 4; Ebf-2, early B-cell factor 2; HGF, hepatocyte growth factor, LIF, leukemia inhibitory factor; Npn-2, neoplastic progression 2; SDF1, stromal cell–derived factor 1. [Republished with permission of Oxford University Press, from Cariboni A, Maggi R, Parnavelas JG. From nose to fertility: the long migratory journey of gonadotropin-releasing hormone neurons. Trends Neurosci. 2007;30(12):638–644. Permission conveyed through Copyright Clearance Center, Inc.]

Figure 6.

Genetic regulators in the trans-synaptic and glial control of GnRH neurons during puberty. + Represents an activating signal, whereas − represents a repressing signal. [Adapted with permission from Ojeda SR, Lomniczi A, Mastronardi C, et al. Minireview: the neuroendocrine regulation of puberty: is the time ripe for a systems biology approach? Endocrinology. 2006;147(3):1166–1174.]

Figure 7.

Schematic of the mechanism by which IGSF10 mutations lead to delayed puberty. Reduced levels of IGSF10 expression during embryogenesis in the corridor of nasal mesenchyme from the vomeronasal organ (VNO) to the olfactory bulbs result in delayed migration of GnRH neurons to the hypothalamus. This presents for the first time in adolescence as a phenotype of delayed puberty due to abnormalities of the GnRH neuronal network.