Self-limited delayed puberty segregates within families with complex patterns of inheritance including autosomal dominant, autosomal recessive, bilineal and X-linked, although sporadic cases are also observed. The majority of families display an autosomal dominant pattern of inheritance (with or without complete penetrance) [1-3]. 50 to 75% of subjects with self-limited delayed puberty have a family history of delayed pubertal onset [2]. Self-limited delayed puberty is not sex-specific, as near equal sex ratios amongst family members are seen [3]. Although a predominance of males presenting with the condition has been noted, this may be a consequence of referral bias.

The neuroendocrine pathophysiology and its genetic regulation remain unclear in the majority of patients with delayed puberty [4, 5]. Analysis of self-limited delayed puberty families is complicated by the fact that this phenotype represents the tail of a normally distributed trait within the population, so it is expected that variants that govern the inheritance of this condition may also be present in the general population at a low level. Thus, the absence of these variants in population databases cannot be used as an exclusion criterion during filtering of sequencing data. Instead, a comparison of prevalence of such variants must be made to identify those that are enriched in patients compared to the general population.

In view of the possible overlap between the pathophysiology of delayed puberty and conditions of GnRH deficiency, a few groups have specifically examined the contribution of mutations in CHH genes to the phenotype of self-limited delayed puberty. Studies in cohorts of kindreds with CHH have previously described mutations in Heparan Sulfate 6-O-Sulfotransferase 1 (HS6ST1), Fibroblast Growth Factor Receptor 1 (FGFR1) and more recently in Klotho Beta (KLB) in a small number of CHH individuals and their relatives with delayed puberty [6-8]. Most recently, a comparative study of the frequency of mutations in 24 GnRH deficiency genes between probands with CHH and those with self-limited delayed puberty found a significantly higher proportion of mutations in the CHH group (51% of CHH probands vs 7% of delayed puberty probands, p=7.6x^10-11), with a higher proportion of oligogenicity in the CHH group, suggesting mostly distinct genetic profiles in these two conditions [9]. Mutations in KS genes such as ANOS1 and NSMF have not to date been identified in pedigrees with delayed puberty. 

In studies specially examining delayed puberty cohorts, variants in several CHH genes including Gonadotropin Releasing Hormone Receptor (GNRHR), Tachykinin 3 (TAC3) and its receptor (TACR3), Interleukin 17 Receptor D (IL17RD) and Semaphorin 3A (SEMA3A) have been identified by whole exome sequencing [10]. However, these variants have not been tested in vitro or in vivo for pathogenicity, or investigated for segregation with trait within pedigrees, and thus may be an over-estimation.

Using whole exome and targeted resequencing methods, a deleterious mutation in the CHH gene HS6ST1 was recently found as the likely causal factor for self-limited delayed puberty in one extended pedigree from the same large cohort of patients with familial delayed puberty [11]. The mutation was carried by six family members from three generations, all with typical features of self-limited delayed puberty. The proband had spontaneous onset of puberty at 14.3 years.  Parallel studies in a murine model corroborated heterozygous Hs6st1 deficiency as a cause of delayed pubertal timing without compromised fertility. Thus, Hs6st1+/− mice were born at normal Mendelian ratios without obvious defects in GnRH neuron or testes development, but females showed delayed vaginal opening, a marker of pubertal onset in female rodents. GnRH deficiency was excluded both in male and female Hs6st1+/− mice, by reproductive competence and by normal spermatogenesis in males.

No abnormalities in olfactory bulb morphology, GnRH neuron number in the medial preoptic area or in GnRH neuron innervation of the median eminence were detected in Hs6st1+/- mice. Instead, Hs6st1 expression in the arcuate nucleus and paraventricular nucleus, where kisspeptin neurons and tanycytes modulate GnRH secretion and function [12, 13], raises the possibility that HS6ST1 haploinsufficiency affects the regulation of GnRH neuron activity or other relevant downstream pathways. These findings suggest that perturbations in a single allele of a gene regulating the HPG axis are sufficient to cause self-limited delayed puberty. In contrast, available evidence supports that more deleterious alterations in the same gene, or in combination with additional genes, are required to cause more severe CHH phenotypes [14].

In support of this, using a similar approach with whole exome and targeted resequencing methods, two pathogenic mutations in Immunoglobulin superfamily member 10 (IGSF10) have been implicated as the causal factor for late puberty in six unrelated families from a large Finnish cohort with familial self-limited delayed puberty [15]. A further two rare variants of unknown significance were identified in four additional families from the cohort. Mutations in IGSF10 appear to cause a dysregulation of GnRH neuronal migration during embryonic development (Figure 1), which presents in adolescence as delayed puberty without previous constitutional delay in growth. An intact GnRH neurosecretory network is necessary for the correct temporal pacing of puberty. Pathogenic IGSF10 mutations leading to disrupted IGSF10 signalling potentially result in reduced numbers, or mis-timed arrival, of GnRH neurons at the hypothalamus, producing a functional defect in the GnRH neuroendocrine network. With this impaired GnRH system there would follow an increased ‘threshold’ for the onset of puberty, with an ensuing delay in pubertal timing. IGSF10 loss-of-function mutations were also discovered in patients with a hypothalamic amenorrhoea-like phenotype. Although loss-of-function mutations in IGSF10 were enriched in patients with CHH, these mutations did not alone appear sufficient to cause the phenotype of full GnRH deficiency, in view of lack of complete segregation with trait. These findings represent a fetal origin of self-limited delayed puberty, and suggest a potential shared pathophysiology between delayed puberty and other forms of functional hypogonadism such as hypothalamic amenorrhoea.

As loss-of-function mutations within the GnRH receptor are one of the most frequent causes of CHH, the GNRHR gene has been repeatedly sequenced in patients with self-limited delayed puberty [16]. However, only a small number of pathogenic mutations in this gene have been identified in this cohort of patients. A homozygous partial loss-of-function mutation in GNRHR was found in two brothers, one with self-limited delayed puberty and one with CHH [17], and a further heterozygous mutation found in one male with self-limited delayed puberty [18]. Overall, the current picture indicates that the genetic background of CHH and delayed puberty may be largely different, or shared by as yet undiscovered genes [18].

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6.         Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G et al. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proceedings of the National Academy of Sciences of the United States of America 2011; 108(28):11524-9.[Pubmed]

7.         Pitteloud N, Meysing A, Quinton R, Acierno JS, Jr., Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S et al. Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Molecular and cellular endocrinology 2006; 254-255:60-9.[Pubmed]

8.         Xu C, Messina A, Somm E, Miraoui H, Kinnunen T, Acierno J, Jr., Niederlander NJ, Bouilly J, Dwyer AA, Sidis Y et al. KLB, encoding beta-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadism. EMBO Mol Med. 2017 Oct;9(10):1379-1397. doi: https://doi.org/10.15252/emmm.201607376.

9.         Cassatella D, Howard SR, Acierno JS, Xu C, Papadakis GE, Santoni FA, Dwyer AA, Santini S, Sykiotis GP, Chambion C et al. Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures. Eur J Endocrinol 2018; 178(4):377-88.[Pubmed]

10.       Zhu J, Choa RE, Guo MH, Plummer L, Buck C, Palmert MR, Hirschhorn JN, Seminara SB, Chan YM. A Shared Genetic Basis for Self-Limited Delayed Puberty and Idiopathic Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab 2015;jc20151080.

11.       Howard SR, Oleari R, Poliandri A, Chantzara V, Fantin A, Ruiz-Babot G, Metherell LA, Cabrera CP, Barnes MR, Wehkalampi K et al. HS6ST1 insufficiency causes self-limited delayed puberty in contrast with other GnRH deficiency genes. J Clin Endocrinol Metab 2018;103(9):3420-9. doi: https://doi.org/10.1210/jc.2018-00646.

12.       Parkash J, Messina A, Langlet F, Cimino I, Loyens A, Mazur D, Gallet S, Balland E, Malone SA, Pralong F et al. Semaphorin7A regulates neuroglial plasticity in the adult hypothalamic median eminence. Nat Commun 2015; 6:6385.[Pubmed]

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