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Review

Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism

by
Ali Kemal Topaloglu
1,2,* and
Ihsan Turan
3
1
Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS 39216, USA
2
Division of Pediatric Endocrinology, Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS 39216, USA
3
Division of Pediatric Endocrinology, Faculty of Medicine, Cukurova University, Adana 01230, Turkey
*
Author to whom correspondence should be addressed.
Endocrines 2022, 3(1), 1-15; https://doi.org/10.3390/endocrines3010001
Submission received: 18 October 2021 / Revised: 13 December 2021 / Accepted: 16 December 2021 / Published: 24 December 2021
(This article belongs to the Special Issue Genetics in Pediatric Endocrinology)
Browse Figure
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Abstract

:
Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.

1. Introduction

Idiopathic hypogonadotropic hypogonadism (IHH) refers to instances of hypogonadotropic hypogonadism (HH) that have no known etiology. IHH is divided into two categories with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism (nIHH), and hyposmia or anosmia (Kallmann Syndrome (KS)) and can be congenital or acquired [1]. The most frequent presentation of IHH is a pubertal delay, defined as the absence or inadequacy of mammary gland development in a 13-year-old girl, or the inability to attain a testicular volume of 4 mL in a 14-year-old boy. Micropenis and/or cryptorchidism may be the first sign of IHH in male newborns. Typically, clinical symptoms of IHH do not appear in girls until they are in their early teen years [2]. Constitutional delay in growth and puberty (CDGP) is by far the most frequent cause of delayed puberty, which is not an illness in and of itself, rather an individual variation of timing at the older end. The diagnosis of CDGP can only be made by excluding IHH, which often requires prolonged follow-up periods. Genetic factors are thought to account for 50–80 percent of pubertal timing [3]. From this perspective, IHH and CDGP can be considered severely or mildly affected conditions on the same scale. As accepted, new gene discovery studies have initially reported most severe variants in the functionally crucial genes. Researchers have recently associated more genes with IHH in complex pedigrees, often lacking proper genotype-phenotype segregations. This is probably due to a combination of oligogenic etiology [4] and clinical recovery [5], among other factors.
Despite a long history of research on the topic, it remains unclear what triggers pubertal development. The genetic underpinnings of IHH may provide clues to this enigma. Over the past decades, an exponential number of new IHH genes have been published. The improvement of DNA sequencing has been the mainstay for these studies. The development of Sanger sequencing in 1977 by Frederick Sanger and the first commercialization by Applied Biosystems in 1986 was the beginning of a new era. Subsequently, next-generation sequencing (NGS) technology enormously escalated the production of genetic data. Since 2010, molecular genetic analyses based on NGS entered medical practice and furthered research possibilities. NGS has allowed the systematic identification of variants on a large scale and accelerated the pace of gene discovery and disease diagnosis on a molecular level, particularly for the rare Mendelian disease [6]. The exponentially increased number of articles published in Pubmed about the genetics of normosmic IHH and Kallmann Syndrome is presented in Figure 1.
Preparing this review article, we identified relevant articles from the earliest available online indexing up to November 2021 through systematic searches in the PubMed/MEDLINE database. The search strategy included the following keywords: “idiopathic hypogonadotropic hypogonadism” OR “Kallmann syndrome” OR “puberty” AND “gene” OR “puberty” AND “mutation.” The search results were manually reviewed. Up until present, nearly 60 genes have been reported to be associated with IHH (Table 1). However, the genes reported so far may explain approximately 50% of all seemingly inherited cases [1]. Oligogenicity has been reported for IHH based on Mendelian inheritance [4,7,8,9]. The increasing use of next-generation sequencing in clinical practice has been revolutionary for genetic-based studies (e.g., elucidating disease physiology, rapid diagnosis, or new gene discoveries) [10]. While it has been known that the oligogenic inheritance was about 10–20% in IHH, recent studies have reported that this rate may be much higher, up to 70% [11].
The genes involved in the physiology of IHH can be divided into two main categories: neurodevelopmental and neuroendocrine. However, it has been increasingly reported that these two groups may be intertwined. Thus, a KS-related gene may also be responsible for nIHH (or vice versa) [11,12,13]. Those neurodevelopmental genes closely related to the KS genes are mainly associated with fibroblast growth factor (FGF) signaling, GnRH neuron migration, and olfactory bulb structure. They may occasionally be observed with additional clinical features, such as synkinesia, dental agenesis, hearing loss, and digital bony abnormalities [1,14,15]. Neuroendocrine genes, which represent the normosmic side of the disease (nIHH), are fundamentally related to the function of the hypothalamo-pituitary-gonadal axis. Mutations identified in familial nIHH cases provided a better understanding of the physiology of the HPG axis [16]
The aim of the manuscript is to review the genetic etiology of IHH. We presented the genes associated with IHH in two sections as with or without phenotype numbers of OMIM.

2. IHH-Associated Genes with OMIM Phenotype Number

ANOS1 (HH1, #308700): This gene, formerly known as KAL1, is located on the X chromosome and encodes an extracellular glycoprotein called anosmin-1 [17]. The extracellularly secreted anosmin-1 enhances FGF activity by promoting FGF8-FGFR1 complex formation, which is required for neuronal migration [15] Patients with deleterious ANOS1 variants have absent or severely reduced migration of GnRH cells into the hypothalamus. ANOS1 mutations are seen in male individuals with KS. To date, various mutations have been reported ranging from missense to frameshifts caused by insertion/deletion [18,19]. Accompanying clinical signs may include bimanual synkinesia (mirror movements) and unilateral renal agenesis [20]. In addition, the association of rarely reported clinical signs, such as deafness and vas deferens agenesis, has not been fully clarified.
Fibroblast growth factor family and related genes: FGFR1 (HH2 #1479850), FGF8 (HH6 #612702), HS6ST1 (HH15 #614880), SPRY4 (HH17 #615266), IL17RD (HH18 #615267), DUSP6 (HH19 #615269), FGF17 (HH20 #615270), FLRT3 (HH21 #615271), and KLB (2017): FGFR1 signaling is involved in the morphogenesis of olfactory bulbs. It is required for normal migration, differentiation, and/or survival of GnRH neurons. However, isolated defects in GnRH neuronal migration that occur without the development of olfactory bulbs affected may also be due to FGFR1 mutations. To date, numerous mutations associated with both KS and nIHH have been reported [12,14,21,22,23,24]. Thus, this gene should be prioritized in screening panels for both forms of HH [25].
FGF8 is a ligand of FGFR1, which is involved in GnRH neuron ontogenesis. Falardeau et al. reported missense mutations in FGF8 in six IHH patients with variable olfactory function. They also showed that the hypomorphic homozygous Fgf8 mice lack GnRH neurons and olfactory bulbs in the hypothalamus [26]. The study of Miraoui and colleagues identified heterozygous FGF17 mutations in both normosmic IHH and KS patients [27]. FGF17 has a similar sequence to that of FGF8 and is a critical FGFR1 ligand that plays a role in GnRH neuron ontogeny. Bone defects, cleft lip-palate, and dental agenesis are commonly associated with the FGF group gene mutations [20]. In addition, it has been reported that IL17RD, DUSP6, SPRY4, and FLRT3 have essential roles in the development of GnRH neurons [27].
KLB encodes for beta-klotho a co-receptor in FGF21 signaling. The majority of patients with KLB mutations have various metabolic defects. Klb knockout mice showed a milder hypogonadal phenotype [28].
HS 6-O-sulfotransferase 1 is a sulfation enzyme that catalyzes the transfer of sulfate and is involved in cell-cell communication and neuronal migration. Inactivating HS6ST1 mutations have been identified with oligogenicity in both KS and nIHH. C. elegans studies have shown that HS6ST1 regulates neural branching required for FGF8-mediated FGFR1 signaling [29]. Recently, a heterozygous HS6ST1 variant was shown to be segregated with self-limited delayed puberty, which is effectively synonymous to CDGP in a large pedigree. Accompanying mouse studies corroborated human findings [30].
PROKR2 (HH3 #244200) and PROK2 (HH4 #610628): PROK2 and PROKR2 encode a peptide consisting of 81 amino acids called prokineticin 2 and its G-protein-dependent receptor, respectively. Both serve as origins for neuronal precursors and are involved in various biological processes, including olfactory bulb morphogenesis and sexual maturation [31]. Studies have shown that Prokr2 knockout mice exhibited a significant reduction in olfactory bulb size, while asymmetric olfactory bulb development was observed in prok2 knockout mice [32,33]. PROK2 and PROKR2 mutations cause phenotypic diversity ranging from KS to nIHH. Patients with PROK2 or PROKR2 mutations have been reported with clinical features, such as fibrous dysplasia, synkinesis, and epilepsy. In addition to the known AR and AD transmission model, both genes are associated with oligogenic inheritance [13,34,35].
CHD7 (HH5 #612370): Chromodomain helicase DNA-binding protein 7 (CHD7) mutations are the main causes of CHARGE syndrome, comprising Coloboma, Heart anomalies, choanal Atresia, Retardation, Genital defects, and Ear anomalies [36]. The hypothesis that KS and nIHH may be a milder allelic variant of the CHARGE syndrome has emerged with studies that identified CHD7 mutations in HH patients without CHARGE features [37,38]. Studies in Chd7-deficient mice show that this gene affects the GnRH neuron migration pathway from beginning to end [39]. Accordingly, patients with HH phenotype should be examined for possible CHD7 mutations, even if they do not have any CHARGE syndrome characteristics. CHD7 should be tested in the presence of clinical features, such as coloboma, abnormal ears, deafness, and/or semicircular canal hypoplasia/aplasia [36].
GNRHR (HH7 #146110) and GNRH1 (HH12 #614841): The GnRH receptor encoded by the GNRHR belongs to the G-protein-coupled receptor family consisting of seven helical transmembrane domains. In 1997, de Roux and coworkers reported that inactivating mutations in GNRHR cause nIHH [40]. GNRHR mutations with an autosomal recessive inheritance pattern have a prevalence of approximately 40% in familial cases and 17% in sporadic cases in nIHH [41]. Mutations have been observed in patients with a broad spectrum of reproduction ranging from partial to complete GnRH resistance [42]. GNRH1 encodes gonadotropin-releasing hormone, a hypothalamic decapeptide, and plays an essential role in regulating vertebrate reproduction [43]. The essential role of GnRH in human reproduction was confirmed by inactivating GNRH1 mutations, which were reported as the cause of IHH in the same period by two independent research groups [44,45]. The detection of different mutations of the amino acid arginine at position 31 (p.Arg31Cys and p.Arg31His) that affect the GnRH decapeptide sequence has shown that this region could be a “hot spot” [45,46].
KISS1R (HH8 #614837) and KISS1 (HH13 #614842): KISS1R encodes the kisspeptin receptor, a G-protein-coupled receptor. Autosomal recessive KISS1R mutations were first identified in 2003 by two independent research groups using linkage analysis in familial multiplex IHH cases [47,48]. Subsequently, loss-of-function KISS1R mutations have also been reported in partial or complete nIHH patients with different studies [48]. Studies have shown that KISS1 and its receptor are expressed in the mouse hypothalamus and are an essential neuroendocrine regulator of gonadotropin secretion [49,50].
In 2012, Topaloglu et al. identified a homozygous KISS1 mutation in a large consanguineous family with normosmic IHH. This study reported an inactivating mutation affecting the fourth amino acid of the mature Kisspeptin−10, which has a highly conserved residue [51]. As with other ligands (i.e., GNRH1 and TAC3), mutations in KISS1 are rarer in the etiology of IHH in comparison to their receptor counterparts.
NSMF (HH9 #614838): NSMF, the NMDA receptor synaptonuclear signaling and neuronal migration factor, is expressed in olfactory and GnRH cells during embryonic development. It has been shown to guide olfactory axonal projection and GnRH migration in mice studies. NSMF mutations have been identified in both KS and normosmic IHH patients, some associated with other known IHH genes, such as TACR3, HS6ST1, FGFR1, and ANOS1 [52,53].
TAC3 (HH10 #614839) and TACR3 (HH11 #614840): Neurokinin B is encoded by tachykinin precursor 3 (TAC3), and neurokinin B receptor is encoded by tachykinin receptor 3 (TACR3), a member of the rhodopsin family of G-protein-coupled receptors. Together with kisspeptin and dynorphin, neurokinin B forms KNDy neurons in the hypothalamic arcuate nucleus (ARC) and regulates the secretion of GnRH, which is required for mammalian reproduction [54]. In 2009, Topaloglu and colleagues using single nucleotide polymorphism analyses based on autozygosity mapping, identified the first inactivating homozygous TAC3 and TACR3 mutations in nine patients from four independent families with IHH phenotype [16,55]. Later studies determined that TACR3 mutations were common [56,57]. Clinical reversibility is a phenomenon with unclear mechanisms, seen in approximately 10% of IHH patients. Gianetti et al. reported a clinical reversibility rate of 83% in their TAC3/TACR3 cohort. In contrast, the presence of micropenis and cryptorchidism, which is an indication of severe congenital phenotype, was observed in male infants with TACR3 mutations. These observations may be due to the plasticity of neurokinin B signaling through the reproductive life stages.
WDR11 (HH14 #614858): WDR11 encodes WD repeat-containing protein 11 and is associated with both KS and nIHH. The interaction of EMX1, a homeodomain transcription factor involved in the development of olfactory neurons, and WDR11 have been demonstrated by murine studies [58]. WDR11/PROKR2 coexistence has been reported in association with pituitary stalk interruption syndrome [59].
SEMA3A (HH16 #614897) and SEMA3E (2015): SEMA3A encodes semaphorin 3A, an axonal guide molecule that interacts with neuropilins. Neuropilin-plexin-A1 complex, which is involved in axonal growth during embryonic development, is activated by semaphorin 3A. Cariboni et al. seminally reported that SEMA3A is the critical player in semaphorin signaling during GnRH neuron development [60]. Studies have shown that mice lacking SEMA3A expression have defects in the olfactory system and migration of GnRH cells, thus having a Kallmann-like phenotype [61,62]. Similarly, SEMA3E, another member of the same SEMA3 family and encoding semaphorin 3E, is a secreted protein involved in axonal growth [63]. Studies have shown that mutations in both genes are related to IHH with oligogenic inheritance [64].
FEZF1 (HH22 #616030): In 2014, a study combining autozygosity mapping and whole-exome sequencing identified homozygous loss-of-function and nonsense FEZF1 mutations in two independent consanguineous families with KS. The inheritance pattern is autosomal recessive, and mutations are extremely rare. Studies have shown that Fez-1 deficient mice have a smaller olfactory bulb and no GnRH neuron in their brains due to impaired axonal projection of olfactory receptor neurons. FEZ family zinc finger 1 (encoded by FEZF1) corroborates the presence of protease required for GnRH neurons to enter the brain and reach their ultimate destination [65,66].
NDNF (HH25 #618841): NDNF is a member of the fibronectin-3 superfamily. WES data from a cohort of 240 probands with IHH were screened for rare variants in FN3 domain-containing proteins. Four apparently pathogenic variants in NDNF were identified in four KS probands. In a functional study, delayed GnRH neuron migration and altered olfactory axonal projections to the olfactory bulb were shown by knockdown of the zebrafish ortholog of NDNF [67].
SMCHD1 (#603457): SMCHD1, structural maintenance of chromosome flexible hinge domain containing 1, is an epigenetic regulator gene expressed in the olfactory epithelium. In 2017, Shaw et al. identified missense SMCHD1 mutations in a patient with arrhinia (or absence of the nose). The vast majority of patients had HH, and seven subjects lacked olfactory structures [68]. In a recent study, rare variants of this gene in the spectrum of HH-related disease were reported [69].
SOX10 (#613266): SOX10, a member of the SOX family, encodes a transcription factor expressed by GnRH neuron precursors. Inactivating mutations cause Waardenburg syndrome, a rare genetic condition that can cause pigmentation anomalies of the skin, hair, and/or eyes, and hearing loss. Studies have shown that the olfactory ensheathing cells are absent in SOX10 knockout mice. SOX10 has been reported to be associated with KS. Inactivating SOX10 variants have been observed in approximately one-third of KS patients with deafness (80) [70].
LEP (#614962), LEPR (#614963), and PCSK1 (#600955): Mutations in LEP (encoding leptin) or LEPR (encoding leptin receptor), and PCSK1 (proprotein convertase subtilisin/kexin type 1), account for less than 5% in nIHH [71,72]. These patients have obesity in addition to IHH. It is well-known that energy balance is important for the onset of puberty. Leptin is a fat-derived hormone and regulates food intake and energy expenditure associated with body weight. Therefore, starving and/or loss of body fat suppress reproduction and lead to infertility. Leptin and its receptor are involved in the control of human reproduction [1,73,74]. In mice studies, leptin treatment induced the onset of puberty in normal females and reversed hypogonadism in those with starvation-induced leptin deficiency [75,76].
NR0B1 (#300200): NR0B1 (the nuclear receptor subfamily 0, group B, member 1) is a pleiotropic gene with X-linked inheritance. NR0B1 is involved with a syndromic form of IHH associated with primary adrenal insufficiency due to congenital adrenal hypoplasia. It encodes an orphan receptor expressed in the adrenal cortex and gonads [77].
CPE (#619326): Carboxypeptidase E (CPE) plays a critical role in the biosynthesis of peptide hormones and neuropeptides within the endocrine and central nervous systems, such as alfa-MSH. A 21-year-old woman was reported to have childhood-onset obesity, impaired intellectual disability, type 2 diabetes, and hypogonadotropic hypogonadism [78]. More recently, a homozygous nonsense variant of CPE was reported in three siblings with the same phenotype with appropriate genotype-phenotype segregations [79].
HESX1 (#182230): Homeobox gene expressed in embryonic stem cells 1 (HESX1) encodes a transcription repressor important for cell proliferation and differentiation. The study of Newbern et al. identified heterozygous missense mutations in three patients with an impaired sense of smell out of a total of 217 HH individuals [80].
DMXL2 (#616113): DMXL2 encodes the synaptic protein DmX-like protein 2. Tata et al. showed that DMXL2 causes a highly complex syndrome associated with HH and polyendocrine deficiencies and polyneuropathies in three siblings with homozygous deletion. A low DMXL2 expression in mice leads to partial gonadotropic axis deficiency resulting in reduced fertility [81].
OTUD4 (2013), RNF216 (#212840), STUB1 (#615768), and PNPLA6 (#215470): OTU domain-containing protein 4 (encoded by OTUD4), E3 ubiquitin-protein ligase RNF216 (encoded by RNF216), and carboxy terminus of Hsp70-interacting protein (encoded by STUB1) play roles in ubiquitination. Homozygous mutations in the OTUD4 and RNF216 were identified in a consanguineous family with Gordon Holmes syndrome characterized by cerebellar ataxia and normosmic IHH [82]. Shi et al. identified a homozygous mutation in STUB1 in siblings with IHH and ataxia [83]. Genetic research using WES also showed PNPLA6 mutations to cause both Gordon Holmes and Boucher–Neuhauser syndromes. Neuropathy target esterase encoded by PNPLA6 is a protein involved in phospholipid metabolism. PNPLA6 deficiency results in an impaired gonadotropin release and delayed neurodegeneration [84,85].
POLR3A (#607694) and POLR3B (#614381): POLR3A, the largest of the 17 subunits that make up RNA polymerase III (Pol III), and POLR3B, the second-largest subunit, together form the catalytic center of the enzyme, which transcribes small untranslated RNAs such as tRNA [86]. Recessive mutations in these genes have been reported in association with the 4H syndrome, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism [87,88].

3. The Genes Associated with IHH without Phenotype Numbers of OMIM

Reported mutations in many different genes can explain up to 50% of the causes of genetic cases with IHH. That is the reason why research into new genes that cause IHH is still exciting. Considering that more specific and functionally crucial genes are discovered first, future research will likely elucidate more complex genes. Recent reports of new puberty gene discoveries often lack proper genotype-phenotype segregations in given pedigrees, possibly as a result of oligogenic inheritance, variable penetrance, and clinical heterogeneity of the disease.
SOX3 (2014): SOX3 encodes a transcription factor involved in pituitary morphogenesis. Previously, duplications and deletions of alanine residues SOX3 were associated with X-linked panhypopituitarism. Subsequently, two different reports identified an in-frame deletion of the polyalanine tract in SOX3 in IHH patients without other pituitary hormone deficiencies [89].
AXL (2014): AXL, a member of TAM family, receptor tyrosine kinases, is differentially expressed in GnRH neuronal cells and implicated in GnRH neuron migration and/or survival. Four AXL variants were detected in four patients with Kallmann syndrome or nIHH [90].
IGSF10 (2016): Using candidate gene sequencing and WES, Howard et al. identified rare mutations in the IGSF10 in six families with self-limited delayed puberty. The potential role of immunoglobulin superfamily member 10 (IGSF10) in the regulation of GnRH neuronal migration was demonstrated, with its strong expression in embryonic nasal mesenchyme during GnRH neuronal migration. IGSF10 knockdown has been shown to impair GnRH neuron migration in zebrafish. Patients with IGSF10 mutations were normosmic, despite impaired migration of GnRH. Notably, rare variants in IGSF10 were also identified in a few patients with functional hypothalamic amenorrhea [91].
SRA1 (2016): SRA1 was the first gene discovered to function through both protein and non-coding functional RNA products [92]. Nuclear receptors, such as SF-1 and LRH-1, are co-regulated SRA1 products. SRA1 is required by NR0B1 to synergistically enhance SF-1 transcriptional activity (85). Using the autozygosity mapping and WES, SRA1 mutations in three independent families with IHH were identified [93].
PLXNA1 (2017): Plexin-A1 protein, encoded by PLXNA1, is a coreceptor of SEMA3A, SEMA3C, SEMA3F, and SEMA6D. Marcos et al. found the PLXNA1 variants in a large cohort of KS. These studies revealed 13 heterozygous missense variants in 15 patients from 13 pedigrees. [94]. More recently, Kotan et al. identified 10 variant in PLXNA1 s in nine patients from seven independent families, seven of whom were normosmic. They concluded that PLXNA1 variants cause not only anosmic but also normosmic IHH [11].
CCDC141 (2018): CCDC141 encodes the coiled-coil domain-containing protein 141, a cytoskeletal associated protein expressed in GnRH neurons. Turan et al. reported inactivating CCDC141 mutations in four independent families with IHH [95]. Knockdown of Ccdc141 resulted in reduced embryonic GnRH neuronal migration [96]. In another extensive cohort report, 14 variants were detected in 12 unrelated pedigrees. The allele frequency of CCDC141 RSVs was significantly higher in CHH patients compared to the controls. However, CCDC141 pathogenic variants were insufficient to cause IHH alone, as 75% of patients had additional IHH gene variants [97].
IRF2BPL (2019): IRF2BPL encodes probable E3 ubiquitin-protein ligase that is included within the proteasome-mediated ubiquitin-dependent degradation of target proteins, and probably plays a role in the development of the central nervous system and neuronal maintenance. Functional analyses of the gene indicated its pivotal role in pubertal timing [98]. Mancini et al. reported one in-frame deletion and one missense variant in two independent families with delayed puberty [99].
AMH and AMH2R (2019): In a recent study, AMH has been shown to be expressed in migratory GnRH neurons in both mouse and human fetuses. AMH acts as a pro-motility factor for GnRH neurons. Furthermore, inactivating heterozygous mutations were identified in AMH and its receptor AMH2R in a large cohort of IHH [100].
SEMA3F and PLXNA3 (2021): Variants in members of class 3 semaphorins, SEMA3A, SEMA3E, and SEMA3G, have been associated with IHH [61,63,101]. Additionally, heterozygous variants in PLXNA1 were reported to cause KS and nIHH [11,94]. Kotan et al. recently screened whole-exome sequencing data from a cohort of 216 probands with congenital hypogonadotropic hypogonadism for rare variants in SEMA3F and PLXNA3. They identified 10 monoallelic variants in 15 patients from 11 unrelated families. Further studies suggested that SEMA3F signaling via PLXNA3 is essential for the guidance of migrating GnRH neurons [102].
RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20: Martsolf syndrome and Warburg Micro syndrome are phenotypically overlapping disorders characterized by intellectual disability, eye anomalies (i.e., congenital cataract, optic atrophy), and hypogonadism. RAB3GAP1 (RAB3 GTPase-activating protein 1), RAB3GAP2 (RAB3 GTPase-activating protein 2), RAB18 (RAS-associated protein RAB18), and TBC1D20 (TBC1 domain protein, member 20) mutations have been associated with these syndromes [103]. Disease-causing variants in these genes directly (RAB18) or indirectly (RAB3GAP1, RAB3GAP2, and TBC1D20) cause dysfunction of a GTPase, resulting in a rare syndromic presentation of IHH [104,105].

4. Concluding Remarks

The contributions from human genetics to our current understanding of GnRH neuron function have been enormous. The unprecedented identification of kisspeptin (KISS1, KISS1R) and neurokinin B (TAC3, TACR3) ligand-receptor gene pair mutations in human families with IHH have paved the way to the identification of the long-sought GnRH pulse generator as the KNDy neurons in the arcuate (infundibular) nucleus. This reverse translational pathway of discovery, thanks to the improvement of genetic sequencing technology, promises to continue to deliver even more insights into the central control of reproduction. Most notably, what triggers the GnRH pulse generator to reawaken after childhood remains an enigma. Close to 60 genes have been reported to date to be associated with IHH. However, gene discoveries have been noticeably more complex in recent years, probably due to more complex variants and phenotypes. It is exciting for clinical as well as basic neuroendocrinologists to note that continued gene discoveries for IHH will likely help further our understanding of the complex regulation of the HPG axis throughout human life stages.
Table
Table 1. Genetic causes of idiopathic hypogonadotropic hypogonadism.
Table 1. Genetic causes of idiopathic hypogonadotropic hypogonadism.
GeneHGNC IDClinical PhenotypeGene FunctionPhenotype Number of OMIM (or Ref.)
AMH464KS, nIHHGnRH neuron migrationMalone et al. [100]
AMHR2465nIHHGnRH neuron migrationMalone et al. [100]
ANOS16211KS, nIHHGnRH neuron migration308700
AXL905KS, nIHHGnRH neuron migration109135
CCDC14126821nIHHGnRH neuron migrationTuran et al. [95]
CHD720626KS, nIHH, CHARGEGnRH neuron migration612370
CPE2303nIHHNeuropeptide biosynthesisAlsters et al. [78]
DCC2701KS, nIHHGnRH neuron migrationBouilly et al. [106].
DLG22901DPNeuroendocrine regulationJee et al. [107]
DMXL22938nIHH, PEPNSATPase regulation616113
DUSP63072KS, nIHHGnRH neuron migration615269
FEZF122788KSGnRH neuron migration616030
FGF173673KS, nIHH, DWSGnRH neuron development615270
FGF83686KS, nIHHGnRH neuron development612702
FGFR13688KS, CPHD, SOD, SHFM, HSNeuroendocrine regulation, Hypothalamus/pituitary development147950
FLRT33762KSGnRH neuron migration615271
FSHB3964nIHHHypothalamus/pituitary development229070
GNRH14419nIHHNeuroendocrine regulation614841
GNRHR4421nIHHNeuroendocrine regulation146110
HESX14877KS, CPHD, SODHypothalamus/pituitary development182230
HS6ST15201KS, nIHHGnRH neuron migration614880
IGSF1026384DPGnRH neuron migrationHoward et al. [91]
IL17RD17616KS, nIHHGnRH neuron migration615267
IRF2BPL14282DPUbiquitinationMancini et al. [99]
KISS16341nIHHNeuroendocrine regulation614842
KISS1R4510nIHHNeuroendocrine regulation614837
KLB15527KS, nIHHGnRH neuron developmentXu et al. [28]
LEP6553nIHH, ObesityNeuroendocrine regulation614962
LEPR6554nIHH, ObesityNeuroendocrine regulation614963
LHB6584nIHHHypothalamus/pituitary development228300
NDNF26256KSGnRH neuron migration618841
NR0B17960nIHH, CAHHypothalamus/pituitary development300200
NSMF29843KSGnRH neuron migration614838
NTN18029KS, nIHHGnRH neuron migrationBouilly et al. [106]
OTUD424949nIHH, GHSUbiquitination212840
PCSK18743nIHH, ObesityHypothalamus/pituitary development600955, 162150
PLXNA19099KS, nIHHGnRH neuron migration601055
PLXNA39101KS, nIHHGnRH neuron migrationKotan et al. [102]
PNPLA616268nIHH, GHS, BNSPhospholipid homeostasis215470, 603197
POLR3A300744HDNA-dependent RNA polymerase607694
POLR3B303484HDNA-dependent RNA polymerase614381
PROK218455KS, nIHHGnRH neuron migration610628
PROKR21836KS, nIHH, CPHD, MGSGnRH neuron migration244200
RAB1814244WMS 3GTPase regulation614222
RAB3GAP117063WMS 1GTPase regulation600118
RAB3GAP217168MSGTPase regulation212720
RNF21621698nIHH, GHSUbiquitination212840
SEMA3A10723KSGnRH neuron migration614897
SEMA3E10727KS, nIHHGnRH neuron migration608166
SEMA3F10728 GnRH neuron migrationKotan et al. [102]
SMCHD129090nIHH, CPHD, BAMSDNA methylationShaw et al. [68]
SOX1011190KS, WSHypothalamus/pituitary development613266
SOX311199nIHHPituitary development
SPRY415533KSGnRH neuron migration615266
SRA111281nIHHNeuroendocrine regulationKotan et al. [93]
STUB111427Spinocerebellar ataxiaUbiquitination615768
TAC311521nIHHNeuroendocrine regulation614839
TACR311528nIHHNeuroendocrine regulation614840
TBC1D2016133WMS 4Vesicle-mediated transport regulation615663
WDR1113831KS, CPHDGnRH neuron migration614858
KS: Kallmann Syndrome; nIHH: Normosmic Idiopathic Hypogonadotropic Hypogonadism; DP: delayed puberty; PEPNS: Polyendocrine Polyneuropathy Syndrome; DWS: Dandy-Walker Syndrome; SOD: septo-optic dysplasia; SHFM: split hand/foot malformation; HS: Hartsfield Syndrome; CAH: Adrenal hypoplasia congenital; GHS: Gordon Holmes syndrome; BNS: Boucher-Neuhauser Syndrome; CPHD: combined pituitary hormone deficiencies; MGS: morning glory syndrome; WMS 3-1-4: Warburg Micro Syndrome 3-1-4; MS: Martsolf syndrome; BAMS: Bosma Arhinia Microphthalmia Syndrome; WS: Waardenburg syndrome.

Author Contributions

A.K.T. and I.T. conceptualized and wrote this article. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. The exponential increase in the number of articles published in Pubmed over the past several decades regarding mutations in IHH genes.
Figure 1. The exponential increase in the number of articles published in Pubmed over the past several decades regarding mutations in IHH genes.
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Topaloglu, A.K.; Turan, I. Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism. Endocrines 2022, 3, 1-15. https://doi.org/10.3390/endocrines3010001

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Topaloglu AK, Turan I. Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism. Endocrines. 2022; 3(1):1-15. https://doi.org/10.3390/endocrines3010001

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Topaloglu, Ali Kemal, and Ihsan Turan. 2022. "Genetic Etiology of Idiopathic Hypogonadotropic Hypogonadism" Endocrines 3, no. 1: 1-15. https://doi.org/10.3390/endocrines3010001

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