Article:Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. (5790323)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q49437047. Its title is Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. and the publication date was 2017-12-30. The initial author is A. Kemal Topaloğlu.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.



Converted JATS paper:

Journal Information

Title: Journal of Clinical Research in Pediatric Endocrinology

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

  • A. Kemal Topaloğlu

1 University of Mississippi Medical Center, Department of Pediatrics, Division of Pediatric Endocrinology and Department of Neurobiology and Anatomical Sciences, Jackson, Mississippi, USA

2 Çukurova University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Adana, Turkey

Publication date (ppub): 12/2017

Publication date (epub): 12/2017

Abstract

Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases. It is now well established that about 10-20% of IHH cases recover from IHH either spontaneously or after receiving some sex steroid replacement therapy. Moreover, there may be an overlap or transition between constitutional delay in growth and puberty (CDGP) and IHH. It has been increasingly observed that oligogenic inheritance and clinical recovery complicates the phenotype/genotype relationship in IHH, thus making it challenging to find new IHH-associated genes. In a clinical sense, recognizing those IHH genes and associated phenotypes may improve our diagnostic capabilities by enabling us to prioritize the screening of particular gene(s) such as synkinesia (ANOS1), dental agenesis (FGF8/FGFR1) and hearing loss (CHD7). Also, IHH-associated gene studies may be translated into new therapies such as for polycystic ovary syndrome. In a scientific sense, the most significant contribution of IHH-associated gene studies has been the characterization of the long-sought gonadotropin releasing hormone pulse generator. It appears that genetic studies of IHH will continue to advance our knowledge in both the biological and clinical domains.

Paper

INTRODUCTION

The activity level of the hypothalamo-pituitary-gonadal (HPG) axis is remarkably variable throughout life. A gradual increase of HPG activity around the beginning of the second decade of life brings about sex-specific, secondary sexual features and a maturing reproductive system. This specialized phase of human development is called puberty and lasts from two to five years. Absence of puberty manifests itself as sexual immaturity and reproductive incompetence, which can be succinctly termed as hypogonadism. If lack of such development is due to anatomical or functional defects, resulting in reduced gonadotropin releasing hormone (GnRH) and/or gonadotropin release, the condition is called hypogonadotropic hypogonadism (HH).

1. Idiopathic Hypogonadotropic Hypogonadism

The term idiopathic HH (IHH) is used to define those IHH cases with no apparent causes. Traditionally, IHH is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). IHH can be congenital or acquired. The great majority of hereditary causes of IHH are congenital. Typically, in girls there is no clinical manifestation of IHH before the early teen years. In boys, since the HPG axis is very active roughly between the 16th and 22nd week of gestation and androgenic end products of this period are required for normal virilization of the 46,XY fetus, male infants with IHH may have micropenis and/or cryptorchidism at birth. Under-virilization of the male can be severe enough to call for an evaluation of a “disorder of sexual development”. A slight and temporary reactivation of the HPG axis in early infancy (around four to sixteen weeks) is called “minipuberty” and provides a unique opportunity to diagnose both male and female infants with congenital IHH ([1]).

KS is often due to the embryonic maldevelopment and/or interrupted migration of GnRH specific neurons. Since the embryonic migration of GnRH neurons from the nasal placode towards their final destination in the hypothalamus occurs in association with olfactory receptor neurons, the resulting phenotype includes anosmia in addition to HH. KS cases often have additional congenital anomalies such as cleft palate, unilateral renal agenesis, split hands and feet, short metacarpals, deafness, and mirror movements (synkinesia).

In contrast nIHH refers to those IHH cases not associated with anosmia ([2]). nIHH results from the dysfunction of the normally sited GnRH neurons in the hypothalamus. These cases typically do not have any accompanying congenital lesions.

However, one should be careful when using these terms because the line between KS and nIHH is sometimes blurred, as most typically seen with FGFR1 mutations. Furthermore, there may be pathophysiological overlaps between the two entities. For example, patients with CCDC141 or IGSF10 mutations have nIHH despite showing in vitro evidence of impaired migration of the GnRH neurons ([3],[4]).

Pubertal delay is the most typical presentation of IHH. Pubertal delay is defined as absence of breast development (Tanner breast stage 1) in a girl at age 13 or failure to achieve a testicular volume of 4 mL in a boy by age 14 ([5]). By far the most common cause of delayed puberty is constitutional delay in growth and puberty (CDGP), which is not a disease per se but a maturational delay in development at the extreme of the population standards. CDPG accounts for pubertal delay in two third of boys and one third of girls ([6]). CDGP is a diagnosis of exclusion and should often be considered in the differential diagnosis of IHH. To distinguish between these two conditions often requires lengthy workup and observation periods.

It has been shown that some variants in known puberty genes such as TAC3 and TACR3 are shared by individuals with IHH or CDGP within the same family, suggesting that CDGP shares an underlying pathophysiology with IHH, only representing a milder form of the same genetic dysfunction ([7]). Clinicians often successfully try a low dose sex steroid course to “jump start” pubertal development in patients with suspected CDGP. It is now well established that about 10-20% of IHH cases recover either spontaneously or more typically after receiving some sex steroid replacement therapy ([8],[9]). These foregoing observations further suggest that CDGP and IHH may have common pathophysiological underpinnings. Therefore, it appears that there is a continuum of phenotype from normal timing of pubertal development all the way to extreme IHH, encompassing CDGP along the way.

2. Genes Associated with Idiopathic Hypogonadotropic Hypogonadism

Currently known genetic defects account for up to 50% of all IHH cases ([10]). To date mutations in around 50 genes have been reported to cause IHH. The full current list of genes associated with IHH is shown in Table 1. Presence of more than one IHH-associated mutant gene in a patient/pedigree (oligogenic inheritance) is thought to account for 10-20% of all IHH cases ([11],[12],[13],[14]). With the increasing use of unbiased comprehensive genetic studies such as whole exome sequencing (WES), it is now known that oligogenic inheritance is more common than previously thought in various Mendelian disorders ([15]).

2a. Kallmann Syndrome Associated Genes

X-linked recessive, autosomal dominant (AD) and autosomal recessive (AR) patterns of inheritance have been reported. However, KS is often sporadic; even if it is familial, a substantial variability in clinical phenotype of the same genetic defect among affected family members may be seen ([16],[17],[18]). According to the presence of certain associated clinical features, genetic screening for particular gene(s) may be prioritized: synkinesia (KAL1), dental agenesis (FGF8/FGFR1), digital bony abnormalities (FGF8/FGFR1) and hearing loss (CHD7, SOX10) ([19]). As a common pathophysiological denominator with KS genes, fibroblast growth factor signaling, prokineticin signaling and Anosmin-1 appear to interact with heparin sulfate glycosominoglycan compounds within an extracellular signaling complex to promote GnRH neuronal migration ([20],[21]).

ANOS1 (KAL1)

The ANOS1 gene, encoding an extracellular glycoprotein called Anosmin-1, associates with the cell membrane via heparin sulphate proteoglycans (HSPG) ([22]). Ten to twenty percent of males with KS carry KAL1 mutations or intragenic microdeletions are present ([23],[24]). Most pathogenic mutations entirely disrupt protein function. The inheritance pattern is X-linked recessive. The KS phenotype produced by ANOS1 mutations seem not only more severe but also less variable than that seen with other known molecular defects ([24],[25]). Accompanying clinical features include synkinesia and unilateral renal agenesis, which occurs in 75% and 30% of patients respectively ([26]).

FGFR1 requires both HSPG as a co-receptor and Anosmin-1, which is also HSPG-associated. Anosmin-1 is likely to play a role in mediating FGFR1 signaling ([21]). Loss of FGFR1 function has been reported to elicit reproductive abnormalities ranging from severe AD KS through fully penetrant nIHH to delayed puberty ([29],[30],[31],[32],[33]). Around 10% of patients with KS were found to have inactivating mutations in FGFR1 ([20],[29],[30]). More recently, loss-of-function mutations in FGFR1 were detected in 7% of 134 nIHH patients, suggesting that FGFR1 should be one of the major genes in screening panels for nIHH patients ([34]).

In 2008, FGF8, one of 11 ligands of FGF signaling was found to be mutated in six out of 461 (1.5%) IHH patients. These patients exhibited varying levels of olfactory function and HH ([27]). Furthermore, mice homozygous for the hypomorphic FGF8 allele exhibited absent olfactory bulbs and lacked GnRH neurons in the hypothalamus ([27]). As for the features of FGF8/FGFR1 loss of function, cleft palate is found in up to 30% of patients, while cartilage abnormalities in either ear or nose and some digital anomalies have been reported ([26]). Further screening for FGF8 related genes in a group of 388 congenital IHH patients revealed inactivating variants in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 ([28]).

KLB

KLB is the most recently reported Fibroblast growth factor related IHH gene ([35]). KLB encodes for Beta-Klotho, which is a co-receptor in FGF21 signaling through the FGFR1 product. The authors of this paper screened more than 300 IHH patients and found 13 patients with loss of function mutations. They also reported that the majority of patients with KLB mutations exhibited some degree of metabolic defect such as insulin resistance or dyslipidemia. The KLB knock out mouse model revealed a milder hypogonadal phenotype when compared to the corresponding human phenotype ([35]).

PROKR2 and PROK2

The PROK2 gene encodes prokinetecin 2, an 81 amino acid peptide that signals via the G protein-coupled product of the PROKR2 gene. This ligand and its receptor were recognized as strong candidates for KS as PROK2 ([36],[37]) or PROKR2 knockout mice had defective olfactory bulbs and failed migration of GnRH neurons ([38]). Subsequently, inactivating variants in PROKR2 or PROK2 were detected in KS patients. Most of these mutations were heterozygous, although both homozygous and compound heterozygous mutations have been described ([39]). Patients with PROK2 or PROKR2 mutations have considerable phenotypic variability ([37],[40],[41]), ranging from KS to nIHH. A variety of accompanying clinical features including fibrous dysplasia, synkinesia and epilepsy have been reported in patients with PROK2 or PROKR2 mutations. It appears that mutations in PROKR2 and PROK2 are often found in combination with other mutations in IHH with oligogenic inheritance.

CHD7

The CHD7 gene encodes a chromatin-remodeling factor and is mutant in CHARGE syndrome, which has the constellation of Colobomata, Heart Anomalies, choanal Atresia, Retardation, Genital and Ear anomalies ([42]). Some patients also have IHH and hyposmia. Based on the hypothesis that KS and nIHH may be a milder allelic variant of CHARGE syndrome, CHD7 was screened in 197 patients with KS or nIHH but devoid of CHARGE features. Mutations were identified in three KS and four nIHH patients ([43]). In another study, three of 56 KS/nIHH patients had mutations in CHD7 ([44]). The authors suggest that patients diagnosed with KS should be screened for clinical features consistent with CHARGE syndrome. If such features are present, particularly deafness, anomalous ears, coloboma and/or hypoplasia or aplasia of the semicircular canals, CHD7 should be tested ([44]).

WDR11

The WDR11 gene product partners EMX1, a homeodomain transcription factor involved in the development of olfactory neurons. By positional cloning, heterozygous mutations were discovered in several patients with KS ([45]). Recently, a digenic combination of monoallelic variants in PROKR2 and WDR11 has been reported to be responsible for a pituitary stalk interruption syndrome in a child ([46]).

SEMA3A

SEMA3A encodes for semaphorin 3A, a protein that interacts with neuropilins. Mice lacking semaphorin 3A expression have been demonstrated to have a Kallmann-like phenotype. Screening large groups of patients with KS revealed a variety of monoallelic mutations. Some of these mutations coexist with other KS causing gene mutations, further showing oligogenic inheritance in IHH ([47],[48]). In a recent study in patients with IHH, heterozygous missense variants in SEMA3A and SEMA7A were found in association with second variants in other IHH genes ([49]).

SEMA3E

Semaphorin 3E (SEMA3E) is a secreted protein that modulates axonal growth. A SEMA3E missense mutation was recently reported in two brothers with KS ([50]). Functional studies have shown that SEMA3E may act as a survival factor for maturing hypothalamic GnRH neurons.

SOX10

Inactivating mutations in SOX10 cause Waardenburg syndrome, a rare disorder characterized by pigmentation abnormalities and hearing impairment. Screening for SOX10 mutations in KS patients with deafness revealed inactivating variants in approximately one-third of them. SOX10 knockout mice showed absence of olfactory ensheathing cells along the olfactory nerve pathway ([51]).

HS6ST1

HS 6-O-sulfotransferase 1 is a sulfation enzyme that specifically and non-randomly modifies heparan sulfate, an important extracellular matrix component, which is probably required for optimal cell-cell communication, such as during olfactory neuronal migration and ligand-receptor interactions. Recently, inactivating HS6ST1 mutations, in association with other KS gene mutations, have been reported in seven families with KS ([52]).

CCDC141

CCDC141 encodes a coiled-coil domain containing protein that is expressed in GnRH neurons. We have reported inactivating CCDC141 variants in four separate families with IHH. Affected individuals had normal olfactory function and anatomically normal olfactory bulbs ([53]). In a rodent nasal explant model, knockdown of CCDC141 resulted in decreased embryonic GnRH cell migration without interrupting olfactory axon outgrowth ([3]).

FEZF1

FEZF1 encodes a transcriptional repressor that is expressed during embryogenesis in the olfactory epithelium, amygdala and hypothalamus. The FEZF1 gene product promotes the presence of a protease to enable olfactory receptor neurons, and thus accompanying GnRH neurons, to enter the brain ([54]). Recently, using autozygosity mapping and WES in a cohort of 30 individuals with KS, we identified homozygous, loss-of-function mutations in FEZF1 in two independent consanguineous families, each with two affected siblings ([55]).

IGSF10

GSF10 is a member of the immunoglobulin superfamily. Howard et al ([4]) obtained WES data on more than 100 individuals with delayed puberty and identified IGSF10 mutations in six families. The knock down studies revealed reduced GnRH migration in the GN11 cell line. Despite having impaired migration of GnRH neurons, the patients carrying these mutations had a normal sense of smell. The authors suggested that reduced number or delayed arrival of neurons in the hypothalamus leads to a somewhat milder functional defect in the formation of the GnRH neuronal network with eventual delayed puberty but not permanent IHH. Interestingly, they also identified mutations in adult individuals with functional hypothalamic amenorrhea, which is considered a form of mild, transient HH ([4]).

SMCHD1

SMCHD1 encodes for an epigenetic repressor which is expressed in the human olfactory epithelium. Shaw et al ([56]) demonstrated inactivating SMCHD1 mutations as the cause of congenital absence of nose in 41 cases. The great majority of patients (97%) also had hypogonadal features such as cryptorchidism, microphallus or amenorrhea, along with absent olfactory structures and anosmia.

2b. Normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH) Associated Genes

nIHH-causing genes are more pertinent to the understanding of the function of the HPG axis and puberty. Identified mutations in familial cases of nIHH has led to greater understanding of this function. In a study on 22 consecutive, multiplex families with nIHH, we identified mutations in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of them. GNRHR and TACR3 mutations were the two most common causative mutations, occurring with about equal frequency in two third of the mutation identified cases ([57]).

LEP and LEPR

Leptin deficiency with mutations in either encoding leptin (LEP) or encoding the leptin receptor (LEPR) is associated with IHH ([58],[59]). The administration of leptin in LEP-deficient patients restores normal pubertal development but does not cause early puberty in prepubertal children, which implies that leptin is a permissive factor for the development of puberty in humans ([60]). These patients are easily recognizable among other IHH patients with because of the presence of early onset obesity and hyperphagia.

NR0B1 (DAX1)

NR0B1 is an orphan member of the nuclear receptor superfamily. Inactivating variants in the NR0B1 gene cause X-linked congenital adrenal hypoplasia with HH ([61]). Adrenal hypoplasia typically presents as adrenal insufficiency during infancy, whereas HH becomes manifest in affected males who survive into the second decade of life.

SRA1

SRA1 was the first gene shown to function through both its protein and noncoding, functional RNA products ([62]). These products act as co-regulators of nuclear receptors, including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. SRA1 is required for the synergistic enhancement of SF-1 transcriptional activity by DAX-1 (NR0B1), mutations in which also cause IHH, as discussed above ([63]). WES and autozygosity mapping studies revealed three independent families in which IHH was associated with inactivating SRA1 variants ([64]).

GNRHR and GNRH1

GNRH1 and GNRHR are the most obvious candidate gene in the etiology of IHH. GNRHR defects produce AR, isolated nIHH, with no evidence of accompanying developmental defects such as hyposmia ([65],[66],[67]). GNRHR mutations have been suggested to account for about 40-50% of familial AR nIHH, and around 17% of sporadic nIHH ([66]). In a recent survey of 110 patients with nIHH, eleven IHH patients (10%) carried biallelic GNRHR mutations while none of the 50 patients studied with CDGP had any deleterious variants ([68]). To date, more than 25 different mutations have been reported. Interestingly, only seven years ago the first inactivating homozygous mutations in GNRH1 itself causing IHH were reported by two independent groups ([69],[70]). In these cases IHH was shown to be reverseable by pulsatile GnRH administration, confirming the pivotal role of GnRH in human reproduction ([69]). Out of 310 patients with IHH, only one case was found, attesting to the rarity of mutations in this gene as a cause of IHH ([70]). We recently reported further GNRH1 mutations located in the region encoding the decapeptide which is the same region involved in earlier reported mutations ([71]).

KISS1R and KISS1

KISS1R (formerly GPR54) encodes for the receptor for small peptides derived from the KISS1 gene and it was previously thought not to play a role in the HPG axis ([72]). Mutations in KISS1R were first reported in IHH familial multiplex cases in 2003 ([73],[74]). Ensuing studies established kisspeptin signaling as an essential, positive regulator of GNRH secretion. In a mutational screening study, only five out of 166 (3%) probands with nIHH were found to have rare variants in KISS1R ([75]). Studying a large, consanguineous family with four sisters with nIHH, we found inactivating mutations altering the 4th amino acid of Kisspeptin-10. Overnight frequent LH sampling did not reveal any LH pulsatility, further confirming the essential role of kisspeptin signaling in the GnRH pulse generator ([76]).

TACR3 and TAC3

Tachykinin receptor-3 encoded by TACR3 is the mediator of biologic actions of neurokinin B (NKB) encoded by TAC3. In an effort to identify novel genes playing a role in driving the HPG axis, based on autozygosity mapping ([77]), we identified homozygous non-synonymous mutations in the coding sequences of TAC3 or TACR3 in nine patients from four families with an nIHH phenotype ([78]). With the additional cases identified in our cohort, it became clear that TACR3 mutations are almost as common as GNRHR mutations ([57]). Other groups have made similar observations concerning the prevalence of TACR3 mutations. Gianetti et al ([79]) found 19 among 345 (5.5%) cases while a very similar rate (5.2%) was observed by Francou et al ([80]) from a cohort of 173 cases of familial and sporadic nIHH. The frequent presence of a micropenis and cryptorchidism in mutant TACR3 male patients indicates that intact TACR3 function is also required for normal fetal gonadotropin secretion, which stimulates testicular size and descent and penile growth ([1]).

Clinical reversibility, evident by spontaneous progression of puberty, often following a period of exogenous sex steroid treatment, was seen in 10% of an unselected nIHH cohort ([8]). A much greater percentage of reversibility (83%) was reported by Gianetti et al ([79]) in their TAC3/TACR3 cohort 2010 ([79]). In our cohort four patients from three independent and ethnically different families showed clinical recovery among 16 (25%) patients. Interestingly, all of these families harbored the same TACR3 mutation (p.T177K). Our studies are ongoing in an attempt to gain insight into the clinical recoverability and/or reversibility of this variant. With such a high rate of reversibility, a legitimate question arose as to whether CDGP was a form of IHH caused by TACR3 mutations. To answer this question, Vaaralahti et al ([81]) screened these genes in 146 Finnish subjects with CDGP and found no variants to account for this phenotype.

Other clinical studies have provided additional valuable insight in to the biology of the HPG axis. Young et al ([82]) were able to produce pubertal levels of gonadotropin and sex steroids with repeated administration of GnRH in patients with Null mutations in TAC3, indicating that the site of NKB action is proximal to GnRH and the pituitary ([82]).

3. Scientific Significance of Identifying IHH-Associated Genes

Undoubtedly, the most significant contribution of IHH-associated gene studies has been the characterization of the long sought-after GnRH pulse generator. A surge of studies over the past ten years on Kisspeptin and NKB signaling, following the identifications of their inactivating mutations among familial patients with nIHH, has led to characterization of the GnRH pulse generator. According to the current understanding there is a network of sex-steroid responsive neurons in the arcuate (infindubular) nucleus that coexpress Kisspeptin, NKB, Dynorphin and ERα (KNDy or Kisspeptin neurons). Within these cells, the stimulatory NKB starts an action potential that is suppressed by the inhibitory Dynorphin. When the inhibitory effect of Dynorphin is overcome another stimulatory NKB action takes over. The net result is continuous, intermittent action potentials. Each action potential translates into a pulsatile secretion of Kisspeptin on to the axons of the GnRH neurons in the median eminence, thence GnRH is released towards the pituitary gonadotropes, via the portal circulation. Synchronization of KNDy cells is believed to be provided by NKB-NK3R signaling through ipsi- and contralateral projections among these cells ([83],[84],[85]).

4. Clinical Significance of Identifying IHH-Associated Genes

IHH-associated gene studies have provided clues for targetting diagnostic molecular genetic studies. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes in a clinical setting for equivocal cases, such as constitutional delay in puberty vs. IHH. In KS, according to the presence of certain accompanying clinical features, genetic screening for particular gene(s) may be prioritized, for example if the patient has synkinesia then KAL1 would be suggested, dental agenesis is associated with FGF8/FGFR1, digital bony abnormalities also with FGF8/FGFR1 and hearing loss with CHD7 and SOX10.

IHH-associated gene studies may be translated into new therapeutic modalities. For instance, an antagonist of the TACR3 gene product has been in clinical trial for polycystic ovarian syndrome ([86]).

5. Concluding Remarks

Currently, around half of the IHH genes remain to be identified. Complicated genotype/phenotype relationships in IHH, due to two well-established phenomena, oligogenic inheritance and spontaneous or induced clinical reversibility, make identifying these unknown genes challenging. Nonetheless, with the help of contemporary sequencing technologies, it appears that studies into the genetics of hypogonadotropic hypogonadism will continue to advance our knowledge in both the biological and clinical domains.

References

  1. MM GrumbachA window of opportunity: the diagnosis of gonadotropin deficiency in the male infantJ Clin Endocrinol Metab2005903122312715728198
  2. RK SempleAK TopalogluThe recent genetics of hypogonadotrophic hypogonadism - novel insights and new questionsClin Endocrinol (Oxf)20107242743519719764
  3. BI HutchinsLD KotanC Taylor-BurdsY OzkanPJ ChengF GurbuzJD TiongE MengenB YukselAK TopalogluS WrayCCDC141 Mutation Identified in Anosmic Hypogonadotropic Hypogonadism (Kallmann Syndrome) Alters GnRH Neuronal MigrationEndocrinology20161571956196627014940
  4. SR HowardL GuastiG Ruiz-BabotA ManciniA DavidHL StorrLA MetherellMJ SternbergCP CabreraHR WarrenMR BarnesR QuintonN de RouxJ YoungA Guiochon-MantelK WehkalampiV AndréY GothilfA CariboniL DunkelIGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed pubertyEMBO Mol Med2016862664227137492
  5. MR PalmertL DunkelClinical practice. Delayed pubertyN Engl J Med201236644345322296078
  6. IL SedlmeyerMR PalmertDelayed puberty: analysis of a large case series from an academic centerJ Clin Endocrinol Metab2002871613162011932291
  7. J ZhuRE ChoaMH GuoL PlummerC BuckMR PalmertJN HirschhornSB SeminaraYM ChanA shared genetic basis for self-limited delayed puberty and idiopathic hypogonadotropic hypogonadismJ Clin Endocrinol Metab2015100E64665425636053
  8. T RaivioJ FalardeauA DwyerR QuintonFJ HayesVA HughesLW ColeSH PearceH LeeP BoeppleWF Jr CrowleyN PitteloudReversal of idiopathic hypogonadotropic hypogonadismN Engl J Med200735786387317761590
  9. VF SidhoumYM ChanMF LippincottR BalasubramanianR QuintonL PlummerA DwyerN PitteloudFJ HayesJE HallKA MartinPA BoeppleSB SeminaraReversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine systemJ Clin Endocrinol Metab20149986187024423288
  10. WF Jr CrowleyN PitteloudS SeminaraNew genes controlling human reproduction and how you find themTrans Am Clin Climatol Assoc2008119293718596868
  11. SD QuaynorHG KimEM CappelloT WilliamsLP ChorichDP BickRJ SherinsLC LaymanThe prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndromeFertil Steril2011961424143022035731
  12. N PitteloudR QuintonS PearceT RaivioJ AciernoA DwyerL PlummerV HughesS SeminaraYZ ChengWP LiG MaccollAV EliseenkovaSK OlsenOA IbrahimiFJ HayesP BoeppleJE HallP BoulouxM MohammadiW CrowleyDigenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadismJ Clin Invest200711745746317235395
  13. GP SykiotisL PlummerVA HughesM AuS DurraniS Nayak-YoungAA DwyerR QuintonJE HallJF GusellaSB SeminaraWF Jr CrowleyN PitteloudOligogenic basis of isolated gonadotropin-releasing hormone deficiencyProc Natl Acad Sci USA2010107151401514420696889
  14. U BoehmPM BoulouxMT DattaniN de RouxC DodéL DunkelAA DwyerP GiacobiniJP HardelinA JuulM MaghnieN PitteloudV PrevotT RaivioM Tena-SempereR QuintonJ YoungExpert consensus document: European Consensus Statement on congenital hypogonadotropic hypogonadism--pathogenesis, diagnosis and treatmentNat Rev Endocrinol20151154756426194704
  15. JX ChongKJ BuckinghamSN JhangianiC BoehmN SobreiraJD SmithTM HarrellMJ McMillinW WiszniewskiT GambinZH Coban AkdemirK DohenyAF ScottD AvramopoulosA ChakravartiJ Hoover-FongD MathewsPD WitmerH LingK HetrickL WatkinsKE PattersonF ReinierE BlueD MuznyM KircherK BilguvarF López-GiráldezVR SuttonHK TaborSM LealM GunelS ManeRA GibbsE BoerwinkleA HamoshJ ShendureJR LupskiRP LiftonD ValleDA NickersonCenters for Mendelian Genomics, Bamshad MJThe Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and OpportunitiesAm J Hum Genet20159719921526166479
  16. R QuintonVM DukePA de ZoysaAD PlattsA ValentineB KendallS PickmanJM KirkGM BesserHS JacobsPM BoulouxThe neuroradiology of Kallmann’s syndrome: a genotypic and phenotypic analysisJ Clin Endocrinol Metab199681301030178768867
  17. SB SeminaraFJ HayesWF Jr CrowleyGonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerationsEndocr Rev1998195215399793755
  18. LB NachtigallPA BoeppleFP PralongWF Jr CrowleyAdult-onset idiopathic hypogonadotropic hypogonadism--a treatable form of male infertilityN Engl J Med19973364104159010147
  19. FA Costa-BarbosaR BalasubramanianKW KeefeND ShawN Al-TassanL PlummerAA DwyerCL BuckJH ChoiSB SeminaraR QuintonD MoniesB MeyerJE HallN PitteloudWF Jr CrowleyPrioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypesJ Clin Endocrinol Metab201398E94395323533228
  20. C DodéJ LevilliersJM DupontA De PaepeN Le DûN Soussi-YanicostasRS CoimbraS DelmaghaniS Compain-NouailleF BaverelC PêcheuxD Le TessierC CruaudM DelpechF SpelemanS VermeulenA AmalfitanoY BachelotP BouchardS CabrolJC CarelH Delemarre-van de WaalB Goulet-SalmonML KottlerO RichardF Sanchez-FrancoR SauraJ YoungC PetitJP HardelinLoss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndromeNat Genet20033346346512627230
  21. JP HardelinC DodéThe complex genetics of Kallmann syndrome: KAL1, FGFR1, FGF8, PROKR2, PROK2, et alSex Dev2008218119318987492
  22. B FrancoS GuioliA PragliolaB IncertiB BardoniR TonlorenziR CarrozzoE MaestriniM PierettiP Taillon-MillerCJ BrownHF WillardC LawrenceM Graziella PersicoG CamerinoA BallabioA gene deleted in Kallmann’s syndrome shares homology with neural cell adhesion and axonal path-finding moleculesNature19913535295361922361
  23. JR Pedersen-WhiteLP ChorichDP BickRJ SherinsLC LaymanThe prevalence of intragenic deletions in patients with idiopathic hypogonadotropic hypogonadism and Kallmann syndromeMol Hum Reprod20081436737018463157
  24. LM1q OliveiraSB SeminaraM BeranovaFJ HayesSB ValkenburghE SchipaniEM CostaAC LatronicoWF Jr CrowleyM VallejoThe importance of autosomal genes in Kallmann syndrome: genotype-phenotype correlations and neuroendocrine characteristicsJ Clin Endocrinol Metab2001861532153811297579
  25. S SalenaveP ChansonH BryM PugeatS CabrolJC CarelA MuratP LecomteS BraillyJP HardelinC DodéJ YoungKallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutationsJ Clin Endocrinol Metab20089375876318160472
  26. PS TsaiJC GillMechanisms of disease: Insights into X-linked and autosomal-dominant Kallmann syndromeNat Clin Pract Endocrinol Metab2006216017116932275
  27. J FalardeauWC ChungA BeenkenT RaivioL PlummerY SidisEE Jacobson-DickmanAV EliseenkovaJ MaA DwyerR QuintonS NaJE HallC HuotN AloisSH PearceLW ColeV HughesM MohammadiP TsaiN PitteloudDecreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and miceJ Clin Invest20081182822283118596921
  28. H MiraouiAA DwyerGP SykiotisL PlummerW ChungB FengA BeenkenJ ClarkeTH PersP DworzynskiK KeefeM NiedzielaT RaivioWF Jr CrowleySB SeminaraR QuintonVA HughesP KumanovJ YoungMA YialamasJE HallG Van VlietJP ChanoineJ RubensteinM MohammadiPS TsaiY SidisK LageN PitteloudMutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadismAm J Hum Genet20139272574323643382
  29. N PitteloudA MeysingR QuintonJS Jr AciernoAA DwyerL PlummerE FliersP BoeppleF HayesS SeminaraVA HughesJ MaP BoulouxM MohammadiWF Jr CrowleyMutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypesMol Cell Endocrinol2006254-255606916764984
  30. EB TrarbachEM CostaB VersianiM de CastroMT BaptistaHM GarmesBB de MendoncaAC LatronicoNovel fibroblast growth factor receptor 1 mutations in patients with congenital hypogonadotropic hypogonadism with and without anosmiaJ Clin Endocrinol Metab2006914006401216882753
  31. N PitteloudJS Jr AciernoAU MeysingAA DwyerFJ HayesWF Jr CrowleyReversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 geneJ Clin Endocrinol Metab2005901317132215613419
  32. N PitteloudJS Jr AciernoA MeysingAV EliseenkovaJ MaOA IbrahimiDL MetzgerFJ HayesAA DwyerVA HughesM YialamasJE HallE GrantM MohammadiWF Jr CrowleyMutations in fibroblast growth factor receptor 1 cause both Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadismProc Natl Acad Sci USA20061036281628616606836
  33. N XuY QinRH ReindollarSP ThoPG McDonoughLC LaymanA mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadismJ Clin Endocrinol Metab2007921155115817200176
  34. T RaivioY SidisL PlummerH ChenJ MaA MukherjeeE Jacobson-DickmanR QuintonG Van VlietH LavoieVA HughesA DwyerFJ HayesS XuS SparksUB KaiserM MohammadiN PitteloudImpaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadismJ Clin Endocrinol Metab2009944380489019820032
  35. C XuA MessinaE SommH MiraouiT KinnunenJ Jr AciernoNJ NiederländerJ BouillyAA DwyerD CassatellaGP SykiotisR QuintonC De GeyterM DirlewangerV SchwitzgebelTR ColeAA ToogoodJM KirkL PlummerU AlbrechtWF Jr CrowleyM MohammadiM Tena-SempereV PrevotN PitteloudKLB, encoding β-Klotho, is mutated in patients with congenital hypogonadotropic hypogonadismEMBO Mol Med201791379139728754744
  36. KL NgJD LiMY ChengFM LeslieAG LeeQY ZhouDependence of olfactory bulb neurogenesis on prokineticin 2 signalingScience20053081923192715976302
  37. N PitteloudC ZhangD PignatelliJD LiT RaivioLW ColeL PlummerEE Jacobson-DickmanPL MellonQY ZhouWF Jr CrowleyLoss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadismProc Natl Acad Sci USA2007104174471745217959774
  38. S MatsumotoC YamazakiKH MasumotoM NaganoM NaitoT SogaH HiyamaM MatsumotoJ TakasakiM KamoharaA MatsuoH IshiiM KoboriM KatohH MatsushimeK FuruichiY ShigeyoshiAbnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2Proc Natl Acad Sci USA20061034140414516537498
  39. C DodéL TeixeiraJ LevilliersC FouveautP BouchardML KottlerJ LespinasseA Lienhardt-RoussieM MathieuA MoermanG MorganA MuratJE ToublancS WolczynskiM DelpechC PetitJ YoungJP HardelinKallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2PLoS Genet20062e17517054399
  40. AP AbreuEB TrarbachM de CastroEM Frade CostaB VersianiMT Matias BaptistaHM GarmesBB MendoncaAC LatronicoLoss-of-function mutations in the genes encoding prokineticin-2 or prokineticin receptor-2 cause autosomal recessive Kallmann syndromeJ Clin Endocrinol Metab2008934113411818682503
  41. LW ColeY SidisC ZhangR QuintonL PlummerD PignatelliVA HughesAA DwyerT RaivioFJ HayesSB SeminaraC HuotN AlosP SpeiserA TakeshitaG Van VlietS PearceWF Jr CrowleyQY ZhouN PitteloudMutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrumJ Clin Endocrinol Metab2008933551355918559922
  42. LE VissersCM van RavenswaaijR AdmiraalJA HurstBB de VriesIM JanssenWA van der VlietEH HuysPJ de JongBC HamelEF SchoenmakersHG BrunnerJA VeltmanAG van KesselMutations in a new member of the chromodomain gene family cause CHARGE syndromeNat Genet20043695595715300250
  43. HG KimI KurthF LanI MelicianiW WenzelSH EomGB KangG RosenbergerM TekinM OzataDP BickRJ SherinsSL WalkerY ShiJF GusellaLC LaymanMutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndromeAm J Hum Genet20088351151918834967
  44. MC JongmansCM van Ravenswaaij-ArtsN PitteloudT OgataN SatoHL Claahsen-van der GrintenK van der DonkS SeminaraJE BergmanHG BrunnerWF Jr CrowleyLH HoefslootCHD7 mutations in patients initially diagnosed with Kallmann syndrome--the clinical overlap with CHARGE syndromeClin Genet200975657119021638
  45. HG KimJW AhnI KurthR UllmannHT KimA KulharyaKS HaY ItokawaI MelicianiW WenzelD LeeG RosenbergerM OzataDP BickRJ SherinsT NagaseM TekinSH KimCH KimHH RopersJF GusellaV KalscheuerCY ChoiLC LaymanWDR11, a WD protein that interacts with transcription factor EMX1, is mutated in idiopathic hypogonadotropic hypogonadism and Kallmann syndromeAm J Hum Genet201088746547920887964
  46. SE McCormackD LiYJ KimJY LeeSH KimR apaportMA LevineDigenic Inheritance of PROKR2 and WDR11 Mutations in Pituitary Stalk Interruption SyndromeJ Clin Endocrinol Metab20171022501250728453858
  47. NK HanchateP GiacobiniP LhuillierJ ParkashC EspyC FouveautC LeroyS BaronC ampagneC VanackerF CollierC ruaudV MeyerA García-PiñeroD ewaillyC ortet-RudelliK GersakC MetzG ChabrierM PugeatJ YoungJP HardelinV PrevotC DodéSEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndromePLoS Genet20128e100289622927827
  48. J YoungC MetayJ BouligandB TouB FrancouL MaioneL ToscaJ SarfatiF BrioudeB EstevaA Briand-SuleauS BrissetM GoossensG TachdjianA Guiochon-MantelSEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system developmentHum Reprod2012271460146522416012
  49. J KänsäkoskiR FagerholmEM LaitinenK VaaralahtiP HackmanN PitteloudT RaivioJ TommiskaMutation screening of SEMA3A and SEMA7A in patients with congenital hypogonadotropic hypogonadismPediatr Res20147564164424522099
  50. A CariboniV AndréS ChauvetD CassatellaK DavidsonA CaramelloA FantinP BoulouxF MannC RuhrbergDysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndromeJ Clin Invest20151252413242825985275
  51. V PingaultV BodereauV BaralS MarcosY WatanabeA ChaouiC FouveautC LeroyO Vérier-MineC FrancannetD Dupin-DeguineF ArchambeaudFJ KurtzJ YoungJ BertheratS MarlinM GoossensJP HardelinC DodéN BondurandLoss-of-function mutations in SOX10 cause Kallmann syndrome with deafnessAm J Hum Genet20139270772423643381
  52. J TornbergGP SykiotisK eefeL PlummerX HoangJE HallR QuintonSB SeminaraV HughesG Van VlietS Van UumWF CrowleyH abuchiK imataN PitteloudHE BülowHeparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadismProc Natl Acad Sci USA2011108115241152921700882
  53. I TuranBI HutchinsB HacihamdiogluLD KotanF GurbuzA UlubayE MengenB YukselS WrayAK TopalogluCCDC141 Mutations in Idiopathic Hypogonadotropic HypogonadismJ Clin Endocrinol Metab20171021816182528324054
  54. MJ EcklerWL McKennaS TaghvaeiSK McConnellB ChenFezf1 and Fezf2 are required for olfactory development and sensory neuron identityJ Comp Neurol20115191829184621452247
  55. LD KotanBI HutchinsY OzkanF DemirelH StonerPJ ChengI EsenF GurbuzYK BicakciE MengenB YukselS WrayAK TopalogluMutations in FEZF1 cause Kallmann syndromeAm J Hum Genet20149532633125192046
  56. ND ShawH BrandZA KupchinskyH BenganiL PlummerTI JonesS ErdinKA WilliamsonJ RaingerA StortchevoiK SamochaBB CurrallDS DunicanRL CollinsJR WillerA LekM LekM NassanS PereiraT KamminD LucenteA SilvaCM SeabraC hiangY AnM AnsariJK RaingerS JossJC SmithMF LippincottSS SinghN PatelJW JingJR LawN FerraroA VerloesA RauchK SteindlM ZweierI ScheerD SatoN OkamotoC JacobsenJ TryggestadS ChernausekLA SchimmentiB rasseurC esarettiJE García-OrtizTP BuitragoOP SilvaJD HoffmanW MühlbauerKW RuprechtBL LoeysM ShinoAM KaindlCH ChoCC MortonRR MeehanV7 van HeyningenEC LiaoR BalasubramanianJE HallSB SeminaraD MacarthurSA MooreKI YoshiuraJF GusellaJA MarshJr Graham JMAE LinN KatsanisPL JonesJr Crowley WFEE DavisDR FitzPatrickME TalkowskiSMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndromeNat Genet20174923824828067909
  57. F GürbüzLD KotanE MengenZ ŞıklarM BerberoğluS DökmetaşMF KılıçlıA GüvenB KirelN SakaŞ PoyrazoğluY CesurM DoğanS ÖzenMN ÖzbekH DemirbilekMB KekilF TemizN Önenli MunganB YükselAK TopaloğluDistribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadismJ Clin Res Pediatr Endocrinol2012412112622766261
  58. A StrobelT IssadL CamoinM OzataAD StrosbergA leptin missense mutation associated with hypogonadism and morbid obesityNat Genet1998182132159500540
  59. IS FarooqiT WangensteenS CollinsW KimberG MatareseJM KeoghE LankB ottomleyJ Lopez-FernandezI Ferraz-AmaroMT DattaniO ErcanAG MyhreL RetterstolR StanhopeJA EdgeS McKenzieN LessanM GhodsiV De RosaF PernaS FontanaI BarrosoDE UndlienS O’RahillyClinical and molecular genetic spectrum of congenital deficiency of the leptin receptorN Engl J Med200735623724717229951
  60. IS FarooqiSA JebbG LangmackE LawrenceCH CheethamAM PrenticeIA HughesMA McCamishS O’RahillyEffects of recombinant leptin therapy in a child with congenital leptin deficiencyN Engl J Med199934187988410486419
  61. F MuscatelliTM StromAP WalkerE ZanariaD RécanA MeindlB ardoniS GuioliG ZehetnerW RablHP SchwarzJC KaplanG CamerinoT MeitingerAP MonacoMutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadismNature19943726726767990958
  62. S Chooniedass-KothariE mberleyMK HamedaniS TroupX WangA CzosnekF HubeM utawePH WatsonE LeygueThe steroid receptor RNA activator is the first functional RNA encoding a proteinFEBS Lett2004566434715147866
  63. VR KellyB XuR KuickRJ KoenigGD HammerDax1 up-regulates Oct4 expression in mouse embryonic stem cells via LRH-1 and SRAMol Endocrinol2010242281229120943815
  64. LD KotanC ooperŞ DarcanIM CarrS ÖzenY anMK HamedaniF GürbüzE Mengenİ TuranA UlubayG AkkuşB YükselAK1 TopaloğluE LeygueIdiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1J Clin Res Pediatr Endocrinol2016812513427086651
  65. N de RouxJ YoungM israhiR GenetP ChansonG SchaisonE MilgromA family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptorN Engl J Med1997337159716029371856
  66. M BeranovaLM OliveiraGY BédécarratsE SchipaniM VallejoAC AmminiJB QuintosJE HallKA MartinFJ HayesN PitteloudUB KaiserJr Crowley WFSB SeminaraPrevalence, phenotypic spectrum, and modes of inheritance of gonadotropin-releasing hormone receptor mutations in idiopathic hypogonadotropic hypogonadismJ Clin Endocrinol Metab2001861580158811297587
  67. N de RouxGnRH receptor and GPR54 inactivation in isolated gonadotropic deficiencyBest Pract Res Clin Endocrinol Metab20062051552817161329
  68. D BeneduzziEB TrarbachL MinAA JorgeHM GarmesAC RenkM FichnaP FichnaKA ArantesEM CostaA ZhangO AdeolaJ WenRS CarrollBB MendonçaUB KaiserAC LatronicoLF SilveiraRole of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delayFertil Steril201410283884625016926
  69. J BouligandC GhervanJA TelloS Brailly-TabardS alenaveP ChansonM LombèsRP MillarA Guiochon-MantelJ YoungIsolated familial hypogonadotropic hypogonadism and a GNRH1 mutationN Engl J Med20093602742274819535795
  70. YM ChanA de GuillebonM Lang-uritanoL PlummerF CerratoS TsiarasA GaspertHB LavoieCH WuJr Crowley WFJK AmoryN PitteloudSB SeminaraGNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadismProc Natl Acad Sci USA2009106117031170819567835
  71. E MengenS TuncLD KotanO NalbantogluK DemirF GurbuzI TuranG SekerB YukselAK TopalogluComplete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous GNRH1 Mutations in the Mutational Hot Spots in the Region Encoding the DecapeptideHorm Res Paediatr20168510711126595427
  72. T OhtakiY ShintaniS HondaH MatsumotoA HoriK anehashiY TeraoS KumanoY TakatsuY MasudaY IshibashiT WatanabeM AsadaT YamadaM SuenagaC KitadaS UsukiT KurokawaH OndaO NishimuraM FujinoMetastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptorNature200141161361711385580
  73. SB SeminaraS MessagerEE ChatzidakiRR ThresherJr Acierno JSJK ShagouryY Bo-AbbasW KuohungKM SchwinofAG HendrickD ZahnJ DixonUB KaiserSA SlaugenhauptJF GusellaS O’RahillyMB CarltonJr Crowley WFSA AparicioWH ColledgeThe GPR54 gene as a regulator of pubertyN Engl J Med20033491614162714573733
  74. N de RouxE GeninJC CarelF MatsudaJL ChaussainE MilgromHypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54Proc Natl Acad Sci USA2003100109721097612944565
  75. F CerratoJ ShagouryM KralickovaA DwyerJ FalardeauM OzataG Van VlietP BoulouxJE HallFJ HayesN PitteloudKA MartinC WeltSB SeminaraCoding sequence analysis of GNRHR and GPR54 in patients with congenital and adult-onset forms of hypogonadotropic hypogonadismEur J Endocrinol2006155(Suppl 1)S3S1017074994
  76. AK TopalogluJA TelloLD KotanMN OzbekMB YilmazS ErdoganF GurbuzF TemizRP MillarB YukselInactivating KISS1 mutation and hypogonadotropic hypogonadismN Engl J Med201236662963522335740
  77. ES LanderD BotsteinHomozygosity mapping: a way to map human recessive traits with the DNA of inbred childrenScience1987236156715702884728
  78. AK TopalogluF ReimannM GucluAS YalinLD KotanKM PorterA SerinNO MunganJR CookS ImamogluNS AkalinB YukselS O’RahillyRK SempleTAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproductionNat Genet20094135435819079066
  79. E GianettiC TussetSD NoelMG AuAA DwyerVA HughesAP AbreuJ CarrollE TrarbachLF SilveiraEM CostaBB de MendonçaM de CastroA LofranoJE HallE BoluM OzataR QuintonJK AmorySE StewartW ArltTR ColeWF CrowleyUB KaiserAC LatronicoSB SeminaraTAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthoodJ Clin Endocrinol Metab2010952857286720332248
  80. B FrancouJ BouligandA VoicanL AmazitS TrabadoJ FagartG MeduriS Brailly-TabardP ChansonP LecomteA Guiochon-MantelJ YoungNormosmic congenital hypogonadotropic hypogonadism due to TAC3/TACR3 mutations: characterization of neuroendocrine phenotypes and novel mutationsPLoS One20116e2561422031817
  81. K VaaralahtiK WehkalampiJ TommiskaEM LaitinenL DunkelT RaivioThe role of gene defects underlying isolated hypogonadotropic hypogonadism in patients with constitutional delay of growth and pubertyFertil Steril2011952756275821292259
  82. J YoungJ BouligandB FrancouML Raffin-SansonS GaillezM JeanpierreM GrynbergP KamenickyP ChansonS Brailly-TabardA Guiochon-MantelTAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humansJ Clin Endocrinol Metab2010952287229520194706
  83. MN LehmanLM CoolenRL GoodmanMinireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretionEndocrinology20101513479348920501670
  84. VM NavarroML GottschC havkinH OkamuraDK CliftonRA SteinerRegulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouseJ Neurosci200929118591186619776272
  85. L PinillaE AguilarC DieguezRP MillarM Tena-SempereKisspeptins and reproduction: physiological roles and regulatory mechanismsPhysiol Rev2012921235131622811428
  86. JT GeorgeR KakkarJ MarshallML ScottRD FinkelmanTW HoJ VeldhuisK SkorupskaiteRA AndersonS McIntoshL WebberNeurokinin B Receptor Antagonism in Women With Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled TrialJ Clin Endocrinol Metab20161014313432127459523
The underlying source XML for this text is taken from https://www.ebi.ac.uk/europepmc/webservices/rest/PMC5790323/fullTextXML. The license for the article is Creative Commons Attribution 2.5 Unported. The main subject has been identified as hypogonadism.