Fig. 1The hypothalamic-pituitary-gonadal (HPG) axis. During early brain development, gonadotrophin-releasing hormone (GnRH)-releasing neurons (green) migrate from the nasal region to the hypothalamus, where they permanently reside and differentiate. Hypothalamic GnRH neurons secrete GnRH at the median eminence into the hypophyseal portal system and release pulsatile GnRH to the anterior pituitary. GnRH then binds to GnRH receptor 1 on the gonadotrophs to stimulate these cells to produce luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which enter the systemic blood stream through the hypophyseal veins. LH and FSH act on the gonads (Sertoli and Leydig cells in testes and cumulus, mural and thecal cells in ovaries) to induce steroidogenesis and germ cell production which, in turn, maintains sexual competence. The release of kisspeptin from the hypothalamic neurons located in the arcuate (ARC) and anteroventral periventricular nuclei within the preoptic area is critically important for the re-initiation of pulsatile GnRH secretion at puberty. The developmental failure or misregulation of any one or combination of the genes involved in GnRH migration, secretion, and activity at any stage of development may result in congenital hypogonadotropic hypogonadism and Kallmann syndrome. AVPV, anteroventral periventricular nucleus.
Table 1Current List of Genes Associated with Only Kallmann Syndrome
Gene and protein (alternative names) |
OMIM |
Known biological activity |
Reversible |
Oligogenicity |
Inheritance |
ANOS1(KAL1) (anosmin-1) |
300836 |
Extracellular matrix protein modulating FGFR1 and integrin signaling. Guidance molecule for GnRH neuronal migration and survival. |
Yes |
Yes |
X-linked recessive |
FEZF1 (FEZ family zinc finger 1) |
613301 |
Zinc finger-containing transcriptional repressor regulating the development of forebrain and neo-cortex. GnRH neuronal migration and survival. |
ND |
ND |
Autosomal recessive |
HESX1 (homeobox gene expressed in ES cells 1) |
182230 |
Transcription repressor for homeodomain-containing genes. Also involved in combined pituitary hormone deficiency and septo-optic dysplasia. |
ND |
ND |
Autosomal recessive/dominant |
IL17RD(SEF) (interleukin 17 receptor D) |
606807 |
Negative regulator and interactant of FGFR1. |
ND |
Yes |
Autosomal dominant |
SEMA3A (semaphorin-3A) |
614897 |
Guidance molecule for GnRH neuronal migration and axonal pathfinding. |
ND |
Yes |
Autosomal dominant |
SOX10 (SRY-related HMG-box 10) |
602229 |
Related to testis-determining transcription factor SRY. Regulate neural crest development. Also involved in Waardenburg-Shah syndrome. |
ND |
ND |
Autosomal dominant |
Table 2Current List of Genes Associated with Only Congenital Hypogonadotropic Hypogonadism
Gene and protein (alternative names) |
OMIM |
Known biological activity |
Reversible |
Oligogenicity |
Inheritance |
DMXL2 (Rabconnectin-3α) |
616113 |
Synaptic protein involved in stimulation and homeostasis of GnRH neurons and gonadotrophs. Also mutated in polyendocrine-polyneuropathy syndrome. |
ND |
ND |
Autosomal recessive |
GNRH1 (gonadotropin-releasing hormone 1) |
614841 |
Exclusively expressed by GnRH-releasing neurons. Binds to its receptor GnRHR to stimulate HPG axis. |
ND |
ND |
Autosomal recessive |
GNRHR (gonadotropin-releasing hormone receptor) |
146110 |
G-protein-coupled 7-transmembrane-domain receptor for GnRH, expressed in the gonadotrophs in the pituitary. |
Yes |
Yes |
Autosomal recessive |
KISS1 (kisspeptin; metastin) |
614842 |
Secreted by the hypothalamic neurons of arcuate and anteroventral periventricular nucleus. Binds to its receptor GPR54 to regulate GnRH neurons. |
ND |
ND |
Autosomal recessive |
KISS1R (G-protein-coupled receptor 54) |
614837 |
G-protein-coupled receptor for kisspeptin, expressed in hypothalamic GnRH neurons. |
ND |
Yes |
A utosomal recessive/dominant |
LEP (leptin) |
614962 |
Adipocyte-specific hormone regulating food intake, energy balance and fat metabolism. Associated with obesity. |
ND |
ND |
Autosomal recessive |
LEPR (leptin receptor) |
614963 |
Single-transmembrane-domain receptor for leptin. Preferentially expressed in hypothalamus. |
ND |
ND |
ND |
NR0B1(DAX1) (nuclear receptor subfamily 0, group B) |
300200 |
Negative regulator of retinoic acid receptor. Mutated in X-linked congenital adrenal hypoplasia with HH. |
ND |
ND |
X-linked recessive |
OTUD4 (OTU domain-containing protein 4) |
611744 |
De-ubiquitinase found to be mutated in Gordon Holmes syndrome, a hypogonadism associated with cerebellar ataxia. |
ND |
ND |
Autosomal recessive |
PCSK1 (proprotein convertase-1) |
162150 |
Required for processing of various pre-hormones including proopiomelanocortin, proinsulin, and proglucagon. |
ND |
ND |
ND |
PNPLA6 (patatin-like phospholipase domain-containing protein 6) |
603197 |
Catalyzes the de-esterification of membrane phosphatidylcholine. Also mutated in Gordon Holmes and Boucher-Neuhauser syndrome. |
ND |
ND |
Autosomal recessive |
RNF216 (ring finger protein 216) |
609948 |
Zinc finger protein that binds and inhibits TNF and NF-κB. Also mutated in Gordon Holmes syndrome. |
ND |
ND |
Autosomal recessive |
TAC3 (tachykinin 3; neurokinin B, neuromedin-K) |
614839 |
Secreted in the hypothalamic neurons of arcuate nucleus. Binds to its receptor TACR3 to regulate the secretion and homeostasis of GnRH neurons. |
Yes |
Yes |
Autosomal recessive |
TACR3 (tachykinin receptor 3; neurokinin B receptor, neuromedin-K receptor) |
614840 |
G-protein-coupled receptor for TAC3. Expressed in hypothalamic GnRH neurons to regulate secretion and homeostasis of GnRH. |
Yes |
Yes |
Autosomal recessive |
Table 3Current List of Genes Associated with Both Congenital Hypogonadotropic Hypogonadism and Kallmann Syndrome
Gene and protein (alternative names) |
OMIM |
Known biological activity |
Reversible |
Oligogenicity |
Inheritance |
AXL (AXL receptor tyrosine kinase) |
109135 |
Receptor tyrosine kinase containing fibronectin type III domain with oncogenic activity. Required for GnRH neuron migration. |
ND |
ND |
ND |
CHD7 (chromodomain helicase DNA-binding protein 7) |
612370 |
Transcriptional regulator essential for the formation of neural crest and the development of forebrain, craniofacial bones and heart. |
Yes |
ND |
Autosomal dominant |
FGF8 (fibroblast growth factor 8) |
612702 |
Ligand for FGFR1. Essential morphogen for development of forebrain, olfactory GnRH system, skeletal structure and heart. |
ND |
Yes |
Autosomal dominant |
FGF17 (fibroblast growth factor 17) |
603725 |
Similar to FGF8 as a ligand for FGFR1, but more in patterning the dorsal frontal cortex. |
ND |
Yes |
ND |
FGFR1 (fibroblast growth factor receptor 1) |
147950 |
Receptor tyrosine kinase essential for development of forebrain, craniofacial niche, and stimulation and secretion of GnRH neurons and gonadotrophs. |
Yes |
Yes |
Autosomal dominant |
HS6ST1 (heparan-sulphate 6O-sulphotransferase 1) |
614880 |
Catalyzes the transfer of sulphate to position 6 of the N-sulfoglucosamine residue of heparan sulphate, essential for FGFR1 signaling activity. |
Yes |
Yes |
Autosomal dominant |
NSMF (nasal embryonic luteinizing hormone-releasing hormone factor; NELF) |
614838 |
Guidance molecule for olfactory axon projections required for the axonophilic migration of GnRH neurons. |
Yes |
Yes |
ND |
PROK2 (prokineticin 2) |
610628 |
Secreted by the hypothalamic neurons of suprachiasmatic nucleus that regulate circadian clock. Chemoattractant for subventricular zone neuronal progenitors. Involved in olfactory bulb morphogenesis and the migration and stimulation of GnRH neurons. |
ND |
Yes |
A utosomal recessive/dominant |
PROKR2 (prokineticin receptor-2; GPR73L 1) |
607123 |
G-protein-coupled receptor for PROK2. Regulate the formation of olfactory bulb, GnRH neuron and reproductive organs. |
Yes |
Yes |
A utosomal recessive/dominant |
SEMA7A (semaphorin 7A) |
607961 |
Membrane-anchored guidance molecule of the semaphorin family. Enhances axon outgrowth and interacts with integrin receptors. |
ND |
Yes |
ND |
WDR11 (WD repeat protein 11) |
614858 |
Member of the WD repeat-containing protein family. Expressed in the forebrain and HPG axis. |
ND |
Yes |
Autosomal dominant |