Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism

Deficient hypothalamic GnRH secretion underlies the markedly abnormal gonadotropin secretion patterns in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. The result is hypogonadism; infertility; and absent, incomplete, or partial pubertal maturation.

Some of the genes involved in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism have been identified. However, the genes involved remain unidentified in over 50% of patients. ^[1]  These conditions can be transmitted as autosomal dominant, autosomal recessive or X linked traits. Of note, oligogenic inheritance has been well-described.

Mutations of the KAL1 gene, which encodes a putative neural cell adhesion molecule (anosmin), have been described in several patients with X-linked Kallmann syndrome. In these patients, GnRH deficiency and anosmia are believed to be secondary to abnormalities of neuronal migration during development.

Loss-of-function mutations of the gene encoding fibroblast growth factor receptor 1 (FGFR1) have been described in patients with autosomal dominant Kallmann syndrome. ^{[2, 3]} Heterozygous loss-of-function mutations of the gene encoding FGFR1 have also been described in individuals with idiopathic hypogonadotropic hypogonadism, normal smell sense, and normal MRI of the olfactory system. ^[4]  Of note, anosmin may enhance fibroblast growth factor signaling through the fibroblast growth factor receptor 1.

Mutations of the gene encoding fibroblast growth factor 8 have been found in a small minority of patients with autosomal dominant Kallmann syndrome. ^[3] In addition, mutations of the gene encoding chromodomain-helicase DNA-binding protein 7 (CHD7) have been found in some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, some of whom have features of the CHARGE syndrome (characterized by delayed growth and development, congenital cardiac defects, dysmorphic ears, hearing loss, coloboma of the eyes).

Loss-of-function mutations of critical components of the prokineticin pathway have been implicated in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. ^{[5, 6]} Specifically, homozygous mutations of prokineticin 2 were found in 2 brothers with Kallmann syndrome and in their sister, who had idiopathic hypogonadotropic hypogonadism. ^[7] Homozygous, heterozygous or compound heterozygous mutations of the prokineticin receptor 2 have also been associated with Kallmann syndrome. ^[8] Digenic inheritance has been suggested in an individual carrying heterozygous mutations of prokineticin receptor 2 and KAL1. ^{[8, 9]}

Mutations of the DAX1 gene, which encodes a nuclear transcription factor, lead to X-linked idiopathic hypogonadotropic hypogonadism associated with adrenal hypoplasia congenita (AHC). ^[10] Mutations of genes encoding either leptin or the leptin receptor underlie isolated cases of autosomally transmitted idiopathic hypogonadotropic hypogonadism associated with early-onset obesity. ^[11] Several loss-of-function mutations of the GnRH receptor gene leading to GnRH resistance and autosomally transmitted hypogonadotropic hypogonadism have been described. ^[12] In addition, autosomal recessive mutations of the GnRH gene may underlie hypogonadotropic hypogonadism.

Rarely, hypogonadotropic hypogonadism occurs as a result of isolated follicle-stimulating hormone (FSH) deficiency due to homozygous mutations in the FSH beta subunit gene. In one patient, isolated bioinactive luteinizing hormone (LH) was present as a result of a homozygous mutation in the LH beta subunit gene, which prevented binding of LH to its receptor. This patient presented with hypogonadotropic hypogonadism, despite high levels of immunoreactive serum LH. A second patient had a different homozygous mutation in the LH beta subunit gene that prevented LH heterodimerization and secretion. He presented with hypogonadotropic hypogonadism and undetectable serum LH.

In another patient, a mutation in the prohormone convertase gene (PC1) led to hypogonadotropic hypogonadism, in addition to extreme obesity, hypocortisolemia, and deficient conversion of proinsulin to insulin.

Homozygous mutations in KISS1R (kisspeptin 1 receptor gene, also known as GPR54), a gene encoding a G protein–coupled receptor, which binds kisspeptin 1, have been reported as a cause of hypogonadotropic hypogonadism. ^[13] Inactivating mutations of the gene encoding kisspeptin 1 may also underlie hypogonadotropic hypogonadism. ^[14] Kisspeptin 1 and its receptor have an important role in the regulation of GnRH and the onset of puberty. ^{[15, 16]}

Homozygous mutations in the genes encoding neurokinin B (TAC3) or its receptor (TACR3) have also been described in some patients with autosomal recessive idiopathic hypogonadotropic hypogonadism. Interestingly, reversal of hypogonadism during adult life has been described in patients with these mutations.

Heterozygous missense mutations of the NSMF (NMDA receptor synaptonuclear signaling and neuronal migration factor, also known as NELF) gene have been associated with Kallmann syndrome. ^[17] Mutations of additional genes have been implicated in the pathogenesis of Kallmann syndrome and/or hypogonadotropic hypogonadism, including the following genes: WDR11, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, AXL, SOX10,SEMA3A, and HS6ST11. ^{[3, 18, 19, 20, 21, 22, 23]}

A study by Turan et al that described the phenotype and prevalence of CCDC141 mutations in idiopathic hypogonadotropic hypogonadism/Kallmann syndrome confirmed that inactivating CCDC141 variants cause normosmic idiopathic hypogonadotropic hypogonadism but not Kallmann syndrome. ^[24]

Classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are congenital genetic disorders. ^{[25, 26]}  Approximately one third of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases appear to be inherited. The remaining two thirds of all Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases appear to be sporadic and may represent new mutations. Genetic transmission appears to be autosomal dominant (approximately 64% of families), autosomal recessive (about 25% of families), or X-linked (about 11% of families). Oligogenic inheritance is also well-described.

Some of the genes associated with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism have been identified, including mutations of the KAL1 gene, which cause X-linked Kallmann syndrome. The KAL1 gene (present on band Xp22.3) encodes anosmin-1, a putative neural cell adhesion molecule that is essential for the migration of olfactory neuron axons toward the olfactory bulb and the establishment of synaptic connections between these axons and the mitral cells present in the olfactory bulb. The GnRH synthesizing neurons originate in the olfactory placode (outside the brain) and migrate along the olfactory neuron axons to their final location in the brain in a process that is also critically dependent on the presence of anosmin-1.

Several mutations of the KAL1 gene have been reported in about 50% of patients with X-linked Kallmann syndrome. In these patients, lack of anosmin-1 leads to disruption of the olfactory pathway, causing anosmia and absence of GnRH neuronal migration, resulting in GnRH deficiency (hypothalamic secretory defect only) and hypogonadotropic hypogonadism.

Some patients presenting with X-linked Kallmann syndrome and ichthyosis have a contiguous gene syndrome secondary to large interstitial deletions of Xp22.3 that include at least part of the coding regions of the KAL1 gene and the steroid sulfatase gene.

Loss-of-function mutations of the gene encoding FGFR1 have been described in patients with autosomal dominant Kallmann syndrome. In addition, mutations of the gene encoding fibroblast growth factor 8 have been found in a small minority of patients with autosomal dominant Kallmann syndrome. Furthermore, mutations of the gene encoding chromodomain-helicase DNA-binding protein 7 have been found in some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Loss-of-function mutations of critical components of the prokineticin pathway have been implicated in the pathogenesis of Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. ^{[5, 6]}  Specifically, homozygous mutations of prokineticin 2 were found in 2 brothers with Kallmann syndrome and in their sister, who had idiopathic hypogonadotropic hypogonadism. ^[7]  Homozygous, heterozygous, or compound heterozygous mutations of the prokineticin receptor 2 have also been associated with Kallmann syndrome. ^[8]  Digenic inheritance has been suggested in an individual carrying heterozygous mutations of prokineticin receptor 2 and KAL1. ^{[8, 9]}

Mutations of the DAX1 gene lead to X-linked idiopathic hypogonadotropic hypogonadism and AHC. ^[27] The DAX1 gene (present on band Xp21) encodes a putative orphan receptor (without known ligand) that belongs to the steroid hormone receptor superfamily and is believed to be a transcription factor with a critical function in the development of the hypothalamic-pituitary-gonadal axis and the adrenal cortex. Males with mutations in the DAX1 gene present with AHC (primary adrenocortical insufficiency in infancy or childhood) and idiopathic hypogonadotropic hypogonadism. Limited data suggest that, in these patients, idiopathic hypogonadotropic hypogonadism may be acquired postnatally but before the expected onset of puberty. In contrast to patients with Kallmann syndrome and most other patients with idiopathic hypogonadotropic hypogonadism, these individuals have hypothalamic and pituitary gonadotroph secretory defects and may also have intrinsic defects in spermatogenesis. One case involving a female patient with a homozygous DAX1 mutation and idiopathic hypogonadotropic hypogonadism without AHC has been reported.

Mutations of either the leptin gene or the leptin receptor gene lead to autosomal recessive idiopathic hypogonadotropic hypogonadism and early-onset obesity. ^[11]  Patients with homozygous mutations of the leptin gene present with early onset, severe obesity, and idiopathic hypogonadotropic hypogonadism secondary to a hypothalamic defect in GnRH secretion.

Patients with homozygous mutations of the leptin receptor also present with early-onset, morbid obesity and idiopathic hypogonadotropic hypogonadism. In contrast to patients with Kallmann syndrome, as well as the vast majority of idiopathic hypogonadotropic hypogonadism cases, reported patients with leptin receptor mutations have central hypothyroidism as well as decreased growth hormone (GH) secretion, presumably on the basis of hypothalamic dysfunction.

Mutations of the GnRH receptor gene cause GnRH resistance and autosomal recessive idiopathic hypogonadotropic hypogonadism. In addition, mutations of the gene encoding for GnRH itself have been described in patients with hypogonadotropic hypogonadism. ^[3]  

Homozygous or compound heterozygous mutations of the GnRH receptor have been found in approximately 40% of autosomal recessive and 15% of sporadic cases of patients with idiopathic hypogonadotropic hypogonadism, who may present with either complete hypogonadotropic hypogonadism secondary to GnRH resistance or who may have some evidence of pubertal maturation, albeit incomplete. ^[28]

Rarely, hypogonadotropic hypogonadism occurs as a result of isolated FSH deficiency due to homozygous mutations in the FSH beta subunit gene. In one patient, isolated bioinactive LH was present because of a homozygous mutation in the LH beta subunit gene, which led to the secretion of LH with reduced binding affinity to its receptor, causing hypogonadotropic hypogonadism. A second patient was found to have a different homozygous mutation in the LH beta subunit gene; the mutation prevented LH heterodimerization and secretion.

In another patient, a mutation in PC1 led to hypogonadotropic hypogonadism, in addition to extreme obesity, hypocortisolemia, and deficient conversion of proinsulin to insulin.

Homozygous mutations in KISS1R (kisspeptin 1 receptor gene, also known as GPR54), a gene encoding a G protein–coupled receptor which binds kisspeptin 1, have been reported as a cause of hypogonadotropic hypogonadism. In addition, mutations of the gene encoding kisspeptin 1 may underlie the presence of hypogonadotropic hypogonadism. Kisspeptin 1 and its receptor have an important role in the regulation of GnRH and the onset of puberty.  ^[13] Also of note, heterozygous missense mutations of the NSMF (NMDA receptor synaptonuclear signaling and neuronal migration factor, also known as NELF) gene have been associated with Kallmann syndrome.

Homozygous mutations in the genes encoding neurokinin B (TAC3) or its receptor (TACR3) have also been described in some patients with autosomal recessive idiopathic hypogonadotropic hypogonadism. Interestingly, reversal of hypogonadism during adult life has been described in patients with these mutations.

Mutations of many additional genes have been implicated in the pathogenesis of Kallmann syndrome and/or hypogonadotropic hypogonadism, including the following genes: WDR11, FGF17, IL17RD, DUSP6, SPRY4, FLRT3, AXL, SOX10, SEMA3A, and HS6ST11. ^[3]  A systematic review by Patil et al showed that FGFR1 and ANOS1 were the most commonly affected genes worldwide in patients with Kallmann syndrome. ^[29]

Although no risk factors can be identified in a large subset of patients with hypothalamic amenorrhea, the condition is associated with strenuous exercise (eg, running >20 min/wk), excessive weight loss, anorexia nervosa, and psychogenic stress. Data indicate that mutations in some of the genes associated with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism are also implicated in the pathogenesis of hypothalamic amenorrhea in some patients. ^[30]

The cause of adult-onset idiopathic hypogonadotropic hypogonadism in males is unknown. Notably, strenuous exercise, excessive weight loss, an eating disorder, or psychogenic stress is absent.

International statistics

The prevalence of idiopathic hypogonadotropic hypogonadism was approximately 1 in 10,000 men in a study of French conscripts. ^[31] A study of Sardinian military recruits reports the prevalence of hypogonadism associated with anosmia (Kallmann syndrome) as 1 in 86,000 men. ^[32] Methodological limitations of case ascertainment by medical record review should be kept in mind when interpreting these findings.

Sex- and age-related demographics

The male-to-female ratio ranges from 4:1 to 5:1. The male-to-female ratio is approximately 2.5:1 among strictly familial Kallmann syndrome and idiopathic hypogonadotropic hypogonadism cases. ^[33]

Classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are both congenital disorders.

Adult-onset or acquired idiopathic hypogonadotropic hypogonadism has recently been described in men aged 30-50 years.

Hypothalamic amenorrhea represents an acquired form of GnRH deficiency that occurs predominantly among young women and may be associated with excessive exercise, extreme weight loss, or psychogenic stress. This may occur particularly in patients with anorexia nervosa.

Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism can survive for lengthy periods in the absence of associated life-threatening conditions.

Fertility can be restored in most patients with classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism.

Although Kallmann syndrome and idiopathic hypogonadotropic hypogonadism were previously thought to be lifelong disorders, cases of patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism who experienced spontaneous complete recovery of gonadal function have been reported. ^[34]

Women with hypothalamic amenorrhea may also experience complete recovery of gonadal function, particularly if precipitating factors are corrected.

Some patients with congenital heart disease or neurologic manifestations may experience a limited lifespan.

Adrenocortical insufficiency is fatal unless recognized and treated; however, patients who are treated adequately should have long-term survival.

Osteoporosis increases the risk of fracture, which may compromise patient survival and quality of life.

Morbidity/mortality

Associated complications affect the patient's quality of life and his/her survival.

Patients with Kallmann syndrome and those with idiopathic hypogonadotropic hypogonadism survive long term if they do not have associated conditions such as congenital heart disease or neurologic manifestations.

Adrenocortical insufficiency is fatal unless recognized and treated. Thyroid function must also be assessed. In patients who do not receive adequate gonadal steroid replacement, hypogonadal osteoporosis may develop insidiously.

Complications

Complications include the following:

• Congenital heart disease: Various cardiac lesions have been reported in a small subset of patients with Kallmann syndrome, including the following: ASD, atrioventricular block, Ebstein anomaly, right aortic arch, right bundle-branch block and WPW syndrome, transposition of the great vessels, and VSD. Early diagnosis and management of these conditions is important in order to minimize patient mortality and morbidity.

• Primary adrenocortical insufficiency: Male patients with X-linked idiopathic hypogonadotropic hypogonadism and AHC usually present in infancy or childhood with adrenal insufficiency. This is fatal unless diagnosed and treated appropriately.

• Neurologic manifestations: Anosmia or hyposmia occurs in all Kallmann syndrome cases. Some patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism exhibit a variable neurologic symptomatology, including the following: cerebellar ataxia, gaze abnormalities, impaired vision, mental retardation, seizures, sensorineural deafness, spastic paraplegia, and synkinesia (mirror movements).

• Osteoporosis: Patients with hypogonadism, including all individuals with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism, are at increased risk for osteoporosis. Osteoporosis may be prevented or treated by adequate gonadal steroid replacement. Additional therapies for osteoporosis, including diet and exercise, bisphosphonates, and calcitonin, may be needed.

• Short metacarpals and pes cavus

• Ichthyosis

• Cleft lip or palate

Patients should be made aware of the risks and benefits of gonadal steroid replacement therapy.

Patients should know that current therapies permit fertility in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Patients should know that, although Kallmann syndrome or idiopathic hypogonadotropic hypogonadism are usually life-long conditions, spontaneous recovery of gonadal function is possible in some individuals.

Patients with adrenocortical insufficiency should be familiar with sick day rules.

Activity restrictions should be discussed in patients with osteoporosis, congenital heart disease, or seizures.