Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism Clinical Presentation

Because classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are both congenital disorders, the terms classic and congenital are used interchangeably to refer to Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. ^[27]

Patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism may not experience puberty or may experience incomplete puberty and have symptoms associated with hypogonadism. For men, these symptoms include decreased libido, erectile dysfunction, decreased muscle strength, and diminished aggressiveness and drive. For women, symptoms include amenorrhea and dyspareunia. Notably, patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism do not experience hot flashes.

All patients with Kallmann syndrome have either anosmia or severe hyposmia and may exhibit symptoms of associated conditions including those of congenital heart disease (eg, fatigue, dyspnea, cyanosis, palpitations, syncope) or neurologic manifestations (eg, color blindness, hearing deficit, epilepsy, paraplegia). ^[28]

Absent or incomplete puberty

Some male patients may present with microphallus and cryptorchidism during the neonatal period. Patients with either classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism report no pubertal maturation; however, occasionally, individuals have a history of partial progression through puberty. These male patients were previously labeled fertile eunuchs.

Family members of patients with idiopathic hypogonadotropic hypogonadism may have a history of delayed, although otherwise normal, puberty. This occurs in 12-15% of family members, versus 1% in the general population. Whether these individuals actually represent one end of the spectrum of idiopathic hypogonadotropic hypogonadism is unclear.

Delayed, but otherwise normal, puberty has also been reported in female carriers of DAX1 mutations who have family members with X-linked idiopathic hypogonadotropic hypogonadism associated with AHC.

Decreased libido and erectile dysfunction

These symptoms are almost universal in men with either Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Androgen replacement improves libido and erectile function.

Amenorrhea

Primary amenorrhea develops in the vast majority of women with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Women with hypothalamic amenorrhea present with secondary amenorrhea, typically precipitated by excessive exercise, weight loss, or psychological stress.

Dyspareunia

This may occur in women because of decreased vaginal lubrication.

Infertility

Almost all untreated patients are infertile.

Individuals with adult-onset idiopathic hypogonadotropic hypogonadism may present with infertility and a history of previously documented fertility.

In either Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, restoring fertility is possible in patients who generally respond to treatment with pulsatile GnRH or gonadotropins.

Decreased muscle strength and diminished aggressiveness and drive (in men)

These symptoms are ameliorated significantly by androgen replacement.

Cautioning patients' families about possible behavioral changes in response to such therapy is helpful.

Osteoporosis

All hypogonadal patients are at high risk of osteoporosis if untreated.

Although asymptomatic, patients have a greater fracture risk.

Androgen or estrogen replacement therapy may prevent or ameliorate osteoporosis in men or women, respectively.

Anosmia or hyposmia

Male and female patients with Kallmann syndrome have either an absent or severely impaired sense of smell.

Patients may not be aware of the deficit and must be specifically tested.

Family members of patients with Kallmann syndrome, including female obligate carriers in X-linked Kallmann syndrome pedigrees, may have anosmia or hyposmia without hypogonadism and may represent one end of the spectrum of Kallmann syndrome.

Fatigue, dyspnea, cyanosis, palpitations, syncope

Patients with Kallmann syndrome may have any of these symptoms as manifestations of congenital heart disease such as atrial septal defect (ASD), ventricular septal defect (VSD), Ebstein anomaly, transposition of the great vessels, right aortic arch, atrioventricular block, right bundle-branch block, and Wolff-Parkinson-White (WPW) syndrome.

A detailed discussion of these conditions is beyond the scope of this review.

Color blindness, sensorineural deafness, paraplegia, or epilepsy

These occur in a minority of patients with Kallmann syndrome.

Skeletal abnormalities

Patients with mutations interfering with FGF signaling may have cleft lip, cleft palate or syndactyly.

Symptoms of primary adrenocortical insufficiency

This occurs in males with X-linked idiopathic hypogonadotropic hypogonadism and AHC.

These patients typically present in infancy or childhood with adrenal crisis.

A detailed discussion of these symptoms is beyond the scope of this review.

Physical findings associated with hypogonadism include eunuchoidal skeletal proportions.

A low ratio, less than 1:1 in adults, of the upper body segment (crown to pubis) to the lower body segment (pubis to heels) is present only in patients with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Similarly, an arm span greater than height by more than 5 cm is observed only in patients with congenital Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Height for age is normal in these patients, distinguishing them during adolescence from individuals with constitutional delay in growth and development because adolescents in the latter group tend to be short for chronological age.

Absence of terminal facial hair and decreased body hair is observed in men with Kallmann syndrome or who have congenital idiopathic hypogonadotropic hypogonadism. Men with adult-onset idiopathic hypogonadotropic hypogonadism may report decreased shaving frequency. In addition, lack of temporal hair recession (male-type baldness) is noted in men with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

High-pitched voice is present only in men with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism.

Lack of breast development is observed in women with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism. Women with long-standing hypothalamic amenorrhea may experience a decrease in breast size.

Gynecomastia is observed only rarely in men with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism at the time of diagnosis, but it may occur as an adverse effect of androgen replacement therapy in these patients.

Muscle mass is decreased, muscle strength is diminished, and fat is distributed over the hips and chest, particularly in men with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism.

Axillary and pubic terminal hair may be scantly present in these patients (with the exception of patients with X-linked idiopathic hypogonadotropic hypogonadism and AHC) because of circulating adrenal androgens. Males with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism lack terminal hair growth along the midline towards the umbilicus.

Men with Kallmann syndrome or congenital idiopathic hypogonadotropic hypogonadism have prepubertal testes (< 4 mL) and lack scrotal pigmentation. Some patients (previously known as fertile eunuchs) experience some testicular growth in association with partial GnRH deficiency. Testicular volumes in patients with adult-onset idiopathic hypogonadotropic hypogonadism are either within the normal range or mildly decreased (10-15 mL). Cryptorchidism is present in a minority of men with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

Males with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism have small penises (< 8 cm long in adults). In addition, prostate size is decreased, particularly in men with classic Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.

In women, the vaginal mucosa has a deep red color because of the lack of squamous epithelial differentiation.

All patients with Kallmann syndrome by definition have anosmia or severe hyposmia. Formal smell testing can be carried out by administering the Smell Identification Test (SIT, Sensonics, Haddon Heights, NJ), which is a standardized, multiple choice test that includes 40 scratch-and-sniff panels, each with 4 possible answers. Alternatively, the sense of smell can be evaluated by using serial dilutions of multiple odorants such as dimethyl sulfide, menthone, acetic acid, exaltolide, amyl acetate, cineole, and pm-carbinol (Olfacto Laboratories, El Cerrito, Calif), according to the protocol of Rosen and Rogol.

A small percentage of patients with Kallmann syndrome experience color blindness, as assessed by Ishihara plate testing. In addition, sensorineural hearing loss has been reported in some Kallmann syndrome patients.

Some patients with X-linked Kallmann syndrome and a contiguous gene syndrome may have ichthyosis.

Cleft lip, cleft palate, or high (arched) palate has been reported in 6-22% of patients with Kallmann syndrome. Short metacarpals and pes cavus also have been reported in a minority of Kallmann syndrome patients.

Cardiovascular findings are present in some patients with Kallmann syndrome who have congenital heart disease (including ASD, VSD, Ebstein anomaly, transposition of the great vessels, right aortic arch, atrioventricular block, right bundle-branch block, and WPW syndrome). A detailed discussion of these findings is beyond the scope of this review.

Neuropsychiatric findings that exist in a minority of patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism include abnormal eye movements (including gaze-evoked horizontal nystagmus, abnormal pursuit, and saccades), synkinesia (mirror movements of the opposite upper extremity), paraplegia, cerebellar ataxia, and learning disability (secondary to mental retardation). Synkinesia has been reported only in X-linked Kallmann syndrome patients.

Conditions associated with primary adrenocortical insufficiency are present in males with X-linked idiopathic hypogonadotropic hypogonadism and AHC. A detailed discussion of these conditions is beyond the scope of this review.

Early-onset obesity is present in patients with idiopathic hypogonadotropic hypogonadism and mutations of either the leptin gene or the leptin receptor gene.

Classic Kallmann syndrome and idiopathic hypogonadotropic hypogonadism are congenital genetic disorders. ^{[29, 30]} 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. ^[31] 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. ^[32]

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]

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. Recent 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. ^[33]

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.