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. ^[35]

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). ^[36]

Absent or incomplete puberty

Some male patients may present with microphallus and cryptorchidism during the neonatal period. ^[37] 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.