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The prevalence is estimated at 1/8,000 males and 1/40,000 females, but is probably underestimated.

Most cases are diagnosed at the time of puberty due to lack of sexual development, but KS may also be suspected in infancy in males with cryptorchidism, micropenis or associated non reproductive signs. The main clinical features consist of the absence of complete spontaneous puberty and a partial or total impairment of the sense of smell (anosmia) in both sexes. Untreated adult males usually have decreased bone density and muscle mass, decreased testicular volume (< 4 mL), erectile dysfunction, diminished libido and infertility. Untreated adult females almost always experience primary amenorrhea with absent, little or normal breast development. Rare presentations include unilateral (occasionally bilateral and lethal at birth) renal agenesis, hearing impairment, cleft lip or palate, dental agenesis or bimanual synkinesis persisting beyond childhood.

KS is caused by impaired development of the olfactory system and disrupted embryonic migration of the GnRH-synthesizing neurons from the olfactory epithelium to the hypothalamic region of the brain. The majority of reported cases are sporadic but familial forms have been described. Causative genes include: KAL1 (Xp22.32), in the X-linked recessive form, FGFR1 (8p12), FGF8 (10q25-q26), CHD7 (8q12.2) and SOX10 (22q13.1) in the AD form, and PROKR2 (20p12.3) and PROK2 (3p21.1), in both the AR and oligogenic forms. More evidence is needed to determine if other genes (ex: SEMA3A), presumably involved in KS, are indeed causal.

Diagnostic methods consist of hormone evaluation (sex steroids, gonadal peptides and pituitary gonadotropin dosage), as well as evaluation of the sense of smell (olfactometry). Morphological analysis of the olfactory bulbs by MRI can be useful, especially in young children. Genetic testing can identify a disease causing mutation, and is mandatory before starting infertility treatment.

Differential diagnoses include isolated congenital gonadotropin deficiency and CHARGE syndrome (see these terms).

In a familial context of FGFR1, FGF8, KAL1, or CHD7 mutations, bone abnormalities, cleft lip/palate, renal agenesis, or multiple developmental defects can be found in the fetus by ultrasonography.

Genetic counseling should be adapted to each family, taking into account the potential mode of inheritance (AD/AR, X-linked, or presumably oligogenic) and the great variability in clinical expression, even within the same family, as well as the risk, in sporadic cases, of neomutations.

Hormonal replacement therapy is used to induce puberty, and later, fertility. Testosterone esters are usually used and sometimes human chorionic gonadotropin (hCG) injections in combination with follicle-stimulating hormone (FSH) or in monotherapy are given to males to achieve normal virilization and increased testicular volume. In adults combined gonadotropin therapy is mandatory to stimulate spermatogenesis. In females, estrogen is administered to induce breast development and genital development along with progestin to establish endometrial cyclicity. Pulsatile GnRH administration or exogenous gonadotropins are used to induce folliculogenesis and ovulation and therefore to restore fertility. There is currently no treatment for anosmia.

KS is not a life threatening disease. With hormonal treatment, pubertal feminization or virilization occurs in all patients. Fertility, when desired, is achieved in most cases but cryptorchidism has a poor prognosis in males.