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.
