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Kallmann syndrome (KS) is a congenital genetic disorder characterized by the association of hypogonadotropic hypogonadism (HH) due to gonadotropin-releasing hormone (GnRH) deficiency, and anosmia or hyposmia (with hypoplasia or aplasia of the olfactory bulbs). The prevalence is reported at 1/8,000 males and 1/40,000 females, but may be 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 and micropenis. The main clinical features consist of the absence of spontaneous puberty and a partial or total loss of the sense of smell (anosmia) in both sexes. Other possible signs include mirror movements of the upper limbs (bimanual synkinesis), unilateral (occasionally bilateral and lethal) renal aplasia, cleft lip or palate, dental agenesis, and hearing impairment. 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 were sporadic. Three modes of inheritance have been described in familial forms: X-linked recessive, autosomal dominant (with incomplete penetrance) and, more rarely, autosomal recessive. However, in an undetermined proportion of the patients, transmission may be digenic or oligogenic. To date, five causative genes have been identified: KAL1 (Xp22.3), responsible for the X-linked form, and FGFR1 (8p12) FGF8 (10q24), PROKR2 (20p13), and PROK2 (3p21.1), which are involved in the autosomal forms. Other genes involved in KS remain to be discovered as mutations in the genes identified so far are detected in less than 30% of the patients. Diagnostic methods consist of hormone evaluation (sex hormone dosage and GnRH stimulation tests), as well as qualitative and quantitative evaluation of the sense of smell (olfactometry). Morphological analysis of the olfactory bulbs by magnetic resonance imaging (MRI) can be useful (especially in young children, whose sense of smell is difficult to evaluate). Differential diagnoses include isolated GnRH deficiency (normosmic idiopathic hypogonadotropic hypogonadism) and CHARGE syndrome, which combines KS with various additional developmental anomalies (see these terms). Genetic counseling should be adapted to each family, taking into account the wide variability in clinical expression, even within the same family, as well as the possibility, in sporadic cases, of an FGFR1 neomutation. Hormonal replacement therapy is used to induce puberty, and later, fertility. There is no current treatment available for anosmia. With treatment, onset of puberty occurs in all cases, and fertility is achieved in most cases.
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