Kallmann syndrome (KS) is characterized by the association of isolated GnRH deficiency (IGD) and anosmia (absent sense of smell). Infant boys often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with KS tend to have pre-pubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, decreased bone densities, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Body habitus is usually eunuchoidal with arm span exceeding height by 5 cm or more. Although skeletal maturation is delayed, the rate of linear growth is usually normal (except for the absence of a distinct pubertal growth spurt). Individuals with anosmia may or may not be aware of their olfactory deficiency. Additional non-reproductive findings can include synkinesia of the digits, unilateral renal agenesis, sensorineural hearing loss, cleft lip and/or palate, agenesis of one or more teeth, brachydactyly, syndactyly, and agenesis of the corpus callosum.
The diagnosis of KS in adults is based on clinical findings, low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the face of low circulating concentrations of sex steroids, normal pituitary and hypothalamus on MRI, and absence of other hypothalamic or pituitary abnormalities. Six genes have been definitely proven to be associated with KS to date: KAL1 (KS1), FGFR1 (KS2), PROKR2 (KS3), PROK2 (KS4), CHD7 (KS5), and FGF8 (KS6). Together, mutations in these six genes account for about 25%-35% of all KS. Deletion of KAL1 by FISH or CMA (chromosomal microarray) is an extremely rare cause of KS. Sequence analysis of KAL1 can identify KAL1 point mutations in 5%-10% of familial and simplex cases (i.e., a single occurrence in a family). Approximately 10% of individuals with KS have mutations in FGFR1, approximately 5% in PROKR2 or CHD7, and fewer than 5% in FGF8 or PROK2. Testing for KAL1, FGFR1, PROKR2, PROK2, and FGF8 is available on a clinical basis.
KS1, caused by mutations in KAL1, is inherited in an X-linked manner. KS2 (FGFR1), KS3 (PROKR2), KS4 (PROK2), KS5 (CHD7), and KS6 (FGF8) are predominantly inherited in an autosomal dominant manner. KS3 (PROKR2) and KS4 (PROK2) can also be inherited in autosomal recessive manner. The mode of inheritance is often unclear within families and is likely to be dependent on mutation of more than one gene (i.e., digenic inheritance). Carrier testing for relatives at risk for X-linked and autosomal recessive KS and prenatal testing for pregnancies at increased risk for Kallmann syndrome1, 2, 3, 4, 5, or 6 (caused by mutations in KAL1, FGFR1, PROKR2, PROK2, CHD7, and FGF8 respectively) are possible if the disease-causing mutation has been identified in an affected relative.