Kallmann syndrome E23.07

The cause of KS is a developmental disorder of the olfactory system and an interrupted embryonic migration of GnRH-synthesizing neurons from the olfactory epithelium to the hypothalamic region. Most cases are sporadic, but familial forms have been described. Causative genes are

in the X-linked recessive form KAL1 (Xp22.32)

in the autosomal dominant form FGFR1 (8p12), FGF8 (10q25-q26), CHD7 (8q12.2) and SOX10 (22q13.1)

in the autosomal recessive and oligogenic form PROKR2 (20p12.3) and PROK2 (3p21.1).

Whether other genes (e.g. SEMA3A) are involved in the genesis of KS has not yet been clarified.

The leading symptom is absent or incomplete pubertal development with pronounced secondary hypogonadism (testicular volume around 3 ml, underdevelopment of the penis and prostate, absent or slightly pronounced secondary body hair, eunuchoid growth, feminine fat distribution pattern), often unilateral or bilateral cryptorchidism (see maldescensus testis) or condition after orchidopexy, rarely gynecomastia. Without therapy there is impotentia gestandi ( aspermia or azoospermia).

Second cardinal symptom is hypo- or anosmia (based on aplasia or hypoplasia of the bulbi and tractus olfactorii). In addition, synkinesia, pes cavus, unilateral renal agenesis, unilateral vas deferens aplasia, cleft lip and palate, and patchy hyperpigmentation of the skin are common.

Some patients present with skin lesions of X-linked recessive ichthyosis.

Hormone analyses (sex hormones, gonadal peptides, pituitary gonadotropin test) and examination of the sense of smell (olfactometry) lead to the diagnosis. Morphologic analysis of the olfactory bulbs by MRI may be helpful, especially in young children. Genetic testing can identify a mutation-causing disease and is mandatory before starting infertility treatment.

Prenatal diagnosis: In a familial setting with FGFR1, FGF8, KAL1 or CHD7 mutations, bone abnormalities, cleft lip/palate, renal agenesis or multiple developmental defects in the fetus can be detected by ultrasound examination.

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