[Congenital hypogonadotropic hypogonadism and Kallmann syndrome in males]

Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are a group of rare disorders responsible for complete or partial pubertal failure due to lack or insufficient secretion of the pituitary gonadotropins LH and FSH. The underlying neuroendocrine abnormalities are classically divided into two main groups: molecular defects of the gonadotrope cascade leading to isolated normosmic CHH (nCHH), and developmental abnormalities affecting the hypothalamic location of GnRH neurons, but also olfactory bulbs and tracts morphogenesis and responsible for KS. Identification of genetic abnormalities related to CHH/KS has provided major insights into the pathways critical for the development, maturation and function of the gonadotrope axis. In patients affected by nCHH, particularly in familial cases, genetic alterations affecting GnRH secretion (mutations in GNRH1, GPR54/KISS1R and TAC3 and TACR3) or the GnRH sensitivity of gonadotropic cells (GNRHR) have been found. Mutations in KAL1, FGFR1/FGF8/FGF17, PROK2/PROKR2, NELF, CHD7, HS6ST1, WDR11, SEMA3A, SOX10, IL17RD2, DUSP6, SPRY4, and FLRT3 have been associated with KS but sometimes also with its milder hyposmic/normosmic CHH clinical variant. A number of observations, particularly in sporadic cases, suggest that CHH/KS is not always a monogenic mendelian disease as previously thought but rather a digenic or potentially oligogenic condition. Before the age of 18 years, the main differential diagnosis of isolated nCHH is the relatively frequent constitutional delay of growth and puberty (CDGP). However, in male patients with pubertal delay and low gonadotropin levels, the presence of micropenis and/or cryptorchidism argues strongly in favor of CHH and against CDGP. CHH/KS are not always congenital life-long disorders as initially thought, because in nearly 10 % of patients the disease seems not permanent, as evidenced by partial recovery of the pulsatile activity of the hypothalamic-pituitary-gonadal axis after discontinuation of treatment in adulthood (the so-called reversible CHH/KS). The clinical and hormonal diagnosis and the therapeutic management as well as the genetic counseling of these patients will be discussed here based on the experience acquired in our department during the past 30 years, from monitoring more than 400 patients with these rare conditions.