Hypogonadotropic hypogonadism (hypogonadotropic hypogonadism) - Genes GnRHR, GNRH1, KISS1R, TAC3 and TACR3.

Hypogonadotropic hypogonadism (HH) is a disorder characterized by a partial or complete lack of pubertal development or sexual maturation, due to an impaired secretion of pituitary gonadotropins LH and FSH, as a result of deficiency of GnRH (gonadotrophin releasing hormone ).

Some of the characteristic signs of hypogonadotropic hypogonadism may include absence of secondary sexual characteristics, such as pubic, axillary and facial hair, anosmia, lack of development at puberty with incomplete development or significant delay, underdeveloped testes and, in some cases, short stature. HH it may be suspected from birth by the presence of a micropenis in males, usually associated with cryptorchidism, a delay or absence of puberty in adolescence or infertility in adulthood. HH is also a feature of various syndromes such as Prader-Willi syndrome, Bradet-Biedl syndrome Laurence-Moon syndrome, Kallmann syndrome CHARGE.

Mutations that alter or inactivate GnRH receptor were first detected as genetic alterations cause HH. In recent years, moreover, have identified certain neuropeptides and their receptors involved in controlling various stages of action of GnRH, whose alterations, they are also associated with the development of HH. Thus, mutations in GnRHR, GNRH1, KISS1R, TAC3 and TACR3 HH genes are cause to interfere with synthesis, secretion or action of GnRH, respectively.

Alterations in the GnRHR gene are responsible for most cases of hypogonadotropic hypogonadism (HH). The GnRHR gene, located on the long arm of chromosome 4 (4q21.2), encoding the receptor type 1 of gonadotropin releasing hormone (GnRH) receptor activation through G - proteins, causes the release of the gonadotropin luteinizing hormone (LH) and follicle stimulating hormone (FSH). They have identified at least 20 GnRHR gene mutations in patients with HH. They generate synthesis defects in the transport of the cell membrane and / or internalization, recycling or degradation receptors deteriorate ligand binding and / or signal transduction induced by the ligand, leading various types of deficiencies of LH and FSH responsible for hypogonadotropic hypogonadism.

The GNRH1 gene located on the short arm of chromosome 8 (8p21-p11.2) encoding GnRH and has always been a candidate to explain certain cases of HH, given the fundamental role GnRH in reproduction, even knowing that mutations in genes encoding the receptors are usually more frequent than in the genes encoding ligands. However, until 2009 there was not detected any responsible mutation in patients with HH. During this year was detected in the amino terminal region (c.18-19insA), and another (c.87delA) in the C-terminal region that generates a premature stop codon. But in any case, despite suspicions that there may be more alterations in the gene sequence GNRH1 may lead to HH, so far mutations in this gene are a very rare cause of HH.

The KISS1R gene, also called GPR54, is located on the short arm of chromosome 19 (19p13.3). This gene encodes the receptor kisspeptinas and has high homology with the galanin receptor family. Binding of kisspeptinas to its receptor triggers activation of phospholipase C, which leads to greater production of IP3 and facilitates intracellular calcium mobilization. In the central nervous system (CNS), the highest expression of kisspeptinas occurs in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV), which send signals to the medial preoptic area, where abundant GnRH and therefore KISS1R, since the latter is expressed on the surface of GnRH neurons. In fact, kisspeptinas are considered the most potent stimulator of the secretion of GnRH dependent LH. Mutations have been detected in the KISS1R gene that cause loss of function, leading to an uncommon form of HH because they account for 5% of the total cases, although this figure rises to 20.8% of familial cases, while sporadic represents a scant 1.6%.

On the other hand, neurokinin B ARC is expressed in the CNS and plays a key role in the reproductive axis. It exercises his suspected role in reproduction by releasing GnRH in the hypothalamus, although the exact mechanism is unknown. Have been identified in certain patients with HH with severe deficiencies of various gonadotropins homozygous mutations of loss of function in the TAC3 gene, located on the long arm of chromosome 12 (12q13.3) encoding neurokinin B, and the TACR3 gene, encoding its receptor located on the long arm of chromosome 4 (4q25) ,. All cases of males with mutations in these genes had a symptom implicit presence Micropenis, suggesting that these genetic abnormalities involve an alteration of normal intrauterine and perinatal activation.

In addition to mutations in these genes have been described cases of hypogonadotropic hypogonadism associated with alterations in LEPR (1p31), LEP (7q31.3), LHB (19q13.32), FEZ1 (7q31.32), SPRY4 genes (5q31 .3), FGF17 (8p21) and FSHB (11p13).

Most cases of hypogonadotropic hypogonadism (HH) are sporadic and occur in people with no history of disease in your family. However, in approximately 30% of cases are inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with hypogonadotropic hypogonadism (HH) by PCR amplification of complete exons of GnRHR, GNRH1, KISS1R, TAC3 and TACR3 genes, respectively, and subsequent sequencing. We recommend starting the study by the GnRHR gene where most changes are localized, with possible reduction of time and cost involved in most cases. If not found the mutation in this gene, it offers the possibility of completing the study by those genes with greater frequency of mutations.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).