TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans.

in Journal of Clinical Endocrinology and Metabolism (2010), 95(5), 2287-95

CONTEXT: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic ... [more ▼]

CONTEXT: Missense loss-of-function mutations in TAC3 and TACR3, the genes encoding neurokinin B and its receptor NK3R, respectively, were recently discovered in kindreds with nonsyndromic normosmic congenital hypogonadotropic hypogonadism (CHH), thus identifying a fundamental role of this pathway in the human gonadotrope axis. OBJECTIVE: The objective of the study was to investigate the consequences on gonadotrope axis of TAC3 deletion and TACR3 truncation in adult patients with normosmic complete CHH. RESULTS: We identified three unrelated patients with the same homozygous substitution in the TAC3 intron 3 acceptor splicing site (c.209-1G>C) and three siblings who bore a homozygous mutation in the TACR3 intron 2 acceptor splicing site (c.738-1G>A). We demonstrated that these two mutations, respectively, deleted neurokinin B and truncated its receptor NK3R. We found in three patients with TAC3 mutation originating from Congo and Haiti a founding event in a more distant ancestor by means of haplotype analysis. We calculated that time to this common ancestor was approximately 21 generations. In several patients we observed a dissociation between the very low LH and normal or nearly normal FSH levels, this gonadotropin responding excessively to the GnRH challenge test. This particular hormonal profile, suggests the possibility of a specific neuroendocrine impairment in patients with alteration of neurokinin B signaling. Finally, in these patients, pulsatile GnRH administration normalized circulating sex steroids, LH release, and restored fertility in one subject. CONCLUSION: Our data demonstrate the hypothalamic origin of the gonadotropin deficiency in these genetic forms of normosmic CHH. Neurokinin B and NK3R therefore both play a crucial role in hypothalamic GnRH release in humans. [less ▲]

Pseudo-Bartter syndrome in a pregnant mother and her fetus

in Pediatric Nephrology (2006), 21(7), 1037-1040

Pseudo-Bartter syndrome presents the same clinical and biological characteristics as Bartter syndrome but without primary renal tubule abnormalities. We relate the case of a premature baby presenting at ... [more ▼]

Pseudo-Bartter syndrome presents the same clinical and biological characteristics as Bartter syndrome but without primary renal tubule abnormalities. We relate the case of a premature baby presenting at birth with severe hypokalemic metabolic alkalosis associated with hyponatremia and hypochloremia. Maternal blood at the time of delivery showed the same electrolyte perturbations. The baby's mother had suffered from anorexia and vomiting during pregnancy. A few weeks after birth the baby's blood abnormalities had almost returned to normal. Chloride depletion is at the origin of both maternal and fetal hypokalemic alkalosis. [less ▲]