Naturally occurring mutations of the luteinizing hormone receptor gene affecting reproduction.

The luteinizing hormone receptor (LHR) plays a critical role in reproductive physiology in both males and females. Naturally occurring mutations in this receptor can cause genetically transmitted disorders by producing either gain or loss of receptor function. The clinical phenotype of the heterozygous activating mutations of the LHR gene has been exclusively described in males, who present familial or sporadic pseudoprecocious puberty. Affected boys were usually fertile at an adult age. In contrast, homozygous inactivating mutations of the LHR gene can cause a distinct spectrum of phenotypes. Severe inactivating mutations of the LHR have been recognized as the cause of Leydig cell hypoplasia, a rare form of male pseudohermaphroditism, in genetic males and as a novel cause of amenorrhea and infertility in genetic females. In addition, inactivating mutations that partially inactivate LH signaling can cause micropenis, sometimes accompanied by hypospadias and cryptorchidism. Both males and females with homozygous inactivating mutations of the LHR gene have suppression of fertility, which can represent the chief complaint of these patients.