In two 46,XY sibs with Leydig cell hypoplasia (238320) born to consanguineous parents, Kremer et al. (1995) found homozygosity for a missense ala593-to-pro mutation in the sixth transmembrane domain of the LHCGR gene. In vitro expression studies showed that this mutated receptor binds human choriogonadotropin normally, but the ligand binding does not result in increased production of cAMP. They concluded that a homozygous LH receptor gene mutation underlies the syndrome of autosomal recessive congenital Leydig cell hypoplasia in this family. The 2 sibs had presented with female external genitalia, primary amenorrhea, and lack of breast development. Their parents, who were first cousins, had 14 additional offspring. Both patients had short blind-ending vagina, without uterus or fallopian tubes. Sperm levels of testosterone and testosterone precursors were abnormally low and did not respond to stimulation with human choriogonadotropin. Basal levels of luteinizing hormone were markedly increased. On histologic examination, the gonads were found to be testes with normal Sertoli cells but no mature Leydig cells.
Toledo et al. (1996) evaluated a 46,XX sister of the two 46,XY male pseudohermaphrodites with Leydig cell hypoplasia described by Kremer et al. (1995). The patient presented with amenorrhea due to hypergonadotropic hypogonadism (see 238320), but had structurally normal ovaries. Analysis of her LH receptor genes showed that she was homozygous for the same mutation that caused an ala593-to-pro substitution in her 2 brothers. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells showed that the receptor is unable to stimulate adenylyl cyclase in response to CG. These results document the existence of inherited LH resistance as a cause of primary amenorrhea in women.
