Luteinizing Hormone Beta Mutation and Hypogonadism in Men and Women

Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism.We describe the clinical features of a consanguineous family in which three siblings, two men and one woman, had hypogonadism related to isolated luteinizing hormone deficiency.These subjects have a newly discovered homozygous mutation of a 5′ splice site in LHB: IVS2+1G→C.This mutation disrupts the splicing of messenger RNA (mRNA), generating a gross abnormality in the processing of the luteinizing hormone beta-subunit mRNA, which abrogates the secretion of luteinizing hormone.We also determined that the female phenotype of this LHB mutation is characterized by normal pubertal development, secondary amenorrhea, and infertility.L uteinizing hormone plays an essential role in normal pubertal development and reproductive function in humans.It consists of two glycosylated, noncovalently linked subunits: a hormone-specific beta subunit and an alpha subunit common to all members of the glycoprotein hormone family.Selective luteinizing hormone deficiency is predicted to compromise reproductive capacity markedly in both sexes.1,2 Inactivating mutations of the human luteinizing hormone beta-subunit gene (LHB) were previously described in three men with hypogonadism who had normal genitalia at birth but had no pubertal development and had infertility due to selective luteinizing hormone deficiency.[3][4][5] To our knowledge, no female phenotype of such inactivating mutations in the LHB gene has been described.We describe the clinical and hormonal characteristics of three siblings, two men and a woman, all of whom had hypogonadism associated with a newly discovered mutation of the LHB gene. c a se r ep or t SThe proband (Subject II-5) (Fig. 1), a 38-year-old Brazilian man born to consanguineous parents, was referred to the Endocrinology Unit of the University Hospital of Brasília for hypogonadism.He presented with a eunuchoid habitus, a juvenile voice, and bilateral gynecomastia, with scant axillary hair and no facial hair (Tanner stage, genitalia 1 and pubic hair 4).He was 181 cm tall, weighed 87 kg, and had an arm span of 193 cm.He had a micropenis (4.5 cm in length; mean [±SD] normal length, 13.3±3.8)and underdeveloped, though descended, testes.