Hypogonadism in a patient with two novel mutations of the luteinizing hormone β-subunit gene expressed in a compound heterozygous form

CONTEXT: LH gene mutations are rare; only four mutations have been described. The affected individuals are hypogonadal. PATIENT: We describe the clinical features of a 31-yr-old man who presented with delayed puberty and azoospermia and was found to have hypogonadism associated with an absence of circulating LH. MAIN OUTCOME MEASURES AND RESULTS: The patient had a 12-bp deletion in exon 2 in the LH β-subunit gene and a mutation of the 5' splice site IVS2+1G→T in the same gene present in a compound heterozygous state. The first mutation predicts a deletion of four leucines of the hydrophobic core of the signal peptide. The second mutation disrupts the splicing of mRNA, generating a gross abnormality in the processing. The patient's heterozygous parents were clinically normal. The phenotype of a 16-yr-old sister of the proband, carrying the same mutations, was characterized by normal pubertal development and oligomenorrhea. CONCLUSION: This report unravels two novel mutations of the LH gene critical for synthesis and activity of the LH molecule. The insight gained from the study is that normal pubertal maturation in women can occur in a state of LH deficiency, whereas LH is essential for maturation of Leydig cells and thus steroidogenesis, puberty, and spermatogenesis in man. These mutations should be considered in girls and boys with selective deficiency of LH.