LHB – Hypogonadotropic Hypogonadism 23 with or without Anosmia

LHB encodes the beta subunit of luteinizing hormone, essential for gonadal steroidogenesis. Biallelic inactivating variants in LHB have been reported in patients with isolated LH deficiency presenting as hypogonadotropic hypogonadism. The condition follows an autosomal recessive inheritance pattern and manifests with pubertal failure and infertility without anosmia, consistent with MONDO:0009223.

The first homozygous case involved an 18-year-old man with fertile eunuch syndrome carrying Trp8Arg and Ile15Thr substitutions, leading to normogonadotropic hypogonadism and preserved intratesticular testosterone (PMID:14709845). Pubertal induction with hCG restored virilization and spermatogenesis in this proband.

A consanguineous family with two affected brothers harboring a homozygous c.118_120del (p.Lys40del) LHB variant displayed severe LH deficiency, Tanner stage G1PH1, and undetectable serum LH. Cellular assays demonstrated intracellular hormone retention and diffuse cytoplasmic distribution of mutant LH, with successful pubertal development upon hCG therapy (PMID:27656125).

A female patient with congenital hypogonadotropic hypogonadism was compound heterozygous for c.252C>G (p.Phe84Leu) and c.364G>A (p.Gly122Ser) LHB variants. Mutagenesis, confocal microscopy, and secretion assays revealed normal dimerization but impaired LH release. Pulsatile GnRH administration effectively induced puberty and ovulation (PMID:39786527).

Functional studies in HeLa and HEK293 cells confirm that LHB loss-of-function leads to intracellular hormone sequestration and secretion failure. hCG rescue experiments validate the mechanism of isolated LH deficiency across these variants, supporting a loss-of-function pathogenic mechanism (PMID:27656125; PMID:39786527).

By contrast, the common LHB polymorphism Trp8Arg/Ile15Thr exhibits high population frequency, normal reproductive phenotypes, increased in vitro bioactivity, and accelerated clearance without clinical hypogonadism (PMID:7714098; PMID:11823449), indicating a benign variant spectrum.

References

• Endocrine journal • 2003 • Fertile eunuch syndrome with the mutations (Trp8Arg and Ile15Thr) in the beta subunit of luteinizing hormone. PMID:14709845
• The Journal of clinical endocrinology and metabolism • 1995 • Occurrence and biological properties of a common genetic variant of luteinizing hormone. PMID:7714098
• Human molecular genetics • 2002 • Synthesis, purification and structural and functional characterization of recombinant form of a common genetic variant of human luteinizing hormone. PMID:11823449
• The Journal of endocrinology • 2016 • A vital region for human glycoprotein hormone trafficking revealed by an LHB mutation. PMID:27656125
• Journal of assisted reproduction and genetics • 2025 • Mechanism of female CHH caused by compound heterozygous mutations in the LHB gene. PMID:39786527

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