FSHB – hypogonadotropic hypogonadism 24 without anosmia

Follicle-stimulating hormone β-subunit (FSHB) deficiency is an autosomal recessive disorder characterized by selective failure of FSH production, leading to hypogonadotropic hypogonadism 24 without anosmia (FSHB; hypogonadotropic hypogonadism 24 without anosmia). Affected females present with absent breast development and primary amenorrhea (HP:0000786), while males exhibit azoospermia with normal testosterone levels, often manifesting as infertility (HP:0000789).

Genetic evidence supports autosomal recessive inheritance with biallelic loss-of-function variants. Three unrelated probands have been reported: two Kashmiri sisters born to consanguineous parents homozygous for c.343C>T (p.Arg115Ter) (PMID:30602350), one unrelated 29-year-old female with primary amenorrhea harboring a homozygous Arg97Ter variant (PMID:32367462), and a Chinese male with azoospermia carrying the same c.343C>T (p.Arg115Ter) mutation (PMID:28392474). Parental heterozygosity confirmed segregation; two affected siblings demonstrate clear cosegregation in a consanguineous pedigree.

Functional assays corroborate the pathogenicity of these nonsense variants. RT-PCR and Western blot analyses showed that Arg97Ter does not impact mRNA or protein levels but abolishes generation of bioactive FSH in immunometric and bioassay systems (PMID:32367462). Structural modeling revealed disrupted α/β-subunit interface by locking mutant β-subunit binding. Similarly, truncation at Arg115Ter eliminates the C-terminal tail essential for receptor interaction and FSH bioactivity (PMID:30602350).

No studies have refuted this association, and experimental data from multiple in vitro assays and segregating pedigrees are concordant.

Overall, the cumulative evidence supports a Moderate clinical validity classification: several AR probands with clear segregation and concordant functional data. Genetic evidence is Limited (three probands, biallelic LoF variants); functional evidence is Moderate (in vitro and structural assays demonstrating loss of FSH activity).

Clinically, FSHB mutation screening should be considered in patients with delayed puberty, primary amenorrhea, or unexplained infertility with low FSH and normal LH/testosterone, enabling targeted diagnosis and management.

References

• Gynecological endocrinology • 2019 • FSH β-subunit mutations in two sisters: the first report from the Indian sub-continent and review of previous cases PMID:30602350
• Journal of assisted reproduction and genetics • 2020 • Clinical and genetic analysis of an isolated follicle-stimulating hormone deficiency female patient. PMID:32367462
• European journal of medical genetics • 2017 • Novel FSHβ mutation in a male patient with isolated FSH deficiency and infertility PMID:28392474

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