TSHB – Isolated Thyroid-Stimulating Hormone Deficiency

TSHB encodes the β-subunit of thyroid-stimulating hormone and is implicated in isolated thyroid-stimulating hormone deficiency under an autosomal recessive inheritance model. A single 5-month-old proband presented with undetectable serum TSH, T3 and T4 and failed to respond to TRH, leading to diagnosis of central hypothyroidism. Sequencing revealed a homozygous single-base deletion, c.373del (p.Cys125fs), resulting in a truncated β-subunit and replacement of Cys105, critical for α-β dimerization; her parents and grandparents were heterozygous carriers, confirming segregation with disease (PMID:9589689).

Functional studies demonstrate that the C105Vfs114X variant abolishes cAMP signaling through TSHR while leaving MAPK activation intact, consistent with loss-of-function and conformational disruption of the hormone (PMID:31703413). No conflicting reports have challenged this association. Collectively, genetic and experimental data support a Limited clinical validity due to a single family report and Moderate functional evidence demonstrating a clear pathogenic mechanism. Key take-home: TSHB biallelic LoF variants cause definitive isolated TSH deficiency, guiding genetic diagnosis and early hormone replacement.

References

• The Journal of clinical endocrinology and metabolism • 1998 • Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta-subunit gene follows an autosomal recessive inheritance. PMID:9589689
• International journal of molecular sciences • 2019 • The Pathogenic TSH β-subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR PMID:31703413

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