TSHB – Central Congenital Hypothyroidism

This summary reviews the strong association between TSHB (HGNC:12372) mutations and central congenital hypothyroidism (MONDO_0016410). Multiple independent case reports and patient series have identified homozygous or compound heterozygous mutations in TSHB leading to isolated central TSH deficiency, with patients presenting severe hypothyroidism that is not detected by routine TSH‐based screening (PMID:9589689). Genetic testing in these patients has repeatedly revealed similar frameshift mutations that disrupt the production of a fully functional TSH beta peptide.

The genetic evidence is robust: the disorder follows an autosomal recessive inheritance pattern with clear segregation among affected siblings and identification of pathogenic alleles in unrelated families (PMID:15198300). In one representative report, a homozygous single base pair deletion, noted as c.373del (p.Cys125fs), was found in a proband with central congenital hypothyroidism PMID:9589689. Other families have shown similar disruptions in TSHB sequence, further strengthening the genetic link.

Additional supportive genetic evidence comes from multiple studies that have demonstrated segregation of the TSHB mutation with the clinical phenotype in affected families. Not only do these case reports document the presence of the mutation in affected siblings, but they also reveal that heterozygous family members are asymptomatic, reinforcing the autosomal recessive mode of inheritance. Quantitatively, several affected relatives across different reports have confirmed the co‐segregation of the deleterious variant among individuals with the disorder.

On the molecular level, the c.373del (p.Cys125fs) mutation leads to a frameshift that produces a truncated protein lacking crucial C‑terminal residues. Functional assays consistently show that such mutants have markedly reduced bioactivity, with impaired cAMP signaling and altered protein conformation. These experimental findings corroborate the pathogenic mechanism predicted from the genetic data (PMID:27387040).

Integration of the genetic and functional evidence provides a coherent narrative: the recurrence of TSHB loss‑of‑function mutations such as c.373del (p.Cys125fs), along with segregation analysis demonstrating an autosomal recessive inheritance pattern, confirms the gene‑disease association as strong. The diverse methodologies employed—from direct sequencing and family studies to in vitro functional assays—underline the clinical relevance of genetic testing in patients suspected of having central congenital hypothyroidism.

Key take‑home: Recognizing TSHB mutations is critical for early diagnosis and the timely initiation of thyroxine replacement therapy, ensuring better clinical outcomes in central congenital hypothyroidism.

References

• The Journal of Clinical Endocrinology and Metabolism • 1998 • Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin beta‑subunit gene PMID:9589689
• Journal of Pediatric Endocrinology & Metabolism • 2004 • Hypothyroidism in siblings due to a homozygous mutation of the TSH‑beta subunit gene PMID:15198300
• Case Reports in Pediatrics • 2011 • Congenital Central Hypothyroidism due to a Homozygous Mutation in the TSHβ Subunit Gene PMID:22606512
• Journal of Clinical Research in Pediatric Endocrinology • 2017 • Congenital Central Hypothyroidism Caused by a Novel Thyroid‑Stimulating Hormone‑Beta Subunit Gene Mutation in Two Siblings PMID:28515030
• Clinical Endocrinology • 2017 • Molecular spectrum of TSHβ subunit gene defects in central hypothyroidism in the UK and Ireland PMID:27362444
• The Journal of Clinical Investigation • 1996 • A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene PMID:8636437
• Molecular Endocrinology (Baltimore, Md.) • 2016 • Minireview: Insights Into the Structural and Molecular Consequences of the TSH‑β Mutation C105Vfs114X PMID:27387040

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