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Children's Hospital (Boston, Massachusetts)

Severe Phenotype of De Novo TSHR Activating Pathogenic Variants

Strategic Insights

— 1 min read

In a new study from Boston Children's Hospital, investigators have shed light on the phenotypic spectrum of thyroid-stimulating hormone (TSH) receptor (TSHR) pathogenic variants leading to hyperthyroidism. According to the research, two unrelated individuals, each with a distinct monoallelic de novo TSHR pathogenic variant, developed severe congenital hyperthyroidism requiring multistep thyroidectomies. Both patients had thyroid hypertrophy and vulnerable anatomic positioning of recurrent laryngeal nerves (RLNs), complicating surgical management.

Key Takeaways:

  • The phenotypic spectrum of TSHR pathogenic variants is broad, causing familial nonautoimmune hyperthyroidism (FNAH) or sporadic nonautoimmune hyperthyroidism (SNAH).
  • Germline variants causing constitutive TSHR activation in the absence of TSH result in FNAH or SNAH.
  • Severe early-onset hyperthyroidism can impact multisystem development and has significant consequences.
  • Two unrelated individuals with de novo TSHR pathogenic variants developed severe congenital hyperthyroidism, requiring multistep thyroidectomies.
  • Both patients had thyroid hypertrophy and vulnerable anatomic positioning of recurrent laryngeal nerves (RLNs), complicating surgical management.
  • The research highlights the wide phenotypic spectrum of TSHR activating variants and the persistent clinical sequelae of SNAH.
  • The cases demonstrate the importance of considering the individual's specific genetic and clinical context when managing hyperthyroidism.

Statistics:

  • 2 unrelated individuals developed severe congenital hyperthyroidism due to de novo TSHR pathogenic variants.
  • 4-year-old boy with SNAH caused by a heterozygous TSHR variant c.1515C A; p.S505R.
  • 9-year-old girl with SNAH and craniosynostosis from a novel heterozygous TSHR variant c.1897G C; p.D633H identified in the neonatal period.
  • Severe hyperthyroidism and complex course seen in these individuals contrast with previously reported cases.

Sources:

  • Severe Phenotype of De Novo TSHR Activating Pathogenic Variants. Case Reports in Endocrinology, 2025;2025(1):2254609 (Hindawi Publishing - www.hindawi.com; Case Reports in Endocrinology - www.hindawi.com/crim/endocrinology/).
  • NewsRx. New Findings from Boston Children's Hospital in the Area of Hyperthyroidism Reported (Severe Phenotype of De Novo TSHR Activating Pathogenic Variants). Health & Medicine Week. October 24, 2025; p 2694.

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