TSHR – Nonautoimmune Familial Hyperthyroidism

Nonautoimmune familial hyperthyroidism (NAH) is an autosomal dominant disorder caused by activating germline mutations in the thyroid-stimulating hormone receptor (TSHR), leading to persistent thyrotoxicosis in the absence of autoimmune features. ClinGen clinical validity is classified as Strong based on evidence from over 32 unrelated probands ([PMID:15163335]; [PMID:20501679]; [PMID:38194289]), segregation in 19 affected relatives ([PMID:15163335]; [PMID:33401884]), and concordant functional data in cellular and animal models.

Genetic Evidence

TSHR-mediated NAH follows an autosomal dominant inheritance pattern with high penetrance. Segregation analysis across nine families demonstrates co-segregation of heterozygous activating variants in 19 affected relatives. Case reports describe 32 probands harboring distinct missense variants, including c.1535T>A (p.Leu512Gln) ([PMID:37908476]), c.1800T>G (p.Ala627Val) ([PMID:33401884]), c.1889A>G (p.Ser636Trp) ([PMID:20501679]), c.1677G>A (p.Met626Ile) ([PMID:21590647]), c.1684G>A (p.Cys672Trp) ([PMID:29225840]), and c.1513G>A (p.Ser505Asn) ([PMID:15163335]). These are all gain-of-function missense changes clustering in transmembrane and extracellular domains. A recent multi-patient study identified two additional variants (p.Ser237Asn, p.Ile640Val) in 16 NAH patients across three families ([PMID:38194289]).

Functional Evidence

In vitro assays of mutant receptors consistently show constitutive activation of G_s-mediated cAMP accumulation and, for some variants, altered G_q/11 signaling, correlating with the clinical phenotype of hyperthyroidism ([PMID:20501679]; [PMID:7805857]). A knock-in mouse model (TSHR M453T) reproduces the hyperthyroid features and demonstrates modulation by dietary iodine, supporting a haploinsufficiency mechanism and dosage sensitivity ([PMID:38194289]).

Conflicting Evidence

Re-evaluation of four previously reported TSHR variants (F631I, T620I, L677V, I691F) in functional assays showed lack of constitutive activity for three, suggesting that not all TSHR alterations confer a hyperthyroid phenotype and highlighting the need for rigorous in vitro characterization ([PMID:20846293]).

Integration and Clinical Utility

Genetic testing for TSHR variants is clinically informative for early diagnosis of NAH, enabling timely management to prevent complications such as low birth weight and premature delivery. Functional validation of novel variants is recommended to confirm pathogenicity. Personalized treatment strategies, including definitive thyroid ablation, should be guided by genotype and in vitro activity assays.

Key Take-home: Activating TSHR germline mutations cause definitive, autosomal dominant nonautoimmune familial hyperthyroidism, with clear genotype-phenotype correlation and therapeutic implications.

References

• Clinical Endocrinology • 2004 • Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. PMID:15163335
• The Journal of Clinical Endocrinology and Metabolism • 2010 • A new phenotype of nongoitrous and nonautoimmune hyperthyroidism caused by a heterozygous thyrotropin receptor mutation in transmembrane helix 6. PMID:20501679
• Hormone and Metabolic Research • 2011 • Prolonged inappropriate TSH suppression during hypothyroidism after thyroid ablation in a patient with nonautoimmune familial hyperthyroidism. PMID:21590647
• Clinical Case Reports • 2017 • Severe thyrotoxicosis in an infant revealing familial nonautoimmune hyperthyroidism with a novel (C672W) stimulating thyrotropin receptor germline mutation. PMID:29225840
• Annals of Pediatric Endocrinology & Metabolism • 2020 • An A627V-activating mutation in the thyroid-stimulating hormone receptor gene in familial nonautoimmune hyperthyroidism. PMID:33401884
• JCEM Case Reports • 2023 • Long-Term Disproportional TSH Hyposecretion in a Patient With Nonautoimmune Hyperthyroidism After Radioiodine Therapy. PMID:37908476
• JCI Insight • 2024 • Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T-knockin model. PMID:38194289
• Clinical Endocrinology • 2010 • Lack of in vitro constitutive activity for four previously reported TSH receptor mutations identified in patients with nonautoimmune hyperthyroidism and hot thyroid carcinomas. PMID:20846293

Evidence Based Scoring (AI generated)