Severe Phenotype of De Novo TSHR Activating Pathogenic Variants

The phenotypic spectrum of thyroid-stimulating hormone (TSH) receptor (TSHR) pathogenic variants is broad. Germline variants causing constitutive TSHR activation in the absence of TSH result in familial nonautoimmune hyperthyroidism (FNAH) or sporadic nonautoimmune hyperthyroidism (SNAH). This hyperthyroid state, if present in utero or early childhood, can impact multisystem development. The consequences of severe early-onset hyperthyroidism have not been well described.

Here, we report two unrelated individuals, each with a distinct monoallelic de novo TSHR pathogenic variant leading to severe congenital hyperthyroidism that required multistep thyroidectomies. Both patients had thyroid hypertrophy and vulnerable anatomic positioning of recurrent laryngeal nerves (RLNs), complicating surgical management. Case 1 is a 4-year-old boy with craniosynostosis and mitral valve dysplasia with SNAH caused by a heterozygous TSHR variant c.1515C >A; p.S505R. Hyperthyroidism was detected with thyroid storm at 17 months of age. Case 2 is a 9-year-old girl with SNAH and craniosynostosis from a novel heterozygous TSHR variant c.1897G >C; p.D633H identified in the neonatal period.

The severe hyperthyroidism and complex course seen in these individuals contrast with previously reported cases. These cases highlight the wide phenotypic spectrum of TSHR activating variants and the persistent clinical sequelae of SNAH.