A novel PTH1R missense variant in a patient with early-onset primary hyperparathyroidism

We report a 30-year-old male with early-onset primary hyperparathyroidism (PHPT) and incidental papillary thyroid carcinoma. Biochemical tests showed hypercalcemia, hypophosphatemia, elevated PTH and normal renal function. Planar ⁹⁹ᵐTc-MIBI scintigraphy projected a parathyroid lesion to the left thyroid inferior pole, while surgery revealed an ectopic solitary parathyroid adenoma in the left upper mediastinum; serum calcium, phosphate and PTH normalized two months postoperatively. Whole-exome sequencing detected a novel heterozygous PTH1R variant c.982G > A (p.Gly328Ser), classified as a variant of uncertain significance by ACMG/AMP criteria. The identical variant was identified in the proband's father, whose annual routine calcium and phosphorus tests remained persistently normal, so he declined additional parathyroid-related biochemical testing. Unlike previously reported PTH1R mutations linked to skeletal/dental defects, this patient presented isolated PHPT without skeletal or dental abnormalities. Neither classic loss-of-function nor canonical gain-of-function mechanisms fully explain this unique phenotype, and no in vitro functional data are available to validate variant pathogenicity. This case expands the phenotypic spectrum of PTH1R-related disorders and offers a new genetic clue for early-onset PHPT. Further functional experiments and long-term family follow-up are needed to verify the clinical relevance of this variant.