Abstract
BACKGROUND: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are key differential diagnoses in parathyroid hormone (PTH)-mediated hypercalcemia. While PHPT often arises from single-gland parathyroid adenomas, CaSR mutations are typically associated with FHH. However, the coexistence of CaSR mutations and PHPT represents an unusual presentation, and the variability in their clinical impact remains underexplored. This report highlights two distinct cases of heterozygous CaSR mutations, including a novel mutation, shedding light on their potential roles in disease pathogenesis and management. CASE PRESENTATION: The first case involves a 54-year-old Caucasian female with a heterozygous Ala986Ser CaSR mutation, PHPT due to a parathyroid adenoma, and autoimmune Graves' disease. She presented with recurrent sicca syndrome, fatigue, hypercalcemia, elevated PTH, and hypercalciuria. Post-parathyroidectomy, persistent hypercalcemia and abnormal laboratory findings, alongside TRAK and TG antibodies, suggested a multifactorial pathogenesis. Imaging showed patchy hypoechoic thyroid parenchyma and recurrent adenoma. DXA revealed mild osteopenia, while calcimimetic therapy with cinacalcet was initiated but subsequently discontinued due to gastrointestinal intolerance. This unusual overlap of autoimmune and genetic factors emphasizes the complexity of managing PHPT with coexisting CaSR mutations. The second case describes a 52-year-old Caucasian male with a heterozygous Glu1011Gln CaSR mutation. He presented with severe hypercalcemia, elevated PTH, nausea, and diffuse musculoskeletal pain. Imaging revealed no adenomas, but sonography later identified a hypoechoic lesion with central vascularization, suggestive of a potential adenoma. Initial symptomatic improvement occurred despite persistently elevated biochemical markers; however, clinical worsening with recurrent abdominal symptoms and progressive bone mineral density loss was observed during follow-up. This case highlights a possible association between CaSR variants and sporadic adenomas, underscoring diagnostic complexity rather than direct causality. CONCLUSIONS: These cases highlight the complex clinical presentations in patients carrying CaSR variants and autoimmune components, suggesting a broader spectrum of clinical phenotypes and pathogenesis than previously understood. The findings emphasize the importance of genetic analysis in atypical cases and underscore the need for further research into the role of CaSR mutations in PHPT, which may inform future diagnostic and therapeutic strategies.