Clinical and Genetic Profile of Chinese Familial Hypocalciuric Hypercalcemia Type 1 (FHH1): A Retrospective Study.

PURPOSE: To characterize the clinical and genetic features of Chinese FHH type 1 (FHH1) patients and evaluate biochemical discriminators between FHH1 and sporadic primary hyperparathyroidism (s-PHPT). METHODS: This retrospective study included 11 genetically confirmed FHH1 and 55 s-PHPT patients. Their clinical, biochemical, and imaging data were compared. Genetic testing was conducted via targeted next-generation or whole-exome sequencing. The key discriminators were assessed by receiver operating characteristic (ROC) analysis. RESULTS: Among the 11 FHH1 patients, 63.6% were females and 63.6% had a family history. Incidentally detected hypercalcemia was the most common cause (72.7%). Compared with s-PHPT, FHH1 were younger at diagnosis [38.1 ± 17.4 years vs. 53.6 ± 14.0, P = 0.002], had lower parathyroid hormone level [41.80 (28.89, 124.00) pg/mL vs. 233.90 (136.6, 521.6) pg/mL, P < 0.001], higher serum phosphate (1.06 ± 0.28 mmol/L vs. 0.77 ± 0.17 mmol/L, P = 0.008), and lower 24-hour urinary calcium excretion (24hUCa) (P < 0.001). Bone turnover markers (BTMs) were lower (P ≤ 0.001), low bone mass was less frequent (P = 0.005), and parathyroid imaging results were frequently negative in FHH1. Eight CASR variants were identified, including 4 novel variants (c.197G > C, c.488 C >T, c.1042del, c.2386 A >G). ROC analysis indicated that 24hUCa < 3.71 mmol/24 h optimally distinguished FHH1 from s-PHPT. CONCLUSION: The relatively large single-center Chinese FHH1 cohort presented younger with similar serum calcium, milder PTH elevation, relatively normal BTMs, and less target-organ involvement than s-PHPT. A new cut-off value of 24hUCa may serve as a practical pre-genetic screening tool.