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Hypercalcemia is broadly categorized as either PTH-dependent or PTH-independent. Among PTH-dependent causes, primary hyperparathyroidism (PHPT) accounts for the majority of cases. However, hypocalciuric hypercalcemia (HH), characterized by suppressed urinary calcium excretion, also falls into this category and includes both congenital and acquired forms.
Familial hypocalciuric hypercalcemia (FHH), caused by heterozygous inactivating mutations in the calcium-sensing receptor (CaSR), is the prototypical congenital form. In contrast, acquired hypocalciuric hypercalcemia (AHH), typically attributed to blocking autoantibodies against CaSR, has long been recognized but remains underdiagnosed. We have identified a distinct subtype of AHH caused not by conventional blocking antibodies, but by biased CaSR autoantibodies that differentially modulate downstream signaling pathways. These biased autoantibodies impair CaSR-mediated Gi/o signaling while paradoxically preserving or enhancing Gq/11 signaling.