AP2S1 and hypercalcemia disease: Before age 8, almost all cases of PTH-dependent hypercalcemia are caused by familial hypocalciuric hypercalcemia (mostly from mutation in CASR, AP2S1, or GNA11) or by neonatal severe primary hyperparathyroidism, both of which have near 100% penetrance for hypercalcemia already in the neonate (12, 18).