Disruptions in Ca<sup>2+</sup>-dependent pathways-whether genetic, metabolic, or acquired-underlie a spectrum of pediatric endocrine diseases often presenting with neurological manifestations This review summarizes calcium's roles in hormone secretion, parathyroid and vitamin D metabolism, and neuronal excitability, and discusses monogenic and metabolic disorders affecting calcium sensing and signaling, including <i>CASR</i>, <i>GNA11</i>, <i>AP2S1</i>, <i>STIM1</i>, and <i>ORAI1</i> mutations. This evidence concerns the gene AP2S1 and metabolic disease.