Genetic causes of neonatal and infantile hypercalcaemia

Abstract

The causes of hypercalcaemia in the neonate and infant are varied, and often distinct from those in older children and adults. Hypercalcaemia presents clinically with a range of symptoms including failure to thrive, poor feeding, constipation, polyuria, irritability, lethargy, seizures and hypotonia. When hypercalcaemia is suspected, an accurate diagnosis will require an evaluation of potential causes (e.g. family history) and assessment for physical features (such as dysmorphology, or subcutaneous fat deposits), as well as biochemical measurements, including total and ionised serum calcium, serum phosphate, creatinine and albumin, intact parathyroid hormone (PTH), vitamin D metabolites and urinary calcium, phosphate and creatinine. The causes of neonatal hypercalcaemia can be classified into high or low PTH disorders. Disorders associated with high serum PTH include neonatal severe hyperparathyroidism, familial hypocalciuric hypercalcaemia and Jansen's metaphyseal chondrodysplasia. Conditions associated with low serum PTH include idiopathic infantile hypercalcaemia, Williams-Beuren syndrome and inborn errors of metabolism, including hypophosphatasia. Maternal hypocalcaemia and dietary factors and several rare endocrine disorders can also influence neonatal serum calcium levels. This review will focus on the common causes of hypercalcaemia in neonates and young infants, considering maternal, dietary, and genetic causes of calcium dysregulation. The clinical presentation and treatment of patients with these disorders will be discussed.

Keywords: Calcium homeostasis; Genetic disease; Parathyroid hormone; Phosphate; Vitamin D.

Fig. 1

Calcium regulation at the parathyroid-bone-kidney-gut axis. Serum calcium concentrations are detected by the calcium-sensing receptor (CaSR) on parathyroid cell surfaces. CaSR signalling inhibits PTH secretion. In the presence of low serum calcium or magnesium, this inhibition is relieved, allowing PTH secretion to occur. PTH acts at bone to increase resorption and calcium release, and kidney reducing calcium excretion. At kidney proximal tubules, PTH1R activates signalling pathways that stimulate NaPi-IIa internalisation which reduces phosphate uptake and alters CYP27B1 and CYP24A1 expression, resulting in 1,25(OH)₂D₃ synthesis. Vitamin D activation involves hydroxylation in the liver by 25-hydroxylase (CYP2R1) to form 25-hydroxyvitamin D3, and at the kidney, by 1α-hydroxylase (CYP27B1), to generate the active 1,25(OH)₂D₃, which can bind to the vitamin D receptor. Inactivation requires 24-hydroxylase (CYP24A1). In the FGF23-klotho axis (shown in green), FGF23 is secreted by osteocytes and binds to the FGF receptor (FGFR)-klotho complex at kidney proximal tubules, where it reduces PTH transcription and plasma membrane expression of NaPi-IIa and NaPi-IIc, resulting in increased phosphate excretion. FGF23 also reduces synthesis of 1,25(OH)₂D by inhibiting CYP27B1 and stimulating CYP24A1.