Hypercalcemic Disorders in Children

Abstract

Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.

Keywords: GENETICS; NEONATES; PARATHYROID HORMONE; SYNDROMES; VITAMIN D.

Figure 1

Hormonal regulation of extracellular calcium homeostasis. PTH is the principal calciotropic hormone, and acts to elevate calcium levels by promoting osteoclastic activity on bone, increasing reabsorption of calcium from renal distal tubules and collecting ducts, and stimulating renal enzyme 1α‐hydroxylase conversion of 25(OH)D₃ into the active 1,25(OH)₂D₃. 25(OH)D₃ is produced from vitamin D₃, formed by the action of solar UVB on the skin or taken in through the diet, by the liver enzyme 25‐hydroxylase. 1,25(OH)₂D₃ is released into the circulation and stimulates calcium uptake from the gut. Rising serum calcium levels are detected by the CaSR, which facilitates a negative feedback on the parathyroid glands and PTH secretion attenuates to maintain homeostasis. 1,25(OH)₂D₃ is also regulated by FGF23, the main function of which is to regulate plasma phosphate concentrations. It is secreted by osteocytes in response to an elevated 1,25(OH)₂D₃ concentration and acts on the kidney proximal tubules to inhibit reabsorption and increase excretion of phosphate. It also inhibits 1α‐hydroxylase, thereby exerting a negative feedback on 1,25(OH)₂D₃ and promotes the action of 1,25(OH)₂D₃ 24‐hydroxylase, leading to lower levels of 1,25(OH)₂D₃ and reduced calcium absorption from the gut. 25(OH)D₃ = 25‐hydroxyvitamin D₃; 1,25(OH)₂D₃ = 1,25‐dihydroxyvitamin D₃; CaSR = calcium‐sensing receptor; FGF23 = fibroblast growth factor‐23; PTH = parathyroid hormone.

Figure 2

Clinical approach to investigation of causes of hypercalcemia in a child. ^aConfirm hypercalcemia, defined as plasma (or serum) adjusted calcium > 10.5  mg/dL (2.60 mmol/L) or ionized calcium > 5.25 mg/dL (1.32 mmol/L) (see Table 2). ^bPTH–parathyroid hormone. ^c25(OH)D–25‐hydroxyvitamin D. ^dFHH1‐3– Familial Hypocalciuric Hypercalcemia types 1‐3; MEN1–Multiple Endocrine Neoplasia type 1; MEN2–Multiple Endocrine Neoplasia type 2; MEN3–Multiple Endocrine Neoplasia type 3; MEN4–Multiple Endocrine Neoplasia type 4; NSHPT–Neonatal Severe Primary Hyperparathyroidism; HPT‐JT–Hyperparathyroid‐Jaw Tumour syndrome. ^eFamilial Isolated Hyperparathyroidism. ^fConditions affecting neonates (shown in italics). ^g1,25(OH)₂D–1,25‐dihydroxyvitamin D. ^hInborn errors of metabolism, e.g. Hypophosphatasia, Congenital Lactase Deficiency (CLD) and blue diaper syndrome. ⁱThese syndromes may be associated with dysmorphic features, e.g. Williams syndrome, Jansen's metaphyseal chondrodysplasia, Hypophosphatasia.