Persistent hypercalcaemia is usually attributed to some combination of the following mechanisms: (1) excessive intestinal absorption of calcium; (2) excessive bone resorption of mineral; and (3) abnormal renal retention of calcium. Infants are usually asymptomatic with mild to moderate hypercalcaemia (11.0– 13.0 mg/ dl).
More severe hypercalcaemia may lead to failure to thrive, poor feeding, abdominal pain, constipation, hypotonia, vomiting, seizures, lethargy, polyuria, and hypertension. Hypercalcaemia is dis cussed in detail in Chapter 4.2. Congenital causes of hypercalcaemia are more frequent in children than acquired causes such as malignancy, which are more common in adults. Several syndromes with specific childhood features are described next.
Severe neonatal hyperparathyroidism is a rare condition pre senting with hypercalcaemic symptoms in the first few days of life. Serum calcium levels may range as high as 15– 30 mg/ dl. The serum phosphate level is usually low, and serum PTH is elevated. The hypercalcaemia is predominantly due to increased bone re sorption, but elevated intestinal absorption of calcium, as well as in creased renal calcium retention probably occur. Radiographs of the clavicles typically reveal features of primary hyperparathyroidism. Nephrocalcinosis may be present on ultrasonographic examination. Severe neonatal hyperparathyroidism may occur in families with FHH. FHH is manifest by modest asymptomatic hypercalcaemia with relative hypocalciuria and normal or slightly increased serum PTH levels. FHH is an autosomal dominant, genetically heterogeneous disorder with three clinically indistinguishable variants acting in a negative manner on parathyroid cells (FHH1- FHH3) . FHH1 (OMIM #145980) is a loss- of- function mutation in the CASR gene (encoding the CaSR, a G- protein- coupled receptor) on parathyroid cells. FHH2 is due to loss- of- function mutations of GNA11 which encodes G protein family member Gα11 and FHH3 (OMIM #600740) is due to loss of function of the adaptor- related protein complex 2, sigma 1 subunit (AP2σ1). This gene product protein forms a heterotetramer with other subunits and mediates the endocytosis of the CaSR.
Severe neonatal hyperparathyroidism has been shown to result in homozygous or compound heterozygous of loss- of- function mutations in CASR. This disorder usually requires emergency parathyroidectomy. Intravenous bisphosphonates (such as pamidronate) has been used for treatment while waiting for surgery. Another approach has employed cinacalcet, a calcimimetic, or positive allosteric modulator of CaSR, that partially restores the sensitivity of a mutant CaSR to calcium. However, this approach is not effective in the setting where homozygous null mutations of CaSR are present. Severe hypercalcaemia that requires surgery has also been described in infants in FHH families that have only one mutant copy of the CaSR gene.
In severe Williams syndrome (OMIM #194050) symptoms may be present from the neonatal period, but more frequently recognized later in the first few years of life. Infantile hypercalcaemia may be a presenting feature, in addition to pre- and postnatal growth failure. Characteristic unusual facies are often present, as well as cardiovascular abnormalities (usually supravalvular aortic stenosis or peripheral pulmonic stenosis), delayed psychomotor development, and selective mental deficiency. The genetic marker of the syndrome is a deletion at chromosome 7q11.23 involving elastin and LIM- Kinase genes. The serum calcium levels may range as high as 12– 19 mg/ dl. The hypercalcaemia usually subsides spontaneously by the age of 4 years. The pathogenesis of hypercalcaemia is uncertain, although various metabolic disturbances have been described including abnormal 1,25(OH)2D production, and decreased calcitonin production. Treatment has traditionally consisted of placing the child on a low calcium diet, free of vitamin D. Short- term therapy with corticosteroids has been applied, however a more recent approach employs intravenous bisphosphonate therapy, which has been quite effective in controlling hypercalcaemia in Williams syndrome patients in our hands. We usually use pamidronate at a dose of 0.25– 0.5 mg/ kg/ dose, and have found that one to three doses have been sufficient to manage this problem permanently.
Jansen’s metaphyseal chondrodysplasia (OMIM #156400) is an autosomal dominant disease with short limbs, severe hypercalcaemia, and hypercalciuria (despite normal or undetectable PTH and PTHrP levels) due to heterozygous mutations of the PTH/ PTHrP receptor, causing ligand- independent activation of the receptor.
Hypophosphatemia increases circulating levels of 1,25(OH)2D due to the decreased levels of the phosphate- regulating hormone, fibroblast growth factor 23 (FGF23). FGF23 regulates the genes that encode the vitamin D 1α- and 24- hydroxlyases (CYP27B1 and CYP24A1, respectively) in reciprocal fashion, such that in the setting of low FGF23, 1α- hydroxylase activity increases and 24- hydroxylase decreases. This results in higher circulating levels of 1,25(OH)2D. This phenomenon is evident with loss- of- function mutations in SLC34A1 (OMIM #616963), which encodes a major renal proximal tubal phosphate transporter (NaPi- IIa), as recently identified in some forms of idiopathic infantile hypercalcaemia (IIH).
Idiopathic infantile hypercalcaemia (IIH) may also result from loss- of- function mutations in the CYP24A1 (OMIM #616963) resulting in reduced catabolism of both 25- OHD and 1,25(OH)2D. Most forms of this disorder result from biallelic mutations although milder phenotypes have been attributed to heterozygous mutations. The degree of hypercalcaemia can be quite variable among children with a classic phenotype.
Subcutaneous fat necrosis is a self- limited disorder which presents in infancy with symptoms of hypercalcaemia and erythematous or violaceous discoloration of the skin and firm indurated tissue palpable underneath. There is often a history of birth trauma or asphyxia. It is thought that the insult to the fat tissue causes cellular necrosis and infiltration of mononuclear cells and macro phages which may become granulomatous in nature. Small calcified areas may be present. Increased production of 1,25(OH)2D by the inflammatory cells has been considered in some cases as the cause of hypercalcaemia. Thus, a vitamin D- free, low calcium diet and glucocorticoids have traditionally been used to treat this dis order. However, like with Williams syndrome, dietary restriction of calcium intake alone may not be sufficient to correct the serum calcium level, indicating that a component of bone resorption must play a role in the development of hypercalcaemia. Therefore, we have used bisphosphonates (e.g. pamidronate) to successfully control persistent hypercalcaemia in this condition. Often a single dose is sufficient.
Intoxication with vitamin D or vitamin A should be excluded in the older infant with hypercalcaemia [128– 131]. In vitamin D intoxication, it is important to measure the circulating level of 25- OHD, the most abundant circulating vitamin D metabolite. Levels of 1,25(OH)2D are usually low. Toxicity may be mediated by the overwhelming large dosages of 25- OHD interacting with the VDR. Alternatively because 25- OHD has a far greater affinity than 1,25(OH)2D for the circulating vitamin D binding protein (DBP), it has been proposed that the latter, more active metabolite is dis placed from DBP, with toxicity resulting from the increase in free levels of 1,25(OH)2D. Excess intestinal absorption of calcium is pre sent, and there may also be evidence for increased bone resorption. Elevated circulating 1,25(OH)2D levels can cause hypercalcaemia but are not usually elevated in typical cases of vitamin D intoxication. Malignant and granulomatous diseases may cause extrarenal synthesis of 1,25(OH)2D and resultant hypercalcaemia may ensue. Likewise, endogenous overproduction of 1,25(OH)2D has been described in twins with cat- scratch disease induced granulomata. Vitamin A intoxication results in bone pain, hypercalcaemia, headache, pseudotumor cerebri, and a characteristic erythematous skin rash with exfoliation. Alopecia and profuse ear discharge may be present. The hypercalcaemia is thought to be mediated by osteo clastic bone resorption. Although toxicity is not thought to occur when less than 50 000 units of vitamin A or equivalent is ingested on a daily basis, reports of toxicity with less ingestion have been recorded in children. Unrecognized liver disease may decrease the tolerance of vitamin A. In order to establish the diagnosis of vitamin A intoxication, serum retinyl ester levels should be determined in addition to the more common test for serum retinol.
Other conditions in which hypercalcaemia may be manifest in children include Down’s syndrome, renal tubular acidosis, and osteogenesis imperfecta. Indeed, we have observed mild elevations in serum calcium during infancy in association with a variety of skeletal dysplasias. This appears to be a transient phenomenon. Endocrinopathies including pheochromocytoma, Addison’s disease, thyrotoxicosis, and severe con genital hypothyroidism may be associated with development of hypercalcaemia.
Other major causes of hypercalcaemia include those commonly encountered in adults: immobilization, malignancy, and acquired hyperparathyroidism including parathyroid adenomas.
Treatment of Hypercalcaemia
Acute: The medical management of acute symptomatic hypercalcaemia consists of the administration of intravenous saline. Intravenous infusion of bisphosphonates has also been useful in this setting. Specific long- term therapy depends on the specific hypercalcaemic disorder.
The use of bisphosphonate therapy in children has increased in recent years, both when associated with childhood cancers, and in the treatment of hypercalcaemia in Williams syndrome and subcutaneous fat necrosis, as noted earlier. Side effects are minimal and that the therapy appears to be safe. One should be aware of the potential complications of electrolyte disturbances, particularly hypocalcaemia, hypophosphataemia, and hypomagnesaemia.
One interesting approach in patients with IIH due to biallelic mutations of CYP24A1 employs daily rifampin administration. The approach relies on the capacity of rifampin to induce overexpression of CYP3A4, which encodes an enzyme serving as an alternate mechanism for vitamin D inactivation in patients who lack CYP24A1 function.
