Primary hyperparathyroidism

Primary hyperparathyroidism is rare in childhood with an incidence of 2–5 per 100 000 (compared with 1 in 1000 in adults) and accounts for 1% of cases of hypercalcaemia (box 2).1 2 It is characterised by autonomous PTH secretion independent of circulating calcium levels, due to a parathyroid adenoma, parathyroid hyperplasia or rarely carcinoma.

The likelihood of an underlying genetic abnormality is increased with childhood presentations (box 2), and there should be specific enquiry for features of associated syndromes and a family history of hypercalcaemia. The biochemical features of mild primary hyperparathyroidism may be indistinguishable from familial hypocalciuric hypercalcaemia (see below) and mutation analysis of the CaSR may be indicated to avoid unnecessary parathyroidectomy.

In a large case series of primary hyperparathyroidism presenting in childhood, 80% presented in adolescence and 20% in the neonatal period.3 Plasma calcium at presentation was 2.8–4.3.mmol/litre and hypercalciuria was present in 70% of cases. Although elevated PTH is the hallmark for the diagnosis of primary hyperparathyroidism, in rare instances this may not always be the case. A 14-year-old girl with a parathyroid adenoma had a low serum intact PTH, which was likely due to an aberrant PTH molecule produced by the adenoma and was not detected by the standard intact PTH assay.4

The non-specific symptoms in children with primary hyperparathyroidism typically lead to a delay in diagnosis of between 2 and 5 years. In children, end-organ damage is common at presentation5 and the incidence of nephrocalcinosis and nephrolithiasis in children with parathyroid adenomas is up to 70% with bone involvement in 80%. Skeletal findings include subperiosteal resorption, osteopenia, slipped capital femoral epiphysis, pathological fractures and brown tumours that resolve quickly following parathyroidectomy.6 Eye findings at diagnosis include band keratopathy (calcium deposits in the eye). When primary hyperparathyroidism is suspected, imaging of the parathyroid glands is indicated using ultrasound and SestaMibi isotope scan to increase the diagnostic yield.

Neonatal severe hyperparathyroidism

This disorder results from a homozygous inactivating CaSR mutation. The majority present in the first few weeks of life but presentation in later childhood has been reported.7 There is often severe hypercalcaemia (plasma calcium >3.5 mmol/litre), low plasma phosphate and very high PTH levels. Skeletal complications may be life threatening and include multiple fractures, metaphyseal irregularities, cortical dualisation, subperiosteal erosion and bell-shaped thoracic deformation.3 Neck ultrasonography will localise a parathyroid abnormality in only a third of cases.

Total parathyroidectomy is usually required for neonatal cases. Hyperhydration with diuretics and bisphosphonate administration may be required preoperatively and a calcium-poor diet may delay surgery. Following surgery severe hypocalcaemia from a ‘hungry bone’ syndrome may require large quantities of intravenous calcium.

Neonatal hyperparathyroidism

Neonatal hyperparathyroidism (NHPT) is distinct from neonatal severe hyperparathyroidism (NSHPT) and is caused by a de novo heterozygous inactivating mutation of the CaSR gene. In these cases hypercalcaemia may be less marked than NSHPT and symptomatically transient. As the severity of hypercalcaemia may gradually revert to symptomless familial hypocalciuric hypercalcaemia (FHH), in some cases negating the need for surgery, it illustrates the importance of early analysis of the CaSR gene in both NSHPT and NHPT.8 9 Cinacalcet (see later) may be a useful temporising measure in the early symptomatic phase, by its action of reducing PTH secretion.9

Neonatal hyperparathyroidism is also associated with mucolipidosis type II (I-cell disease) and may be severe and is usually transient. The radiological changes are similar to rickets. The pathogenesis is unexplained and unrelated to a CaSR abnormality.

Familial hypocalciuric hypercalcaemia or familial benign hypercalcaemia

This disorder results from a heterozygous inactivating mutation of the CaSR from three different genetic loci (types 1–3) (box 3). Mutations lead to an elevation of the normal set point for maintaining normal plasma calcium levels (figure 1). There is an inappropriate normal or marginally elevated PTH level despite hypercalcaemia, enhanced renal tubular absorption of calcium (hypocalciuria) and apparent tissue resistance to hypercalcaemia.10 Plasma magnesium levels may be high normal or slightly elevated. The disorder may occur spontaneously or be inherited in an autosomal dominant manner, although autosomal recessive transmission has been reported.11

In the classic description of FHH, individuals are asymptomatic and have mild to moderate hypercalcaemia with ionised calcium levels usually within 10% of the upper limit of normal. The urine calcium/creatinine ratio tends to be low in FHH whereas it is usually elevated in primary hyperparathyroidism. Analysis of the CaSR is helpful to distinguish FHH from mild primary hyperparathyroidism. No intervention is required and affected individuals have normal bone mineral density.12

Other phenotypic variations have been described with heterozygous inactivating CaSR mutations including neonatal hyperparathyroidism (with de novo heterozygous inactivating mutation of the CaSR gene,8 see above) and recurrent pancreatitis in later life.13 Autoimmune hypocalciuric hypercalcaemia from blocking auto-antibodies against the CaSR has been described in an adult.14

Childhood malignancy

In contrast to adults with malignant tumours, of whom up to 30% have hypercalcaemia, only 0.4–0.7% of childhood malignancies present with hypercalcaemia (box 3).15 16 Hypercalcaemia is most commonly observed at diagnosis rather than during treatment and, unlike in adults, does not herald a poor prognosis. The mechanism leading to hypercalcaemia varies with the tumour. Local osteolytic hypercalcaemia results from increased osteoclastic activity at the site of the tumour in the bone marrow, and has been observed with acute lymphoblastic leukaemia, acute myeloid leukaemia and lymphoma. Humoral hypercalcaemia of malignancy results from systemic secretion by the tumour of PTH-related peptide (PTHrP) (lymphoma, medulloblastoma, rhabdomyosarcoma, hepatoblastoma and hepatic sarcoma) or 1,25-dihydroxyvitamin D₃ (lymphoma, ovarian dysgerminoma).17,–,21 Hypercalcaemia may also result from tumour synthesis of osteoclast-activating factors such as IL-1, IL-6, TNFα and prostaglandins. Toxicity from 13-cis-retinoic acid, a treatment used for neuroblastoma, may cause hypercalcaemia.22

Immobilisation hypercalcaemia

Hypercalcaemia may result from acute immobilisation, for example in those with head injuries, fractures or spinal cord injuries. Acute immobilisation results in uncoupling of bone remodelling with a reduction in osteoblastic activity and increased osteoclastic activity. This leads to calcium and phosphate release from the skeleton with consequent hypercalcaemia and disuse osteoporosis. Fractures and renal stone formation may also occur. Although hypercalciuria occurs in all completely immobilised individuals, hypercalcaemia arises in those with a high bone turnover state, such as during puberty. Hypercalcaemia and hypercalciuria may resolve with the subsequent onset of weight bearing. Bisphosphonate treatment has been used.23

Idiopathic hypercalcaemia of infancy (Lightwood syndrome)

Hypercalcaemia presents between 6 and 12 months of age, usually resolves by 2 years and there may be nephrocalcinosis at presentation. There are no associated dysmorphic features. Increases in N-terminal PTHrP, 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D₃ have been observed.24 25 Following normalisation of plasma calcium, nephrocalcinosis and hypercalciuria may persist and an increased incidence of behavioural problems and deficit in performance IQ have been reported.25 26 The condition has recently been found to result from mutations in the 1,25-dihydroxyvitamin D₃ metabolising enzyme, 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), and leads to increased sensitivity to vitamin D in these individuals.27 The same mutation may result in a genetic predisposition to symptomatic hypercalcaemia following vitamin D prophylaxis in otherwise healthy children. Treatment of hypercalcaemia is by restricting dietary calcium intake. Locasol (SHS Nutricia, UK), a low calcium and vitamin D formula milk available in the UK, may be used to lower calcium levels.

Williams-Beuren syndrome

Williams-Beuren syndrome occurs in 1 in 10 000 births and is caused by a deletion on chromosome 7 (7q11.23). Approximately two-thirds of infants are born small for gestational age and many have typical facial features. Congenital heart disease occurs in 70%, most commonly supravalvular aortic stenosis and peripheral pulmonary stenosis. Older children have ‘elfin facies’ and a loquacious manner.28 Hypercalcaemia may present in the neonatal period and usually resolves during infancy, although some have reported its return during adolescence. Nephrocalcinosis may be present in 5–10%. The aetiology of hypercalcaemia is unclear but may result from abnormal function of a multiprotein complex (WINAC) that interacts with the Williams syndrome transcription factor and results in augmented recruitment of the vitamin D receptor and increased sensitivity to vitamin D.29 Dietary calcium restriction may be required together with the use of Locasol (SHS Nutricia) milk.

Jansen's metaphyseal chondrodysplasia

This is a rare autosomal dominant disorder that results in short-limbed dwarfism and characteristic skeletal abnormalities, including hyperostosis of the calvarium and a narrow thoracic cage. It is caused by a heterozygous mutation in the PTHR1 gene that results in a constitutively activated PTH/PTHrP receptor, which causes hypercalcaemia and hypophosphataemia, with low or undetectable serum PTH or PTHrP.30 There is usually normal growth in infancy and short stature becomes more apparent during mid-childhood. Calcium levels fall but remain elevated following completion of linear growth.

Subcutaneous fat necrosis

This condition presents in the first few weeks of life with severe symptomatic hypercalcaemia associated with a characteristic cutaneous violaceous rash composed of indurated, painful nodules over the face, trunk, buttocks and arms. There may be a preceding history of birth trauma, hypothermia or asphyxia. Hypercalcaemia is secondary to excessive 1,25-dihydroxyvitamin D₃ production from over-activity of 1-α hydroxylase activity from macrophages in the nodules.31 A similar mechanism may cause hypercalcaemia in other granulomatous diseases such as tuberculosis or sarcoidosis. Initial treatment is with hyperhydration and with bisphosphonates or corticosteroids if hypercalcaemia is refractory.32

Hyperhydration with intravenous 0.9% saline and loop diuretics

The majority of children with symptomatic hypercalcaemia are dehydrated at presentation from reduced fluid intake and the diuretic effect of hypercalcaemia (secondary to hypercalcaemia-induced nephrogenic diabetes insipidus). Inhibiting sodium reabsorption at the proximal convoluted tubule and the loop of Henle will increase urinary calcium excretion. Hyperhydration with 0.9% saline alone is often an effective treatment for hypercalcaemia. A loop diuretic, for example frusemide, may be added to further promote natriuresis and therefore hypercalciuria, but if used long term may increase predisposition to nephrocalcinosis.

Bisphosphonates

Bisphosphonates reduce plasma calcium levels by inhibiting osteoclastic bone resorption. Pamidronate (0.5–1.0 mg/kg infusion over 4–6 h) is the drug of choice in children and a reduction in calcium is observed 12–24 h after administration and may last for 2–4 weeks. Ibandronate and clodronate are licensed for use of treatment of hypercalcaemia of malignancy in adults. There may be a sustained period of hypocalcaemia following the initial pamidronate infusion, which may require calcium supplementation.

The use of bisphosphonates in renal failure is a potential concern but must be balanced against the potential for improving renal function by treatment of hypercalcaemia per se. A reduced dose of pamidronate should be given in the presence of renal failure.

Cinacalcet

Cinacalcet is a calcimimetic and reduces PTH levels by allosteric activation of the CaSR. In adult practice cinacalcet is used for the treatment of primary hyperparathyroidism and may delay the need for surgical intervention. Its use in children is evolving but it has been used in selected cases for primary hyperparathyroidism, neonatal hyperparathyroidism and in dialysis patients with secondary hyperparathyroidism.9 33 34

Glucocorticoids

Glucocorticoids, usually prednisolone, have been used for conditions when there is extra-renal synthesis of 1,25-dihydroxyvitamin D₃, such as granulomatous conditions, tuberculosis, sarcoid and subcutaneous fat necrosis. Glucocorticoids act by inhibiting synthesis of 1,25-dihydroxyvitamin D₃ from 25-hydroxyvitamin D.

Parathyroidectomy

Parathyroidectomy is required for primary hyperparathyroidism and must be undertaken by an experienced surgeon. The timing of the procedure depends on the degree of hypercalcaemia, evidence of end-organ damage from hypercalcaemia and the underlying cause. Parathyroidectomy for NSHPT is undertaken in the first few weeks of life as long-term medical treatment is ineffective and the skeletal complications of NSHPT are life threatening.

Following parathyroidectomy, replacement with maintenance calcium and vitamin D should be commenced. Immediately following surgery, hypocalcaemia secondary to a ‘hungry bone’ syndrome may develop despite maintenance treatment. Serial calcium measurements should therefore be taken following surgery and additional calcium supplementation given if appropriate. If severe hypocalcaemia develops, intravenous calcium may be required.

Haemodialysis

This intervention is reserved for life-threatening hypercalcaemia resistant to medical therapy. Haemodialysis with a dialysate with a low calcium concentration is used.