Pediatrics

Hypercalcemia

Overview: What every practitioner needs to know

Are you sure your patient has hypercalcemia? What are the typical findings for this disease?

Hypercalcemia with a very low serum phosphate concentration suggests the diagnosis of primary hyperparathyroidism. In infants, hyperparathyroidism may result from unrecognized maternal hypoparathyroidism or pseudohypoparathyroidism. Neonatal severe hyperparathyroidism (NSHPT) is a form of primary hyperparathyroidism in infants that may be life threatening. In babies and older children and adolescents, a familial form of mild hyperparathyroidism - Familial hypocalciuric hypercalcemia (FHH) - is associated with minimally elevated calcium levels.

Sporadic primary hyperparathyroidism in children and adolescents may be caused by adenoma or rarely hyperplasia of the parathyroid glands. Familial hypercalcemia may be associated with other pituitary and pancreatic hormone secretion associated with multiple endocrine neoplasia type 1 (MEN1) or MEN2 syndromes. Secondary hyperparathyroidism may develop in response to renal failure or transplant, or prolonged use of lithium, or in states of vitamin D deficiency such as rickets. Vitamin D excess also results in hypercalcemia.

High calcitriol levels may also explain the hypercalcemia of granulomatous and lymphomatous disease, inflammatory conditions with cytokinemia and some solid tumors. Hypercalcemia with rapid onset of hypercalciuria can occur due to acute immobilization of the growing child. Infants with elfin facies and heart murmur due to supravalvular aortic stenosis may have Williams Beuren syndrome.

Acute hypercalcemia can usually be managed with hydration with normal saline with 30 mEq/L potassium at 2 x maintenance followed by use of furosemide diuretic once adequate urine flow is established. Salmon calcitonin is given subcutaneously if hypercalcemia persists despite hydration and furosemide. Other treatment that may be considered includes the use of bisphosphonates that bind to bone and inhibit osteoclast induced bone resorption.

Clinical manifestations of hypercalcemia depend on the age of the patient and include:

Neonate/Infant: failure to thrive, anorexia, constipation, polyuria, irritability, seizures, hypotonia, reflux, bradycardia, heart block (EKG: shortened ST segment).

Child/Adolescent: headache, malaise, fatigue, lethargy, weakness, hypotonia, personality changes, depression, polydipsia, polyuria, abdominal pain due to constipation, pancreatitis, or renal calculus, pathologic fracture

What other disease/condition shares some of these symptoms?

Irritability and seizures in neonates are non-specific signs. In addition to hypercalcemia, they may be due to hypoglycemia or alterations in serum concentrations of magnesium, sodium and other analytes, to infectious diseases, and to traumatic or vascular insults. Polydipsia and polyuria are classically present in children with diabetes mellitus.

What caused this disease to develop at this time?

Hypercalcemia is the consequence of increased absorption of calcium from the intestinal tract (a primary function of calcitriol) or its increased reabsorption from renal glomerular filtrate or bone (due to excessive PTH secretion or functional activity, increased calcitriol levels, exuberant osteoclastogenesis due to inflammatory cytokines), or decreased rate of bone formation in the presence of continued bone reabsorption (immobilization). Nutritional, environmental, and inflammatory factors, as well as genetic variations (e.g., CASR), can lead to hypercalcemia.

Hypercalcemia in the neonate/infant:

Maternal factors - excessive vitamin D intake, hypoparathyroidism.

Patient factors - excessive intake of calcium or vitamin D, phosphate depletion, subcutaneous fat necrosis, Williams-Beuren syndrome of infantile hypercalcemia (in association with supravalvular aortic stenosis and an "elf-like" face), familial hypocalciuric hypercalcemia (CASR), neonatal severe hyperparathyroidism (CASR), hypothyroidism, hyperthyroidism, infantile hypophosphatasia.

Hypercalcemia in the child/adolescent:

Excessive intake of calcium, vitamin D or vitamin A, milk-alkali syndrome, ectopic synthesis of calcitriol, immobilization.

Familial hypocalciuric hypercalcemia (CASR).

Primary hyperparathyroidism - sporadic (adenoma or rarely hyperplasia), multiple endocrine neoplasia types 1 (MEN) or 2A (RET), hyperparathyroid jaw tumor syndrome (CDC73/HRPT2), Jansen's metaphyseal chondrodysplasia (PTHR1).

Secondary hyperparathyroidism - post renal transplantation, chronic lithium use.

Tumor synthesis of PTHrP, cytokine or other osteoclast activating factor.

Medications - thiazide diuretics, lithium, vitamin A analogs.

Among the genetic disorders that cause hypercalcemia are those associated with:

High serum concentrations of PTH:

Familial isolated primary hyperparathyroidism - MENl, CDC73/HRPT2

Multiple endocrine neoplasia type l - MENl

Multiple endocrine neoplasia type II - RET

Multiple endocrine neoplasia type IV - CDKN1B

Hyperparathyroid jaw-tumor syndrome - CDC73/HRPT2

Neonatal severe hyperparathyroidism - CASR

Normal serum concentration of PTH:

Familial hypocalciuric hypercalcemia - CASR

Low serum concentrations of PTH:

Jansen's metaphyseal chondrodysplasia - PTHR1

Williams-Beuren syndrome (MIM 194050) - hemizygous deletion of chromosome 7q11.23

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Accurate determination of the serum calcium concentration with age-appropriate normal ranges is important prior to embarking on an extensive diagnostic evaluation of hypercalcemia. (Physiologic serum calcium concentrations vary with age and are higher in children than adults: infants 0-3 months: 8.8-11.3 mg/dL; toddlers 1-5 years: 9.4-10.8 mg/dL; children 6-12 years: 9.4-10.3 mg/dL). Normal levels of phosphate in infants and children also exceed those of adults.

In patients with an increased total serum calcium concentration associated with elevated serum albumin values, the Ca2+ concentration is normal. Thrombocytemia and calcium binding to M-proteins in disorders such as Waldenstrom's macroglobulinemia may cause persistently elevated total serum calcium levels in the presence of normal Ca2+ values. Venous stasis caused by use of a tourniquet may raise pH locally and thus alter the binding of calcium to serum proteins; consequently the measured Ca2+ concentration may be spuriously low. On the other hand, obtaining a blood specimen from a vein at a site that is "upstream" of a calcium infusion will result in spuriously high calcium values.

When high total calcium concentrations are present, measurement of an ionized calcium value (Ca+2) is obtained to confirm true, biochemical hypercalcemia, and a serum phosphate is requested. A low serum phosphate suggests hyperparathyroidism (HPT), that is confirmed by the finding of a high, or "inappropriately normal" PTH concentration relative to the elevated level of serum calcium. Hyperparathyroidism may be primary or secondary.

Imaging employing 99m-Tc-Sestamibi may be ordered to localize a parathyroid adenoma.

Secondary hyperparathyroidism results from an appropriate parathyroid response to hypocalcemia, for example during renal failure/transplant (measure serum creatinine) or in states of Vitamin D deficiency such as rickets. Unrecognized hypoparathyroidism or pseudohypoparathyroidism in an effected neonate's mother is sought by measuring her serum calcium.

When hypercalcemia is severe in the neonate (14-17 mg/dL, neonatal severe hyperparathyroidism [NSHPT]) or mild hypercalcemia is present with a history of other affected family members, familial hypocalciuric hypercalcemia (FHH), a loss of function mutation of the calcium sensing receptor (CaSR), is suspected by finding a low calcium/creatinine ratio in a random urine collection; results are confirmed with genetic study of the CaSR. Calcium levels should be determined in relatives of the proband in cases of familial hypercalcemia.

The presence of hypercalcemia and hyperparathyroidism with elevated levels of pituitary (e.g. prolactin), pancreatic (e.g. gastrin), thyroid or adrenal hormones suggests multiple endocrine neoplasia type 1 (MEN 1); MEN1 may be genotyped.

The storage form of Vitamin D (25OHD3, calcidiol) is measured when the patient's history suggests excessive intake of Vitamin D by the patient or mother (milk/alkali syndrome or abnormally constituted formula).

If subcutaneous fat necrosis with violaceous nodules on the face or trunk is present, or granulomatous disorders (lymphoma) or states of chronic inflammation and cytokinemia are suspected, elevated levels of 1,25 (OH)D3 (calcitriol) should be sought.

Hypercalcemic infants or children with elfin facies and supravalvular aortic stenosis may have Williams-Beuren syndrome, which may be assessed by FISH of chromosome 7q11.23 or gene microarray; genotyping of ELN may be considered.

In patients undergoing therapy for embryonal renal tumors or other malignancies involving the lung, breast, or ovary, or dysgerminomas, who develop hypercalcemia, measurement of parathyroid hormone related protein (PTHrP) should be performed. Oversecretion of PTHrP may also be present in neonatal iron storage disease.

While consistently elevated PTH levels in the hypercalcemic, hypophosphatemic, hypercalciuric child or adolescent are present in primary hyperparathyroidism, rarely, serum calcium and/or PTH values may be normal in a single specimen. Therefore, repeated determinations of serum calcium and intact PTH levels may be required to establish this diagnosis.

Would imaging studies be helpful? If so, which ones?

In hyperparathyroid states, radiographs of long bones may reveal subperiosteal reabsorption of bone, osteopenia, widened, irregular metaphyses, and varus deformity of the hips.

Rachitic changes may be identified by radiographs of the wrist and knees or recognized incidentally on chest X-ray in neonates by the presence of unsuspected rib fractures or "cupping" and fraying of the ends of the clavicles.

Dual Energy X-Ray Absorptiometry (DEXA) scans normalized to chronologic age, height age, race and gender help to identify osteopenia and osteoporosis.

Ultrasonography, magnetic resonance imaging (MRI), computed tomography (CT), and radionucleotide scans employing 99m-Tc-Sestamibi are utilized to localize a parathyroid adenoma. 99m-Tc-Sestamibi is taken up by the thyroid and parathyroid glands but promptly washed out of the thyroid, allowing differentiation of parathyroid from thyroid accumulation. An alternative method involves simultaneously administration of 99m-Tc-Sestamibi and a second radionucleotide such as radioiodine-123 that concentrates in and remains in the thyroid serving to differentiate it from parathyroid tissue.

In conditions associated with hypercalciuria, renal sonogram is important to identify nephrocalcinosis and/or renal stones.

If you are able to confirm that the patient has hypercalcemia, what treatment should be initiated?

When serum calcium values are <12 mg/dL in the asymptomatic patient, treatment may be deferred until the cause of the hypercalcemia can be determined. Subjects are instructed to increase fluid intake, avoid calcium and vitamin D supplementation, and discontinue medications known to cause hypercalcemia. The child with FHH frequently has total serum calcium levels between 11-13 mg/dL without clinical symptoms, and generally requires no therapy.

Children with William-Beuren syndrome or idiopathic infantile hypercalcemia may have minimally elevated serum concentrations of calcitriol; ingestion of a low calcium formula or reduced calcium diet in the older child may be sufficient to reverse hypercalcemia and hypercalciuria. CalciloXD is a low calcium infant formula without vitamin D that is commonly prescribed. As hypercalcemia remits, the volume of CalciloXD is gradually reduced and mixed with increasing amounts of standard formula or breast milk. Subjects placed on a low calcium diet require close monitoring to avoid hypocalcemia.

When total calcium is >12 mg/dL and the child is symptomatic, it is necessary to lower serum calcium in order to avoid adverse effects of hypercalcemia on cardiac rhythm, the central nervous system, and kidney. Fluid therapy, furosemide and calcitonin are utilized in a stepwise fashion in order to the treat hypercalcemia.

The severely hypercalcemic patient is first hydrated with 0.9% saline containing 30 mEq of potassium chloride per liter at twice maintenance volume administered over 24-48 hours; the goals of therapy are to restore intravascular volume, dilute and lower serum calcium concentrations, increase glomerular filtration rate, decrease renal tubular reabsorption of calcium, and promote calciuresis. Thiazide diuretics should be avoided as they increase renal tubular reabsorption of calcium and reduce intravascular volume. Serum calcium concentrations generally decline 1-3 mg/dL with hydration alone.

After intravascular volume has been successfully restored, furosemide, 1 mg/kg infused slowly intravenously, may be employed if calcium values remain markedly elevated. Loop diuretics such as furosemide lower serum calcium values by blocking resorption of calcium and sodium in the TALH and must be used cautiously to avoid excessive diuresis, dehydration, and a fall in GFR that can aggravate hypercalcemia.

Salmon calcitonin (2-4 U/kg subcutaneously every 6-12 hours) acts rapidly but transiently to lower serum calcium by inhibiting osteoclastic bone resorption and promoting urinary calcium excretion. Its effects wane over time.

In children and adolescents who fail to respond adequately to the use of hydration, furosemide, and calcitonin, bisphosphonates such as pamidronate, etidronate, and zolendronic acid (the most potent inhibitor of bone resorption) may be used for the acute management of hypercalcemia due to increased osteoclastic bone resorption. Bisphosphonates are phosphatase resistant analogs of pyrophosphate that inhibit osteoclast function by inhibiting osteoclastic differentiation, attaching to and coating hydroxyapatite crystal beneath the osteoclast surface, thereby disrupting osteoclast adherence to bone.

Pamidronate infused at a dose of 0.5-1.0 mg/kg over 4-6 hours rapidly lowers serum calcium levels in hypercalcemic infants and children; its effects may last from days to weeks. Transient side effects (seen in about 20% of subjects) may include fever and myalgia. Clinicians must use care to avoid the potential development of severe hypocalcemia, hypophosphatemia, or hypomagnesemia. While osteonecrosis of the jaw following treatment with bisphosphonates is a significant concern in adults, especially following recent dental surgery, this complication has not been reported in children receiving these medications. Bisphosphonates bind to and remain in bone for many years, and their repressive effect on osteoclast function may result on occasion in an osteopetrosis-like state.

Calcimimetic agents, such as Cinacalcet, that affect the CaSR by lowering the set point to calcium, are employed to suppress parathyroid hormone levels in adults and are now being investigated in children.

Glucocorticoids effectively reduce serum calcium levels due to excess vitamin D intake, overproduction of calcitriol by activated monocytes, or hematologic malignancies. They are useful for treatment of hypercalcemia related to overproduction of interleukin-1 beta in juvenile rheumatoid arthritis, but have little effectiveness in patients with hyperparathyroidism or solid malignancies.

The anti-fungal agent, ketoconazole, lowers calcitriol and calcium in patients with granulomatous or inflammatory disorders, but has significant side effects including development of adrenal and gonadal insufficiency and gastrointestinal upset. In rare instances in severely hypercalcemic patients who have been poorly responsive to conventional treatment, peritoneal or hemodialysis with calcium free dialysate may be required.

In infants, children and adolescents, parathyroid adenoma(s) or hyperplastic PTGs may be removed using minimally invasive surgery in which 99m-Tc-Sestamibi administration aides localization and removal of the lesion guided by a handheld gamma probe inserted under the skin at the operative site. A 50% decline in serum concentrations of PTH at the end of the operation compared to preoperative baseline values confirms successful removal of the adenoma.

Calcimimetic drugs (phenylalkylamines) have been successfully employed to treat secondary hyperparathyroidism in children with stage 5 chronic kidney disease (CKD). Calcimimetic agents such as cinacalcet interact with the CaSR at epitopes that differ from the calcium binding site, altering the spatial configuration of the receptor and thereby increasing its sensitivity to calcium. They produce a long term suppression of PTH release, but allow sufficient circadian fluctuation of PTH to permit an anabolic effect on bone.

In adults with mild primary hyperparathyroidism, calcimimetic agents can restore the eucalcemic state. In neonates with severe neonatal hyperparathyroidism, cinacalcet may prevent the need for parathyroidectomy. (Table I).

Table I.

Treatment of Hypercalcemia

What are the adverse effects associated with each treatment option?

Excessive hydration may compromise cardiovascular and pulmonary function. Furosemide and other loop diuretics may cause excessive diuresis resulting in dehydration and pre- renal azotemia that paradoxically aggravates hypercalcemia.

Bisphosphonates may lead to hypocalcemia, hypomagnesemia, and hypophosphatemia. Since bisphosphonates adhere to and coat hydroxyappatite crystals, their presence can be detected in bone many years after administration. In some subjects, excessive amounts of bisphosphonates have resulted in abnormal and potentially weaker bones.

Long-term administration of large amounts of glucocorticoids may inhibit linear growth in children and result in iatrogenic Cushing syndrome. Calcitonin may induce diarrhea. Calcimimetic drugs are contraindicated in patients with stages 3 and 4 chronic renal disease as they may induce hyperphosphatemia.

What are the possible outcomes of hypercalcemia?

Acutely, hypercalcemia is generally amenable to medical or surgical therapy. The long term outcome depends upon the underlying cause of hypercalcemia.

What causes this disease and how frequent is it?

Neonatal/Infantile Hypercalcemia:

Hypercalcemia in the neonate or infant may result from exposure to excessive calcium or vitamin D in breast milk when mothers ingest large doses of cholecalciferol or use thiazide diuretics that increase renal tubular reabsorption of calcium or when infants receive excessively large amounts of vitamin D or calcium in their diet. In neonates, calcitriol may be synthesized in large amounts by macrophages present in inflammatory sites such as subcutaneous fat necrosis.

Familial hypocalciuric hypercalcemia (FHH):

FHH is primarily the result of monoallelic loss-of-function mutations in CASR and resetting of the "set point" of calcium-mediated secretion of PTH and reabsorption of calcium from the renal tubule. Inactivating mutations in GNA11 (encoding a G-protein) lead to FHH type II.Loss-of-function mutations in AP2S1 are associated with FHH type III. AP2S1 encodes adaptor-related protein complex 2, Sigma-1 Subunit, a component of the cell plasma membrane clathrin-associated adaptor complex that imports membrane proteins such as the CASR into the cell cytoplasm.Inactivating mutations in AP2S1 reduce signal transduction by the CASR by reducing interaction of CASR with a carboxyl terminal dileucine motif as well as its endocytosis resulting in decreased sensitivity of the cell to interstitial ionized calcium.

The neonate and infant with FHH are asymptomatic; serum calcium concentrations are usually <12 mg/dL, and urine calcium excretion is low. The neonate with biallelic inactivating mutations in CASR has calcium levels that often exceed 15 mg/dL (neonatal severe hyperparathyroidism - NSHPT), resulting in a life-threatening illness.

In addition to hypercalcemia, serum concentrations of PTH, magnesium, alkaline phosphatase, and calcitriol are high and phosphate values are low to normal. Radiographs reveal osteopenia, widened irregular metaphysis, and subperiosteal bone resorption. The fetus who has inherited one mutated CASR from a father with FHH and whose mother is normal may develop substantial parathyroid gland hyperplasia in utero in an attempt to maintain the normally high fetal serum calcium values.

Secondary hyperparathyroidism due to maternal/fetal hypocalcemia:

Neonatal secondary hyperparathyroidism may result from maternal hypoparathyroidism or pseudohypoparathyroidism and reduction in placental transport of calcium to the fetus, leading to hyperplasia of the fetal parathyroid glands in an attempt to maintain the high calcium levels normally present in the fetus. Although 25% of neonates/infants born to hypocalcemic mothers are hypercalcemic, many display the skeletal effects of PTH excess, such as demineralization with fractures or osteopenia measurable by DEXA scan.

Mucolipidosis type II, a Hurler-like disorder due to inactivating mutations of GNPTAB resulting in disordered synthesis of mannose 6-phosphate, leads to mild neonatal hypercalcemia due to impaired placental calcium transport, resultant fetal hypocalcemia, and compensatory hyperplasia of the fetal parathyroid glands.

Constitutive (ligand-independent) activation of PTHRl:

Constitutively activating mutation of PTHR1 leads to hypercalcemia, hypercalciuria, renal calculi, and Murk-Jansen metaphyseal chondrodysplasia. Birth length and physical appearance of the affected neonate are normal despite radiographic changes of chondrodystrophy. Infants develop a phenotype of short-limbed dwarfism, deformed long bones, fingers, toes, spine and pelvis with choanal atresia, micrognathia, highly arched palate, and open fontanelles (in early infancy).

Hypersecretion of PTHrP:

Hypercalcemia due to excessive secretion of PTHrP may occur with neonatal iron storage disease and in association with embryonal renal tumors such as Wilms' and mesoblastic nephromas.

Williams-Beuren syndrome (WBS):

Approximately 15% of infants with WBS have hypercalcemia that typically remits by one year of age but may persist into adulthood. Characteristic findings in affected subjects include: prenatal and postnatal growth retardation, stenoses of multiple vessels including supravalvular aortic stenosis (30%) and narrowing of the pulmonary, renal, mesenteric, and celiac arteries, microcephaly, elfin face (short nose with full tip, prominent lips, long philtrum, full cheeks, and dental malocclusion), hoarse voice, radioulnar synostosis, renal hypoplasia or unilateral agenesis, and hypertension.

Although often developmentally delayed, these subjects have unique musical aptitude, enhanced auditory memory, and large vocabularies. Affected children may be more "sensitive" to vitamin D due to reduced repression of expression of CYP27Bl, the gene encoding 25OHD-1-alpha-hydroxylase. The WBS is associated with haploinsufficiency of chromosome 7q11.23, the site of Williams Syndrome Transcription Factor (WSTF). WSTF binds to WINAC, an ATP dependent chromatin remodeling complex that regulates expression of CYP27B1. Loss of WSTF prevents repression of expression of CYP27B1 by the calcitriol-bound VDR resulting in increased synthesis of calcitriol.

Hypophosphatasia:

Hypophosphatasia is due to loss of function mutations in the gene (ALPL) encoding bone alkaline phosphatase. Clinical and radiologic signs of rickets are associated with very low levels of alkaline phosphatase in these patients. There are six clinical forms of hypophosphatasia: perinatal lethal, perinatal benign, infantile, childhood, adult, and odontohypophosphatasia (premature shedding of deciduous teeth).

Inborn errors of metabolism:

Congenital lactase deficiency and disaccharide intolerance lead to increased intestinal levels of lactose that enhance intestinal absorption of calcium resulting in hypercalcemia and metabolic acidosis. The blue diaper syndrome is due to a defect in tryptophan metabolism that causes hypercalcemia, hypercalciuria, nephrocalcinosis and increased urinary excretion of indole derived compounds that turn the baby's wet diaper blue.

Bartter syndrome is primarily associated with hypercalciuria, but hypercalcemia may be present in infants with homozygous inactivation of the genes encoding the furosemide-sensitive NaK-2Cl-cotransporter or the inwardly rectifying potassium channel - ROMK. Hypercalcemia has been observed in infants with primary oxalosis, congenital hypothyroidism, and the IMAGe syndrome of intrauterine growth retardation, metaphyseal dysplasia, congenital adrenal hypoplasia, and genital abnormalities.

Idiopathic Hypercalcemia of Infancy (Lightwood syndrome):

Affected children present in the first year of life without dysmorphic features. Hypercalcemia is more prolonged than that seen in Williams syndrome. PTH is suppressed, and in some patients there are elevated concentrations of calcidiol and high normal calcitriol values.

Hypercalcemia in older children and adolescents:

Children with mild, asymptomatic hypercalcemia (11-13 mg/dL) found unexpectedly on a chemical panel or through family screening often have FHH due to heterozygous inactivating mutations in CASR. Older children and adolescents may have fatigue, weakness, or polyuria. Recurrent pancreatitis, cholelithiasis, chondrocalcinosis, and vascular calcification may also occur, although bone mass and fracture rate are normal. There is PTH-dependent total and ionized hypercalcemia with hypocalciuria, mild hypermagnesemia, hypomagnesuria, and hypophosphatemia.

Primary hyperparathyroidism is usually a sporadic illness in children and adolescents with an incidence of 2-5/100,000. The disorder is either discovered incidentally on a chemical screen or during evaluation of nephrolithiasis or pathologic fracture through a bone cyst. Two thirds of affected children (mean age 12.8 years, range 3-19 years; 3:2 female: male incidence) have a chief cell parathyroid adenoma of monoclonal origin involving one parathyroid gland. In approximately 17% of sporadic parathyroid adenomas, a somatic loss-of-function mutation of the tumor suppressor factor menin encoded by MEN1 (germline inactivating mutations result in MEN1) is present.

Secondary hyperparathyroidism results from chronic renal insufficiency, malabsorption syndromes with vitamin D deficiency, or ingestion of thiazide diuretics or lithium. Tertiary hyperparathyroidism occurs when monoclonal tumors whose function is independent of serum calcium levels develop in response to chronic hypocalcemia.

The multiple endocrine neoplasia (MEN) syndromes are familial autosomal dominant disorders with high penetrance, associated with formation of tumors in two or three endocrine glands (parathyroid gland, pituitary, pancreas, and others). MEN1 is due to mutations in MEN1 encoding the tumor suppressor factor - menin. The disorder is caused by a germ-line loss of function mutation in MEN1and subsequent somatic loss of MEN1 in the tumor-bearing tissue. Hyperparathyroidism is due to parathyroid adenoma(s) or hyperplasia affecting all four parathyroid glands. Hypercalcemia due to hyperparathyroidism is the most common clinical manifestation of MEN1 in childhood.

The frequency of endocrine tumors increases with advancing age in MEN1. Pituitary tumors secreting prolactin or growth hormone develop in 30% of affected patients. Gastrinomas (Zollinger-Ellison syndrome), insulinomas, and glucagon secreting tumors of the pancreatic islets occur in 40% of subjects. Cushing syndrome may result from oversecretion of adenocorticotropin by a pituitary adenoma or by excessive glucocorticoid production by a primary adrenal tumor. In 25% of MEN1 patients, benign or malignant thyroid tumors may develop. Dermatologic and non-endocrine tumors also develop in MEN1 subjects and include facial angiofibromas, collagenomas, lipomas, or Schwannomas, intestinal and bronchial carcinoids.

MEN2A and MEN2B are due to distinctive gain of function mutations in RET, encoding a transmembrane tyrosine kinase receptor. Medullary carcinoma of the thyroid (MCT) is the most frequently identified neoplasm in MEN 2A and is present in 95% of patients who also develop parathyroid hyperplasia or adenoma, localized cutaneous lichen amyloidosis, and/or megacolon. Patients with MEN 2B have a Marfanoid habitus and develop MCT, pheochromocytoma, mucosal neuromas, and ganglioneuromas of the gastrointestinal tract.

Hyperparathyroidism may rarely occur in children with McCune-Albright syndrome due to a gain-of-function mutation of GNAS.

Parathyroid tumors occur rarely in teenagers after external radiation of the neck for treatment of neoplasia.

Autosomal-dominant familial primary hyperparathyroidism associated with multiple ossifying fibromas of the jaw results from heterozygous inactivating germline mutation of the tumor suppressor gene HRPT2encoding parafibromin. Hyperparathyroidism typically appears in the third decade of life, but may also occur before 10 years of age. The parathyroid lesion may be a premalignant cystic adenoma (65%), hyperplasia (20%), or carcinoma (15%) and may occur alone or in association with maxillary or mandibular tumors or renal lesions.

Hypervitaminosis D may result from iatrogenic overtreatment of rickets or hypocalcemia with vitamin D or calcitriol or topical overapplication of vitamin D containing creams or analogs such as 22-oxacalcitriol for management of psoriasis or treatment of acne with a vitamin A analogue such as transretinoic acid can result in severe hypercalcemia. Megavitamin therapy and improper vitamin D fortification of milk have also resulted in hypervitaminosis D.

In subjects with vitamin D intoxication, serum concentrations of 25(OH)D3 (calcidiol) are increased, calcitriol values are usually normal (unless the patient is receiving calcitriol), and PTH levels are suppressed. Increased intake of calcium and alkali in calcium rich antacids such as calcium carbonate taken for peptic ulcer disease or as dietary supplements may lead to absorptive hypercalcemia, hypercalciuria, and nephrocalcinosis. Parenteral treatment with excessive amounts of calcium or aluminum or a deficit of required phosphate may also cause hypercalcemia.

Children and adolescents with granulomatous diseases such as noninfectious sarcoidosis, berylliosis, eosinophilic granuloma, leprosy, tuberculosis, histoplasmosis, coccidiodomycosis, candidias, or cat scratch disease may develop hypercalcemia as activated T cells and macrophages express 25OHD-1-alpha hydroxylase activity that converts 25(OH)D3 to calcitriol. Hypercalcemia in patients with acquired immune deficiency disease may result from infection with granuloma forming organisms or by the action of osteoclast activating cytokines released during the illness. Hypercalcemia has also been reported in adolescents with juvenile rheumatoid arthritis due to increased production of interleukin (IL)-1-beta.

Patients with neoplastic syndromes such as B-cell lymphoma, Hodgkins disease, and other malignancies may develop hypercalcemia, although tumor-induced hypercalcemia occurs in less than 1% of children with cancer. Hypercalcemia results from osteolysis due to direct skeletal invasion by tumor or by tumor generated osteoclastic bone resorption factors ([e.g., IL-1, IL-6, transforming growth factor-beta, and tumor necrosis factor) or by tumoral synthesis of PTHrP.

In late prepubertal and adolescent females and young adult women, hypercalcemia may occur in association with small cell carcinoma of the ovary, hypercalcemic type, which is due to either germline or somatic inactivating mutations in SMARCA4.The pathogenesis of hypercalcemia in patients with this tumor is unknown but is likely related to tumoral production of a hypercalcemic product such as PTH-RP, analogues of vitamin D, or various interleukins as curative treatment of the tumor restores and maintains eucalcemia. SMARCA4 encodes a catalytic subunit of the ATP-dependent SWI/SNF (switching and sucrose non-fermenting) nuclear complex that is essential for chromatin remodeling that precedes transcriptional regulation of target genes.Small cell carcinoma of the ovary, hypercalcemic type, is not a carcinoma but rather a member of the extracranial rhabdoid tumor group of mesenchymal origin.

Acute immobilization of the rapidly growing child or adolescent due to femoral fracture, spinal cord injury, or myopathy results in rapid deceleration in the rate bone mineral accretion with continued bone mineral reabsorption leading initially to hypercalciuria; when this process exceeds the renal tubular capacity for excretion of calcium, hypercalcemia ensues, a disorder termed "acute disuse osteoporosis."

Various medications may cause hypercalcemia including thiazide diuretics that increase renal tubular reabsorption of calcium while lowering plasma volume, vitamin A and its retinoic acid analogs that increase bone resorption, and lithium, a cation that raises the set point for PTH release, thereby increasing serum calcium concentrations and lowering urinary calcium excretion.

Hypercalcemia may be associated with hyperthyroidism (due to enhanced osteoclastic bone resorption), pheochromocytomas, and some islet cell tumors (co-secretion of PTHrP), and adrenal insufficiency.

Hypercalcemia can occur in children with chronic renal failure as a result of immobilization, aluminum toxicity, or excessive intake of calcium antacids or vitamin D or its analogs. During recovery from acute renal failure, calcium may be mobilized from ectopic sites into which it had been deposited during periods of hyperphosphatemia. Following renal transplantation, hypercalcemia may be seen due to secondary hyperparathyroidism related to hypertrophy and hyperplasia of the parathyroid chief cells that follows the PTH stimulatory effects of hyperphosphatemia, hypocalcemia and decreased synthesis and response to calcitriol. Rhabdomyolysis with renal failure may result in hypercalcemia as calcium is released from injured muscle in the face of compromised renal excretion.

What is the evidence?

Root, AW, Sperling, MA. "Disorders of calcium and phosphorus homeostasis in the newborn and infant". Pediatric Endocrinology. Elsevier/Saunders. 2014. pp. 209-276.

Root, AW, Diamond, FB, Sperling, MA. "Disorders of mineral homeostasis in children and adolescents". Pediatric Endocrinology. Elsevier/Saunders. 2014. pp. 734-845.

Hendy, GN, Canaff, L, Newfield, RS. "Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations". J Clin Endocrinol Metab. vol. 99. 2014. pp. E1311-E1315.

Jelinic, P, Mueller, JJ, Olivera, N. "Recurrent SMARCA4 mutations in small cell carcinoma of the ovary". Nature Genet. vol. 46. 2014. pp. 424-426.

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