Pediatric Hyperparathyroidism

Primary hyperparathyroidism (PHPT) entails an abnormality in parathyroid cell function leading to hypercalcemia with an inappropriately normal or elevated PTH level. The etiology and pathology of PHPT is very different in neonates and older children. Most neonatal cases are due to inactivating mutations of the calcium sensing receptor (CASR) causing severe neonatal hyperparathyroidism (NSHPT). On the other hand, in children and adolescents PHPT is most frequently (80-92%) due to a single benign parathyroid adenoma, and less commonly due to multiglandular disease (MGD).[1, 2, 3, 4, 5, 6, 7, 8]  MGD is more commonly observed in the multiple endocrine neoplasia syndromes MEN1, MEN2A, and MEN4 or as part of the hyperparathyroidism jaw tumor syndrome (HPT-JT). Germline mutations in several genes have been identified in MGD as well as in non-syndromic familial isolated hyperparathyroidism. Somatic mutations in different genes have been related to a minority of cases of sporadic parathyroid adenomas.[9, 10] The differential diagnosis for primary hyperparathyroidism includes a usually asymptomatic form of primary hyperparathyroidism due to heterozygous inactivating CASR mutations, familial hypocalciuric hypercalcemia (FHH). Parathyroid carcinoma is very rare in adults and children(< 1%).[11]

A meta-analysis by Roizen et al concluded that hypercalcemia and hypercalciuria is greater in juvenile primary hyperparathyroidism than adult primary hyperparathyroidism with serum intact PTH at similar concentrations which suggested a different pathophysiology between pediatric and adult cases.[12]

Secondary hyperparathyroidism refers to an elevated PTH level in the context of low or normal serum calcium levels. This disorder may be caused by hyperphosphatemia as observed in chronic renal failure, or by hypocalcemia as in malabsorption or vitamin D deficiency. The elevated PTH level in these cases reflects a normal response to a stimulus, and it normalizes by treating the underlying pathology.

Tertiary hyperparathyroidism occurs when parathyroid hyperplasia becomes so severe that removal of the underlying cause does not eliminate the stimulus for PTH secretion and hypertrophic chief cells become autonomous. This usually presents as the progression of chronic secondary hyperparathyroidism

This chapter will focus on primary hyperparathyroidism.  In these cases, inappropriately elevated parathyroid hormone secretion leads to hypercalcemia and hypophosphatemia. PTH increases renal calcium reabsorption at the distal convoluted tubule and increases intestinal calcium absorption indirectly by increasing the production of 1,25 (OH)2 vitamin D by stimulating the 1 α hydroxylation of 25 OH vitamin D in the proximal renal tubules. 1,25 (OH)2 Vitamin D in turn stimulates active intestinal calcium transport. PTH also leads to hypercalcemia by increasing bone resorption. PTH indirectly stimulates bone resorption by acting on the osteoblast PTH receptor, which then signals the osteoclast to produce various substances, among them is the ligand of the receptor activator of the nuclear transcription factor NF-kappa B (RANK), known as RANK ligand (RANKL), which can stimulate osteoclast differentiation and proliferation.  PTH leads to hypophosphatemia by decreasing renal phosphate reabsorption.

The main causes of hyperparathyroidism by age groups are detailed in Table 1. Homozygous inactivating CASR mutations lead to NSHPT, while heterozygous mutations are observed mainly in the milder form, familial hypocalciuric hypercalcemia (FHH), although cases of NSHPT with heterozygous mutations have been reported.[13]  FHH is inherited in an autosomal dominant manner, but may be sporadic. Additionally, mutations in the G protein subunit α 1 and AP2S1 gene have recently been found to cause FHH.[14, 15]  FHH manifests with mild hypercalcemia  associated with hypocalciuria, most often not requiring specific treatment.

In older children and adolescents primary hyperparathyroidism is most often caused by isolated sporadic parathyroid adenomas (80-92%).[16]  The remaining are due to multiglandular parathyroid hyperplasia observed in familial endocrine neoplastic syndromes, in which cases a family history of endocrine tumors  with an autosomal dominant pattern of inheritance often exists. Multiple endocrine neoplasia type 1 is caused by a mutation in the gene MEN1 which encodes menin, a tumor suppressor protein. Hyperparathyroidism is the presenting sign in 95% of patients with MEN1, while pancreatic and pituitary tumors develop in 40 and 30% of cases respectively.[9]  MEN 2A is caused by mutations in the c-ret proto-oncogene (RET), which encodes a tyrosine kinase receptor. MEN 2A presents with medullary thyroid carcinoma associated with hyperparathyroidism (20%) and pheochromocytoma (50%). MEN 4 is caused by mutations in CDKN1B, a cyclin dependent kinase inhibitor, and has been diagnosed in a small percentage of patients with the tumors associated with MEN1 in addition to adrenal, gonadal and thyroid tumors.  Hyperparathyroidism jaw tumor syndrome is caused by mutations in cell division cycle 73 gene (CDC73), which codes for parafibromin, a nuclear protein thought to be a tumor suppressor gene. In this syndrome, osseous fibromas of the jaw are associated with parathyroid adenomas or carcinomas, and renal and uterine tumors may also be found.[9]  In general, parathyroid carcinoma is very rare in children with 11 cases reported in the English literature in the past 41 years.[11]

Table 1. Causes of hyperparathyroidism (Open Table in a new window)

The estimated incidence of primary hyperparathyroidism (PHPT) in pediatric patients is 1 per 200-300,000 and its prevalence is 2-5 in 100,000.[1, 6]  It has a higher predominance in adolescents, but its incidence is still much lower in this population than in adults where it has been estimated at 1:500-2000.[17]  In adults, PHPT is more frequent in females, while most pediatric series find no difference in distribution by sex.[4]

Prognosis depends on the etiology. For primary hyperparathyroidism due to a parathyroid adenoma, parathyroidectomy should be curative if the condition occurs in isolation. However, if it is associated with other tumors, prognosis would depend on the management of accompanying tumors. NSHPT has a high mortality rate if untreated. Secondary hyperparathyroidism is cured by treating the underlying pathology.

Complications

Acute complications if untreated are those of hypercalcemia.

Chronic complications include the following:

• Failure to thrive
• Low bone mineral density
• Fractures
• Nephrolithiasis or nephrocalcinosis
• Renal failure

Surgical complications include recurrent laryngeal nerve injury, bleeding, and infection. Complications of primary hyperparathyroidism include consequences of hypercalcemia, such as nephrolithiasis, dehydration, and cardiac arrhythmias, and complications due to end organ involvement such as renal failure and fractures.

Patients with primary hyperparathyroidism must understand the following:

• Location and function of parathyroid gland and PTH

• Effects of hypercalcemia on the body (eg, dehydration, neurological symptoms, arrhythmia, stones, bone demineralization, increased fracture risk)

• Lack of success in managing most cases of primary hyperparathyroidism medically, need for surgical consultation, and resection of one or more parathyroid glands

NSHPT represents a severe form of hyperparathyroidism observed in neonates, with a high mortality rate if untreated. Symptoms include dehydration secondary to polyuria, feeding difficulties and vomiting, altered mental status, hypotonia, respiratory distress and fractures. FHH is milder, often asymptomatic.[18]

Unlike adults, the majority of children and adolescents with primary hyperparathyroidism are symptomatic, with symptoms secondary to hypercalcemia or the effects of PTH on target organs. Hypercalcemia affects cell depolarization leading to gastrointestinal, neurologic and cardiac signs and symptoms.  Gastrointestinal symptoms are common, and are partly due to increased gastric acid secretion. These symptoms include abdominal pain, nausea, anorexia, constipation and vomiting. Polyuria is caused by the direct effects of hypercalciuria on the nephron and by the stimulation of the CASR in the collecting tubules leading to decreased antidiuretic hormone action. Headache, depression, fatigue, and anxiety are amongst the most frequent neurological symptoms. Renal calculi, hematuria, dehydration, bone pain, and fractures are presenting symptoms in more than 50% of pediatric cases.[4] Bradycardia and heart block may be observed with severe hypercalcemia. In cases where hyperparathyroidism is part of a multiglandular syndrome, there may be a history of symptoms associated with other endocrine tumors, and a positive family history for similar tumors. The proportion of asymptomatic pediatric patients diagnosed by the  incidental finding of hypercalcemia during routine blood chemistry is lower than that reported in adults, with a range of 14 to 25% in a pediatric series.

Clinical features include the following:

• Depressed mood, anxiety, and altered mental status 
• Poor weight gain and failure to thrive in younger children and infants
• Bradycardia, with or without irregular heartbeat
• Signs of dehydration, such as dry mucous membranes, prolonged capillary refill, tenting of skin
• Abdominal pain due to increased gastric acid secretion, constipation, peptic ulcers, or acute pancreatitis
• Hypotonia
• Flank pain due to renal calculi
• Signs of fractures such as bone pain and deformities are more common in neonates with NSHPT

Serum biochemistry studies include the following:

• Parathyroid hormone (PTH) level using immunometric assays to detect the intact PTH molecule (PTH 1-84).
• Serum calcium, total or ionized calcium. Note that if the patient has hypoalbuminemia, the serum calcium level should be corrected for the albumin level, or serum ionized calcium level should be measured ( adjusted total Ca=measured total Ca +[0.8x(4.0- albumin)]). In primary hyperparathyroidism there are high levels of calcium and PTH, whereas in secondary disease, levels of calcium are within the reference range or low.
• Serum albumin

• Serum phosphorus. Phosphorus levels in primary hyperparathyroidism are in the low or low-normal range. In secondary hyperparathyroidism due to renal failure phosphorus serum levels are elevated because of the inability of the kidney to excrete phosphorus. In Vitamin D deficiency, serum phosphorus levels may be low.

• 25 OH Vitamin D level should be determined and treated if deficient to differentiate primary from secondary hyperparathyroidism

Urine studies include the following:

• A calcium/creatinine ratio from a spot urine sample may be used as a screening test for hypercalciuria. Urinary calcium excretion is measured in a timed urine collection to determine fractional excretion of calcium. This will distinguish primary hyperparathyroidism from FHH since the former will usually present with hypercalciuria, while FHH is associated with a fractional excretion of calcium of less than 1%. There is however some overlap in urinary calcium excretion within these two entities. ^[18] Hypercalciuria in children is defined by a calcium excretion which is higher than an age appropriate Ca/creat ratio, or greater than 4mg/kg/day.

Biochemical markers of bone turnover include the following:

• Serum levels of osteocalcin or bone-specific alkaline phosphatase are elevated reflecting increased bone formation

• Serum C-telopeptide of type I collagen and Urinary N-telopeptide (NTx) are elevated because of increased bone resorption.

Genetic tests include the following:

• Genetic tests for familial forms of primary hyperparathyroidism are available and should be done to determine further work-up, management and genetic counseling. CASR mutation studies are recommended in cases suggestive of FHH or NHSHPT. MEN1, RET, CDKN1B and CDC73  in cases of MGD or those with a positive family history of endocrine neoplasia.[9]

Note that a case has been reported describing a 14-year-old girl with a parathyroid adenoma who presented with hypercalcemia, pancreatitis, and nephrolithiasis, yet had a low serum intact PTH level.[19] A turbo assay, however, showed very high PTH levels, as did a C-terminal assay. There was no mutation in the PTH gene sequence, which may well indicate that there was a post-translational modification of PTH not recognized by DNA sequencing. More than one assay may be required if there is biochemical evidence of hyperparathyroidism.

Imaging studies of the parathyroids to confirm the biochemical diagnosis of primary hyperparathyroidism

Sestamibi scanning paired with single-photon emission computerized tomography (SPECT)/CT to localize the parathyroid lesions prior to surgery is complementary with ultrasonography (US).  Sestamibi scan was found to have an accuracy of 86% in a recent review of all studies to date in children, while the accuracy for US was 79%  in the same review. In adult hyperparathyroidism, the largest review found a sensitivity of 88% for sestamibi scan and 75.5% for US.[2, 17]  The sensitivity of both US and sestamibi scans was much lower for MGD  (35 and 45% respectively) as well as for double adenomas (16 and 30% respectively) in the adult hyperparathyroidism review.  Ectopic adenomas, mediastinal, intrathyroidal and intrathymic, accounted for 9.5%-12% in some of the larger pediatric series, leading to the lower sensitivity for US.[2, 8]  

Complementary imaging studies to look at the effect of hyperparathyroidism on target organs

Bone densitometry, determined by dual energy x-ray absorptiometry (DEXA) is an areal or 2-dimensional measurement but can be followed longitudinally to evaluate the severity of the effect on bone and the effectiveness of therapy. Bone mineral density in the lumbar spine and whole body less head are expected to be low compared with age-related reference range values. In children with short stature these values must be adjusted for height. ​ 

Renal US is used to look for nephrocalcinosis and nephrolithiasis.

Skeletal radiographs may exhibit stigmata of hyperparathyroidism in relatively few cases are not need for the diagnosis of hyperparathyroidism. Cortical bone is primarily affected, as opposed to cancellous or trabecular bone.

Radiography may reveal the following:

• Multiple areas of subperiosteal bone resorption of the distal phalanges
• Tapering of the clavicles
• Brown tumors of the long bones and a salt-and-pepper appearance of the skull: These occur in less than 5% of US patients with primary      disease.

In most cases of primary hyperparathyroidism, an adenoma involving only 1 of 4 glands is present. Less frequently, adenomas involve multiple glands, and parathyroid carcinoma is very rare. MGD involves hyperplasia of 2 or more glands.

All histologic findings have been described in adults. An adenoma is defined by shape, size, consistency and histology. Histological findings include decreased intracellular and stromal fat.[20]

FHH is mild, usually asymptomatic, and therefore does not require specific therapy. Treatment for NSHPT has been surgical but the development of new drugs has allowed for successful medical management in several cases. These therapies are considered experimental and include calcimimetics (cinacalcet) and bisphosphonates (pamidronate), which have been used as monotherapy or as combination therapy.[21, 22]

Cinacalcet, an allosteric modulator of the CASR, has not been approved in children and requires close supervision. Hypocalcemia has been the principal side effect described when used for NSHPT, and a trial was suspended because of one death in an older child which may or may not be related to the medication.[22, 23] A study by Bernardor et al reported that the off-label use of cinacalcet in children reduced PTH and calcium levels without a significant increase in adverse effects.[24] Bisphosphonates are similarly not approved in children but have been used more extensively in osteogenesis imperfecta and pediatric osteoporosis. Treatment is surgical if medical therapy fails, with total parathyroidectomy being the preferred approach to avoid recurrence.[25]

Patients with calcium levels at 12-14 mg/dL should be admitted to the hospital. If asymptomatic, saline hydration may suffice. The treatment of acute severe hypercalcemia (serum calcium level >14 mg/d, or 12-14 mg/dl but symptomatic) includes hydration with isotonic sodium chloride solution to restore extracellular fluid volume that may be depleted secondary to vomiting and to induce calciuresis. Loop diuretics (eg, furosemide) should be avoided as they may worsen dehydration. Additional forms of medical treatment that can be used to decrease bone resorption include calcitonin and bisphosphonates such as pamidronate or zoledronate. These rapid acting therapies may be followed by cinacalcet while awaiting surgery.

Primary hyperparathyroidism due to a solitary adenoma is cured by resection of the adenoma. Total or subtotal parathyroidectomy with autotransplantation of a parathyroid gland is curative for multiglandular disease. As in adults, a minimally invasive approach with the use of intraoperative PTH (iPTH) measurements is the gold standard for surgical resection of solitary adenomas in children.[8, 1, 7, 26]  Rapid PTH assays have been used more routinely in adults; Nussbaum first described the use of  iPTH using sensitive immunoradiometric assay (IRMA) and demonstrated that a decrease of PTH levels to less than 40% of baseline values 15 minutes after parathyroidectomy confirmed cure.[27] According to the Miami criteria, cure is confirmed by a drop of  ≥ 50% of  the highest pre incision or pre excision PTH level when PTH is measured 10 min post complete resection.[28] The use of iPTH has significantly improved surgical outcome in cases with negative imaging studies.[8] Surgical outcome depends on the experience of the surgeon.

A study by Ramonell et al showed that outpatient parathyroidectomy for primary hyperparathyroidism can be safely performed in pediatric patients (aged 8-18 years). The only complications were permanent hypoparathyroidism in one patient and temporary hypocalcemia in another.[29]

Postoperative complications include transient hypocalcemia until parathyroids regain their sensitivity to circulating calcium. This requires treatment with calcitriol and calcium supplements until parathyroid function recovers. If hypocalcemia is mild calcium supplements may suffice. Hungry bone syndrome, a prolonged period of hypocalcemia, can occur postoperatively in those cases of primary hyperparathyroidism that demonstrated significant bone demineralization. Bones reaccumulate calcium at the expense of circulating levels and calcium supplements are needed for a longer time period. Finally, as in thyroid surgery, a risk of damage to the recurrent laryngeal nerve resulting in permanent hoarseness of the voice may be observed.

Outpatient care for postparathyroidectomy patients involves continued monitoring of serum calcium levels (if low at discharge) and observation of wound healing. Furthermore, care should include treatment of accompanying tumors, such as in multiple endocrine neoplasia type 1 (MEN I).

Post-parathyroidectomy, the patient's serum calcium level must be closely monitored to determine if any evidence of transient postoperative hypocalcemia or hungry bone syndrome is present. Monitor wound healing and observe for damage to the recurrent laryngeal nerve.

Cases of transient hypoparathyroidism post resection of an adenoma require treatment with calcium or calcium and calcitriol until calcemia has normalized, usually no longer than the first post-operative week. Calcium supplements may be required for a longer period in the presence of hungry bone syndrome.

Transfer to another facility is necessary only if current facilities cannot provide the expertise of an endocrinologist, or experienced surgeon. The surgeon's experience is an important factor in the outcome of parathyroidectomies.

The primary care provider should consult a pediatric endocrinologist.  Consultation with a surgeon may be obtained after consultation with the pediatric endocrinologist.  A urologist would need to be involved in the case of renal calculi. Genetic counseling for the patient and family members should be offered if the diagnosis of a genetic multiple endocrine neoplasia syndrome is made.

No strict dietary requirements are necessary for management of primary hyperparathyroidism. Vitamin D deficiency should be corrected to differentiate primary from secondary hyperparathyroidism.

There are no guidelines for the management of primary hyperparathyroidism in children. Adult guidelines recommend surgery for symptomatic patients and asymptomatic patients whose serum calcium is greater than1 mg/dL above the upper normal limit, have low BMD, vertebral fracture, creatinine clearance < 60 mL/min, 24 hr urine Ca >300 mg/day (males) or >250 mg/day (females), nephrolithiasis or nephrocalcinosis, or age < 50 years.[30]

Class Summary

Sodium chloride 0.9% fluid is used to supply intravenous hydration to replace fluids lost by emesis for patients with acute hypercalcemia of any etiology.

Class Summary

Bisphosphonates are antiresorptive agents that are used to help preserve bone mass. They are available in oral and parenteral forms. The inhibition of bone resorption produces a hypocalcemic effect. These agents are used in the management of conditions associated with increased bone resorption (eg, osteoporosis, Paget disease, management of hypercalcemia [especially that associated with malignancy]).

In case of acute hypercalcemia with vomiting, parenteral therapy is recommended. By reducing bone resorption, a calcium-lowering effect in the blood may occur.

Pamidronate (Aredia)

IV bisphosphonate that acts as an antiresorptive agent. Inhibits normal and abnormal bone resorption. Appears to inhibit bone resorption without inhibiting bone formation and mineralization. Currently accepted uses include the treatment of hypercalcemia associated with neoplasms and metastases as well as for treatment of Paget disease. This category of drugs is not approved for the treatment of hypercalcemia secondary to hyperparathyroidism; however, in practice, can be used for this as well as in the management of postmenopausal osteoporosis. Now being used in pediatrics to treat osteogenesis imperfecta and idiopathic juvenile osteoporosis. Preliminary study results on its use to prevent bone loss following severe burns appear promising.

Zoledronate

Class Summary

These agents are allosteric modulators of the CASR and thus reduce PTH levels

Cinacalcet (Sensipar)

Directly lowers intact parathyroid hormone (iPTH) levels by increasing sensitivity of calcium sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease. Indicated for secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Calcitriol

Calcitriol is used for post -surgical hypoparathyroidism in conjunction with calcium supplements.