Pediatric Hyperparathyroidism

Updated: Apr 17, 2017
  • Author: Edna E Mancilla, MD; Chief Editor: Sasigarn A Bowden, MD  more...
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Overview

Background

Hyperparathyroidism refers to a serum Parathyroid Hormone (PTH) level above the normal range. PTH secretion is regulated by the action of serum ionized calcium on the Calcium Sensing Receptor (CASR) in parathyroid chief cells. Physiologically, calcium level is maintained within normal limits mainly due to this calcium sensing mechanism. Hyperparathyroidism may be classified into three major subtypes based on pathophysiology; primary, secondary and tertiary hyperparathyroidism.

Normal parathyroid glands as seen during a thyroid Normal parathyroid glands as seen during a thyroidectomy. The large arrow points to the superior parathyroid. The thinner arrow points to the inferior parathyroid. The forceps points toward the recurrent laryngeal nerve. The patient's head is toward the right.

 

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Pathophysiology

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.

 

 

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Epidemiology

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. [13]   In adults PHPT is more frequent in females, while most pediatric series find no difference in distribution by sex. [4]

 

 

 

 

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Prognosis

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.

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Patient Education

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
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