In general, hyperplasia of the parathyroid glands due to dysregulation of the normal calcium homeostatic feedback mechanisms results in the inappropriate production of parathyroid hormone despite elevated calcium levels.

Alternatively, a single adenoma can become autonomous in its function.

This results in increased conversion of 25-hydroxyvitamin D to 1, 25-dihydroxyvitamin D with increased intestinal calcium absorption, increased renal calcium excretion due to hypercalcemia resulting in the propensity for stone formation, and, most concerning, increased cortical bone resorption.

Secondary hyperparathyroidism occurs due to an inciting stimulus. Most commonly, this is seen in vitamin D deficiency or in renal disease with urinary calcium losses and poor conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D .

The genetic defect in MEN1 is an autosomal dominant loss-of-function mutation in the MEN1 gene, located on chromosome 11. This gene codes for menin, which is involved in the regulation of DNA replication and transcription [3, 4].

The genetic defect in MEN2a is a gain-of-function mutation in the RET proto-oncogene, located on chromosome 10. Though hyperparathyroidism occurs in a minority of patients with MEN2a, it is more prevalent in patients with mutations in codon 634 of the RET proto-oncogene [3].

The molecular pathways linking these genetic mutations to the development of hyperparathyroidism are incompletely understood.

The genetic defect in familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism is in the calcium-sensing receptor gene (CASR) on chromosome 3 [4, 5].

Primary hyperparathyroidism is extremely rare in children, with an incidence of 2–5 per 100,000 [2, 6].

MEN1 is the most common of the familial forms of primary hyperparathyroidism, accounting for 2–4 % of all cases of hyperparathyroidism, approximately 20 % of primary hyperparathyroidism, and 57 % of hyperplasia. MEN1 has a prevalence of 2–3 per 100,000 [3, 4, 6].

Hyperparathyroidism occurs in approximately 20 % of patients with MEN2a. In contrast to MEN1, the other features of MEN2a, specifically medullary thyroid cancer (~ 90 %) and pheochromocytoma (50 %), have a higher penetrance than does hyperparathyroidism [3].

In adults, the peak incidence of hyperparathyroidism occurs in the seventh decade [5].

Hyperparathyroidism in infancy is rare and can be associated with severe neonatal primary hyperparathyroidism, usually due to biallelic loss-of-function mutation(s) in the calcium sensing receptor gene [2, 4, 5].

In MEN1, primary hyperparathyroidism is usually the first detected endocrinopathy, can often be diagnosed by age 20, and is present in 95 % of patients by age 40 [3].

Primary hyperparathyroidism is found to be more common in females than males, with a ratio somewhere between 3:1 and 3:2 [2].

MEN1 has equal incidence in males and females [3].

There is not a known specific ethnic or geographic distribution of parathyroid disease in children.

Primary hyperparathyroidism has been linked to childhood neck irradiation and to long-term lithium use [5].

As mentioned above, parathyroid disease in children is related to several other disease states and syndromes. Specifically, MEN1 and MEN2, both result in hyperparathyroidism. In addition, renal failure can result in secondary hyperparathyroidism due to chronic calcium losses and poor vitamin D production. Tertiary hyperparathyroidism occurs when hyperparathyroidism becomes autonomous of the inciting stimulus in secondary hyperparathyroidism, such as when hyperparathyroidism persists after renal transplantation in cases of renal failure with secondary hyperparathyroidism [2, 3].

Diagnosis of MEN1 requires a genetic confirmation, which is sometimes difficult due to variable genotype/phenotype correlation and a significant prevalence (10 %) of de novo germline mutation [7]. Alternatively, a clinical diagnosis may be given if the patient has a tumor in two of the three classic organ systems (parathyroid, pancreas/duodenum, pituitary) or a family history of MEN1 and a tumor in one of the three organs [3].

In cases of known or newly diagnosed MEN1, first-degree relatives and known gene carriers should be screened with annual serum calcium tests. The utility of concomitant PTH levels is not clear. A similar screening plan for MEN2a may be used, especially as less aggressive surgery for parathyroid disease at the time of childhood thyroidectomy for medullary thyroid cancer prevention is becoming more widespread [3].

Specific features of hyperparathyroidism and the differential management of this entity in these related disease states and syndromes are discussed throughout this chapter.

The differential diagnosis of hypercalcemia is broad and can involve pathology related to multiple organ systems. A sample differential diagnosis is provided in Table 34.2, adapted from Safford et al. [2].