The total mass of all parathyroid tissue in a newborn is between 6 and 9 mg. The glands are compact, consisting of distinct groups of functionally active chief cells that are heterogeneous in size. The total number of glandular cells in a newborn is about 4.3 × 10⁶ [21]. During the first year of life, the total parathyroid mass increases three- to four-fold. By age 5, their mass increases an additional two-fold, and around age 10, another three-fold. Progressively, total parathyroid mass increases to by 35–50 years of age and then stabilizes until the eighth decade of life [21].

Age-related changes in the parathyroids of children and adolescents include an increase in the number of chief cells and the appearance of oxyphil elements [22]. These changes are paralleled by progressive development of follicular structures lined by chief cells and filled with colloid-like fluid which reacts with amyloid. While stromal fat is a prominent part of normal adult parathyroid histopathology, the stroma of the pediatric parathyroid is significantly less adipose. The pediatric parathyroid appears denser with significant development of adipose tissue beginning in puberty. The adipose composition of the glands reaches 10–25 % of total gland mass by age 25–30 and 60–70 % in patients over 80 [21].

Most patients with familial hypocalciuric hypercalcemia (FHH) are heterozygous for mutations in the CaSR. Generally, these patients are asymptomatic and diagnosed only incidentally. Neonatal severe hyperparathyroidism (NSHPT) is a very rare and severe form of FHH that may present in the neonatal period in patients who are homozygous for this mutation. NSHPT is associated with severe metabolic bone disease and often life-threatening hypercalcemia (e.g., calcium levels >20 mg/dL). The diagnosis of NSHPT relies on the documentation of markedly elevated PTH levels, severe hypercalcemia, and relative hypocalciuria. A family history of early-onset hypercalcemia in a sibling or parent will further substantiate the diagnosis of FHH. It is important to recognize the distinction between NSHPT and the neonatal hyperparathyroidism associated with maternal hypocalcemia, which is transient and occurs in infants born to mothers with either severe vitamin D deficiency or hypoparathyroidism.

In the vast majority of cases that have been analyzed to date, NSHPT has been associated with homozygous inactivating mutations in the CASR gene, which encodes the CaSR located at 3p13.3 [23]. CaSR is expressed widely throughout the body, but its most significant physiologic role is the regulation of calcium homeostasis through its expression on the plasma membranes of parathyroid and renal tubule cells. Binding of extracellular calcium ions (Ca²⁺) to CaSRs leads to activation of signaling pathways that inhibit secretion of PTH by parathyroid cells and enhance urinary calcium excretion in distal renal tubule cells. Most neonates with NSHPT carry inactivating mutations on both CASR alleles, which leads to complete or near-complete absence of functional CaSRs in the parathyroid and in other cells in the body. This loss of calcium-sensing ability promotes enlargement of all four of the parathyroid glands and increased secretion of PTH, as well as decreased renal excretion of calcium [23, 24]. Subsequently, severe hypercalcemia results. It is postulated that the exposure of the affected fetus to normal maternal calcium concentrations intensifies development of hyperparathyroidism in utero, and leads to more severe hypercalcemia after birth [25–27].

A recent review article by Roizen and Levine pooled data from several studies on NSHPT. They found nearly equal distribution between males and females. The most common presenting symptoms were skeletal abnormalities (83 %), hypotonia (55 %), failure to thrive/feeding difficulties (43 %), and hyaline membrane disease/respiratory distress (22 %) [3, 8, 28]. Mallet et al. reported a mean serum calcium level of 3.64 mmol/L with a range of 2.75–6.75 mmol/L (normal range 2.1–2.6 mmol/L) and a mean intact PTH of 36 pg/mL with a range of 56–2214 pg/mL (normal range 10–70 pg/mL) [8]. While historically NSHPT had a mortality rate of nearly 50 %, the advent of automated serum calcium measurements in the 1980s drastically decreased mortality from this disease to nearly zero [3, 8]. Thus, improved outcomes in NSHPT have resulted from the availability of simple assays for serum calcium, and the common practice of measuring serum calcium concentrations in infants who are failing to thrive. In neonates of parents with FHH, early screening of serum calcium allows for rapid diagnosis and early treatment [3, 8].

While genetic syndromes that are associated with multi-gland disease (MGD) are relatively more common to present in patients <40 years of age than in older patients, solitary adenomas remain the most common cause of PHPT in younger patients, and account for over 80 % of primary hyperparathyroidism cases in children and adolescents [29–31]. Multiple gland hyperplasia accounts for only 16–17 % [32]. Double adenomas, normal parathyroid pathology, and parathyroid carcinoma have been reported in the pediatric population, but are exceedingly rare [31]. MGD in younger patients is generally due to hereditary disorders including multiple endocrine neoplasia type 1 (MEN-1), type 2a (MEN-2a), or familial isolated hyperparathyroidism. As discussed earlier, FHH heterozygotes who generally have asymptomatic disease may be diagnosed at any age, often incidentally when having lab work done for other reasons. While there is a well-established association between radiation exposure and later development of PHPT in adults [33, 34], there is only a single case report of childhood PHPT occurring in association with previous therapeutic radiation exposure [35].

Historically, pretreatment localization was not performed in adults or children with hyperparathyroidism. Intraoperative identification of the diseased gland was performed via bilateral cervical exploration. As imaging techniques have evolved, so has their application in the diagnosis and treatment of parathyroid disease. Most notably, the ability to localize parathyroid adenoma preoperatively using ultrasonography, nuclear medicine scans, computed tomography, and magnetic resonance imaging has ushered in the age of minimally invasive surgical techniques for pediatric patients as well as adults. No single large study has looked at the sensitivity or specificity of different imaging modalities in hyperparathyroidism in children or adolescents. The imaging modality of choice is often extrapolated from studies in adults looking at the same.