Decreased bone density
Shortened QT interval
Prolonged PR interval
In newborns, there is a very rare homozygous form of familial hypocalciuric hypercalcemia (FHH) , caused by hereditary mutation of the CaSR gene [18, 19]. Severe, symptomatic, and often life-threatening hypercalcemia along with increased PTH and relatively low urine calcium is seen and a history of early-onset hypercalcemia in a family member is highly suggestive. Conversely, heterozygotes are often asymptomatic and usually present later in life with incidental hypercalcemia and slightly elevated PTH .
In older children and adolescents, PHPT most often develops in isolation and presents as a single adenoma. PHPT can occasionally present secondary to multi-gland disease which is more likely to develop as part of an inherited genetic disorder such as multiple endocrine neoplasia type 1 (MEN1) or type 2A (MEN2A) or familial isolated hyperparathyroidism (Table 48.2).
Etiology of primary hyperparathyroidism in pediatric patients
Neonatal severe hyperparathyroidism (NSHPT)
Homozygous form of FHH CaSR mutation. Severe, can be life threatening. Multi-gland disease.
Familial hypocalciuric hypercalcemia (FHH)
Often heterozygotes for CaSR mutations, asymptomatic and diagnosed at any age. Mildly elevated calcium and PTH with low urine calcium.
Familial isolated hyperparathyroidism
Several different mutations, usually autosomal dominant. Usually multi-gland disease but can have adenomas.
PHPT can be presenting symptom. Usually multi-gland disease. Prolactinoma and pancreatic islet cell tumor complete triad.
Mutation in RET oncogene. Less common to present with PHPT (10–20 %). Medullary thyroid carcinoma and pheochromocytoma.
Sporadic single adenomas
>80 % of PHPT cases in both children and adults. Classically symptomatic. High calcium levels in blood and urine, high or high-normal PTH.
Extremely rare (<1 %). Single gland. High PTH, serum, and urine calcium.
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 . 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 .
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 . 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 .
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 . 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) . 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].
Childhood and Adolescent PHPT
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 % . Double adenomas, normal parathyroid pathology, and parathyroid carcinoma have been reported in the pediatric population, but are exceedingly rare . 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 .
The number one cause of PHPT in the pediatric population is a single adenoma. Nearly all of these are monoclonal proliferations of benign pathology and arise from sporadic mutations, the molecular basis of which is variable. For example, one subset of parathyroid adenomas is caused by chromosomal rearrangements in which the PTH promoter is placed upstream of cyclin D1 such that the PTH promoter then drives overexpression of this cell cycle regulator resulting in hyperparathyroidism .
Childhood and adolescent PHPT usually presents with symptoms, including most notably bone pain and abdominal symptoms such as cramping and constipation. Of the 15 % of patients who report few or no symptoms, the majority of these actually have skeletal or renal pathology. Laboratory tests typically will show classic hypercalcemia, hypophosphatemia, hypercalciuria, and either elevated or inappropriately normal concentrations of intact PTH.
Parathyroid adenomas may originate in any of the four parathyroid glands, but are more common in the inferior glands [37, 38]. Up to 10 % of parathyroid adenomas are found in ectopic sites, including the mediastinum (often within the thymus), thyroid, esophagus, and retroesophageal tissue. Adenomas are usually well circumscribed but lack a definitive capsule . Chief cells are the dominant cell types in the majority of parathyroid adenomas; however, oxyphil cells can also be seen in varying proportions [40, 41] and a few adenomas are comprised exclusively of oxyphil cells [42, 43]. Adenomas are virtually devoid of adipocytes, which are only observed in a rim of the compressed normal parathyroid tissue.
Multi-Gland Disease: Multiple Endocrine Neoplasia and Familial Isolated Hyperparathyroidism
Multiple endocrine neoplasia (MEN) is a group of disorders that cause neoplastic growths in multiple endocrine glands. MEN-1 syndrome, or Wermer’s syndrome , affects the parathyroids, pituitary, and pancreas and is generally associated with multi-gland PHPT, prolactinoma, and pancreatic islet cell tumors. Parathyroid involvement is usually the earliest manifestation of the syndrome and is generally detectable by 20–30 years of age. Treatment for the hyperparathyroidism is four-gland exploration with removal of at least three-and-a-half parathyroid glands. MEN-2a syndrome, or Sipple syndrome , is caused by a mutation in the RET proto-oncogene on chromosome 10q11.2. It is associated with multi-gland PHPT, pheochromocytoma, and medullary carcinoma of the thyroid . PHPT is only seen in 10–20 % of patients with MEN2a, and MGD is less common than in MEN1, some patients presenting with a single adenoma [45–47].
Familial isolated hyperparathyroidism can also present with MGD. The majority of cases are inherited in an autosomal dominant pattern; however, a few families show autosomal recessive inheritance. Parathyroid pathology most commonly show chief cell hyperplasia in all four glands; however, some may present with single adenomas. Additionally, there have been reports of an increased risk for parathyroid carcinoma, and other non-endocrine tumors [46–48].
Parathyroid Carcinoma and Hyperparathyroidism Jaw Tumor Syndrome
In adults, parathyroid carcinoma occurs in <1 % of parathyroid tumors and is usually associated with various somatic or germline mutations . The incidence of parathyroid carcinoma in the pediatric patient is even lower. Hyperparathyroidism-jaw tumor syndrome (HPJTS) is a genetic syndrome with a 10–15 % incidence of parathyroid carcinoma and is associated with ossifying fibromas of the mandible and maxilla and, less commonly, renal lesions such as cysts, hamartomas, or Wilms tumors [38, 50, 51]. HPJTS is due to a germline mutation in the tumor-suppressor gene CDC73 (formerly HRPT2). CDC73 mutations have been found in 66–100 % of sporadic parathyroid carcinoma .
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.
In 2013, a review by Belcher et al. noted that ultrasound was the most commonly used technique in preoperative localization in the adolescent patient . They report overall good results using ultrasound in adolescents with an average sensitivity of 79 % . An example of ultrasound localization of suspected parathyroid adenoma is shown in Fig. 48.1. Since the 2000’s, however, there has been a marked increase in the use of sestamibi nuclear imaging. The same adenoma localized using Tc99m-sestamibi imaging is shown in Fig. 48.2.
Sagittal view of left parathyroid adenoma using ultrasound without color Doppler
Tc99m-sestamibi scintigraphy in the typical coronal view shows a suspicious left inferior parathyroid gland
A study published in 2002 of 287 patients, ages ranging from 13 to 88 years, showed excellent sensitivity of Tc99m-sestamibi scintigraphy for single adenomas . Sensitivity in detecting single adenomas was 96 %; sensitivity for detecting double adenomas and four-gland hyperplasia was 83 % and 45 %, respectively . This study is representative of the majority of studies looking at Tc99m-sestamibi scans, showing excellent sensitivity for a single adenoma. The literature regarding the sensitivity of sestamibi specifically in adolescents is lacking, largely due to the rare nature of the disease, but the benefits of its use can be extrapolated.
Computed Tomography and Magnetic Resonance Imaging with Contrast
Typically reserved for use when other modalities fail, CT and MRI may also be effective in localizing parathyroid adenomas. Specifically, contrast-enhanced three-dimensional studies are best utilized when an ectopic parathyroid is suspected . Thin-section contrast-enhanced CT is reported to have sensitivity ranging from 46 to 87 % for identifying single adenomas . When compared with 99mTc-sestamibi scanning alone, fusion with CT images allows three-dimensional localization of adenoma, as seen in Fig. 48.3 . The sensitivity of MRI to identify adenomas has been reported to range from 65 to 80 % .
SPECT/CT fusion allows localization of the parathyroid adenoma (gray arrow) in the coronal (a), sagittal (b), and axial (c) views. The adenoma was identified in the left inferior parathyroid gland
Imaging Considerations Unique to Pediatric Patients
Since the mid-1990s, emphasis has been placed on limiting ionizing radiation exposure in children and adolescents. The risks of developing cancer after radiation exposure are multiplied in children for several reasons:
Children are considerably more sensitive to radiation than adults.
Children have a longer life expectancy than adults.
Children may receive a higher radiation dose than necessary if CT settings are not adjusted for their smaller body size .
With these considerations, it is no surprise that clinicians are willing to accept a slightly less sensitive test such as ultrasound as the primary mode of localization. There continues to be an increase in the application of Tc99m-sestamibi scanning in children. CT and MRI are therefore typically reserved only when other techniques fail to localize a lesion.
Definitive treatment for primary hyperparathyroidism is surgical removal of the offending parathyroid gland or glands. Historically, PHPT in the pediatric population has been managed with a standard bilateral neck exploration with identification of all four glands. This approach continues to be the standard of care for MGD in which at least three-and-a-half glands should be removed for resolution of hypercalcemia. However, with the discovery that PHPT is due to single adenomas in the majority of cases, and with the advent of successful preoperative localization imaging methods such as Tc99m-sestamibi, the trend has been towards minimally invasive surgical exploration with focused excision of a single gland. Norman et al. first described this technique in 1998 , and since that time minimally invasive parathyroid surgery (MIPS) has emerged as a leading method of treatment for PHPT caused by single adenoma.
While the literature supporting MIPS in adults is robust, there is currently very little published support for MIPS in the pediatric population. A 2010 paper by Durkin et al. from the University of Wisconsin looked at 25 patients aged 10–25 who underwent surgery for PHPT from 2003 to 2009 . In their series, all children 18 years or younger without a family history of disease were found to have a single adenoma at the time of surgery. MIPS was successful in 78 % of patients with positive preoperative localizing imaging (either Tc99m-sestamibi scanning or ultrasound). Only one patient who was 18 years or younger required conversion to a bilateral exploration, and this patient was found to have single-gland disease on the side contralateral to the positive localization study .
MIPS can be achieved through either the standard Kocher incision, a small transverse midline incision, a small transverse incision with endoscopy (either purely endoscopic or video-assisted), or an extra-cervical incision with endoscopy. Intraoperative parathyroid hormone (IOPTH) levels may be measured during the procedure, or a gamma probe used during radio-guided parathyroidectomy , to confirm that the correct gland has been removed and that no further hyper-functioning tissue remains. MIPS has many advantages in adults including that it can be performed using local anesthesia, requires less operative time, has fewer complications, and offers an improved cosmetic result and greater patient satisfaction . Additional advantages of MIPS are earlier hospital discharge and decreased overall associated costs [58, 59]. The same advantages are likely to be observed in children, except perhaps performing the procedure under local anesthesia.