Key Points:• Primary Hyperparathyroidism (PHPT) is rare in children and adolescents.
• Patients commonly present with bone pain and fractures.
• X-ray and DEXA scan show lytic bone lesions, cortical thinning, and low BMD.
• Solitary parathyroid adenoma is the most common cause.
• Parathyroidectomy is the gold standard for treatment.
Description:Primary Hyperparathyroidism (PHPT) is a rare disease in children and adolescents. The classic clinical presentation of PHPT is described as “stones, bones, abdominal groans, and psychiatric overtones.” While 80% of adults with PHPT are asymptomatic, only 15% of pediatric cases are asymptomatic (Roizen, 2012). Children present with hypercalcemia, skeletal disease, and kidney involvement, and often have more severe disease than adults. Skeletal involvement of PHPT manifests as low bone density, fractures, or Osteitis Fibrosa Cystica (OFC), which presents with bone pain and lytic bone lesions (brown tumors). Brown tumors are formed by excess parathyroid hormone (PTH) inducing osteoclast mediated bone demineralization, microfractures and microhemorrhage (Naji Rad, 2021). In children presenting with symptoms of hypercalcemia and skeletal disease, PHPT should be considered.
Epidemiology:The incidence of PHPT in children is rare, estimated as 2-5 in 100,000 people (Roizen, 2012). Childhood cases, usually in adolescents, make up approximately 5% of all PHPT cases (Roizen, 2012). While adult cases have a female predominance, studies have shown that pediatric PHPT cases are nearly equal among females and males (George, 2010; Roizen, 2012). PHPT in childhood is shown to have clinically significant morbidity.
Clinical Findings:In children with PHPT, skeletal symptoms are the most common finding. Patients often present with bone pain, skeletal deformities, and kidney stones. Additional symptoms include abdominal pain and neurological symptoms. Studies have shown that, compared to adults, children with PHPT have more severe bone disease and less severe kidney disease (George, 2010). Skeletal findings include osteopenia, subperiosteal resorption, often of the phalanges and distal radius, and pathologic fractures. Rarely, patients may present with osteitis fibrosa cystica or slipped capital femoral epiphysis. Genu valgum is a rare skeletal finding that has been reported in pediatric patients with PHPT where the lower extremities appear with the knees together and ankles apart. It may present at the age of puberty and patients may report chronic bone pain of the lower extremities (Ramkumar, 2014). Patients presenting with skeletal symptoms of PHPT have often been misdiagnosed as rickets even when blood tests have been consistent with PHPT. Physicians should be aware of the possibility of PHPT when patients present with skeletal abnormalities representative of rickets, and a biochemical profile should be performed.
Imaging Studies:X-ray: Osteitis fibrosa cystica, the classical presentation of PHPT in bone, will appear as a thinning of the cortex due to bone demineralization. Lytic bone lesions with pathologic fractures may be found in the pelvis and long bones. These lesions have often been misdiagnosed as bone malignancies including giant-cell tumor, osteosarcoma, and metastatic carcinoma (Misiorowski, 2017). Additional x-ray findings in PHPT include a salt and pepper appearance of the skull, and subperiosteal bone erosion of distal and middle phalanges.
Dual- energy X-ray absorptiometry (DEXA) scan: DEXA scans, which measure bone mineral density (BMD), can identify low bone mineral density due to PHPT, sometimes prior to the onset of symptoms or findings on x-ray. In PHPT, regions with more cortical bone, such as the distal radius, are subject to the most severe resorption, resulting in significantly decreased BMD. Structures with more trabecular bone, such as vertebrae, have only mildly decreased BMD.
Trabecular Bone score (TBS): TBS, an indirect index of trabecular bone microarchitecture, may be useful in differentiating bone qualities with similar densities on DEXA scan. Low TBS indicates poor microarchitecture and poor strength, which may be found in PHPT.
High resolution peripheral quantitative computed tomography (HR-pQCT): HR-pQCT measures cortical and trabecular bone quality. Measurements include volumetric bone density, bone geometry, skeletal microarchitecture, and bone strength in cortical and trabecular parts. Findings in PHPT include low volumetric bone density in trabecular and cortical regions. Trabecular compartments may be more widely spaced with heterogeneous distribution and cortices may be thinner (Stein, 2013).
Parathyroid/Thyroid Ultrasound: Parathyroid and thyroid ultrasound can be used to assess for gland enlargement and nodules.
- Blood tests: elevated PTH and calcium, decreased phosphate and vitamin D
- Urine Tests: Elevated Urine Calcium
- Bone formation markers: osteocalcin, type 1 procollagen peptide, alkaline phosphatase.
- Bone resorption markers: deoxypyridinoline, N-telopeptide, C-telopeptide.
- Renal Function tests should be performed to assess for secondary causes of hyperparathyroidism.
- Genetic Testing: Mutations in MEN1, RET, CDKN1B, and HPRT2 genes are associated with PHPT. CASR gene mutations should be assessed if there is concern for Neonatal Severe Hyperparathyroidism (NSHPT) or Familial Hypocalciuric Hypercalcemia (FHH).
Treatment:Surgical Intervention: Parathyroidectomy is the definitive treatment for children and adult PHPT patients with skeletal involvement. Osteitis Fibrosa Cystica is usually resolved following surgery, and bone mineral density is usually improved within the first postoperative year (Khedr, 2017; Marcocci, 2012). Risk of fractures has also been shown to decrease following surgery (VanderWalde, 2006; Yeh, 2016).
For patients who require surgical fracture management, simultaneous procedures may be performed to limit time under anesthesia, decrease length of hospital stay and recovery time. By removing the underlying cause of the skeletal abnormalities, parathyroidectomy with simultaneous fracture care has been shown to improve orthopaedic outcomes (Singhal, 2001).
For patients who do not undergo simultaneous procedures, the order of procedures is usually indicated by comparing the severity of orthopaedic and endocrine concerns. In pediatric patients with slipped capital femoral epiphysis (SCFE), SCFE fixation and parathyroidectomy should both be performed (El Scheich, 2012). In an orthopaedic emergency, SCFE fixation should be performed first, followed by parathyroidectomy as soon as possible. In cases of severe hypercalcemia, parathyroidectomy should be performed first, followed by SCFE. For patients who undergo parathyroidectomy first, surgeons should monitor the patient for development of hungry bone disorder (HBS). If a patient develops HBS, orthopaedic surgery should be delayed until calcium levels are normalized (Vanitcharoenkul, 2021). The literature has not discerned specific surgical considerations for pediatric patients with PHPT versus non-PHPT patients undergoing orthopaedic procedures.
If surgery is not an option, medical treatments can be useful in regulating PTH, calcium, phosphate and vitamin D levels.
Alendronate (bisphosphonate): Bisphosphonates inhibit osteoclast induced bone resorption, which will limit the demineralization caused by PTH. Alendronate is a bisphosphonate commonly used in PHPT and has been shown to increase BMD (Marcocci, 2012).
Cinacalcet: Cinacalcet increases sensitivity of the Calcium sensing receptor, inhibiting PTH synthesis and secretion. It is used to decrease serum calcium levels in PHPT patients with moderate to severe hypercalcemia (Marcocci, 2012; Tuli, 2021).
Vitamin D: Vitamin D supplementation is indicated for patients with vitamin D deficiency. It has been shown to decrease PTH levels (Rolighed, 2011). Plasma and urinary calcium should be monitored in patients receiving vitamin D.
Complications:Fractures are commonly seen in the legs, arms, and spine. Hungry Bone Syndrome (HBS) is a post-operative complication found in 50% of children with PHPT who undergo parathyroidectomy (George, 2010). It is caused by a sudden decrease in PTH inducing rapid bone mineralization and prolonged hypocalcemia due to the movement of calcium from circulation into bone. It is often defined as hypocalcemia less than 8.4 mg/dL for four or more days following surgery (Witteveen, 2013). Patients may present with signs of hypocalcemia including carpopedal spasm (Trousseau sign), perioral paresthesia (Chvostek sign), tingling of extremities, and convulsions that may cause pathologic fractures (Witteveen, 2013). Additionally, patients may experience rapid increases in BMD, even within the first few days following surgery (Agarwal, 2002). HBS is more common in PHPT patients with skeletal manifestations including subperiosteal erosion, brown tumors, and pathologic fractures. A systematic review reported that 47-100% of patients who developed HBS had osteitis fibrosa cystica (Witteveen, 2013). Patients with HBS should be treated with IV calcium and high dose vitamin D. While HBS is a rare finding in adults with PHPT, HBS is much more common in children with PHPT due to the increased severity of disease.
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