Fourteen-Year-Old With Recurrent Fractures

A 14-year-old boy with a history of recurrent left distal fibular fractures presents to the University of Florida orthopedic clinic for evaluation of a cystic bone lesion on the left distal fibula (Figure 1). The patient developed a fracture in his left distal fibula after a basketball injury 2 years ago that had healed completely. He fractured his left fibula again after another sports injury 2 months prior to his visit. Radiographs at that time were noted to have abnormal physes of the tibia and fibula, prompting referral to the orthopedics clinic. Since his first fracture 2 years ago, he has walked with an abnormal gait. He denies any additional history of trauma or metabolic diseases. He has had recent mood changes, lower abdominal pain, and polydipsia, but denies constipation, back pain, and dysuria. There is no family history of metabolic or bone disorders. A physical examination reveals an abnormal gait with the legs externally rotated bilaterally and a positive Trendelenburg sign bilaterally. The patient has pain and difficulty with internal rotation of the hips bilaterally. A skeletal survey shows bilateral slipped capital femoral epiphyses, and he had evidence of widened physes in wrists, shoulders, ankles, and knees. Several areas demonstrate abnormal physes, mainly the left distal tibia and fibula (Figure 2). Radiographs also reveal abnormal calcifications of the left kidney. His growth parameters include a height of 166.4 cm (39%, Z = −0.27), a weight of 72.8 kg (92%, Z = 1.4), and a body mass index of 26.29 kg/m2 (94%, Z = 1.59).Laboratory testing reveals a calcium of 11.6 mg/dL (ref range 8.9–10.4 mg/dL), phosphorus of 2.6 mg/dl (ref range 3.4–5.5 mg/dL), parathyroid hormone of 1004 pg/mL (ref 15–65 pg/mL), alkaline phosphatase of 611 IU/L (ref 114–375 IU/L), and 25-hydroxy vitamin D of 7.5 ng/mL (ref 20.0–100 ng/mL). Serum urea nitrogen and creatinine are normal at 9 mg/DL and 0.71 mg/dL, respectively. Imaging studies using computed tomography and technetium Tc 99m sestamibi scan reveal an ectopic parathyroid adenoma located just superior to the left thyroid lobe extending to the carotid bifurcation (Figure 3 and Figure 4). Laboratory and imaging results reveal the diagnosis.Based on the elevated parathyroid hormone levels with elevated calcium and low phosphorus levels, the patient was diagnosed with primary hyperparathyroidism. Imaging confirms the primary hyperparathyroidism is caused by a parathyroid adenoma.To identify the underlying cause of the patient’s widened physes and other bone abnormalities and recurrent pathologic fractures, laboratory and imaging studies must be obtained. An assessment of calcium, phosphorus, vitamin D, and parathyroid hormone levels are needed to identify metabolic etiologies, whereas a complete blood count with differential and lactate dehydrogenase would aid in the diagnostic workup for neoplasms. Additional imaging studies for parathyroid abnormalities may include imaging of the parathyroid glands by ultrasonography, computed tomography, or nuclear medicine scans (eg, technetium Tc 99m sestamibi scan), whereas if there is concern for a bony neoplasm, magnetic resonance imaging may be indicated. The patient’s recent mood changes, polydipsia, and abdominal pain as well as the presence of widened epiphyses and renal calcification suggest the patient is hypercalcemic and in a state of bone resorption. Hypercalcemia is most often associated with hyperparathyroidism. Primary hyperparathyroidism, resulting in an overproduction of parathyroid hormone (PTH), can lead to hypercalcemia, hypophosphatemia, and decreased bone density leading to increased fracture risk. Imaging studies, including a technetium Tc 99m sestamibi scan, may be useful in identifying a parathyroid adenoma. An assessment of the patient’s vitamin D levels must also be considered. In severe cases, nutritional rickets resulting from a decreased intake of vitamin D can lead to bone abnormalities, as seen in this case. Laboratory studies in a patient who has vitamin D–deficient rickets would typically reveal low or normal calcium levels, hypophosphatemia, low 25-hydroxyvitamin D, and elevated levels of alkaline phosphatase. Radiographs of a child with rickets often show multiple areas of decreased bone mineralization, most prominently along the epiphyseal plate. Additional findings include pigeon breast deformity, frontal bossing, fraying of the metaphyseal plate, and bowing of the legs. Although this patient had several of these bony findings, his renal calcifications and polydipsia are not consistent with the diagnosis of rickets. Finally, bony malignancies such as Ewing sarcoma and osteosarcoma may also be on this patient’s differential, although these are less likely given the lack of characteristic radiographic features on this patient’s initial radiographs. Ewing sarcoma most commonly presents in the femoral diaphysis and has a mixed radiolucent and radiopaque appearance with a lamellated (onion skin) periosteal reaction, whereas osteosarcoma will appear as mixed areas of radiolucency and radiodensity and often has an associated soft tissue mass.1Primary hyperparathyroidism (pHPT) is characterized by the overproduction of PTH by the parathyroid glands. PTH is essential for maintaining calcium and phosphate levels in the blood. High levels directly stimulate osteoclast differentiation, leading to increased bone resorption. In the kidneys, PTH increases calcium resorption in the distal convoluted tubule while promoting phosphate excretion. Ultimately, patients with pHPT can experience severe hypercalcemia and hypophosphatemia.1 This calcium imbalance impacts several organ systems. Prominent symptoms include nephrolithiasis, psychological changes, cardiac arrhythmias, gastric ulcers, abdominal pain, constipation, and fatigue.2–6 Notably, although the effect of pHPT on bone commonly leads to osteoporosis and osteopenia, severe pHPT produces a unique form of osteoporosis referred to as osteitis fibrosa cystica or a brown tumor, in which fibrotic tissue replaces normal bone.2 The development of slipped capital femoral epiphysis is also associated with pHPT. This occurs because of chronic elevations in PTH that inhibit ossification of the epiphyses as well as interrupting the connections between metaphysis and epiphysis through increased osteoclastic activity. In combination, the effect is an increase in the risk of epiphyseal slipping.7Although rare, pHPT impacts about 2 to 5 children per 100 000 live births.3,4 Compared with adults, children are more likely to present with symptoms, but this may be because of a lack of regular biochemical screening. Often, children with pHPT are misdiagnosed in their youth, delaying treatment until they reach adulthood.3,5,6 Children are more likely to have a higher serum calcium level and lower serum phosphate levels but similar PTH levels to adults. These findings are likely because of increased target organ sensitivity to PTH in childhood.3,5 Presentation of pHPT has been reported to vary with age. A retrospective cohort analyzing the presentation and treatment of patients under the age of 20 years old who had pHPT found that children under the age of 15 years old were more likely to have bone-related disease, whereas patients over the age of 15 presented predominantly with renal issues. The male to female ratio differed among age groups, with a 2:1 ratio in children under 15 years old and a 1:1.7 ratio in children over 15 years old. In adults, this ratio typically falls around 1:4.3 The etiology for these age-related differences in presentation is not well known.The underlying etiology of pHPT varies. The majority of cases of pHPT are caused by a single parathyroid adenoma; multiglandular adenomas are rare.2,3 Hyperplasia of the parathyroid glands can also lead to pHPT and occurs because of increased proliferation of chief cells. Biopsies are needed to distinguish between adenomas and parathyroid hyperplasia. In rare instances, parathyroid carcinomas may also lead to pHPT. These malignancies are slow growing and easily cured by surgical removal. They often cause severely elevated calcium levels (∼14 mg). Relapse and metastasis to the lungs, liver, and bones are possible.2Although most cases of pHPT occur sporadically, some familial endocrine disorders are linked to pHPT. Multiple endocrine neoplasia disorders are autosomal-dominant conditions caused by mutations in the RET oncogene. Multiple endocrine neoplasia type 1 (MEN1) is associated with hyperparathyroidism caused by parathyroid hyperplasia, involving all 4 glands, and tumors in the pituitary gland and pancreas. MEN2A is associated with parathyroid adenomas, resulting in hyperparathyroidism. Additionally MEN2A increases a patient’s risk for developing medullary thyroid carcinoma and pheochromocytomas.2,6 Finally, familial non-MEN pHPT can lead to parathyroid adenomas but lacks the other features of MEN1 and 2A. Family history of parathyroid disease or hypercalcemia may be linked to pHPT in children, and screening for MEN syndromes should be strongly considered in children presenting with pHPT.6Regardless of the underlying pathology, surgical removal is the mainstay treatment of parathyroid masses producing symptomatic hyperparathyroidism. In the case of an adenoma, the affected gland is removed. If multiple glandular involvement is suspected, open bilateral exploration can be performed, and a partial or total parathyroidectomy may result. Partial parathyroidectomies are also performed for children with MEN1 or MEN2A. Complete surgical removal with clean margins is performed in the case of parathyroid carcinoma. In most patients, PTH and serum calcium levels reach a normal reference range within a day.3 Intraoperative PTH can be used to assess for adequate removal. Transient or permanent hypoparathyroidism and transient vocal cord paralysis are common complications of the surgery. Multiple operations may be necessary if hypercalcemia persists. This is often a result of the development of a recurrent adenoma.6There is some debate over delaying treatment of pHPT in both adults and children. Although the surgical removal of an adenoma can lead to scarring and potential nerve damage, chronic hypercalcemia and hypophosphatemia may result in nephrocalcinosis that can progress to pyelonephritis, nephrolithiasis, and permanent renal damage. If surgery must be delayed, calcimimetics such as cinacalcet and bisphosphonates can be used to lower PTH, calcium levels, and rates of bone resorption. Additionally, patients should be advised to maintain a low-calcium diet.3–6The patient initially underwent in situ fixation to correct his bilateral slipped capital femoral epiphysis without complication. He then had a left parathyroidectomy to remove the adenoma. The patient’s PTH levels fell from over 1000 to 9 pg/mL after the operation. He experienced facial paresthesia after surgery, but these symptoms resolved once he started calcium supplementation. He continues to experience hypoparathyroidism and requires treatment with calcitriol, calcium carbonate, and cholecalciferol. Genetic testing results for MEN1/MEN2A were negative.SummaryChildren presenting with abnormal bone findings, including rickets or bilateral slipped capital femoral epiphysis, should be evaluated for primary hyperparathyroidism (pHPT).Children with pHPT should be screened for genetic causes including MEN1 and MEN2A.Surgical removal of overactive parathyroid tissue should be considered first-line therapy for the treatment of pHPT in children.