Multiple Lytic Skeletal Lesions and Hypercalcemia in a 13-Year-Old Girl

A 13-year, 8-month old girl presented with worsening left hip pain after kicking a soccer ball 2 weeks previously. The pain was a dull, aching discomfort located in the groin. During the previous month, she also complained of occasional pain in both hips, and in the left arm and hand. For the last 6 months, she often felt tired and weak, and sometimes had nausea and vomited. There was no history of fever, chills, weight loss, or night pain, no significant medical history, and no family history of musculoskeletal disorders or cancer. Her childhood development was normal, her menarche was at 11 years of age, and her menstrual cycles were regular. On physical examination, she appeared healthy. She was obese (85 kg) and had Tanner Stage 513 development of secondary sexual characteristics. She had a slight antalgic gait of her left lower limb. She had bilateral groin pain with hip internal rotation and left shoulder pain with internal and external rotation of the glenohumeral joint. She had mild tenderness to palpation of the second metacarpal head of her left hand. Neurologic examination was normal and the patient had symmetric reflexes and full strength. Radiographs of her pelvis and hips (Fig 1), left humerus (Fig 2), and left hand (Fig 3) were obtained. Magnetic resonance images of her pelvis and hips (Fig 4) and a bone scan were obtained.Fig 1A: C. (A) Anteroposterior radiograph of pelvis. (B) Frog leg lateral radiograph of right hip. (C) Frog leg lateral radiograph of left hip.Fig 2: Anteroposterior radiograph of left shoulder.Fig 3: Anteroposterior radiograph of left hand.Fig 4: T2-weighted axial MRI scan of pelvis.Based on the history, physical examination, and imaging studies, what is the differential diagnosis? RADIOGRAPHIC INTERPRETATION The frontal radiograph of the pelvis (Fig 1A) revealed multiple lucent areas involving the femoral necks, most of the left iliac wing, the right supraacetabular region, and the left ischium and pubis. The lesions were confluent, with well-defined margins, and without matrix. Frog leg lateral views of both hips (Figs 1B-C) showed that the lesions involved the entire femoral neck, and extended through the metaphysis to involve most of the proximal femoral epiphyses. The lesions in the ilium and ischium were multilobulated. There were no erosions in the pubic symphysis or ischial tuberosities. A frontal radiograph of the left shoulder (Fig 2) showed a similar multilobulated epimetaphyseal lucent lesion in the proximal humerus. A frontal radiograph of the left hand (Fig 3) showed an expansile lucent lesion in the head of the second metacarpal. The bony trabeculae were lacy and there were cortical erosions. Subcortical tunneling and subperiosteal bone resorption were most prominent in the radial aspect of the phalanges. An axial fat-suppressed T2-weighted image of the pelvis (Fig 4) showed bilateral high signal intensity lesions in the iliac wings. The abnormalities were confined to the bone, and there was no evidence of perilesional edema or soft tissue mass. On the left, the lesion had septation, indicating that it was cystic. In the left anterior and superior iliac spine, there was a small area of cortical buckling with adjacent edema, most likely representing a small pathologic fracture. DIFFERENTIAL DIAGNOSIS Lymphangiomatosis of bone Leukemia Langerhans' cell histiocytosis Hyperparathyroidism Ollier's disease Multiple bone cysts Multiple nonossifying fibromas Metastatic disease Multicentric giant cell tumor CLINICAL COURSE The patient was scheduled for open biopsy of one of the pelvic lesions for diagnosis. Preoperatively, she was fatigued and nauseated with intermittent emesis during the past few days. She was alert and oriented, but appeared pale and tired. Laboratory evaluation revealed severe hypercalcemia with a serum calcium level of 19.3 mg/dL (normal, 8-10.5 mg/dL), a serum ionized calcium level of 2.37 mmol/L (normal, 1.14-1.29 mmol/L), a urinary calcium level of 20.7 mg/dL, and a serum parathyroid hormone level of 1595.4 pg/mL (normal, 10-65 pg/mL). Other abnormal laboratory values included hematocrit (30.9%), serum alkaline phosphatase (1034 U/L; normal, 50-165 U/L), serum potassium (2.4 mmol/L; normal, 3-4.5 mmol/L), serum chloride (98 mmol/L; normal, 99-111 mmol/L), serum creatinine (1.3 mg/dL; normal, 0.3-1 mg/dL), and serum magnesium (1 mg/dL; normal, 1.5-2.2 mg/dL). An electrocardiogram revealed ST depression and T wave inversion in inferolateral leads. The patient was admitted to the intensive care unit in serious condition. She was placed on a cardiac monitor and treated for hypercalcemia with normal saline fluid replacement, intravenous Lasix every 6 hours, and subcutaneous calcitonin. A thyroid scan was obtained (Fig 5) that showed increased uptake at the base of the neck suggestive of a parathyroid adenoma. Ultrasonagraphy and computed tomography (CT) confirmed a right inferior parathyroid mass of approximately 3 × 1 × 2 cm size. The patient subsequently underwent right inferior and superior parathyroidectomy (Fig 6).Fig 5: Thyroid scan.Fig 6A: C. (A) Right inferior parathyroidectomy specimen. (B) Histologic specimen of right inferior parathyroid adenoma (Stain, hematoxylin and eosin; magnification ×40). (C) Histologic specimen of right superior parathyroid gland (Stain, hematoxylin and eosin; magnification ×40).Based on the history, physical examination, laboratory studies, imaging studies, and histologic pictures, what is the diagnosis and what additional treatment is indicated in this patient? PATHOLOGY The right inferior parathyroid specimen (Fig 6A) consisted of an encapsulated adenoma measuring 2.8 × 2 × 1.5 cm. On cut section, the mass appeared fleshy, homogeneous, and light tan. Histologically, the adenoma (Fig 6B) was composed of nests of uniform cells surrounded by vascular delicate septae. Occasional nuclei were eight to 10 times larger, but had homogeneous chromatin and no evidence of anaplasia. Mitoses were not identified. For histologic comparison, the unremarkable right superior parathyroid gland also is shown (Fig 6C). DIAGNOSIS Parathyroid adenoma with primary hyperparathyroidism. DISCUSSION Primary hyperparathyroidism includes disorders of the parathyroid glands characterized by an excessive and inappropriate secretion of parathyroid hormone, resulting in hypercalcemia. It is caused by a solitary adenoma in one parathyroid gland in 80% to 85% of patients, multiple adenomas in 2% to 4% of patients, diffuse hyperplasia of all four parathyroid glands (that frequently occurs as a hereditary trait such as multiple endocrine neoplasia) in approximately 15% of patients, and parathyroid carcinoma in less than 1% of patients.2,11 The precise etiology of primary hyperparathyroidism is unknown but familial syndromes, prior neck irradiation, chromosomal rearrangements, inactivation of tumor-suppressor genes, and mutations in calcium-receptor or vitamin D-receptor genes have been implicated.2 The number of cases of primary hyperparathyroidism has increased during the last several decades because of the use of routine biochemical screening and is estimated at a prevalence of 100 per 100,000 population and an annual incidence of 28 per 100,000 population or 100,000 new cases per year in the United States.6,8 The disorder is most common in patients in the fifth and sixth decades of life and occurs in women with at least twofold greater incidence than men.6,8 Primary hyperparathyroidism in infants or children is rare and is unusual in adolescents.3,4,7,10 Virtually all infants with primary hyperparathyroidism have parathyroid hyperplasia, whereas children and adolescents with primary hyperparathyroidism typically have a parathyroid adenoma.3,4,7,10 Unlike the adult-onset form, there is a male predominance in childhood-onset hyperparathyroidism as reported in several series.3,4,7,10 The incidence of chronic, asymptomatic primary hyperparathyroidism in children is unknown because routine blood chemistry screening is uncommon. However, hyperparathyroidism appears to be distinctly uncommon in children compared with adults in whom asymptomatic hypercalcemia is the most common (> 80%) presentation of primary hyperparathyroidism.1-3,7 Infants typically present with hypercalcemic crisis attributable to severe disease; however, older children may present with subtle signs and symptoms such as fatigue, exhaustion, lethargy, poor appetite, polyuria, weight loss, abdominal pain, constipation, nausea, or vomiting.3,7 Findings may include nephrocalcinosis, nephrolithiasis, corneal or conjunctival calcification, hematuria, diminished reflexes, muscle weakness, slipped capital femoral epiphysis, or a poorly defined neuropsychiatric spectrum ranging from decreased attentiveness to severe depression or stupor. Skeletal involvement includes polyostotic lytic bone lesions or diffuse osteoporosis attributable to bone resorption induced by elevated parathyroid hormone and manifested clinically by bone pain or pathologic fracture.5 Radiographic findings include osteopenia, subperiosteal resorption (particularly of the radial aspect of the middle phalanges of the index and long fingers), distal tapering of the clavicles, "salt and pepper" appearance of the skull, resorption of the distal phalanges, chondrocalcinosis, and destructive lytic lesions such as "brown tumors" and osteitis fibrosa cystica in patients with more advanced stages of the disease. Hypercalcemia, hypophosphatemia, and hypercalciuria are the laboratory hallmarks of primary hyperparathyroidism. Other biochemical features include a mild metabolic acidosis, increased 1,25 dihydroxyvitamin D, increased urinary excretion of cyclic adenosine monophosphate, and decreased tubular resorption of phosphate. The diagnosis is confirmed by elevated serum levels of parathyroid hormone. Localization of abnormal parathyroid glands can be accomplished by ultrasonography, dual isotope scans, CT scans, and magnetic resonance imaging. Hypercalcemia of malignancy and hyperparathyroidism account for more than 90% of cases of hypercalcemia, with other entities in the differential diagno-sis of hypercalcemia including renal failure, glucocorticoid use, lithium use, chlorothiazide diuretic use, vitaminosis A or D, multiple endocrine neoplasia Types I and IIa, granulomatous disorders, Addisonian crisis, and familial hypocalciuric hypercalcemia.2,11 The treatment of primary hyperparathyroidism in children and adolescents is surgical, whereas treatment of adults depends on the patient's age and symptoms. Before routine serum chemistry screening, primary hyperparathyroidism usually was diagnosed symptomatically and the treatment was surgical parathyroidectomy. With a higher proportion of patients who are symptom-free in whom hyperparathyroidism was detected by screening, new questions have arisen concerning the necessity of surgical parathyroidectomy. The National Institutes of Health convened a consensus development conference in 1991 and recommended surgery for the following conditions: age younger than 50 years, history of hypercalcemic crisis, total serum calcium concentration more than 1 mg/dL above the upper limit of the normal range or greater than 11.5 mg/dL, evidence of overt bone disease, cortical mean bone density more than 2 standard deviations below the adjusted mean for age and gender, reduced renal function, nephrocalcinosis or nephrolithiasis, and hypercalciuria (> 400 mg/day).9 It is estimated that because approximately 20% of patients are symptomatic and because these criteria identify approximately 30% of patients who are symptom-free, then approximately 40% of patients with primary hyperparathyroidism are surgical candidates.2,11 Parathyroidectomy has high curative success rates with restoration of calcium homeostasis and improvement in bone mineral density.12 Improvement also typically is seen with respect to fatigue, lethargy, nausea, vomiting, nephrolithiasis, and weakness. Lytic skeletal lesions tend to heal gradually after parathyroidectomy; however, persistent symptomatic lesions or persistent lesions in high stress locations may require curettage, bone grafting, and prophylactic stabilization.2,5 Surgical complications of parathyroidectomy include tumor recurrence, hypoparathyroidism, and recurrent laryngeal nerve injury with attendant vocal cord dysfunction.2 Medical treatment of primary hyperparathyroidism consists of urgent treatment of hypercalcemic crises and monitoring of patients with mild hyperparathyroidism. The natural history of mild primary hyperparathyroidism may be fairly benign. Treatment in these patients includes regular followup to detect complications that would justify surgical referral, avoidance of diuretics, avoidance of dehydration, avoidance of immobilization, estrogen replacement in postmenopausal women, and moderation of dietary calcium. Safe and effective therapeutic agents for the chronic medical treatment of primary hyperparathyroidism still are lacking, although phosphate, estrogen, calcitonin, bisphosphonates, and calcimimetic agents have been suggested.2,11 The differential diagnosis of multiple lesions in children includes multiple enchondromatosis, histiocytosis, hereditary multiple osteocartilaginous exostoses, leukemia, metastatic disease, neurofibromatosis, fibrous dysplasia, and metabolic bone disease. With a systemically involved skeleton, particular consideration should be given to possible metabolic bone disease. Laboratory evaluation of children and adolescents with multiple skeletal lesions is essential, because metabolic bone disease may result in life-threatening metabolic abnormalities, as in the current patient who had critical hypercalcemia. After right parathyroidectomy, this patient's serum calcium level normalized, her nausea and emesis resolved, her fatigue improved, and her osteopenia and lytic lesions showed evidence of improvement. Although rare, hyperparathyroidism should be considered in patients with multiple osteolytic lesions or in children and adolescents with a systemically involved skeleton.