Published online August 1, 2006
PEDIATRICS
Vol. 118
No. 2
August 2006, pp.
e537-e539
(doi:10.1542/peds.2006-0337)
Primary Hyperparathyroidism Mimicking Vaso-occlusive Crises in Sickle Cell Disease
Preetha Krishnamoorthy, MDa,
Saif Alyaarubi, MDa,
Sharon Abish, MDb,
Marie Gale, BScb,
Pedro Albuquerque, MDc and
Nada Jabado, MD, PhDb
a Divisions of Endocrinology
b Hemato-Oncology, Department of Pediatrics
c Department of Radiology, Montreal Children's Hospital, Montreal, Quebec, Canada
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ABSTRACT
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We report a case of bone pain associated with primary hyperparathyroidism in a patient with sickle cell disease. A 17-year-old girl with sickle cell disease (SS phenotype) was seen for bilateral knee and back pain. She had had recurrent severe vaso-occlusive crises and acute chest syndrome in the course of her disease. In the last 2 years, she had frequent visits to the emergency department for severe bone pain. She complained of long-standing fatigue and lethargy. Her physical examination was normal. Hydroxyurea treatment, as well as and long- and short-acting narcotics were given, with little improvement in symptoms. Poor compliance with medication, family dysfunction, and potential narcotic addiction were felt to be significant contributors to the patient's symptoms. She was incidentally found to have an extremely elevated total calcium level of 3.19 mmol/L (range: 2.25–2.76) with an ionized calcium level of 1.9 mmol/L (range: 1.15–1.35). Phosphorus level was 0.82 mmol/L (range: 0.90–1.50), alkaline phosphatase level was elevated at 519 U/L (range: 10–170), and parathyroid hormone level was extremely high at 1645 pg/mL (range: 10–60). Her renal function was normal. Ultrasonography of the neck and a Sestamibi scan revealed a single left inferior parathyroid adenoma adjacent to the thyroid lobe. There was no evidence of an underlying multiple endocrine neoplasia. The patient was diagnosed with primary hyperparathyroidism. Fluid hydration, hydrocortisone, calcitonin, and bisphosphonates were initiated for acute hypercalcemia management before surgical excision of the left parathyroid adenoma. On review of previous blood work, a borderline calcium level of 2.72 was present 18 months before this admission. Two years postsurgery, she has normal renal function, calcium, and parathyroid hormone levels. The weekly visits to the emergency department for pain episodes decreased to 1 every 2 months within the first few months after her surgery. The decrease in pain episodes, even if it coincided with the treatment of primary hyperparathyroidism, may still reflect the natural evolution of sickle cell disease in this patient. However, the high morbidity associated with primary hyperparathyroidism was successfully prevented in this patient. Primary hyperparathyroidism is rare in childhood. In a recent study, it occurred more commonly in female adolescents and was because of a single adenoma, as in our patient. Significant morbidity, mainly secondary to renal dysfunction, was because of the delay in diagnosis after the onset of symptoms (2.0–4.2 years), emphasizing the need for a rapid diagnosis. Sickle cell disease affects 
1 of every 600 blacks in North America. Acute episodes of severe vaso-occlusive crisis account for >90% of sickle cell-related hospitalizations and are a significant cause of morbidity in patients. There is no known association between sickle cell disease and primary hyperparathyroidism, and this case is most probably a random occurrence. However, as emphasized by this case report, pain may also be a harbinger of other disease processes in sickle cell disease. Because management may vary, we suggest that care providers consider the diagnosis of vaso-occlusive crisis as the diagnosis of exclusion and that other etiologies for pain be envisaged in this patient population, especially in the presence of prolonged pain or unusual clinical, radiologic, or biological findings.
Key Words: primary hyperparathyroidism • sickle cell • vaso-occlusive crisis • hypercalcemia
Abbreviations: SCD, sickle cell disease • PHT, primary hyperparathyroidism • MEN, multiple endocrine neoplasia
Sickle cell disease (SCD) is one of the most common hemoglobinopathies and inherited disorders in the world. It affects 1 of every 600 blacks in North America1 and is characterized by chronic hemolysis, intermittent vaso-occlusion, and marked variations in the character and severity of symptoms among individuals.1,2 Pain is the most common clinical problem encountered in the care of a patient with SCD. Acute episodes of severe vaso-occlusive crisis account for >90% of SCD-related hospitalizations and are a significant cause of morbidity in patients.2–5 Severe pain in the chest, back, abdomen, or extremities (pain episodes), often with multiple areas involved simultaneously, and symmetric involvement of the extremities is common. In a given year, 60% of patients with SCD will have an episode of severe pain. A small minority of patients has almost constant severe pain.3,4,6,7 Despite advances in management, the tolerance, adverse effects, and potential addiction to narcotic analgesics remain challenging problems facing physicians.
Primary hyperparathyroidism (PHT) affects predominantly adult patients (incidence of 1 in 1000) and is rare in childhood (incidence of 2–5 in 100000).8–11 It can be related to a sporadic isolated parathyroid adenoma or parathyroid hyperplasia or it can be associated with multiple endocrine neoplasia (MEN) I and IIA and familial non-MEN.8,9,11,12 MEN-I is an endocrinopathy characterized by hyperplasia of parathyroid cells, as well as pituitary and pancreatic islet cell neoplasms. MEN-IIA is associated with medullary thyroid carcinoma, pheochromocytoma, and, occasionally, hyperparathyroidism. Familial non-MEN PHT is a hereditary condition characterized by a positive family history of PHT, adenomatous changes, and the absence of other MEN features. PHT is mostly asymptomatic in adults, resulting in a delay in diagnosis and irreversible morbidity. Even if it is often more symptomatic in children, clinical findings of PHT include nonspecific complaints, such as polyuria, fatigue, poor appetite, weight loss, abdominal and bone pain, nausea, and emesis, resulting in a similar delay in diagnosis. We report herein the unusual case of an adolescent girl with known SCD and a history of recurrent painful episodes that were found to be potentially associated with PHT.
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CASE REPORTS
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A 17-year-old girl with SCD (SS phenotype) was seen at the Montreal Children's Hospital for bilateral knee and back pain. She had been followed at this institution since the age of 4 months and had had recurrent severe vaso-occlusive crises and acute chest syndrome in the course of her disease. In the last 2 years, she had frequent visits to the emergency department for severe bone pain. She had no headaches, nausea, or vomiting but complained of long-standing fatigue and lethargy. Hydroxyurea treatment, as well as long- and short-acting narcotics, was given, with little improvement in symptoms. Acute and chronic pain services were subsequently involved, again with no improvement in the control of her pain, despite various combinations of opioid and nonopioid analgesics and pain relaxation techniques. Poor compliance with medication, family dysfunction, and potential narcotic addiction were felt to be significant contributors to the patient's symptoms, and she was, therefore, followed by psychiatry.
Her physical examination was normal. She was incidentally found to have an elevated total calcium level of 3.19 mmol/L (reference range: 2.25–2.76) with an ionized calcium level of 1.9 mmol/L (reference range: 1.15–1.35). Phosphorus levels were 0.82 mmol/L (reference range: 0.90–1.50), alkaline phosphatase levels were elevated at 519 U/L (reference range: 10–170) and parathyroid hormone levels were high at 1645 pg/mL (reference range: 10–60). Her renal function was normal, with a creatinine of 28 µmol/L (reference range: 50–110), a urea of 3.5 mmol/L (reference range: 3–7.5), and a creatinine clearance of 1.83 mL/second per 1.73 square meters (reference range: 1.48-2.78).
Ultrasonography of the neck and a Sestamibi scan revealed a single left inferior parathyroid adenoma adjacent to the thyroid lobe (Fig 1, left). Dual energy radiograph absorptiometry showed decreased bone mineral density (forearm and lumbar spine, z scores of –4.61 and –3.00, respectively). Radiographs of the hands showed osteopenia and diffuse intracortical, subperiosteal, and endosteal bone resorption (Fig 1, middle and right). There was no nephrocalcinosis and no evidence of an underlying MEN: cortisol, calcitonin, and thyroid hormone levels were normal, and screening for urinary catecholamines was negative. There was no family history of parathyroid hyperplasia or adenoma.
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FIGURE 1 A, Planar Technetium-99-m-labeled 2-methoxy-isobutyl-isonitrile (Sestamibi) scintigraphy of the neck showed a solitary focus of increased tracer uptake over the lower pole of the left lobe of the thyroid, compatible with a hyperfunctioning left inferior parathyroid adenoma. B and C, Radiographs of the right hand and wrist, showing osteopenia and multiple intracortical, subperiosteal, and endosteal erosions of the phalanges and distal radius, typical of hyperparathyroidism.
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The patient was diagnosed with PHT. Fluid hydration, hydrocortisone, calcitonin, and bisphosphonates were initiated for acute hypercalcemia management before surgical excision of the left parathyroid adenoma. Postoperatively, the patient had transient hypocalcemia, likely secondary to hungry bone syndrome, requiring calcium infusion and supplementation with 1,25-hydroxy-vitamin D. Intranasal calcitonin was given, in addition, for treatment of bone pain. On review of previous blood work, it was found that a borderline calcium level of 2.72 had been measured 18 months before this admission.
Previous to her admission, the patient had been taking increasing doses of long-acting and short-acting opioids for 2 years. Short-acting opioids were decreased by 20% on discharge and tapered to one third of her former doses within 3 months after surgery. Long-acting opioids were decreased by half within the same period of time. Two years postsurgery, she has normal calcium and parathyroid hormone levels. The weekly visits to the emergency department for pain episodes decreased to 1 every 2 months within the first few months after her surgery. Moreover, her management of the pain episodes is more efficient; she has required fewer hospitalizations and shorter courses and lower doses of pain medication. The decrease in pain episodes, even if it coincided with the treatment of PHT, may still reflect the natural evolution of SCD in this patient. However, the high morbidity associated with PHT, especially renal failure, was successfully prevented in this patient.
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DISCUSSION
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PHT among pediatric patients is rare. In a recent study that included 50 patients and reviewed 30 additional patients that had been reported previously, it was found to occur more commonly in female adolescents than in younger children and was because of a single adenoma, as in our patient.9 Significant morbidity, mainly secondary to renal dysfunction, was because of the delay in diagnosis after the onset of symptoms (2.0–4.2 years), emphasizing the need for a rapid diagnosis.9 The clinical symptoms present in our patient could have been easily attributed to either of the 2 diagnoses of SCD and PHT. Polyuria is common in sickle cell patients and is linked to renal changes associated with ischemic vaso-occlusive lesions of tubules. Fatigue and lethargy are also often encountered in these patients with chronic severe anemia. Abdominal or bone painful episodes are the most common features of SCD. There is no known association between SCD and PHT, and this case is most probably a random occurrence. However, this report serves to emphasize that pain may also be a harbinger of other disease processes in SCD. Because of their frequency, a painful episode in a given patient with known SCD is usually downplayed. We wish to stress that other medical conditions may masquerade as a pain episode in patients with SCD and must, therefore, be excluded. Abdominal emergencies, including appendicitis, delayed hemolytic transfusion reactions,13 osteomyelitis,5 evolving stroke, avascular necrosis of the hip or shoulder,5 or other more rare causes may all be misinterpreted as uncomplicated pain crises. Patients with SCD should be assessed like the normal pediatric population in the course of a pain crisis. The diagnosis of vaso-occlusive crisis should be considered as the diagnosis of exclusion and, importantly, should be revised in the presence of prolonged pain or unusual clinical, radiologic, or biological findings.
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ACKNOWLEDGMENTS
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Dr Jabado is the recipient of a Chercheur Boursier Award from the Fonds de la recherche en santé du Québec. This work was supported by the Penny Cole Foundation.
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FOOTNOTES
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Accepted Apr 20, 2006.
Address correspondence to Nada Jabado, MD, PhD, Montreal Children's Hospital Research Institute, 4060 Ste Catherine West, PT 239, Montreal, Quebec, Canada H3Z 2Z3. E-mail: nada.jabado{at}mcgill.ca
Drs Krishnamoorthy and Alyaarubi contributed equally to this work.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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