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Endocrine Care |
Section of Endocrinology, Department of Medicine, National University Hospital (K.B., B.T., J.B.), N-0027 Oslo, Norway; Department of Medicine, Aust-Agder Central Hospital (A.Q.P.), N-4087 Arendal, Norway; and Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital (H.B.), N-5021 Bergen, Norway
Address all correspondence and requests for reprints to: Jens Bollerslev, M.D., Section of Endocrinology, National University Hospital, N-0027 Oslo, Norway. E-mail: . jens.bollerslev{at}rikshospitalet.no
Abstract
A middle-aged woman presented with a history of constipation, easy fatigue, depressive mood, lassitude, polydipsia, and polyuria. The patient posed a challenging diagnostic dilemma due to the presence of persistent severe hypercalcemia and relative lack of clinically manifested symptoms. Clinical, biochemical, and genetic examinations confirmed the diagnosis of familial hypocalciuric hypercalcemia as a result of C562Y calcium-sensing receptor mutation, and a coexisting parathyroid adenoma. After adenectomy, the patient’s clinical situation improved markedly, and a modest equilibrium hypercalcemia persisted. This case presents an unusual combination of two relatively common endocrine disorders.
FAMILIAL HYPOCALCIURIC hypercalcemia (FHH), a benign, autosomal, dominantly inherited atypical form of primary hyperparathyroidism (PHPT) with high penetrance, is characterized by moderate equilibrium hypercalcemia and relative hypocalciuria (1, 2). FHH results from inactivating mutations (loss of function) of the calcium-sensing receptors (CaSR) (3, 4, 5). The major function of the CaSR is to maintain calcium balance via changes in parathyroid and renal function (6). Parathyroid cells with a defective CaSR require a higher than normal serum calcium level to reduce PTH release. In the kidney, inactivating mutations result in an increase in tubular calcium and magnesium reabsorption (7). FHH is a common cause of asymptomatic hypercalcemia, particularly at early ages. The serum PTH (S-PTH) level is inappropriately in the high normal range or only slightly elevated. The diagnosis requires particular alertness to urinary calcium excretion (6, 7). Biochemical distinction between patients with FHH and other forms of hyperparathyroidism is based on the ratio of calcium to creatinine clearance (Ca/Cr). A value below 0.01 separates most patients with FHH from those with PHPT due to parathyroid adenoma or hyperplasia (8). Although the parathyroid glands may show moderate hyperplasia in FHH, high resolution ultrasonography has shown a conceivably normal size of the glands (9). Mild symptoms similar to those in typical moderate PHPT are quite common. These patients, however, will not achieve normocalcemia by parathyroidectomy and therefore should be followed without any surgical intervention.
Case Report
A 45-yr-old Caucasian female presented with a 10-yr history of constipation, easy fatigue, lassitude, polydipsia, polyuria, borderline personality disorder, and depressive disorder. The patient had previously been treated for gastric ulcer. She was referred by her physician after unsuccessful treatment of hypercalcemia with loop diuretics.
The patient was in good general condition, with a body mass index of 29. Blood pressure was 210/85 mm Hg, and pulse rate was 68/min. The thyroid gland was asymmetrically enlarged, with palpable lumps on each site. The heart rate was regular, with a noncharacteristic systolic murmur grade 2–3 over the mitral valve. Total serum calcium (S-Ca) was extremely high (4.48 mmol/liter; range, 2.15–2.50), and ionized calcium was 2.75 mmol/liter (range, 1.19–1.35), seemingly in discord with her general condition. The S-PTH level was markedly increased (63 pmol/liter; range, 1.1–6.8), alkaline phosphatase was increased (485 U/liter; range, 80–275), serum phosphate was low, and vitamin D metabolites indicated activation of the 1
-hydroxylase. The Ca/Cr remained below 0.01, which strongly indicates FHH. Thyroid function was normal, and no concrements were revealed in the gall bladder or urinary tract.
Ultrasonography of the thyroid gland disclosed a 4- to 5-cm cystic process in the left caudal pole and a single nodule in the lower part of the right lobe. Parathyroid (Sesta-MIBI) scintigraphy showed a well defined hyperactive area of 2.5-cm diameter in the right caudal pole, suggesting a parathyroid adenoma. Electrocardiogram showed sinus bradycardia with short QT time. No other clinical signs of hypercalcemia were observed. The above-mentioned symptoms and laboratory results raised the question of the possible combination of a typical and an atypical form of PHPT.
After rehydration and clodronate (300 mg, iv, daily for 3 d; 800 mg, orally, three times per day for 3 wk) and calcitonin (600 IU, iv, daily for 3 d) treatments, S-Ca was gradually reduced to 3.65 mmol/liter. A right hemithyroidectomy combined with resection of the lower part of the left thyroid lobe was performed. Histopathological examination confirmed the presence of a 15 x 20 x 25-mm parathyroid adenoma at the right caudal pole, a small suppressed parathyroid gland in the upper pole, and colloid cysts without parathyroid tissue in the tissue from left lobe. Postoperatively, the patient remained in a good general condition, her polydipsia and polyuria were significantly reduced, and her general mood improved. In the postoperative phase S-Ca dropped to 2.28 mmol/liter (total) and 1.32 mmol/liter (ionized). S-PTH settled at the upper reference level (7.7 pmol/liter). During 5 months postoperative follow-up, the patient remained clinically and biochemically euthyroid, with slightly increased S-Ca (Fig. 1
).
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TAC) destroys a wild-type restriction site, allowing for a diagnostic test for this particular mutation. The C562Y mutation has previously been identified by direct sequencing of the CaSR gene (both strands) in a fluorescence-based DNA sequencing system (ABI PRISM 310 Genetic Analyzer, PE Applied Biosystems, Foster City, CA) (10). Reference to another 80 CaSR mutations may be found in the Calcium Sensing Receptor Locus Mutation Database (http://data.mch.mcgill.ca/CaSRdb/index.shtml). Discussion
This patient presented with symptoms and signs typical for sporadic primary hyperparathyroidism. Hypercalcemia apparently caused by a solitary parathyroid adenoma in a middle aged woman (8). However, a positive family history for hypercalcemia (Table 1), relatively mild symptoms despite pronounced hypercalcemia, and low urinary calcium excretion were all findings suggestive of FHH. The demonstration of the C562Y mutation in the CaSR gene clearly established the FHH diagnosis. This mutation has previously been found in a number of seemingly unrelated Norwegian FHH families shown by haplotype analysis to be descendants from a common ancestor for this mutation (10). Despite serum calcium and PTH levels very much higher than usually found in FHH, her urinary Ca/Cr excretion ratio remained diagnostic for this condition.
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An obvious question is whether the combination of FHH and parathyroid adenoma in this case is a coincidental event or the adenoma is secondary to her CaSR mutation. A precise estimate of the prevalence of each of these two disorders in middle-aged women is not available (8). However, as an example, given that PHPT and FHH are found in 1 in 1,000 (8) and 1 in 10,000 persons, respectively, their co-occurrence should be observed by chance in 1 in 10 million middle-aged women, making the combination a rare, but not improbable, event. Single or multiple parathyroid adenomas have recently been described in several family members in a setting of apparent FHH based on a mutation in the cytoplasmic tail of the CaSR (11).
Solitary parathyroid adenomas are usually monoclonal in origin. As in other tumors, it is likely that two or more genes have mutated in parathyroid adenomas, reflecting a stepwise development. However, somatic inactivating mutations of the CaSR gene are not found in parathyroid adenomas (8), and large parathyroid masses are not found in classical forms of FHH (9). Thus, a causative link between the CaSR mutation in this patient and her parathyroid adenoma is not obvious. We cannot exclude the possibility that the observed co-occurrence is coincidental and suggest that functional parathyroid adenomas be surgically removed in patients with FHH.
Acknowledgments
Footnotes
Abbreviations: Ca/Cr, Ratio of calcium to creatinine clearance; CaSR, calcium-sensing receptor; FHH, familial hypocalciuric hypercalcemia; PHPT, primary hyperparathyroidism; S-Ca, serum calcium; S-PTH, serum PTH.
Received June 6, 2001.
Accepted December 4, 2001.
References
This article has been cited by other articles:
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  P. H. Nissen, S. E. Christensen, L. Heickendorff, K. Brixen, and L. Mosekilde Molecular Genetic Analysis of the Calcium Sensing Receptor Gene in Patients Clinically Suspected to Have Familial Hypocalciuric Hypercalcemia: Phenotypic Variation and Mutation Spectrum in a Danish Population J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4373 - 4379. [Abstract] [Full Text] [PDF]
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A. Scillitani, V. Guarnieri, C. Battista, S. De Geronimo, L. A. Muscarella, I. Chiodini, M. Cignarelli, S. Minisola, F. Bertoldo, C. M. Francucci, et al. Primary Hyperparathyroidism and the Presence of Kidney Stones Are Associated with Different Haplotypes of the Calcium-Sensing Receptor J. Clin. Endocrinol. Metab., January 1, 2007; 92(1): 277 - 283. [Abstract] [Full Text] [PDF]
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