Successful treatment of hyperphosphatemic tumoral calcinosis with long-term acetazolamide

Bone Vol. 16, No. 4, Supplement April 1995:247S-250S ELSEVIER

Successful Treatment of Hyperphosphatemic Tumoral Calcinosis with Long-Term Acetazolamide T. Y A M A G U C H I , 1 T. S U G I M O T O , 1 Y. I M A I , 2 M. F U K A S E , 1 T. F U J I T A , 3 and K. C H I H A R A 1 1 Third Division, Department of Medicine, Kobe University School of Medicine, Kobe, Japan 2 Saiseikai Hyogo-Prefecture Hospital, Kobe, Japan 3 National Sanatorium, Hyogo Central Hospital, Sanda, Hyogo, Japan

hyperphosphatemia, normocalcemia, and increased renal tubular phosphate reabsorption, 4 suggesting that these patients have a reduced ability to excrete phosphorus and that the resulting positive mineral balance with an elevated serum calcium phosphate solubility product may stimulate the deposits of calcium phosphate in the subcutaneous tissue and bone marrow. While most treatment has consisted of surgical excision, there have been attempts to manage extensive tumoral calcinosis with pharmaceutical phosphorus deprivation, especially in the hyperphosphatemic patients. 2'5-9 However, treatment with a low phosphorus diet in combination with oral aluminum hydroxide has failed to regress the calcium deposits in most patients, 2'5-7 except only three successfully treated cases. 8"9 Acetazolamide, an inhibitor of carbonic anhydrase, is known to cause phosphaturia in both men and animals, t°'at Although Lufkin et al. 5 has reported that this drug was also phosphaturic in patients with tumoral calcinosis, its efficacy on tumoral calcinosis by provoking phosphorus deprivation has not been previously examined. We describe a typical case of hyperphosphatemic tumoral calcinosis and report its noticeable response to treatment with long-term oral acetazolamide.

We describe a patient with tumoral calcinosis, in which acetazolamide (ACZ) was, for the first time, tested for its therapeutic efficacy. The 19-year-old Japanese man had been suffering from multiple recurrent calcifie masses with tenderness around the finger, knee, and toe joints since 10 months of age. Radiographs revealed several calcific subcutaneous masses around the finger joints, and calcific myelitis around the right knee joint and in the calvarium. The patient had hyperphosphatemia with elevated maximal threshold of renal phosphate excretion in the presence of normal kidney function and normocaicemia, suggesting a reduced ability to excrete phosphorus in the urine. A delay of disappearance of orally administered phosphate from the blood stream was found. A serum parathyroid hormone (PTH) level was normal, and responses to PTH and ACZ were also normal regarding the induction of phosphaturia. Since the masses tended to recur easily despite repeated surgical resections, we started medical treatment with phosphorus deprivation by oral aluminum hydroxide. However, the drug alone had no effect on hyperphosphatemia or calcific lesions, and ACZ was added in expectation of making the patient's phosphorus balance negative by its phosphaturic effect. Fourteen years of administration of the two drugs apparently improved the patient's symptoms, the biochemical findings, and the calcific lesions on radiographs. Thus, ACZ appeared to be useful for tumoral calcinosis resistant to phosphorus deprivation by aluminum hydroxide alone. (Bone 16:247S-250S; 1995)

Case Report A 19-year-old Japanese man was admitted to our hospital in December 1980 for assessment of the etiology of recurrent firm periarticular masses. No similar problems were found in his other family members. At 10 months of age, he was identified as having a firm mass with tenderness at the dorsum of the right hand, and underwent its surgical removal. This tumor recurred at age 3 and was resected again. At age 4, a similar firm mass occurred at the medial side of the right knee joint, which gradually enlarged to about 6 cm in diameter with hotness during the subsequent 5 years, and necessitated its surgical resection at age 9. Thereafter, multiple firm masses recurrently appeared adjacent to the finger, knee, and toe joints, with tenderness and hotness. These masses occasionally ulcerated the skin and formed a sinus track that drained chalky, milklike fluid when they became large, and then regressed spontaneously. At age 15, he began to complain of gait difficulty because of pain and limitation of motion around the right knee joint. On admission several firm nodules with mild tenderness were found around the extensor surface of the bilateral hands. One of the nodules spontaneously discharged chalky material during admission, and its analysis showed that the constituents were 44% calcium phosphate, 12% calcium carbonate, and 44% protein. The patient's right limb became bowed with the knee joint mildly

Key Words: Tumoral calcinosis; Acetazolamide; Phosphorus deprivation; Aluminum hydroxide; Hyperphosphatemia. Introduction Tumoral calcinosis is a rare but established disorder, which was first described by Duret in 1899, t and, since then, 282 cases have been reportbd, according to an English-language literature search by Tezelman et al.2 Identification of either calcific subcutaneous periarticular masses or calcific myelitis on radiographs is diagnostic of tumoral calcinosis. 3 These lesions mainly contain calcium phosphate, and occur most often in periarticular lesions of the hips, shoulders, elbows, feet, and hands. About one third of the reported cases are known to be complicated with Address for correspondence and reprints: Toshitsugu Sugimoto, M.D., Third Division, Department of Medicine, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650, Japan.

© 1995by ElsevierScienceInc.

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swollen. Radiographs revealed several calcific masses adjacent to the finger joints, as well as obvious calcium deposits in the bone marrow around the right knee joint and of the calvarium, which was compatible with calcific myelitis (Figure 1A-C, respectively). Biochemical investigations showed a serum phosphorus concentration of 7.0 mg/dL (normal range 2.5 to 4.5 mg/dL) and a renal tubular maximum reabsorption rate for phosphorus (TmP/GFR) of 8.2 mg/dL of glomerular filtrate (GF) (normal range 2.5 to 4.5 mg/dL GF), both of which were markedly elevated. The patient's renal function was normal, with blood urea nitrogen 8 mg/dL, serum creatinine 0.8 mg/dL, and creatinine clearance 88 mL/min. Serum calcium (9.7 mg/dL), serum immunoreactive parathyroid hormone (PTH) (0.5 ng/mL) (normal range < 0.546 ng/mL), serum alkaline phosphatase (70 IU/L) (normal range 36 to 100 IU/L), serum 25-hydroxyvitamin D (20 ng/mL) (normal range 14 to 42 ng/mL), serum 1,25dihydroxyvitamin D (44 pg/mL) (normal range 20 to 60 pg/mL), urinary calcium (70.8 rag/day) (normal range 50 to 400 mg/day), and urinary calcium per urinary creatinine ratio (0.079) (normal range < 0.3) were all normal. Other laboratory data including arterial blood gas analysis and the peripheral blood counts showed no abnormal findings. The patient had normal renal tubular responses to PTH and acetazolamide (ACZ) as follows: An intravenous injection of 30 p~g human PTH(1-34) (EllsworthHoward test) caused both significant phosphaturia and cAMP excretion (Table 1). A delay of disappearance of 1.5 g orally administered phosphate from the blood stream was found as compared to the normal control (Figure 2). An intravenous infusion of 500 mg ACZ induced conspicuous phosphaturia with simultaneous reductions of TrnP/GFR and serum phosphorus (Figure 3). The patient was diagnosed as having tumoral calcinosis given the characteristic findings of calcific periarticular masses and myelitis with increased renal tubular phosphate reabsorption. Since the masses had been resistant to the repeated surgical resections with a tendency of recurrence, we began to treat him

Bone Vol. 16, No. 4, Supplement April 1995:247S-250S Table 1. Exogenous human PTH(I-34) loading test (Ellsworth-Howard test): An intravenous injection of 30 wg synthetic human PTH(1-34) (Ellsworth-Howard test) caused both significant phosphaturia and cAMP excretion Synthetic hPTH(1-34): 30 Ixg (3300 IU/mg) load -2

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Although the etiology of tumoral calcinosis is not fully understood at present, several case reports 4's'~2"13 showed the familial occurrence of the disorder, with inappropriately normal to slightly elevated concentrations of 1,25-dihydroxyvitamin D in the presence of pronounced hyperphosphatemia and increased renal phosphate reabsorption, suggesting that the primary cause of the disease might be an inborn error of the metabolism of phosphorus and vitamin D involving a defect in the regulation of renal 25-hydroxy-l-tx-hydroxylase. However, familial occurrence and hyperphosphatemia are not found universally in tumoral calcinosis but are observed in only about one third of the reported cases, respectively. 3"4 Prince et al. 4 suggested that this hyperphosphatemic tumoral calcinosis might represent a unique subgroup, with a distinct clinical entity characterized by familial incidence, occurrence at an early age, and widespread subcutaneous calcific masses around the joints in the presence of hyperphosphatemia, normocalcemia, and normal renal function. Although evidence of genetic transmission was not found in the present case, our patient corresponded well to these described features and is thought to be classified as this subgroup. Lufkin et al. s indicated that patients with tumoral calcinosis had normal serum PTH levels and normal phosphaturic responses to PTH and ACZ, and that the reduced excretion of phosphorus found in the patients was not due to impaired PTH secretion or an abnormal phosphaturic response to this hormone. The present patient was also responsive to both agents and was consistent with their observation. Martinez et al. 3 reported that either calcific periarticular subcutaneous masses or calcium deposits in the bone marrow (calcific myelitis) on radiographs were distinctly diagnostic of tumoral calcinosis. The present case also showed these typical radiological findings, with calcific masses around the finger joints and calcific myelitis around the right knee joint and in the calvarium. Surgical excision was the only definitive treatment of tumoral calcinosis, although recurrence is common in large masses after incomplete excision. 2 Another alternative treatment, especially in the hyperphosphatemic subgroup, is pharmaceutical phosphorus deprivation. 8'9 Since the calcium phosphate in the masses was shown to rapidly exchange with extracellular fluid, 14 treatment by phosphorus deprivation may have the potential for reversal of the calcium deposition. In 1968, Lotz et al. 25 showed that oral aluminum hydroxide could bring about phosphorus depletion in man, leading to the successful use of this treatment in tumoral calcinosis, s,9 However, the results of this treatment have

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T. Yamaguchi et al. Treatment of hyperphosphatemic tumoral calcinosis

varied and no other metabolic or radiological studies s h o w i n g the benefit o f p h o s p h o r u s deprivation h a v e b e e n reported. 2'5-7 In the p r e s e n t case, the repeated surgical resections o f the t u m o r s were not effective, with their rapid recurrence. T h e patient b e l o n g e d to the h y p e r p h o s p h a t e m i c s u b g r o u p as s e e n in the patients s u c c e s s f u l l y treated with oral a l u m i n u m h y d r o x i d e reported previously. 8'9 T h u s , at first we treated the patient with this medication. H o w e v e r , oral a l u m i n u m h y d r o x i d e alone h a d no effect on either h y p e r p h o s p h a t e m i a or the calcific m a s s e s , a n d oral A C Z w a s a d d e d to the r e g i m e n to m a k e the p a t i e n t ' s p h o s phorus balance m o r e n e g a t i v e by its p h o s p h a t u r i c action. A C Z is k n o w n to e v o k e p h o s p h a t u r i a in m a n w i t h o u t affecting urinary excretion o f c A M P , 5"1° in a f a s h i o n different f r o m P T H , a n d thus the phosphaturic effects o f A C Z and P T H were additive. 5,11 A l t h o u g h L u f k i n et al. 5 u s e d t h e s e diuretics for clarifying the m e c h a n i s m o f increased renal p h o s p h a t e reabsorption threshold in tumoral calcinosis, no reports are available that tested A C Z for its therapeutic efficacy o n the disease. In the present case, the calcific s u b c u t a n e o u s t u m o r s around the fingers and the calcific myelitis a r o u n d the right k n e e joint clearly r e g r e s s e d on radiographs as well as the d i s a p p e a r a n c e o f the p a t i e n t ' s s y m p t o m s a n d the i m p r o v e m e n t o f b i o c h e m i c a l data after administration o f A C Z , indicating that this d r u g is effective e v e n in the c a s e s u n r e s p o n s i v e to oral a l u m i n u m h y d r o x i d e alone. H o w e v e r , the calcific myelitis in the c a l v a r i u m w a s not i m p r o v e d despite the l o n g - t e r m A C Z treatment. A l t h o u g h the precise r e a s o n is u n clear, it m i g h t be p o s s i b l e that d i f f e r e n t i a l r e s p o n s i v e n e s s to p h o s p h o r u s deprivation exists b e t w e e n l o n g b o n e s and the calvarium. T h e p r e s e n t case p r o v i d e d considerable insight that tumoral calcinosis resistant to c o n v e n t i o n a l m e d i c a l treatment could be ameliorated b y the c o m b i n e d oral a d m i n i s t r a t i o n o f A C Z and a l u m i n u m hydroxide. T h i s possibility s e e m s to require m o r e exp a n d e d clinical trial o f the r e g i m e n .

References 1. Duret, M. H. Tumours multiples et singuli~res des bourses sereuses (endothrliomes, peuti~tre d'origine parasitaire). Bull Mem Soc Anat Paris 74:725733; 1899. 2. Tezelman, S., Siperstein, A. E., Duh, Q.-Y., and Clark, O. H. Tumoral calcinosis. Controversies in the etiology and alternatives in the treatment. Arch Surg 128:737-745; 1993.

Bone Vol. 16, No. 4, Supplement April 1995:247S-250S 3. Martinez, S., Vogler, J. B., Harrelson, J. M., and Lyles, K. W. Imaging of tumoral calcinosis. New observations. Radiology 174:215-222; 1990. 4. Prince, M. J., Seaefer, P. C., Goldsmith, R. S., and Chausmer, A. B. Hyperphosphatemic tumoral calcinosis. Association with elevation of serum 1,25-dihydroxycholecalciferol concentrations. Ann Int Med 96:586-591; 1982. 5. Lufkin, E. G., Wilson, D. M., Smith, L. H., Bill, N. J., DeLuea, H. F., Dousa, T. P., and Knox, F. G. Phosphorus excretion in tumoral calcinosis. Response to parathyroid hormone and acetazolamide. J Clin Endocrinol Metabol 50:648-653; 1980. 6. Mimick, P. D., Goldfarb, S., Slatopolsky, E., Lemann, J. Jr., Gray, R. W., and Agus, Z. S. Calcium and phosphate metabolism in tumoral calcinosis. Ann Int Med 92:482487; 1980. 7. Zerwekh, J. E., Sanders, L. A., Townsend, J., and Pak, C. Y. C. Tumoral calcinosis. Evidence for concurrent defects in renal tubular phosphorus transport and in 1 alpha,25-dihydroxycholecalciferol synthesis. Caleif Tissue Int 32:1-6; 1980. 8. Davies, M., Clements, M. R., Mawer, E. B., and Freemont, A. J. Tumoral calcinosis. Clinical and metabolic response to phosphorus deprivation. Q J Med 63:493-503; 1987. 9. Mozaffarian, G., Lafferty, F. W., and Pearson, O. H. Treatment of tumoral calcinosis with phosphorus deprivation. Ann Intern Med 77:741-745; 1972. 10. Sinha, T. K., Allen, D. O., Queener, S. F., and Bell, N. H. Effects of aeetazolamide on the renal excretion of phosphate in hypoparathyroidism and pseudohypoparathyroidism. J Lab Clin Med 89:1188-1197; 1977. 11. Knox, F. G., Haas, J. A., and Lechene, C. P. Effect of parathyroid hormone on phosphate reabsorption in the presence of acetazolamide. Kidney Int 10: 216--222; 1976. 12. Steinherz, R., Chesney, R. W., Eisenstein, B., Metzker, A., DeLuca, H. F., and Phelps, M. Elevated serum calcitriol concentrations do not fall in response to hyperphosphatemia in familial tumoral calcinosis. Am J Dis Child 139:816819; 1985. 13. Lyles, K. W., Burkes, E. I.r Ellis, G. J., Lucas, K. S., Dolan, E. A., and Drezner, M. K. Genetic transmission of tumoral calcinosis. Autosomal deminant with variable clinical expressivity. J Clin Endocrinol Metab 60:10931096; 1985. 14. Lafferty, F. W., Reynolds, E. S., and Pearson, O. H. Tumoral calcinosis. A metabolic disease of unknown etiology. Am J Med 38:105-118; 1965. 15. Lotz, M., Zisman, E., and Bartter, F. C. Evidence for a phosphorus-depletion syndrome in man. N Engl J Med 278:409-415; 1968.

Date Received: March 10, 1994 Date Accepted: September 28, 1994