Osteomalacia caused by tumors in facies cranii mimicking rheumatoid arthritis
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- Xian-Ling, W., Jian-Ming, B., Wen-wen, Z. et al. Rheumatol Int (2012) 32: 2573. doi:10.1007/s00296-011-2018-4
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Tumor-induced osteomalacia (TIO) is an extremely rare metabolic bone disease and the occult offending tumor arising in facies cranii is even more uncommon. In this report, we described 2 middle-aged females with TIO caused by the tumor in facies cranii, which had ever been misdiagnosed as rheumatoid arthritis. Case 1 was present with diffuse bone pain and muscle weakness for 4 years, as well as esotropia in the right eye for 1 month. Case 2 was present with progressive bone pain in low back and hip for 2 years. Biochemical studies both showed persistent hypophosphatemia and urinary over wasting phosphate. Radiological examinations revealed the infiltrative mass in right apex partis petrosae ossis temporalis in case 1, and the soft mass in left nasal cavity and ethmoid sinuses in case 2, respectively. The offending tumors were resected completely in case 2, however, incompletely in case 1. Pathology examination revealed mixed connective tissue variant phosphaturic mesenchymal tumors. In conclusion, TIO should be presumed in patients presenting with unexplained persistent hypophosphatemia osteomalacia, also a thorough detection for tumor in facies cranii should be performed.
KeywordsTumor-induced osteomalaciaFacies craniiOctreotideFibroblast growth factorHypophosphatemia
Fibroblast growth factor
Magnetic resonance imaging
Tumor-induced osteomalacia (TIO) is an extremely rare metabolic bone disease. Its characteristic biochemical disorder is tumor-related renal phosphate wasting and abnormal vitamin D metabolism . To date, about 200 cases of TIO have been reported. The tumors causing TIO more frequently arise in the bones and soft tissues of lower and upper extremities, however, uncommonly in facies cranii [2, 3]. In this report, we described 2 middle-aged females with TIO caused by mixed connective tissue variant phosphaturic mesenchymal tumor arising in facies cranii, which had ever been misdiagnosed as rheumatoid arthritis.
Subjects and method
This patient was a 43-year-old female. Four years ago, she was initially present with diffuse and progressive bone pain, muscle weakness, and progressive difficulty in walking. In other hospitals, she was ever diagnosed to have rheumatoid arthritis, but treatment with nonsteroidal anti-inflammatory drugs or glucocorticoids did not achieve any symptomatic relief. One month ago, the symptoms of esotropia in right eye and horizontal diplopia suddenly occurred and the diagnosis of ophthalmoparalysis was suspected. But administration with prednisone could not relieve the symptoms. Her family history was not special for metabolic bone disease.
On admission, the patient was 1.53 m in height and 45 kg in weight. Physical examination revealed a well-nourished kyphotic woman, with a wide-based gait and generalized decreased muscle strength. Esotropia and abduction deficit in right eye and horizontal diplopia was apparent. The most remarkable findings are thoracocyllosis and generalized bony tenderness. No other abnormalities were detected.
In laboratory examination, complete blood count, liver and kidney function, as well as antinuclear antibodies were all normal. Serum calcium (2.14 mmol/l, normal range 2.25–2.65 mmol/l) and parathyroid hormone (PTH) (71 pg/ml, normal range 10–65 pg/ml) were slightly abnormal, while the most evident biochemical abnormality was persistent with hypophosphate(0.43–0.52 mmol/l, normal range 0.9–1.6), highly increased phosphate clearance [45 ml/min (normal range 6.3–15.5 ml/min)], and higher alkaline phosphatase (ALP) activity (260.1 U/l, normal range <130 IU/l).
This patient was a 42-year-old female with a history of progressive bone pain in low back and hip for 2 years. Multiple hospitalizations failed to identify the cause of her symptoms; also, she was misdiagnosed to have rheumatoid arthritis and no improvement of her condition was achieved so far. Her past medical history and family history were not special.
On admission, the patient was 1.42 m in height and 50 kg in weight. Her walking distance was restricted to 10 m with the support of a walking frame. Also, no remarkable findings were detected in lungs, heart, and abdomen.
Detailed biochemical studies showed persistent normocalcemic (2.30 mmol/l), hypophosphatemia (0.49–0.61 mmol/l), increased phosphate clearance [32 ml/min (normal range 6.3–15.5 ml/min)], raised serum ALP activity (358.7 U/l), and normal PTH level (50.74 pg/ml), all of which indicated the diagnosis of osteomalacia.
After operation, serum phosphate elevated gradually to 0.49, 0.37, 0.48, 0.66, 0.51, 0.57, and 0.58 mmol/l after 1, 3, 4, 5, 6, 7, and 8 days, respectively. Bone pain and muscle weakness showed only a slight regress. Since the infiltrative tumor was not completely resected, we suggested her to accept therapy with octreotide in follow-up.
Then, she was referred to Otorhinolaryngology Department for operation. In endoscope operation, the tumor in the right lateral region of sinus sphenoidalis was detected and completely resected. The histology and immunohistochemical examination also revealed a phosphaturic mesenchymal tumor (mixed connective tissue variant). After operation, the serum phosphate elevated more rapidly than the first case, from 0.52 mmol/l in preoperational day to 0.94, 1.05, 1.23, 1.15, and 1.09 mmol/l in postoperative day 2, 3, 4, 5, and 6.
Osteomalacia is a metabolic bone disease resulting from inadequate mineralization of osteoid in mature bone. It has various etiologies, ranging from rare hereditary disorders of metabolism, such as autosomal dominant hypophosphatemic rickets and X-linked hypophosphatemic rickets, to renal tubular acidosis and chronic renal failure in adults .
In clinic, some special patients with refractory hypophosphatemia suffered from progressive bone pain, weakness, and skeletal deformity. They may visit various disciplines, such as orthopedics, endocrinology, and rheumatology. The serious hypophosphatemia always could not be rectified with high-dose oral phosphorus solution and 1,25(OH)2D3, also the symptoms still could not be relieved. These patients have ever been misdiagnosed to have rheumatic arthritis and sacroiliitis and not got the appropriate therapy .
In 1947, McCane first reported a young female case with hypophosphatemic osteomalacia. Till 1959, Prader confirmed the causality between the mesenchymal tumor and osteomalacia. Causative tumors are usually very small and difficult to locate with routine radiological examination [5, 6]. Previous published case series have shown that the median time to diagnosis delay was about 6.0 years and the longest time delay from initial symptoms to correct diagnosis can even be more than 20 years.
About the pathogenesis of TIO, many clinical researches have confirmed that the causative tumors can over secret one or more phosphatonins, in which the most frequently reported is fibroblast growth factor (FGF23). FGF23 can suppress phosphate reabsorption, which works by inactivating the sodium–phosphate pump in the proximal tubule of the kidney, preventing reabsorption of phosphate. This results in renal wasting of phosphate and hyperphosphaturia. Also, it can inhibit the synthesis of 1,25(OH)2 Vit D3, which may explain the low levels of 1,25(OH)2 D3 in patients with TIO [7, 8].
The offending tumor is usually in insidious field,except for a small proportion localized in subcutaneous tissue or surface of long bone, which could be touched with thorough physical examination. For tumors in insidious field, the systemic or aimless imaging scan with X-ray, CT, or MRI always cannot get positive results.
Seufert et al. firstly demonstrated that these tumors frequently express somatostatin receptor subtype-2 and bind 111Indium-labeled octreotide. So, administration of isotope-labeled octreotide permits scintigraphic detection of the tumor [5, 6, 9]. For example, the tumors in our two patients initially had octreotide scan and the tumors were detected definitely. But it should be emphasized that not all TIO tumors have surface somatostatin receptors, so a negative octreotide scan could not exclude the diagnosis of TIO. Now, octreotide scans combined with venous FGF23 sampling has been confirmed to be a very useful method for localizing the offending tumor [7, 8]. Since tumors in TIO arising in craniofacial sinuses are extremely rare, especially when the patients had no relative symptoms, it is even more difficult to localize [3, 10–12]. Most tumors associated with TIO are slow-growing, benign, polymorphous neoplasms of mesenchymal origin, classified as phosphaturic mesenchymal tumor, in which mixed connective tissue variant is the most common.
As for the first patient, the offending tumor could not be resected completely because of right sinus infiltration. That is why the hypophosphatemia was not completely rectified. So, we suggested her to accept the treatment with octreotide for long time . Fortunately, the tumor was resected integrally, resulting in normal serum phosphate and improvement of clinical condition. As for these two cases, we can further realize the important role of octreotide in offending tumor localization.
About therapy, the most effective treatment of TIO is complete surgical excision of the mesenchymal tumor with wide resection margins, such as case 2. The serum levels of phosphate, calcitriol, as well as tubular phosphate reabsorption become normal in hours or days after operations. Serum biochemical markers of bone turnover, such as the osteocalcin level and alkaline phosphates activity tend to take longer to normalize [7, 8]. Unresected tumors that express somatostatin receptors (easily determined with octreotide scan) should be treated with somatostatin analogs, which can result in symptom relief and normal serum phosphate level in some studies .
In summary, TIO should be suspected in patients presenting with refractory hypophosphatemia osteomalacia and normal serum calcium levels. Also, a thorough physical and radiological search for tumor in the extremities and head should be conducted.
Conflict of interest