Division of Nephrology, University Hospital, Medical School, Aachen, Germany
Keywords: Fanconi syndrome; hypophosphatemic osteomalacia; monoclonal gammopathy; oncogenic osteomalacia; renal phosphate wasting
Introduction
Two adult patients underwent skeletal scintigraphy due to debilitating bone pain, which was highly suggestive of diffuse osseous metastases. Disturbances of phosphate metabolism were considered for the first time after a 1-year latency period. Marked hypophosphataemia and hyperphosphaturia were found in both patients and subsequently a bone biopsy showed a typical histologic pattern of osteomalacia. The present case reports demonstrate the broad spectrum of diseases leading to acquired renal phosphate wasting in adults and underline the importance of considering the cheap and simple blood testing for inorganic phosphate during the diagnostic work-up of bone pain.
Case
Patient A (63 years) and patient B (73 years), both Caucasian males, suffered from diffuse, progressive bone pain and tenderness to palpation for more than 12 months before admission. Technetium-99m DPD-labelled scintigraphic examination showed generalized increased bone uptake and numerous focal areas of increased radionuclide accumulation bilaterally, especially in the ribs. Multiple skeletal metastases was the primary diagnosis in both patients. Both were subsequently admitted to our hospital because the search for an underlying malignant tumour had been unsuccessful. Upon admission, both patients had proximal muscle weakness of the lower extremities. Arterial hypertension was the only relevant concomitant disease. The personal and family histories were otherwise unremarkable in both patients. Radiological examination revealed pseudofractures and several bone fractures of different ages without a history of adequate trauma. Skeletal scintigraphy confirmed the previous findings (Figures 1 and 2
). Laboratory tests are listed in Table 1
.
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Patient A had multiple bilateral fractures of the ribs, right fibula, and left metatarsal bone. Besides hyperphosphaturia, no other renal and particularly no tubular dysfunction was present. A mutation analysis of the PHEX-gene (phosphate regulating gene with homologies to endopeptidases located on the X-chromosome) was negative. The 1,25-dihydroxyvitamin D3 level was markedly reduced with 25-hydroxyvitamin D3 and creatinine clearance being in normal ranges. Suspecting oncogenic osteomalacia, a thorough diagnostic work-up was performed, including complete physical examination, CT-scan of head and neck, abdomen and chest, endoscopic GI-tract evaluation, MRT of the extremities, and positron emission tomography with [18F]2-deoxy-2-fluoro-D-glucose. However, no tumour could be identified. The working hypothesis was nevertheless oncogenic osteomalacia with occult underlying tumour. Symptomatic therapy with phosphate substitution (3600 mg/day) and calcitriol (0.75 µg/day) was begun. After 6 months of follow-up, phosphate and vitamin D levels were in low-to-normal ranges and the clinical signs had markedly improved.
In patient B, radiographic examination of the skeleton revealed a right femoral neck fracture and several rib fractures. A 24-h urinary specimen revealed proteinuria (2980 mg/day), glycosuria, aminoaciduria, and renal bicarbonate loss (renal tubular acidosis type II). The gamma-globulin fraction was elevated to 23% (range 1019), IgG was 19.2 g/l (range 716) and immunoelectrophoresis showed BenceJones proteinuria type IgG kappa (1420 mg/l). On iliac crest biopsy, about 10% plasma cells type light chain kappa were seen in bone marrow. Based on these findings, the diagnosis of monoclonal gammopathy with BenceJones proteinuria type kappa and secondary Fanconi syndrome was established. 2.5 years after the onset of bone pain, the patient developed overt multiple myeloma and progressive kidney failure. Symptomatic therapy with phosphate substitution (3600 mg/day) and bicarbonate was begun. After the development of multiple myeloma, chemotherapy with intermittent pulses of melphalan plus prednisone was initiated, leading to a partial remission. Clinical symptoms improved only minimally in the course of the disease.
Comment
A balanced supply of calcium and phosphate is an essential prerequisite for maintaining proper bone metabolism. The kidneys play a pivotal role in phosphate homeostasis as effective phosphate reabsorption takes place in the proximal tubule under the control of different hormonal factors [1,2].
Hypophosphataemic osteomalacia due to renal phosphate wasting may develop as a consequence of a variety of diseases interacting with sodium-phosphate co-transporters located in the proximal tubule. The age of onset of clinical signs and symptoms and the question of whether hyperphosphaturia is isolated or not may help narrow down the number of possible differential diagnoses. Isolated phosphate loss is typically found in oncogenic osteomalacia, X-linked hypophosphataemic rickets (XLH) and autosomal dominant hypophosphataemic rickets/osteomalacia [13]. Phosphate loss in combination with proteinuria, aminoaciduria, renal glycosuria or bicarbonate wasting with renal tubular acidosis is diagnostic for Fanconi syndrome [4]. XLH is usually a paediatric disease but as it may rarely present late in previously asymptomatic elderly patients without growth retardation, it should also be suspected in adult-onset hypophosphataemic osteomalacia [5]. Oncogenic osteomalacia and XLH reveal a similar biochemical phenotype consisting of hypophosphataemia, hyperphosphaturia and impaired vitamin D metabolism [1,2].
Despite remarkable progress, the pathophysiologic mechanisms of these disorders are still incompletely understood. It has been proposed that a humoral factor called phosphatonin, a phosphaturic hormone or a group of hormones, plays a central role by inhibiting proximal tubular phosphate reabsorption and inhibiting renal 25-hydorxyvitamine D 1-hydroxylase activity [1,2,6,7]. Excessive paraneoplastic production of phosphatonin is thought to be involved in the aetiology of oncogenic osteomalacia, whereas impaired degradation and processing of phosphatonin due to endopeptidase mutations (PHEX-gene) is thought to cause the typical findings in XLH [1,2]. The exact biochemical characterization of both the molecular structure of phosphatonin and its mechanism of blocking phosphate reabsorption via interaction with the sodium-dependent phosphate transport is still pending. New insights into the pathophysiology of acquired hyperphosphaturia may arise from recent studies that identified genes abundantly expressed in tumours causing phosphate wasting: FGF-23 (fibroblast growth factor) [8] and MEPE (matrix extracellular phosphoglycoprotein) [9].
Adult onset hypophosphataemic osteomalacia associated with acquired Fanconi syndrome is a rare disorder. Most of the cases previously described were seen in patients with light chain gammopathy [4,10]. In a subgroup of these patients, the toxic effect of urinary light chains on tubular epithelial cells leads to impaired reabsorption of metabolites in the glomerular filtrate [4,10,11]. Kidney biopsy often shows paraprotein deposits in tubular cells [4]. Renal tubular dysfunction also occurs as a complication of heavy metal poisoning and needs to be ruled out [12].
The clinical picture of adult onset hypophosphataemic osteomalacia is grossly identical in familial forms and secondary forms due to Fanconi syndrome or oncogenic osteomalacia [5,10,11,13]. In patients with Fanconi syndrome, the symptoms of underlying monoclonal gammopathy may mask or influence the clinical picture. Moreover, osteomalacia associated with Fanconi syndrome is likely to be of multifactorial aetiology [4] (e.g. renal tubular acidosis, chronic kidney failure). In an adult patient with new-onset hypophosphataemic osteomalacia, oncogenic osteomalacia is the most likely diagnosis when Fanconi syndrome, other toxic tubular defects, nutritional deficits and genetic mutations such as PHEX-mutations have been ruled out [1,2,5,13]. Establishing the correct diagnosis is challenging as tumours associated with oncogenic osteomalacia tend to be difficult to localize [13]. These tumours are often of mesenchymal origin, such as haemangiopericytomas, fibromas or haemangiomas [13], while malignant tumours are rare [14]. The final diagnosis of oncogenic osteomalacia may be delayed for years [13,15]. Multifocal lesions of increased activity seen in skeletal scintigraphy in patients with acquired hypophosphataemic osteomalacia may be misinterpreted as osseous metastases [16,17]. Although isolated hyperphosphaturia is regarded as typical for oncogenic osteomalacia, hypophosphataemic osteomalacia may also develop on the basis of paraneoplastic Fanconi syndrome [18]. If identification and resection of a tumour is possible, healing of skeletal changes has been described [15]. In all other cases and in patients with hyperphosphaturia due to underlying monoclonal gammopathy, a symptomatic therapy should be initiated [4,19].
Teaching points
Notes
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Correspondence and offprint requests to: Dr med Vincent M. Brandenburg, Medizinische Klinik II, Universitätsklinikum der RWTH Aachen, Pauwelsstr. 30, D-52057 Aachen, Germany. Email: Vincent.Brandenburg{at}post.rwth\|[hyphen]\|aachen.de
References