An Unusual Case of Bone Pain, Hypophosphatemia, and a Gastric Mass: A Quiz

A 50-year-old man presented to our hospital with bone pain for 2 years. One year before admission, he quit his job as a miner owing to exacerbating pain. Gradually, fatigue and weakness developed, and he became wheelchair dependent. He was diagnosed with lumbar disc herniation at local hospitals and received physical therapy, but pain persisted. He was previously healthy, took no medications, and had stopped smoking and drinking alcohol since disease onset; he denied hepatitis B infection and other chronic diseases. Laboratory measurements at the local hospital are shown in Table 1. Serum calcium was normal but levels of serum alkaline phosphatase were elevated while serum phosphorus level was low. 68Ga-DOTATATE positron emission tomography / computed tomography (68Ga PET/CT) at another hospital revealed a 2.4 × 1.6 cm gastric mass with increased tracer uptake (Fig 1A-D). The tumor was successfully removed and found to be a nonmalignant tumor from the pancreas, but his serum phosphorus levels remained low following tumor removal.•What is the differential diagnosis of chronic hypophosphatemia?•What additional evaluations should be performed in this case?•What are the renal pathologic findings?•What is the diagnosis and treatment for this patient?Table 1Laboratory TestsVariableValueReference RangeAt the local hospitalSerum calcium, mg/dL9.228.6-10.4Serum phosphorus, mg/dL1.612.5-5Serum potassium, mmol/L3.33.5-5.5Alkaline phosphatase, IU/L26415-112Further evaluationsBlood tests Hemoglobin, g/L157130-175 White blood cell count, ×109/L4.64.5-5.8 Platelets, ×109/L113100-300 Serum creatinine, mg/dL1.060.6-1.3 Uric acid, μmol/L70210-430 Serum calcium, mg/dL9.068.6-10.4 Serum phosphorus, mg/dL1.522.5-5 Serum potassium, mmol/L3.073.5-5.5 Serum total protein, g/L61.560-80 Serum albumin, g/L45.735-55 Alkaline phosphatase, IU/L30315-112 Fasting glucose, mg/dL93.670-108 CTX, ng/L2,823<704 Osteocalcin, ng/mL35.814-46 Parathyroid hormone, pg/mL18.515-65 25-hydroxy vitamin D, ng/mL15.8>20 C-reactive protein1.90-3 ESR, mm/h2.00-21 AutoantibodiesaIncluding anti–cyclic citrullinated peptide antibody (CCP), antinuclear antibody (ANA), extractable nuclear antibodies (ENA), anti–double stranded DNA antibody (dsDNA), antineutrophil cytoplasmic antibody (ANCA), anticardiolipin antibody (ACL), lupus anticoagulant (LAC), β2-glycoprotein 1 antibody (β2GP-1).Negative FGF23, pg/mL<33-800Blood gas analysis pH7.37.35-7.45 PaO2, mm Hg86.875-100 PaCO2, mm Hg34.736-44 Base excess-7.1-3 to +3Urinalysis pH6.04.6-8.0 Glucose++++Negative Protein++Negative 24-h urine volume, mL3,000800-1,500 24-h protein, g/d7.710-0.2 24-h creatine, μmol/d128.890.5-181 24-h phosphorus, mg/d115.250-130 24-h potassium, mmol/d86.825-100 24-h uric acid, μmol/d4,464.01,460-4,880Abbreviations: CTX, C-telopeptide of type I collagen; ESR, erythrocyte sedimentation rate; FGF23, fibroblast growth factor 23.a Including anti–cyclic citrullinated peptide antibody (CCP), antinuclear antibody (ANA), extractable nuclear antibodies (ENA), anti–double stranded DNA antibody (dsDNA), antineutrophil cytoplasmic antibody (ANCA), anticardiolipin antibody (ACL), lupus anticoagulant (LAC), β2-glycoprotein 1 antibody (β2GP-1). Open table in a new tab Abbreviations: CTX, C-telopeptide of type I collagen; ESR, erythrocyte sedimentation rate; FGF23, fibroblast growth factor 23. Chronic hypophosphatemia caused by decreased gastrointestinal absorption is seen in those with chronic diarrhea, vitamin D deficiency/resistance, and dietary restriction. Increased urinary phosphate excretion is the most frequent cause of chronic hypophosphatemia, and it can be either inherited or acquired. Fibroblast growth factor 23 (FGF23) is a phosphatonin that acts on proximal tubules to increase urinary phosphorus excretion.1Minisola S. Peacock M. Fukumoto S. et al.Tumour-induced osteomalacia.Nat Rev Dis Primers. 2017; 317044https://doi.org/10.1038/nrdp.2017.44Crossref Scopus (187) Google Scholar Therefore, if FGF23 levels are not elevated, then increased urinary phosphate excretion may be due to tubulopathies seen in Sjögren syndrome or cystinosis or with paraprotein diseases.2Haffner D. Emma F. Eastwood D.M. et al.Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia.Nat Rev Nephrol. 2019; 15: 435-455https://doi.org/10.1038/s41581-019-0152-5Crossref PubMed Scopus (272) Google Scholar The diagnostic algorithm of chronic hypophosphatemia is summarized in Fig 2. Tumor-induced osteomalacia, a paraneoplastic syndrome characterized by FGF23 overproduction, is the major cause of adult-onset chronic hypophosphatemia. 68Ga PET/CT scan has high specificity and sensitivity in locating culprit tumors and is regarded as a diagnostic tool for tumor-induced osteomalacia. However, the pituitary gland, spleen, pancreas, and others physiologically express somatostatin receptors, which may lead to false-positive results. The patient experienced bone pain for 2 years, and continued to have low serum phosphorus levels. A bone scan confirmed hypophosphatemic osteomalacia (Fig 1E). His serum calcium and parathyroid hormone levels were normal (Table 1), making both primary and secondary hyperparathyroidism and hypercalcemia-related hypophosphatemia unlikely. Although the urinary phosphorus level was normal, the tubular maximum reabsorption of phosphorus per glomerular filtration rate was 1.51 mg/dL (reference range: 2.60-3.80 mg/dL), suggesting inappropriately high urine phophorus excretion. The low serum FGF23 combined with the high urinary phophorus excretion was consistent with a tubulopathic process. Considering his absence of family history, acquired tubulopathy was most likely. Medications, autoimmune diseases, heavy metal intoxication, and paraprotein diseases may lead to proximal tubular functional impairment. The patient denied routine medication use and exposure to heavy metals. No autoantibodies were found on laboratory testing. Urinalysis revealed heavy proteinuria (7.71 g/d). Serum protein electrophoresis and immunofixation showed a monoclonal κ light chain band. Serum-free κ light chain was 1,200 mg/L, and λ light chain was 12.5 mg/L, with a ratio of 95.8. A bone marrow aspirate demonstrated 12% plasma cells with 5.2% aberrant plasma cells by flow cytometry. Biochemical and urinary studies revealed hypouricemia and hypokalemia with increased urinary potassium excretion and normoglycemic glucosuria, indicating impairment of the proximal tubule. Blood gas analysis showed decompensated metabolic acidosis with a normal anion gap, confirming the diagnosis of renal Fanconi syndrome. Although a monoclonal band was identified, the hematological, radiological, and biochemical results did not fulfill the diagnostic criteria for multiple myeloma. Therefore, a percutaneous renal biopsy was performed to figure out renal lesions. Light microscopy showed swollen proximal tubules with acute injury with loss of brush border and epithelial flattening, with some visible fuchsinophilic inclusions on trichrome. Granular κ light chains were deposited in proximal tubular cells by immunofluorescence and immunogold electron microscopy, while crystalline inclusions were absent (Fig 3). According to the consensus of the International Kidney and Monoclonal Gammopathy Research Group,3Leung N. Bridoux F. Batuman V. et al.The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.Nat Rev Nephrol. 2019; 15: 45-59https://doi.org/10.1038/s41581-018-0077-4Crossref PubMed Scopus (285) Google Scholar the final diagnosis is noncrystalline light chain proximal tubulopathy. "Clone-directed" therapy was recommended to be initiated in patients with light chain proximal tubulopathy,4Leung N. Bridoux F. Nasr S.H. Monoclonal gammopathy of renal significance.N Engl J Med. 2021; 384: 1931-1941https://doi.org/10.1056/NEJMra1810907Crossref PubMed Scopus (60) Google Scholar though the optimal regimen remains elusive. Previous study indicated bortezomib-based regimens were related to better hematological and tubular responses.5Wu X. Zhang L. Feng J. et al.Bortezomib-based chemotherapy can improve renal and tubular functions in patients with light chain-associated Fanconi syndrome.Ann Hematol. 2019; 98: 1095-1100https://doi.org/10.1007/s00277-018-3572-6Crossref Scopus (4) Google Scholar Bortezomib-based induction, potassium citrate (1.1 g 3 times/d), oral phosphonate supplement (1.84 mmol/kg/d), and calcitriol (0.25 μg 3 times/d) were administered to the patient. After induction (2 cycles of standard dose bortezomib-dexamethasone therapy followed by 8 cycles of bortezomib-lenalidomide-dexamethasone therapy), his bone pain was relieved, and very good partial remission was realized (serum-free light chains dropped from 1,200 mg/L to 112 mg/L). A repeated bone marrow smear revealed 0.5% plasma cells, with 0.36% minimal residual disease on flow cytometry. Proteinuria was alleviated (dropping from 7.71g/d to 1.88g/d), serum phosphorus increased (from 1.61mg/dL to around 2.3mg/dL), and acidosis and hypokalemia were corrected. Noncrystalline light-chain proximal tubulopathy, secondary Fanconi syndrome, and hypophosphatemic osteomalacia. Xiang Li, MD, Dongsheng Cheng, MD, PhD, Zhenkui Sun, MD, PhD, Qiong Jiao, MD, Chun Wang, MD, PhD, and Ying Fan, MD, PhD. XL and DC contributed equally to this work. This study was supported by National Nature Science Foundation of China (82170727, 81870468), Star Program of Shanghai Jiao Tong University, Key medical and industrial projects (YG2023ZD21), Open project of National Science and Technology Infrastructure of translational medicine (Shanghai, TMSK-2021-109), Emergency project for COVID-19 study by Shanghai Jiao Tong University Affiliated Sixth People's Hospital (ynxg202202), Shanghai Research Center for Endocrine and Metabolic Diseases (2022ZZ01002), and Special Fund of the China International Medical Foundation (Z-2017-26-2202-2). Funders did not have a role in defining the content of the manuscript. The authors declare that they have no relevant financial interests. The authors declare that they have obtained written consent from the patient reported in this article for publication of the information about him that appears within this Quiz. Received March 18, 2023. Direct editorial input from a radiology reviewer, the Pathology Editor, and the Engagement Editor. Accepted in revised form September 7, 2023.