Context: A middle-aged woman with recent-onset painful swollen fingers and widespread periostitis, elevated serum alkaline phosphatase (ALP) activity and erythrocyte sedimentation rate, and accelerated skeletal turnover was found not to have mutations in the gene sequences for exon 1 of receptor activator of nuclear factor-κB (RANK), osteoprotegerin (OPG), or sequestosome-1. Introduction: Hyperphosphatasia refers to disorders that feature elevated serum ALP activity (hyperphosphatasemia) usually from excesses of the bone isoform of ALP. Such conditions include familial expansile osteolysis, expansile skeletal hyperphosphatasia, and a familial form of early-onset Paget's disease of bone (PDB2), all from constitutive activation of RANK, and juvenile Paget's disease from OPG deficiency. Patient and Methods: A 38-yr-old woman developed painful swollen fingers and achy bones after an episode of unexplained pericarditis and restrictive lung disease. Sequence analysis of exon 1 of TNFRSF11A encoding RANK, TNFRSF11B encoding OPG, and SQSTM1 encoding sequestosome-1 searched for mutations responsible for familial expansile osteolysis, expansile skeletal hyperphosphatasia, or PDB2, juvenile Paget's disease, or Paget's disease of bone (PDB), respectively. Results: Serum ALP and osteocalcin and urinary hydroxyproline were increased. Radiographs showed widespread, symmetric hyperostosis in the limbs where bone scintigraphy demonstrated enhanced radionuclide uptake. Iliac crest histology revealed accelerated skeletal turnover. No mutations were detected in the three genes examined. Three years of therapy with 70 mg alendronate orally once weekly improved symptoms, radiographic abnormalities, and biochemical markers. Conclusions: Our patient manifested a unique, sporadic hyperphosphatasia syndrome. Unexplained, transient inflammation seemed to cause her pericarditis, restrictive lung disease, and periostitis with accelerated skeletal turnover that responded well to antiinflammatory drugs and alendronate therapy.