Hypophosphatasia (HPP), an inborn-error-of-metabolism characterized biochemically by subnormal serum levels of alkaline phosphatase (ALP), is caused by deactivating mutations in the gene which encodes the tissue-nonspecific ALP isoenzyme (TNSALP). Radiographs in "childhood" HPP typically show rickets, including "tongues" of lucency that project from physes into metaphyses in major long bones and sometimes, areas of metaphyseal osteosclerosis. Yet children with the most mild form, odontoHPP, have no skeletal radiographic abnormalities and seek medical attention for early tooth loss. Purpose: To define the prevalence of joint and bone pain with various pediatric forms of HPP and to highlight two patients with presentations mimicking chronic recurrent multifocal osteomyelitis (CRMO). Methods: We reviewed 111 HPP patient charts. Nearly all have completed molecular diagnoses. 11 had infantile HPP, 64 had childhood HPP, and 36 had odontoHPP. Patients with complex phenotypes (ie. more than one disease),a marrow transplant recipient, and patients less than 2.5 years at last evaluation were excluded. Results: Among patients who met inclusion criteria: Significant joint and skeletal pain troubled 8 of 8 children (100%) diagnosed with infantile HPP. Of 58 patients with childhood HPP, 72% complained of pain varying from mild to incapacitating (sometimes with morning stiffness) often following physical activity. All reported lower extremity pain. 20% had upper extremity pain as well. Of 32 patients with odontoHPP, 59% complained of pain in their lower extremities and/or back. Hence, joint and or bone pain occur often in each pediatric form of HPP. These, symptoms may often be attributable to obvious rickets, but pain also troubled patients with early tooth loss as their only HPP manifestation. Two of our HPP patients presented with an unusual syndrome of periarticular pain and bone edema mimicking CRMO: A 13-year-old boy without premature loss of deciduous teeth, had life-long a stiff-legged gait and joint pains twice considered elsewhere as possible CRMO. Additionally, he had distal tibial metaphyseal expansion worsening over 2 years that is atypical for HPP. Serum ALP was 94 (133-347 IU/L). Study of the TNSALP gene showed a mutation (Asp361Val) in one allelle. At age 11 years, a girl with infantile HPP (and a history of morning stiffness and joint and bone pain) developed bilateral, incapacitating leg pain and bone edema (detected by MRI) consistent with CRMO on MRI after an epiphyseal stapling procedure to correct knock knee deformity. Serum ALP was 39 (mutational analysis revealed compound heterozygosity: Ala34Ser; Thr117His). Conclusions: Causes of pediatric joint pain are numerous and sometimes are unexplained. Premature tooth loss (less than 5 years of age) and careful assessment for low serum levels of ALP using age-appropriate norms should be included in the differential diagnosis of puzzling pediatric joint and bone pain syndromes.