Three children with lower limb fractures and a mineralization defect: a novel bone fragility disorder? Craig F.J. Munns, Frank Rauch, Rose Travers, Francis H. Glorieux * Genetics Unit, Shriners Hospital for Children, Montre ´al, Que ´bec, Canada H3G 1A6 McGill University, Montre ´al, Que ´bec, Canada H3G 1A6 Received 12 March 2004; revised 21 June 2004; accepted 2 August 2004 Available online 28 September 2004 Abstract In this report, we describe three unrelated children with an apparently novel bone fragility disorder that is associated with an idiopathic mineralization defect. Recurrent lower limb fractures started with weight bearing. The patients had none of the phenotypic, radiological, or histomorphometric features classically associated with known bone fragility disorders such as osteogenesis imperfecta (OI), idiopathic juvenile osteoporosis (IJO), or mild autosomal dominant osteopetrosis. Radiologically, there was increased metaphyseal trabeculation, normal to increased cortical thickness, and no evidence of rickets or osteomalacia. Areal and volumetric bone mineral density (BMD) of the lumbar spine did not show any major alteration. Peripheral quantitative computed tomography of the radius showed elevated cortical thickness and total and trabecular volumetric bone mineral density in one patient. Qualitative histology of iliac bone biopsy specimens showed a paucity of the birefringent pattern of normal lamellar bone. Quantitative histomorphometric analysis demonstrated osteomalacia with a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. There was no biochemical evidence of abnormal calcium or phosphate metabolism. Type I collagen mutation analysis was negative. We conclude that this is a bone fragility disorder of moderate severity that tends to cause fractures in the lower extremities and is associated with the accumulation of osteoid due to an intrinsic mineralization defect. The pathogenetic basis for this disorder remains to be elucidated. D 2004 Elsevier Inc. All rights reserved. Keywords: Bone density; Bone fragility; Histomorphometry; Mineralization; Osteomalacia; pQCT Introduction Bone fragility is rare in otherwise healthy children but may cause severe clinical problems. Bone fragility may result from either an intrinsic abnormality of the skeleton (primary fragility) or from other diseases or their treatment (secondary fragility) [23]. The known primary bone fragility disorders in children fall into two categories: conditions with low bone mass and conditions with high bone mass. The two major primary bone fragility disorders associated with low bone mass are osteogenesis imperfecta (OI) and idiopathic juvenile osteoporosis (IJO) [23]. Fragility with high bone mass is seen in autosomal dominant osteopetrosis [3]. Despite our improved understanding of pediatric bone disorders, children with apparent primary bone fragility often do not fit the pattern of any of the recognized disorders. In this report, we describe three children with multiple lower limb fractures who were otherwise healthy and had no major alterations in bone mass. Bone histology revealed signs of a mineralization defect in bone tissue, but there was no radiographic evidence of rickets. We suggest that these three patients suffer from a novel primary bone disorder. Subjects and methods Patients The three patients described in this report were evaluated at the Shriners Hospital for Children in Montreal, Canada. 8756-3282/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2004.08.004 * Corresponding author. Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montre ´al, Que ´bec, Canada H3G 1A6. Fax: +1 514 842 5581. E-mail address: glorieux@shriners.mcgill.ca (F.H. Glorieux). Bone 35 (2004) 1023 – 1028 www.elsevier.com/locate/bone