There are 21 reported cases of Bruck syndrome (BS), a rare autosomal recessive condition characterized by congenital contractures affecting the large joints, generalized osteopenia, and bone fragility. Genome-wide homozygosity studies of a large family demonstrated linkage to chromosome 17p12 (BS type 1); however, no causative gene has been identified in this region. Mapping studies in other families implicated a region on chromosome 3q23-q24 (BS type 2) that contains the PLOD2 gene, a lysyl hydroxylase isoform involved in the cross-linking of collagen telopeptides. Two families have had homozygous, missense mutations identified in exon 17 of PLOD2, whereas the initial family showing linkage to 17p12 had no identifiable mutations in PLOD2, indicating genetic heterogeneity in BS. Our patient, S.K., is a 12-year-old male who presented with a diagnosis of osteogenesis imperfecta (OI) based on radiographic findings of generalized osteopenia, incomplete fractures of the tibia, and compression fractures of the vertebrae. Photographs and parental interview revealed a history of bilateral congenital knee contractures and significant bowing of the tibias. S.K. has undergone extensive physical therapy for his contractures and had two hamstring release procedures during his early childhood to improve mobility in his knees. More recently, he has had bilateral osteoplasties to correct malunion of his tibia/fibula. Based on the rare combination of OI and a physical examination that showed joint contractures of both the knees and the elbows, S.K. was diagnosed with Bruck syndrome. Commercial testing for Bruck syndrome is not currently available, and we will undertake sequence analysis of exon 17 in the PLOD2 gene, a proposed mutation hotspot in BS type 2. We will also analyze urine to validate a biochemical diagnostic algorithm proposed by Vin Ha et al (Am J Med Genet 2004) using the quantitation of several key products of collagen degradation (hydroxylysylpyridinoline, lysylpyridinoline, and hydroxyproline) to differentiate Bruck syndrome from OI and Ehlers Danlos syndrome type VI. The results of these tests, a review of the clinical features of Bruck syndrome, and the biological mechanisms of PLOD2 gene action that cause this phenotype will be discussed.
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