Skeletal and Metabolic Translational Medicine

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Abstract

Our group has continued to focus on the clinical characterization of patients with rare skeletal dysplasias. One disorder of phosphate metabolism, ENPP1 deficiency, is associated with ectopic calcification and hypophosphatemic rickets from FGF23 excess. In the past year, we have expanded the known natural history of this disorder (reference 1). We are also performing work to understand how the deficiency of ENPP1 leads to an excess of FGF23, and thus to rickets. We have published a manuscript related to another disorder of phosphate metabolism, osteoglophonic dysplasia, characterized by short stature, bone lesions, and increased secretion of a hormone, FGF23, an important regulator of phosphate levels (reference 2). Specifically, we reported new patients with this rare disease and expanded the known clinical features associated with it. We established the first animal model of this disease and are now ready to submit a manuscript detailing our characterization of the skeletal phenotype in the in vivo model, mechanistic studies explaining the phosphate abnormalities, and preclinical data of a potential new therapeutic strategy for this disease. We continue to use genomic and other technologies to discover and validate the cause of skeletal disorders. Our group recently found the cause of Trevor disease and of prenatal Caffey disease, and we are performing work to understand the mechanisms leading to excess skeletal growth in these conditions. We are also trying to identify the molecular basis of genochondromatosis, a rare skeletal dysplasia leading to cartilage overgrowth. We have also collaborated with various colleagues both within and outside NIH, leading to improved characterization of the skeletal phenotype of various conditions, including Jansen metaphyseal chondrodysplasia (reference 3), alkaptonuria (reference 4), and MAGIS syndrome (reference 5).