Disorders of biomineralization (FGF23/phosphate axis)

Osteoglophonic dysplasia (OGD) is a skeletal disorder caused by gain-of-function variants in FGFR1 leading to profound short stature, skeletal deformities, craniofacial abnormalities due to premature fusion of the sutures (craniosynostosis), and FGF23 excess. There is no treatment currently available for patients with OGD. We chose to study this condition to further our understanding of FGF23 biology and to assess the effects of modulation of the overactive FGFR1 signaling pathway. The experience gained by studying OGD will provide expertise in bone biology that will prove fruitful in studying novel skeletal dysplasias identified through the group’s natural history study. We established the first mouse model of OGD, which closely recapitulates the human phenotype, and have shown promising results repurposing an FDA-approved drug in treating disease manifestations in this OGD model. The USG will continue to explore new therapies in this and emerging mouse models of OGD.

A second disorder affecting FGF23/phosphate biology is ENPP1 deficiency, characterized by arterial calcification and stenosis often fatal in the first year of life (Generalized Arterial Calcification of Infancy, or GACI). Those who survive the disease (or those with milder forms of ENPP1 deficiency) develop excess FGF23 by a largely unexplained mechanism (Autosomal Recessive Hypophosphatemic Rickets type 2, or ARHR2). The USG is actively working on characterizing the cause of FGF23 excess in ENPP1 deficiency, hoping to gain better understanding of the pathways regulating FGF23 and phosphate physiology. We are also interested in improving therapeutic options available for patients with ENPP1 deficiency.

Skeletal dysplasias of unknown cause

Trevor disease is characterized by tumors composed of bone and cartilage that develop within the epiphyses of long bones, leading to joint enlargement, deformity, decreased mobility, pain, and abnormal ambulation. We performed exome and genome sequencing in samples from patients with Trevor disease, and identified a pathogenic variant in five patients. We established a mouse model of the disease that closely recapitulates the human phenotype, and we’re currently testing therapies that target the disease mechanism.

The USG is also actively involved in investigating the etiology of genochondromatosis, an autosomal dominant disorder of cartilage development characterized by overgrowth of growth plates into the metaphyses of long bones. The overgrown lesions represent chondromas, or tissue composed of cartilage, and lead to bone pain, deformities, and occasionally fractures, significantly affecting the quality of life of patients. Finally, we study prenatal Caffey disease, characterized by massive new bone formation in utero, before 35 weeks of gestation. The identification of the cause of these disorders might uncover novel pathways involved in cartilage and bone formation.