MON-752 - Cracks in the Architecture: Managing Severe Skeletal Fragility in A Young Patient

Introduction:  
ENPP1 (ectonucleotide pyrophosphate/phosphodiesterase 1) is a gene located on chromosome 6 that plays a key role in skeletal and soft tissue mineralization through the generation of inorganic pyrophosphate. Variants in ENPP1 have been associated with a spectrum of age-dependent clinical disorders, including hypophosphatemic rickets type 2, osteomalacia, osteoporosis, chronic joint pain, and cardiovascular complications. Below, we describe a unique case of a patient with tetraploidy of chromosome 6 and heterozygosity of ENPP1 who presents with osteogenic imperfecta-like syndrome with multiple fractures, bone cysts, and early-onset osteoporosis.  

Case:
This case presents a 34 year old male with a pertinent past medical history of chromosome 6 tetraploidy and thoracic vertebral fractures requiring vertebrae fusion presenting for evaluation of recurrent fractures. The patient's family history was significant for a history of recurrent fractures in his mother who passed away in a motor vehicle accident. His outpatient workup included imaging that demonstrated multiple bone cysts in his spine, tibia, and jaw - many of which have been present for at least 10 years. On physical examination, the patient findings were significant for prominent supraorbital ridges, micrognathia, and macrocephaly. Genetic testing showed a tetraploidy of chromosome 6 and a heterozygous mutation in ENPP1. Skin biopsy was unremarkable and prior bone biopsy done on tibial cyst showed simple bone cyst. Due to the patient history of recurrent fractures and osteoporosis, he was initially placed on pamidronate and subsequently transitioned to zoledronic acid after sustaining more fractures while on treatment. The patient was recently placed on romosozumab for its’ anabolic properties following a sternal fracture while on previous aforementioned treatment.  

Conclusion:
Although this patient’s clinical presentation strongly resembled osteogenesis imperfecta, genetic testing did not confirm a pathogenic variant associated with this condition. Emerging evidence suggests that ENPP1 deficiency as well as tetraploidy of chromosome 6 may contribute to early-onset osteoporosis and paradoxical hyperostosis, providing a potential explanation for this patient’s phenotype. While data remains limited, current studies are analyzing the efficacy of romosozumab compared to bisphosphonates in patients with osteogenesis imperfecta. Management has been directed toward the patient’s osteoporosis and elevated fracture risk which led to the selection of romosozumab, with plans to transition to anti-resorptive therapy to maintain bone density gains thereafter. This case underscores the importance of a clinical picture approach to treatment of rare bone disorders and adds to the growing body of literature supporting anabolic therapy as a viable option in complex cases of early-onset osteoporosis.

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