P-20 EARLY ZOLEDRONIC ACID TREATMENT IN A PEDIATRIC CASE OF OSTEOGENESIS IMPERFECTA TYPE V: CLINICAL OUTCOMES AND THE ROLE OF IFITM5 (BRIL) MUTATION
Authors: Eren Simge , Eren Olcay 
Published: January 2025

Introduction

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility, low bone mass, and frequent fractures. OI is typically associated with mutations in the COL1A1 and COL1A2 genes, but a subset of cases, such as OI type V, is linked to mutations in the IFITM5 gene, also known as BRIL (bone-restricted IFITM-like).

Clinical Case

This report presents a case of a 2-year-old boy diagnosed with OI type V, a rare form of the disease caused by a mutation in BRIL. The patient exhibited multiple recurrent bone fractures beginning in infancy, though there was no family history of bone disease or consanguineous marriage.

Physical examination revealed that the patient was of normal weight and height for his age, with neurodevelopmental milestones met. Laboratory tests showed elevated alkaline phosphatase (ALP) levels, indicative of increased bone turnover, while other values were within normal ranges. Radiological evaluations confirmed an active fracture in the left tibia but showed no additional pathological involvement. Genetic testing identified a de novo C&gt;T variant in the IFITM5 gene, confirming the diagnosis of OI type V.

The patient was treated with intravenous zoledronic acid (ZA), a bisphosphonate therapy, which is currently being tested in infants and toddlers for OI treatment. The treatment led to a significant reduction in fracture recurrence and a decrease in ALP levels, demonstrating its efficacy in managing the disease. Despite these positive outcomes, certain hallmark features of OI type V, such as hyperplastic callus formation and new periosteal bone growth, were not observed during follow-up, possibly due to the early initiation of ZA therapy.

OI type V is distinguished from other forms of OI by hyperplastic callus formation and increased osteoblast activity, often accompanied by elevated ALP levels. Radiographic and histological findings specific to this type include periosteal bone growth and a reticular lamellation pattern in the bone matrix. Although ZA has shown promise in reducing fracture risk and improving clinical outcomes, its long-term efficacy in preventing other disease manifestations, such as intramembranous ossification, remains uncertain.

The underlying pathological mechanisms of OI type V, particularly the role of BRIL, are not yet fully understood. Further research into the activation of BRIL in osteoblasts could lead to the development of targeted therapies that address the root cause of the disease. While ZA therapy has been effective in managing the immediate symptoms of OI type V, a deeper understanding of the disease's genetic and molecular basis is crucial for improving long-term treatment outcomes.

In conclusion, the IFITM5 (BRIL) mutation is recognized as the genetic cause of OI type V. Early intervention with ZA has shown positive effects in managing the disease, but further research is needed to fully understand the pathological mechanisms and to develop treatments that can address all aspects of the disease.Table 1:Lab workout (age 2)ALP = alkaline phosphatase; AST = aspartate transaminase; BUN = blood urea nitrogen; GGT = gamma-glutamyl transferase; CBC: complete blood count