Introduction: Osteogenesis imperfecta (OI), is a genetically heterogeneous connective tissue disorder associated with skeletal fragility, deformity, and growth deficiency. Intravenous bisphosphonate therapy is the mainstay of medical treatment of this condition. Given the paucity of data from Asia we sought to evaluate the genetic epidemiology and the response to pamidronate therapy in a cohort of Malaysian patients.
Method: Genetic analysis was performed in 29 children with OI [Type I n=4, Type III n=16, Type IV n=4 and Type V n=3) from the UKM Medical Centre (UKMMC) and Putrajaya Hospital. 25 patients were on pamidronate treatment. Clinical, biochemical and radiological data was collected prior to and at several times during treatment. Targeted sequencing of genes was performed using the Ion AmpliSeq in the Ion TorrentTM semiconductor sequencer to identify the mutations. The identified mutations were validated using Sanger sequencing and in silico analysis was performed to evaluate the effects of the candidate mutations at protein level.
Results: Genetic analysis revealed that 62% of patients had mutations in collagen genes, 48% (n=14) in COL1A1 and 14% (n=4) in COL1A2. 8 had mutations in IFITM5, BMP1, P3H1 and SERPINF1 and no mutations were discovered in 3 patients. Treatment was started at a median age of 4.8 [1.97.6] years. At the end of the observation period, the median duration of therapy was 5.3 [3.97.2] years. The fracture rate was reduced for all OI types during treatment (P < 0.05). Height SDS scores did not significantly change during pamidronate therapy. Patients with haploinsufficiency mutations had a milder phenotype as compared to those with qualitative mutations. In the group of patients with helical mutations, the type of alpha chain affected did not influence the fracture rate.
Conclusion: Cyclic pamidronate administration reduced the fracture rate effectively in patients with all types of OI. Patients with qualitative mutations had a more severe clinical course.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology