Background: Osteogenesis imperfecta (OI) due to COL1A1 and COL1A2 mutations is the most common cause of primary osteoporosis.
Case presentation: We present a 10-year-old girl with a history of skeletal fragility, starting in the perinatal period. Her parents are not consanguineous and there is no family history of early osteoporosis. To date, she has sustained nineteen low-energy, long bone fractures and she has skeletal deformities (leg length discrepancy, genu varum and scoliosis), blue sclerae and grey teeth. Her cardiac function and hearing are normal. Her baseline bone mineral density at the age of 2.5 years was low (Z-score L2L4=−3.4), but normalized while on treatment with IV bisphosphonates, which started at the age of four years. Her orthopaedic management has been challenging, including a right tibial osteotomy and two Ilizarovs procedures for right tibial pseudarthrosis, which was diagnosed while she was on IV pamidronate; femoral fractures treated with flexible intramedullar nails; double open osteotomies of bowed femoral bones with expandable Duvet Fassier nails. Currently she is on a weight bearing procedure after the union of her femoral osteotomies and out of bisphosphonate treatment.
Methods: Sanger sequencing of COL1A1/COL1A2 was reported as negative initially. However, the strong clinical suspicion of OI led to further investigations. Therefore, whole-genome sequencing (WGS) was performed on the index patient and her healthy parents and brother to identify the genetic cause of the disease.
Results: WGS analysis revealed a novel missense mutation in exon 38 of COL1A2, NM_000089.3: c.2324G>A (p.Gly775Glu), which was further validated by Sanger sequencing. This genetic finding correlated well with the skeletal phenotype of the patient and was thus classified as pathogenic.
Conclusion: This case provides more insight into the molecular background of OI and the association between genotype-phenotype in this rare disease. It also highlights the possibility of pseudarthrosis in OI under treatment, which is a relatively uncommon, poorly described complication of the disease. Finally, perseverance in solving a diagnostic dilemma is of paramount importance. The possibility of falsely reassuring genetic results should always be taken into account and should lead to further investigations when the clinical suspicion is strong.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology