Introduction: Osteogenesis imperfecta (OI) is a hereditary disease characterized by a wide range of skeletal signs. Mutations in COL1A1/A2 have been known to cause dominant OI. Recently, a heterozygous mutation in the 5′-UTR of IFITM5 (c.−14C>T) was identified as a new cause of dominant OI. We present three patients from three different families with two mutations in IFITM5 with extremely different phenotypes.
Description of methods/design: Patient 1 displayed at 20 weeks of gestation with bowing of the lower extremities. Postnatal, he showed white sclera, a hypoplastic thorax, bowing of the long bones. With 19 months the patient presented with a length of −4.8 SDS and a weight of −3.2 SDS. Bone resorption was increased despite antiresorptive bisphosphonate treatment (deoxypyridinoline/creatinine 63.9 nM/mM (19.5±7.2). Patient 2 and 3 were diagnosed with a moderate OI at the age of 1.7/8.7 years based on extremity fractures and hyperplastic callus formation. Bone mineral density was reduced with a DXA ap spine Z-score of −3.3/−2.8 before initiating i.v./oral bisphosphonate treatment. Sanger sequencing of IFITM5 was performed. Written informed consent was given.
Results: In patients 2/3 the IFITM5 c.−14C>T mutation was identified causing the classical postnatal hallmarks of OI V. Patient 1 presented a new heterozygous mutation within the coding region of IFITM5 (c.119C>T; p.S40L). This mutation resulted in severe OI with prenatal onset and extreme short stature. Characteristics of OI type V did not occur yet.
Conclusions: Dominant mutations in the gene IFITM5 are connected to the clinical hallmarks of moderate OI V but also can lead to severe OI with prenatal onset. In patients suspected of OI, the entire gene IFITM5 and not only the 5′-UTR region has to be analyzed to exclude a causal role of IFITM5. We propose that this should be part of the initial diagnostic steps as dominant mutations are most common in OI.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology