Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most 
commonly associated with autosomal dominant mutations in the type I collagen 
genes. Autosomal recessive mutations in a number of genes have also been 
described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and 
its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 
individuals with OI have been identified with BMP1 mutations, with skeletal 
phenotypes ranging from mild to severe and progressively deforming. In the 
majority of patients, bone fragility was associated with increased bone mineral 
density (BMD); however, the full range of phenotypes associated with BMP1 
remains unclear. Here, we describe three children with mutations in BMP1 
associated with a highly variable phenotype: a sibship homozygous for the 
c.2188delC mutation that affects only the shorter BMP1 isoform and a further 
patient who is compound heterozygous for a c.1293C>G nonsense mutation and a 
c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent 
fractures from early childhood, are hypermobile and have no evidence of 
dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD 
by dual energy X-ray absorptiometry whereas the third patient presented with a 
high bone mass phenotype. Intravenous bisphosphonate therapy was started in all 
patients, but discontinued in two patients and reduced in another due to 
concerns about increasing bone stiffness leading to chalk-stick fractures. Given 
the association of BMP1-related OI with very high bone material density, 
concerns remain whether anti-resorptive therapy is indicated in this ultra-rare 
form of OI.© 2016 Wiley Periodicals, Inc.