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AbstractContext:Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI; OMIM 611236) by dysregulating intracellular calcium flux.
Objectives:Clinical and bone material phenotype description and osteoblast differentiation studies.
Design and Setting:Natural history study in paediatric research centres.Patients:Eight patients with type XIV OI.
Main Outcome Measures:Clinical examinations included; bone mineral density, radiographs, echocardiography and muscle biopsy. Bone biopsy samples (n=3) were analysed for histomorphometry and bone mineral density distribution by quantitative backscattered electron microscopy and Raman microspectroscopy. Cellular differentiation studies were performed on proband osteoblasts and normal murine osteoclasts.
Results:The clinical phenotype of type XIV OI ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband L1-L4 bone density Z-score was reduced (median -3.3 [range -4.77 to +0.1; n=7]), and increased by +1.7 (1.17 to 3.0; n=3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone mineralization density is normal/slightly increased. We demonstrate a complex osteoblast differentiation defect with decreased 3 expression of early markers and increased late, mineralisation-related markers.Predominance of TRIC-B over TRIC-A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover.Conclusions: OI type XIV has a bone histology, mineralization and osteoblast differentiation pattern that is distinct from type I OI. Probands are responsive to bisphosphonates but show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities.4