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Osteogenesis imperfecta

Abstract

Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation.

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Figure 1: Clinical features associated with osteogenesis imperfecta.
Figure 2: Structure of collagen.
Figure 3: Type I collagen synthesis and processing.
Figure 4: Defects in bone formation and mineralization in osteogenesis imperfecta.
Figure 5: Prenatal screening for osteogenesis imperfecta.
Figure 6: Lower extremity surgery in patients with osteogenesis imperfecta.

References

  1. 1

    Marini, J. C. et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum. Mutat. 28, 209–221 (2007). A paper that provides the best genotype–phenotype correlation for collagen mutations.

    Google Scholar 

  2. 2

    Marini, J. C. in Nelson Textbook of Pediatrics (eds Kliegman, R. M., Stanton, B., St. Geme, J., Schor, N. & Behrman, R. E. ) 2437–2440 (Elsevier Health Sciences, 2011).

    Google Scholar 

  3. 3

    Kang, H., Aryal, A. C. S. & Marini, J. C. Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia. Transl Res. 181, 27–48 (2017).

    Google Scholar 

  4. 4

    Forlino, A. & Marini, J. C. Osteogenesis imperfecta. Lancet 387, 1657–1671 (2016). An up-to-date review of the genetics of osteogenesis imperfecta.

    Google Scholar 

  5. 5

    Orioli, I. M., Castilla, E. E. & Barbosa-Neto, J. G. The birth prevalence rates for the skeletal dysplasias. J. Med. Genet. 23, 328–332 (1986).

    Google Scholar 

  6. 6

    Stevenson, D. A., Carey, J. C., Byrne, J. L., Srisukhumbowornchai, S. & Feldkamp, M. L. Analysis of skeletal dysplasias in the Utah population. Am. J. Med. Genet. A 158A, 1046–1054 (2012).

    Google Scholar 

  7. 7

    Folkestad, L. et al. Mortality and causes of death in patients with osteogenesis imperfecta: a register-based nationwide cohort study. J. Bone Miner. Res. 31, 2159–2166 (2016).

    Google Scholar 

  8. 8

    Kuurila, K., Kaitila, I., Johansson, R. & Grénman, R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann. Otol. Rhinol. Laryngol. 111, 939–946 (2002).

    Google Scholar 

  9. 9

    Bardai, G., Moffatt, P., Glorieux, F. H. & Rauch, F. DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int. 27, 3607–3613 (2016).

    Google Scholar 

  10. 10

    Ward, L. et al. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 31, 12–18 (2002).

    Google Scholar 

  11. 11

    Cabral, W. A. et al. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet. Med. 14, 543–551 (2012).

    Google Scholar 

  12. 12

    Kurt-Sukur, E. D., Simsek-Kiper, P. O., Utine, G. E., Boduroglu, K. & Alanay, Y. Experience of a skeletal dysplasia registry in Turkey: a five-years retrospective analysis. Am. J. Med. Genet. A 167A, 2065–2074 (2015).

    Google Scholar 

  13. 13

    Morello, R. et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127, 291–304 (2006).

    Google Scholar 

  14. 14

    Volodarsky, M. et al. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum. Mutat. 34, 582–586 (2013).

    Google Scholar 

  15. 15

    Alanay, Y. et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 86, 551–559 (2010).

    Google Scholar 

  16. 16

    Pyott, S. M. et al. WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am. J. Hum. Genet. 92, 590–597 (2013).

    Google Scholar 

  17. 17

    Ishikawa, Y. & Bachinger, H. P. A molecular ensemble in the rER for procollagen maturation. Biochim. Biophys. Acta 1833, 2479–2491 (2013). An exhaustive summary of collagen biochemistry.

    Google Scholar 

  18. 18

    Myllyharju, J. & Kivirikko, K. I. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 20, 33–43 (2004).

    Google Scholar 

  19. 19

    Vranka, J. A., Sakai, L. Y. & Bachinger, H. P. Prolyl 3-hydroxylase 1, enzyme characterization and identification of a novel family of enzymes. J. Biol. Chem. 279, 23615–23621 (2004).

    Google Scholar 

  20. 20

    Weis, M. A. et al. Location of 3-hydroxyproline residues in collagen types I, II, III, and V/XI implies a role in fibril supramolecular assembly. J. Biol. Chem. 285, 2580–2590 (2010).

    Google Scholar 

  21. 21

    Forlino, A., Cabral, W. A., Barnes, A. M. & Marini, J. C. New perspectives on osteogenesis imperfecta. Nat. Rev. Endocrinol. 7, 540–557 (2011).

    Google Scholar 

  22. 22

    Hudson, D. M., Kim, L. S., Weis, M., Cohn, D. H. & Eyre, D. R. Peptidyl 3-hydroxyproline binding properties of type I collagen suggest a function in fibril supramolecular assembly. Biochemistry 51, 2417–2424 (2012). A careful hypothesis of the role of prolyl 3-hydroxylation.

    Google Scholar 

  23. 23

    Ishikawa, Y., Wirz, J., Vranka, J. A., Nagata, K. & Bachinger, H. P. Biochemical characterization of the prolyl 3-hydroxylase 1·cartilage-associated protein·cyclophilin B complex. J. Biol. Chem. 284, 17641–17647 (2009).

    Google Scholar 

  24. 24

    Zeng, B. et al. Chicken FK506-binding protein, FKBP65 a member of the FKBP family of peptidylprolyl cis–trans isomerases, is only partially inhibited by FK506. Biochem. J. 330, 109–114 (1998).

    Google Scholar 

  25. 25

    Saga, S., Nagata, K., Chen, W. T. & Yamada, K. M. pH-dependent function, purification, and intracellular location of a major collagen-binding glycoprotein. J. Cell Biol. 105, 517–527 (1987).

    Google Scholar 

  26. 26

    Satoh, M., Hirayoshi, K., Yokota, S., Hosokawa, N. & Nagata, K. Intracellular interaction of collagen-specific stress protein HSP47 with newly synthesized procollagen. J. Cell Biol. 133, 469–483 (1996).

    Google Scholar 

  27. 27

    Thomson, C. A. & Ananthanarayanan, V. S. Structure–function studies on hsp47: pH-dependent inhibition of collagen fibril formation in vitro. Biochem. J. 349, 877–883 (2000).

    Google Scholar 

  28. 28

    Sillence, D. O., Rimoin, D. L. & Danks, D. M. Clinical variability in osteogenesis imperfecta-variable expressivity or genetic heterogeneity. Birth Defects Orig. Art. Ser. 15, 113–129 (1979).

    Google Scholar 

  29. 29

    Ishida, Y. et al. Autophagic elimination of misfolded procollagen aggregates in the endoplasmic reticulum as a means of cell protection. Mol. Biol. Cell 20, 2744–2754 (2009).

    Google Scholar 

  30. 30

    Forlino, A. et al. Differential expression of both extracellular and intracellular proteins is involved in the lethal or nonlethal phenotypic variation of BrtlIV, a murine model for osteogenesis imperfecta. Proteomics 7, 1877–1891 (2007).

    Google Scholar 

  31. 31

    Bianchi, L. et al. Differential response to intracellular stress in the skin from osteogenesis imperfecta Brtl mice with lethal and non lethal phenotype: a proteomic approach. J. Proteomics 75, 4717–4733 (2012).

    Google Scholar 

  32. 32

    Gioia, R. et al. Impaired osteoblastogenesis in a murine model of dominant osteogenesis imperfecta: a new target for osteogenesis imperfecta pharmacological therapy. Stem Cells 30, 1465–1476 (2012). A paper that delineates defective osteoblast development as part of the pathophysiology of osteogenesis imperfecta.

    Google Scholar 

  33. 33

    Chu, M. & Prockop, D. J. in Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects 2nd edn (eds Royce, P. M. & Steinmann, B. ) 223–248 (Wiley-Liss, 2002).

    Google Scholar 

  34. 34

    Symoens, S. et al. Type I procollagen C-propeptide defects: study of genotype–phenotype correlation and predictive role of crystal structure. Hum. Mutat. 35, 1330–1341 (2014).

    Google Scholar 

  35. 35

    Cabral, W. A. et al. Type I collagen triplet duplication mutation in lethal osteogenesis imperfecta shifts register of alpha chains throughout the helix and disrupts incorporation of mutant helices into fibrils and extracellular matrix. J. Biol. Chem. 278, 10006–10012 (2003).

    Google Scholar 

  36. 36

    Sweeney, S. M. et al. Candidate cell and matrix interaction domains on the collagen fibril, the predominant protein of vertebrates. J. Biol. Chem. 283, 21187–21197 (2008).

    Google Scholar 

  37. 37

    Orgel, J. P., San Antonio, J. D. & Antipova, O. Molecular and structural mapping of collagen fibril interactions. Connect. Tissue Res. 52, 2–17 (2011).

    Google Scholar 

  38. 38

    Canty, E. G. & Kadler, K. E. Procollagen trafficking, processing and fibrillogenesis. J. Cell Sci. 118, 1341–1353 (2005).

    Google Scholar 

  39. 39

    Cabral, W. A. et al. Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers–Danlos syndrome by interference with N-propeptide processing. J. Biol. Chem. 280, 19259–19269 (2005). A paper that delineates the mechanism of osteogenesis imperfecta resulting from defects in the cleavage of the collagen N-propeptide.

    Google Scholar 

  40. 40

    Malfait, F. et al. Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an osteogenesis imperfecta/Ehlers–Danlos syndrome overlap syndrome. Orphanet J. Rare Dis. 8, 78 (2013).

    Google Scholar 

  41. 41

    Wiestner, M. et al. Inhibiting effect of procollagen peptides on collagen biosynthesis in fibroblast cultures. J. Biol. Chem. 254, 7016–7023 (1979).

    Google Scholar 

  42. 42

    Oganesian, A. et al. The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function. J. Biol. Chem. 281, 38507–38518 (2006).

    Google Scholar 

  43. 43

    Byers, P. H. et al. Ehlers–Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen. Am. J. Med. Genet. 72, 94–105 (1997).

    Google Scholar 

  44. 44

    Pace, J. M. et al. Defective C-propeptides of the proalpha2(I) chain of type I procollagen impede molecular assembly and result in osteogenesis imperfecta. J. Biol. Chem. 283, 16061–16067 (2008).

    Google Scholar 

  45. 45

    Cundy, T., King, A. & Byers, P. H. A novel disorder of type I collagen characterized by high bone mass, a mineralization defect and tendon calcification. Calcif. Tissue Int. 82, S41 (2008).

    Google Scholar 

  46. 46

    Martinez-Glez, V. et al. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum. Mutat. 33, 343–350 (2012).

    Google Scholar 

  47. 47

    Asharani, P. V. et al. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am. J. Hum. Genet. 90, 661–674 (2012).

    Google Scholar 

  48. 48

    Kessler, E., Takahara, K., Biniaminov, L., Brusel, M. & Greenspan, D. S. Bone morphogenetic protein-1: the type I procollagen C-proteinase. Science 271, 360–362 (1996).

    Google Scholar 

  49. 49

    Li, S. W. et al. The C-proteinase that processes procollagens to fibrillar collagens is identical to the protein previously identified as bone morphogenic protein-1. Proc. Natl Acad. Sci. USA 93, 5127–5130 (1996).

    Google Scholar 

  50. 50

    Pappano, W. N., Steiglitz, B. M., Scott, I. C., Keene, D. R. & Greenspan, D. S. Use of Bmp1/Tll1 doubly homozygous null mice and proteomics to identify and validate in vivo substrates of bone morphogenetic protein 1/tolloid-like metalloproteinases. Mol. Cell. Biol. 23, 4428–4438 (2003).

    Google Scholar 

  51. 51

    Imamura, Y., Steiglitz, B. M. & Greenspan, D. S. Bone morphogenetic protein-1 processes the NH2-terminal propeptide, and a furin-like proprotein convertase processes the COOH-terminal propeptide of pro-alpha1(V) collagen. J. Biol. Chem. 273, 27511–27517 (1998).

    Google Scholar 

  52. 52

    Uzel, M. I. et al. Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures. J. Biol. Chem. 276, 22537–22543 (2001).

    Google Scholar 

  53. 53

    Syx, D. et al. Defective proteolytic processing of fibrillar procollagens and prodecorin due to biallelic BMP1 mutations results in a severe, progressive form of osteogenesis imperfecta. J. Bone Miner. Res. 30, 1445–1456 (2015).

    Google Scholar 

  54. 54

    Scott, I. C. et al. Bone morphogenetic protein-1 processes probiglycan. J. Biol. Chem. 275, 30504–30511 (2000).

    Google Scholar 

  55. 55

    Vadon- Le Goff, S., Hulmes, D. J. & Moali, C. BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling. Matrix Biol. 44–46, 14–23 (2015).

    Google Scholar 

  56. 56

    Barnes, A. M. et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N. Engl. J. Med. 355, 2757–2764 (2006).

    Google Scholar 

  57. 57

    Cabral, W. A. et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat. Genet. 39, 359–365 (2007).

    Google Scholar 

  58. 58

    van Dijk, F. S. et al. PPIB mutations cause severe osteogenesis imperfecta. Am. J. Hum. Genet. 85, 521–527 (2009).

    Google Scholar 

  59. 59

    Chang, W., Barnes, A. M., Cabral, W. A., Bodurtha, J. N. & Marini, J. C. Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex. Hum. Mol. Genet. 19, 223–234 (2010). A study that delineates the mutual protection relationship of P3H1–CRTAP in the prolyl-3-hydroxylation complex.

    Google Scholar 

  60. 60

    van Dijk, F. S. et al. Lethal/severe osteogenesis imperfecta in a large family: a novel homozygous LEPRE1 mutation and bone histological findings. Pediatr. Dev. Pathol. 14, 228–234 (2011).

    Google Scholar 

  61. 61

    Caparros-Martin, J. A. et al. Clinical and molecular analysis in families with autosomal recessive osteogenesis imperfecta identifies mutations in five genes and suggests genotype–phenotype correlations. Am. J. Med. Genet. A 161A, 1354–1369 (2013).

    Google Scholar 

  62. 62

    Stephen, J. et al. Mutations in patients with osteogenesis imperfecta from consanguineous Indian families. Eur. J. Med. Genet. 58, 21–27 (2015).

    Google Scholar 

  63. 63

    Pyott, S. M. et al. Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes. Hum. Mol. Genet. 20, 1595–1609 (2011).

    Google Scholar 

  64. 64

    Barnes, A. M. et al. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. N. Engl. J. Med. 362, 521–528 (2010).

    Google Scholar 

  65. 65

    Ishikawa, Y., Vranka, J., Wirz, J., Nagata, K. & Bachinger, H. P. The rough endoplasmic reticulum-resident FK506-binding protein FKBP65 is a molecular chaperone that interacts with collagens. J. Biol. Chem. 283, 31584–31590 (2008).

    Google Scholar 

  66. 66

    Nagata, K. HSP47 as a collagen-specific molecular chaperone: function and expression in normal mouse development. Semin. Cell Dev. Biol. 14, 275–282 (2003).

    Google Scholar 

  67. 67

    Christiansen, H. E. et al. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am. J. Hum. Genet. 86, 389–398 (2010).

    Google Scholar 

  68. 68

    Lindert, U. et al. Molecular consequences of the SERPINH1/HSP47 mutation in the Dachshund natural model of osteogenesis imperfecta. J. Biol. Chem. 290, 17679–17689 (2015).

    Google Scholar 

  69. 69

    Nagai, N. et al. Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J. Cell Biol. 150, 1499–1506 (2000).

    Google Scholar 

  70. 70

    Ishida, Y. et al. Type I collagen in Hsp47-null cells is aggregated in endoplasmic reticulum and deficient in N-propeptide processing and fibrillogenesis. Mol. Biol. Cell 17, 2346–2355 (2006).

    Google Scholar 

  71. 71

    Schwarze, U. et al. Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen. Hum. Mol. Genet. 22, 1–17 (2013).

    Google Scholar 

  72. 72

    Kelley, B. P. et al. Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J. Bone Miner. Res. 26, 666–672 (2011).

    Google Scholar 

  73. 73

    Setijowati, E. D. et al. A novel homozygous 5 bp deletion in FKBP10 causes clinically Bruck syndrome in an Indonesian patient. Eur. J. Med. Genet. 55, 17–21 (2012).

    Google Scholar 

  74. 74

    Zhou, P. et al. Novel mutations in FKBP10 and PLOD2 cause rare Bruck syndrome in Chinese patients. PLoS ONE 9, e107594 (2014).

    Google Scholar 

  75. 75

    Steinlein, O. K., Aichinger, E., Trucks, H. & Sander, T. Mutations in FKBP10 can cause a severe form of isolated osteogenesis imperfecta. BMC Med. Genet. 12, 152 (2011).

    Google Scholar 

  76. 76

    Barnes, A. M. et al. Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations. Hum. Mutat. 34, 1279–1288 (2013).

    Google Scholar 

  77. 77

    Venturi, G. et al. A novel splicing mutation in FKBP10 causing osteogenesis imperfecta with a possible mineralization defect. Bone 50, 343–349 (2012).

    Google Scholar 

  78. 78

    Moravej, H. et al. Bruck syndrome — a rare syndrome of bone fragility and joint contracture and novel homozygous FKBP10 mutation. Endokrynol. Pol. 66, 170–174 (2015).

    Google Scholar 

  79. 79

    Kivirikko, K. I. & Pihlajaniemi, T. Collagen hydroxylases and the protein disulfide isomerase subunit of prolyl 4-hydroxylases. Adv. Enzymol. Relat. Areas Mol. Biol. 72, 325–398 (1998).

    Google Scholar 

  80. 80

    Puig-Hervas, M. T. et al. Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome — osteogenesis imperfecta phenotypic spectrum. Hum. Mutat. 33, 1444–1449 (2012).

    Google Scholar 

  81. 81

    Ha-Vinh, R. et al. Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. Am. J. Med. Genet. A 131A, 115–120 (2004).

    Google Scholar 

  82. 82

    van der Slot, A. J. et al. Identification of PLOD2 as telopeptide lysyl hydroxylase, an important enzyme in fibrosis. J. Biol. Chem. 278, 40967–40972 (2003).

    Google Scholar 

  83. 83

    Becker, J. et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 88, 362–371 (2011).

    Google Scholar 

  84. 84

    Homan, E. P. et al. Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J. Bone Miner. Res. 26, 2798–2803 (2011).

    Google Scholar 

  85. 85

    Akiyama, T. et al. PEDF regulates osteoclasts via osteoprotegerin and RANKL. Biochem. Biophys. Res. Commun. 391, 789–794 (2010).

    Google Scholar 

  86. 86

    Semler, O. et al. A mutation in the 5′-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am. J. Hum. Genet. 91, 349–357 (2012).

    Google Scholar 

  87. 87

    Cho, T. J. et al. A single recurrent mutation in the 5′-UTR of IFITM5 causes osteogenesis imperfecta type V. Am. J. Hum. Genet. 91, 343–348 (2012).

    Google Scholar 

  88. 88

    Farber, C. R. et al. A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor. J. Bone Miner. Res. 29, 1402–14011 (2014).

    Google Scholar 

  89. 89

    Hoyer-Kuhn, H. et al. A nonclassical IFITM5 mutation located in the coding region causes severe osteogenesis imperfecta with prenatal onset. J. Bone Miner. Res. 29, 1387–1391 (2014).

    Google Scholar 

  90. 90

    Glorieux, F. H. et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J. Bone Miner. Res. 15, 1650–1658 (2000).

    Google Scholar 

  91. 91

    Glorieux, F. H. et al. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J. Bone Miner. Res. 17, 30–38 (2002).

    Google Scholar 

  92. 92

    Lapunzina, P. et al. Identification of a frameshift mutation in osterix in a patient with recessive osteogenesis imperfecta. Am. J. Hum. Genet. 87, 110–114 (2010).

    Google Scholar 

  93. 93

    Nakashima, K. et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108, 17–29 (2002).

    Google Scholar 

  94. 94

    Cabral, W. A. et al. Absence of the ER cation channel TMEM38B/TRIC-B disrupts intracellular calcium homeostasis and dysregulates collagen synthesis in recessive osteogenesis imperfecta. PLoS Genet. 12, e1006156 (2016).

    Google Scholar 

  95. 95

    Yamazaki, D. et al. Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells and in perinatal lung maturation. Development 136, 2355–2361 (2009).

    Google Scholar 

  96. 96

    Yazawa, M. et al. TRIC channels are essential for Ca2+ handling in intracellular stores. Nature 448, 78–82 (2007).

    Google Scholar 

  97. 97

    Berridge, M. J., Lipp, P. & Bootman, M. D. The versatility and universality of calcium signalling. Nat. Rev. Mol. Cell Biol. 1, 11–21 (2000).

    Google Scholar 

  98. 98

    Keupp, K. et al. Mutations in WNT1 cause different forms of bone fragility. Am. J. Hum. Genet. 92, 565–574 (2013).

    Google Scholar 

  99. 99

    Laine, C. M. et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N. Engl. J. Med. 368, 1809–1816 (2013).

    Google Scholar 

  100. 100

    Palomo, T. et al. Skeletal characteristics associated with homozygous and heterozygous WNT1 mutations. Bone 67, 63–70 (2014).

    Google Scholar 

  101. 101

    Willert, K. & Nusse, R. Wnt proteins. Cold Spring Harb. Perspect. Biol. 4, a007864 (2012).

    Google Scholar 

  102. 102

    Baron, R. & Kneissel, M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat. Med. 19, 179–192 (2013).

    Google Scholar 

  103. 103

    Gong, Y. et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107, 513–523 (2001).

    Google Scholar 

  104. 104

    Ai, M., Heeger, S., Bartels, C. F. & Schelling, D. K. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am. J. Hum. Genet. 77, 741–753 (2005).

    Google Scholar 

  105. 105

    Lara-Castillo, N. & Johnson, M. L. LRP receptor family member associated bone disease. Rev. Endocr. Metab. Disord. 16, 141–148 (2015).

    Google Scholar 

  106. 106

    Scopelliti, D., Orsini, R., Ventucci, E. & Carratelli, D. Van Buchem disease. Maxillofacial changes, diagnostic classification and general principles of treatment [Italian]. Minerva Stomatol. 48, 227–234 (1999).

    Google Scholar 

  107. 107

    Thomas, K. R., Musci, T. S., Neumann, P. E. & Capecchi, M. R. Swaying is a mutant allele of the proto-oncogene Wnt-1. Cell 67, 969–976 (1991).

    Google Scholar 

  108. 108

    Lindert, U. et al. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat. Commun. 7, 11920 (2016).

    Google Scholar 

  109. 109

    Symoens, S. et al. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J.Rare Dis. 8, 154 (2013).

    Google Scholar 

  110. 110

    Murakami, T. et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat. Cell Biol. 11, 1205–1211 (2009).

    Google Scholar 

  111. 111

    Rauch, F., Travers, R., Parfitt, A. M. & Glorieux, F. H. Static and dynamic bone histomorphometry in children with osteogenesis imperfecta. Bone 26, 581–589 (2000). A study that shows that the bone histomorphometry of patients with osteogenesis imperfecta caused by collagen defects shows high turnover.

    Google Scholar 

  112. 112

    Fratzl-Zelman, N. et al. Non-lethal type VIII osteogenesis imperfecta has elevated bone matrix mineralization. J. Clin. Endocrinol. Metab. 101, 3516–3525 (2016).

    Google Scholar 

  113. 113

    Boyde, A., Travers, R., Glorieux, F. H. & Jones, S. J. The mineralization density of iliac crest bone from children with osteogenesis imperfecta. Calcif. Tissue Int. 64, 185–190 (1999).

    Google Scholar 

  114. 114

    Roschger, P. et al. Evidence that abnormal high bone mineralization in growing children with osteogenesis imperfecta is not associated with specific collagen mutations. Calcif. Tissue Int. 82, 263–270 (2008). An article that shows that bone hypermineralization is a common feature of several types of osteogenesis imperfecta.

    Google Scholar 

  115. 115

    Weber, M. et al. Pamidronate does not adversely affect bone intrinsic material properties in children with osteogenesis imperfecta. Bone 39, 616–622 (2006).

    Google Scholar 

  116. 116

    Fratzl-Zelman, N. et al. CRTAP deficiency leads to abnormally high bone matrix mineralization in a murine model and in children with osteogenesis imperfecta type VII. Bone 46, 820–826 (2010).

    Google Scholar 

  117. 117

    Fratzl-Zelman, N. et al. Unique micro- and nano-scale mineralization pattern of human osteogenesis imperfecta type VI bone. Bone 73, 233–241 (2015).

    Google Scholar 

  118. 118

    Misof, B. M. et al. Differential effects of alendronate treatment on bone from growing osteogenesis imperfecta and wild-type mouse. Bone 36, 150–158 (2005).

    Google Scholar 

  119. 119

    Vanleene, M. et al. Ultra-structural defects cause low bone matrix stiffness despite high mineralization in osteogenesis imperfecta mice. Bone 50, 1317–1323 (2012).

    Google Scholar 

  120. 120

    Fratzl-Zelman, N. et al. Mineral particle size in children with osteogenesis imperfecta type I is not increased independently of specific collagen mutations. Bone 60, 122–128 (2014).

    Google Scholar 

  121. 121

    Paschalis, E. P. et al. Evidence for a role for nanoporosity and pyridinoline content in human mild osteogenesis imperfecta. J. Bone Miner. Res. 31, 1050–1059 (2016).

    Google Scholar 

  122. 122

    Hasegawa, K. et al. Impaired pyridinoline cross-link formation in patients with osteogenesis imperfecta. J. Bone Miner. Metab. 26, 394–399 (2008).

    Google Scholar 

  123. 123

    Eyre, D. R. & Weis, M. A. Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta. Calcif. Tissue Int. 93, 338–347 (2013).

    Google Scholar 

  124. 124

    Carriero, A. et al. How tough is brittle bone? Investigating osteogenesis imperfecta in mouse bone. J. Bone Miner. Res. 29, 1392–1401 (2014).

    Google Scholar 

  125. 125

    Kozloff, K. M. et al. Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength. J. Bone Miner. Res. 19, 614–622 (2004).

    Google Scholar 

  126. 126

    Wagermaier, W., Klaushofer, K. & Fratzl, P. Fragility of bone material controlled by internal interfaces. Calcif. Tissue Int. 97, 201–212 (2015).

    Google Scholar 

  127. 127

    Fratzl, P., Paris, O., Klaushofer, K. & Landis, W. J. Bone mineralization in an osteogenesis imperfecta mouse model studied by small-angle X-ray scattering. J. Clin. Invest. 97, 396–402 (1996).

    Google Scholar 

  128. 128

    Glorieux, F. H. et al. Normative data for iliac bone histomorphometry in growing children. Bone 26, 103–109 (2000).

    Google Scholar 

  129. 129

    Camacho, N. P. et al. The material basis for reduced mechanical properties in oim mice bones. J. Bone Miner. Res. 14, 264–272 (1999).

    Google Scholar 

  130. 130

    Misof, K., Landis, W. J., Klaushofer, K. & Fratzl, P. Collagen from the osteogenesis imperfecta mouse model (oim) shows reduced resistance against tensile stress. J. Clin. Invest. 100, 40–45 (1997).

    Google Scholar 

  131. 131

    Andriotis, O. G. et al. Structure–mechanics relationships of collagen fibrils in the osteogenesis imperfecta mouse model. J. R. Soc. Interface 12, 20150701 (2015).

    Google Scholar 

  132. 132

    Rodriguez-Florez, N. et al. An investigation of the mineral in ductile and brittle cortical mouse bone. J. Bone Miner. Res. 30, 786–795 (2015).

    Google Scholar 

  133. 133

    Bishop, N. Bone material properties in osteogenesis imperfecta. J. Bone Miner. Res. 31, 699–708 (2016).

    Google Scholar 

  134. 134

    Sillence, D., Senn, A. & Danks, D. Genetic heterogeneity in osteogenesis imperfecta. J. Med. Genet. 16, 101–116 (1979).

    Google Scholar 

  135. 135

    Bonafe, L. et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am. J. Med. Genet. A 167A, 2869–2892 (2015).

    Google Scholar 

  136. 136

    Marlowe, A., Pepin, M. & Byers, P. Testing for osteogenesis imperfecta in cases of suspected non-accidental injury. J. Med. Genet. 39, 382–386 (2002).

    Google Scholar 

  137. 137

    van Dijk, F. S. et al. EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur. J. Hum. Genet. 20, 11–19 (2012).

    Google Scholar 

  138. 138

    Marini, J. C. & Blissett, A. R. New genes in bone development: what's new in osteogenesis imperfecta. J. Clin. Endocrinol. Metab. 98, 3095–3103 (2013).

    Google Scholar 

  139. 139

    Monti, E. et al. Current and emerging treatments for the management of osteogenesis imperfecta. Ther. Clin. Risk Manag. 6, 367–381 (2010).

    Google Scholar 

  140. 140

    Rauch, F. & Glorieux, F. H. Osteogenesis imperfecta. Lancet 363, 1377–1385 (2004).

    Google Scholar 

  141. 141

    Brizola, E., Staub, A. L. & Felix, T. M. Muscle strength, joint range of motion, and gait in children and adolescents with osteogenesis imperfecta. Pediatr. Phys. Ther. 26, 245–252 (2014).

    Google Scholar 

  142. 142

    Caudill, A. et al. Ankle strength and functional limitations in children and adolescents with type I osteogenesis imperfecta. Pediatr. Phys. Ther. 22, 288–295 (2010).

    Google Scholar 

  143. 143

    Sousa, T., Bompadre, V. & White, K. K. Musculoskeletal functional outcomes in children with osteogenesis imperfecta: associations with disease severity and pamidronate therapy. J. Pediatr. Orthop. 34, 118–122 (2014).

    Google Scholar 

  144. 144

    Takken, T. et al. Cardiopulmonary fitness and muscle strength in patients with osteogenesis imperfecta type I. J. Pediatr. 145, 813–818 (2004).

    Google Scholar 

  145. 145

    Amako, M. et al. Functional analysis of upper limb deformities in osteogenesis imperfecta. J. Pediatr. Orthop. 24, 689–694 (2004).

    Google Scholar 

  146. 146

    Montpetit, K., Palomo, T., Glorieux, F. H., Fassier, F. & Rauch, F. Multidisciplinary treatment of severe osteogenesis imperfecta: functional outcomes at skeletal maturity. Arch. Phys. Med. Rehabil. 96, 1834–1839 (2015).

    Google Scholar 

  147. 147

    Montpetit, K. et al. Rapid increase in grip force after start of pamidronate therapy in children and adolescents with severe osteogenesis imperfecta. Pediatrics 111, e601–e603 (2003).

    Google Scholar 

  148. 148

    Van Brussel, M. et al. Physical training in children with osteogenesis imperfecta. J. Pediatr. 152, 111–116.e1 (2008).

    Google Scholar 

  149. 149

    Biggin, A. & Munns, C. F. Osteogenesis imperfecta: diagnosis and treatment. Curr. Osteoporos Rep. 12, 279–288 (2014).

    Google Scholar 

  150. 150

    Land, C., Rauch, F., Montpetit, K., Ruck-Gibis, J. & Glorieux, F. H. Effect of intravenous pamidronate therapy on functional abilities and level of ambulation in children with osteogenesis imperfecta. J. Pediatr. 148, 456–460 (2006).

    Google Scholar 

  151. 151

    Harrington, J., Sochett, E. & Howard, A. Update on the evaluation and treatment of osteogenesis imperfecta. Pediatr. Clin. North Am. 61, 1243–1257 (2014).

    Google Scholar 

  152. 152

    Cintas, H. L. & Gerber, L. H. Children with Osteogenesis Imperfecta: Strategies to Enhance Performance (The Osteogenesis Imperfecta Foundation, 2005).

    Google Scholar 

  153. 153

    Hoyer-Kuhn, H. et al. A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta. J. Musculoskelet. Neuronal Interact. 14, 445–453 (2014).

    Google Scholar 

  154. 154

    Semler, O. et al. Results of a prospective pilot trial on mobility after whole body vibration in children and adolescents with osteogenesis imperfecta. Clin. Rehabil. 22, 387–394 (2008).

    Google Scholar 

  155. 155

    Esposito, P. W. in Osteogenesis Imperfecta in Operative Techniques in Pediatric Orthopaedics (eds Flynn J. M. & Wiesel, S. W. ) 259–269 (Philadelphia Lippincott Williams and Wilkins, 2011).

    Google Scholar 

  156. 156

    Enright, W. J. & Noonan, K. J. Bone plating in patients with type III osteogenesis imperfecta: results and complications. Iowa Orthop. J. 26, 37–40 (2006).

    Google Scholar 

  157. 157

    Joseph, B., Rebello, G. & Chandra Kant, B. The choice of intramedullary devices for the femur and the tibia in osteogenesis imperfecta. J. Pediatr. Orthop. B 14, 311–319 (2005).

    Google Scholar 

  158. 158

    Li, W. C., Kao, H. K., Yang, W. E., Chang, C. J. & Chang, C. H. Femoral non-elongating rodding in osteogenesis imperfecta — the importance of purchasing epiphyseal plate. Biomed. J. 38, 143–147 (2015).

    Google Scholar 

  159. 159

    Popkov, D. A., Kononovich, N. A., Mingazov, E. R., Shutov, R. B. & Barbier, D. Intramedullary elastic transphyseal tibial osteosynthesis and its effect on segmental growth [Russian]. Vestn. Ross. Akad. Med. Nauk 4, 441–449 (2015).

    Google Scholar 

  160. 160

    Ashby, E., Montpetit, K., Hamdy, R. C. & Fassier, F. Functional outcome of humeral rodding in children with osteogenesis imperfecta. J. Pediatr. Orthop.http://dx.doi.org/10.1097/BPO.0000000000000729 (2016).

  161. 161

    Ashby, E., Montpetit, K., Hamdy, R. C. & Fassier, F. Functional outcome of forearm rodding in children with osteogenesis imperfecta. J. Pediatr. Orthop.http://dx.doi.org/10.1097/BPO.0000000000000724 (2016).

  162. 162

    Ruck, J., Dahan-Oliel, N., Montpetit, K., Rauch, F. & Fassier, F. Fassier–Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J. Child. Orthop. 5, 217–224 (2011).

    Google Scholar 

  163. 163

    Sato, A., Ouellet, J., Muneta, T., Glorieux, F. H. & Rauch, F. Scoliosis in osteogenesis imperfecta caused by COL1A1/COL1A2 mutations — genotype–phenotype correlations and effect of bisphosphonate treatment. Bone 86, 53–57 (2016).

    Google Scholar 

  164. 164

    Rauch, F., Munns, C., Land, C. & Glorieux, F. H. Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J. Clin. Endocrinol. Metab. 91, 1268–1274 (2006).

    Google Scholar 

  165. 165

    Bishop, N. et al. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet 382, 1424–1432 (2013).

    Google Scholar 

  166. 166

    Bishop, N. et al. A randomized, controlled dose-ranging study of risedronate in children with moderate and severe osteogenesis imperfecta. J. Bone Miner. Res. 25, 32–40 (2010).

    Google Scholar 

  167. 167

    Dwan, K., Phillipi, C. A., Steiner, R. D. & Basel, D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst. Rev. 7, CD005088 (2014).

    Google Scholar 

  168. 168

    Sakkers, R. et al. Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study. Lancet 363, 1427–1431 (2004).

    Google Scholar 

  169. 169

    Ward, L. M. et al. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J. Clin. Endocrinol. Metab. 96, 355–364 (2011).

    Google Scholar 

  170. 170

    Orwoll, E. S. et al. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J. Clin. Invest. 124, 491–498 (2014).

    Google Scholar 

  171. 171

    Hald, J. D., Evangelou, E., Langdahl, B. L. & Ralston, S. H. Bisphosphonates for the prevention of fractures in osteogenesis imperfecta: meta-analysis of placebo-controlled trials. J. Bone Miner. Res. 30, 929–933 (2015).

    Google Scholar 

  172. 172

    Rijks, E. B. et al. Efficacy and safety of bisphosphonate therapy in children with osteogenesis imperfecta: a systematic review. Horm. Res. Paediatr. 84, 26–42 (2015). A set of three meta-analyses (references 167, 171 and 172) of bisphosphonate treatment trials that show equivocal effect on fractures in osteogenesis imperfecta.

    Google Scholar 

  173. 173

    Uveges, T. E. et al. Alendronate treatment of the brtl osteogenesis imperfecta mouse improves femoral geometry and load response before fracture but decreases predicted material properties and has detrimental effects on osteoblasts and bone formation. J. Bone Miner. Res. 24, 849–859 (2009).

    Google Scholar 

  174. 174

    Rauch, F., Travers, R., Plotkin, H. & Glorieux, F. H. The effects of intravenous pamidronate on the bone tissue of children and adolescents with osteogenesis imperfecta. J. Clin. Invest. 110, 1293–1299 (2002).

    Google Scholar 

  175. 175

    Letocha, A. D. et al. Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J. Bone Miner. Res. 20, 977–986 (2005).

    Google Scholar 

  176. 176

    Martin, E. & Shapiro, J. R. Osteogenesis imperfecta: epidemiology and pathophysiology. Curr. Osteoporos Rep. 5, 91–97 (2007).

    Google Scholar 

  177. 177

    McAllion, S. J. & Paterson, C. R. Causes of death in osteogenesis imperfecta. J. Clin. Pathol. 49, 627–630 (1996).

    Google Scholar 

  178. 178

    Widmann, R. F. et al. Spinal deformity, pulmonary compromise, and quality of life in osteogenesis imperfecta. Spine (Phila Pa 1976) 24, 1673–1678 (1999).

    Google Scholar 

  179. 179

    Falvo, K. A., Klain, D. B., Krauss, A. N., Root, L. & Auld, P. A. Pulmonary function studies in osteogenesis imperfecta. Am. Rev. Respir. Dis. 108, 1258–1260 (1973).

    Google Scholar 

  180. 180

    Thiele, F. et al. Cardiopulmonary dysfunction in the osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms. Hum. Mol. Genet. 21, 3535–3545 (2012).

    Google Scholar 

  181. 181

    de Vlaming, A. et al. Atrioventricular valve development: new perspectives on an old theme. Differentiation 84, 103–116 (2012).

    Google Scholar 

  182. 182

    McNeeley, M. F., Dontchos, B. N., Laflamme, M. A., Hubka, M. & Sadro, C. T. Aortic dissection in osteogenesis imperfecta: case report and review of the literature. Emerg. Radiol. 19, 553–556 (2012).

    Google Scholar 

  183. 183

    Bonilla Jimenez, V. et al. Cardiac abnormalities in osteogenesis imperfecta. Case–control echocardiographic study [Spanish]. Med. Clin. (Barc.) 135, 681–684 (2010).

    Google Scholar 

  184. 184

    Najib, M. Q. et al. Valvular heart disease in patients with osteogenesis imperfecta. J. Card. Surg. 28, 139–143 (2013).

    Google Scholar 

  185. 185

    Radunovic, Z., Wekre, L. L., Diep, L. M. & Steine, K. Cardiovascular abnormalities in adults with osteogenesis imperfecta. Am. Heart J. 161, 523–529 (2011).

    Google Scholar 

  186. 186

    Migliaccio, S. et al. Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality? Int. J. Cardiol. 131, 200–203 (2009).

    Google Scholar 

  187. 187

    Jackson, S. C., Odiaman, L., Card, R. T., van der Bom, J. G. & Poon, M. C. Suspected collagen disorders in the bleeding disorder clinic: a case–control study. Haemophilia 19, 246–250 (2013).

    Google Scholar 

  188. 188

    Sasaki-Adams, D. et al. Neurosurgical implications of osteogenesis imperfecta in children. Report of 4 cases. J. Neurosurg. Pediatr. 1, 229–236 (2008).

    Google Scholar 

  189. 189

    Byra, P., Chillag, S. & Petit, S. Osteogenesis imperfecta and aortic dissection. Am. J. Med. Sci. 336, 70–72 (2008).

    Google Scholar 

  190. 190

    Swinnen, F. K. et al. Osteogenesis imperfecta: the audiological phenotype lacks correlation with the genotype. Orphanet J.Rare Dis. 6, 88 (2011).

    Google Scholar 

  191. 191

    Hartikka, H. et al. Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients. Hum. Mutat. 24, 147–154 (2004).

    Google Scholar 

  192. 192

    Swinnen, F. K., De Leenheer, E. M., Coucke, P. J., Cremers, C. W. & Dhooge, I. J. Audiometric, surgical, and genetic findings in 15 ears of patients with osteogenesis imperfecta. Laryngoscope 119, 1171–1179 (2009).

    Google Scholar 

  193. 193

    Swinnen, F. K. et al. Audiologic phenotype of osteogenesis imperfecta: use in clinical differentiation. Otol. Neurotol. 33, 115–122 (2012).

    Google Scholar 

  194. 194

    Takagi, Y. & Sasaki, S. A probable common disturbance in the early stage of odontoblast differentiation in dentinogenesis imperfecta type I and type II. J. Oral Pathol. 17, 208–212 (1988).

    Google Scholar 

  195. 195

    American Academy of Pediatric Dentristy. Guideline on dental management of heritable dental developmental anomalies. Pediatr. Dent. 35, E179–E184 (2013).

    Google Scholar 

  196. 196

    Camfield, P. & Camfield, C. Transition to adult care for children with chronic neurological disorders. Ann. Neurol. 69, 437–444 (2011).

    Google Scholar 

  197. 197

    Reid, G. J. et al. Prevalence and correlates of successful transfer from pediatric to adult health care among a cohort of young adults with complex congenital heart defects. Pediatrics 113, e197–e205 (2004).

    Google Scholar 

  198. 198

    Orlando, L. A. et al. Implementing family health history risk stratification in primary care: impact of guideline criteria on populations and resource demand. Am. J. Med Genet. C Semin. Med. Genet. 166C, 24–33 (2014).

    Google Scholar 

  199. 199

    Roberts, T. T., Cepela, D. J., Uhl, R. L. & Lozman, J. Orthopaedic considerations for the adult with osteogenesis imperfecta. J. Am. Acad. Orthop. Surg. 24, 298–308 (2016).

    Google Scholar 

  200. 200

    Bishop, N. J. & Walsh, J. S. Osteogenesis imperfecta in adults. J. Clin. Invest. 124, 476–477 (2014).

    Google Scholar 

  201. 201

    Edouard, T., Glorieux, F. H. & Rauch, F. Predictors and correlates of vitamin D status in children and adolescents with osteogenesis imperfecta. J. Clin. Endocrinol. Metab. 96, 3193–3198 (2011).

    Google Scholar 

  202. 202

    Balkefors, V., Mattsson, E., Pernow, Y. & Saaf, M. Functioning and quality of life in adults with mild-to-moderate osteogenesis imperfecta. Physiother. Res. Int. 18, 203–211 (2013).

    Google Scholar 

  203. 203

    Lindahl, K., Langdahl, B., Ljunggren, O. & Kindmark, A. Treatment of osteogenesis imperfecta in adults. Eur. J. Endocrinol. 171, R79–R90 (2014).

    Google Scholar 

  204. 204

    Saeves, R. et al. Oral findings in adults with osteogenesis imperfecta. Spec. Care Dentist 29, 102–108 (2009).

    Google Scholar 

  205. 205

    Mauri, L. et al. Expanding the clinical spectrum of COL1A1 mutations in different forms of glaucoma. Orphanet J.Rare Dis. 11, 108 (2016).

    Google Scholar 

  206. 206

    Batzdorf, U. Clinical presentation and alternative diagnoses in the adult population. Neurosurg. Clin. N. Am. 26, 515–517 (2015).

    Google Scholar 

  207. 207

    Venugopala, D., Babu, S., Korath, M. P. & Jagadeesan, K. Renal stone disease as extra skeletal manifestation of osteogenesis imperfecta. J. Assoc. Physicians India 48, 1027–1028 (2000).

    Google Scholar 

  208. 208

    Vetter, U. et al. Osteogenesis imperfecta in childhood: cardiac and renal manifestations. Eur. J. Pediatr. 149, 184–187 (1989).

    Google Scholar 

  209. 209

    The WHOQOL Group. The World Health Organization Quality of Life assessment (WHOQOL): position paper from the World Health Organization. Soc. Sci. Med. 41, 1403–1409 (1995).

    Google Scholar 

  210. 210

    Widmann, R. F., Laplaza, F. J., Bitan, F. D., Brooks, C. E. & Root, L. Quality of life in osteogenesis imperfecta. Int. Orthop. 26, 3–6 (2002).

    Google Scholar 

  211. 211

    Dahan-Oliel, N. et al. Quality of life in osteogenesis imperfecta: a mixed-methods systematic review. Am. J. Med. Genet. A 170A, 62–76 (2016).

    Google Scholar 

  212. 212

    Dogba, M. J. et al. The impact of severe osteogenesis imperfecta on the lives of young patients and their parents — a qualitative analysis. BMC Pediatr. 13, 153 (2013).

    Google Scholar 

  213. 213

    Fano, V., del Pino, M., Rodriguez Celin, M., Buceta, S. & Obregon, M. G. Osteogenesis imperfecta: quality of life in children [Spanish]. Arch. Argent. Pediatr. 111, 328–331 (2013).

    Google Scholar 

  214. 214

    Kok, D. H. et al. Quality of life in children with osteogenesis imperfecta treated with oral bisphosphonates (olpadronate): a 2-year randomized placebo-controlled trial. Eur. J. Pediatr. 166, 1155–1161 (2007).

    Google Scholar 

  215. 215

    Lowing, K., Astrom, E., Oscarsson, K. A., Soderhall, S. & Eliasson, A. C. Effect of intravenous pamidronate therapy on everyday activities in children with osteogenesis imperfecta. Acta Paediatr. 96, 1180–1183 (2007).

    Google Scholar 

  216. 216

    Seikaly, M. G. et al. Impact of alendronate on quality of life in children with osteogenesis imperfecta. J. Pediatr. Orthop. 25, 786–791 (2005).

    Google Scholar 

  217. 217

    Vanz, A. P., Felix, T. M., da Rocha, N. S. & Schwartz, I. V. Quality of life in caregivers of children and adolescents with osteogenesis imperfecta. Health Qual. Life Outcomes 13, 41 (2015).

    Google Scholar 

  218. 218

    Szczepaniak-Kubat, A., Kurnatowska, O., Jakubowska-Pietkiewicz, E. & Chlebna-Sokol, D. Assessment of quality of life of parents of children with osteogenesis imperfecta. Adv. Clin. Exp. Med. 21, 99–104 (2012).

    Google Scholar 

  219. 219

    Hill, C. L., Baird, W. O. & Walters, S. J. Quality of life in children and adolescents with osteogenesis imperfecta: a qualitative interview based study. Health Qual. Life Outcomes 12, 54 (2014).

    Google Scholar 

  220. 220

    Rauch, F., Lalic, L., Glorieux, F. H., Moffatt, P. & Roughley, P. Targeted sequencing of a pediatric metabolic bone gene panel using a desktop semiconductor next-generation sequencer. Calcif. Tissue Int. 95, 323–331 (2014).

    Google Scholar 

  221. 221

    Cole, D. E. Psychosocial aspects of osteogenesis imperfecta: an update. Am. J. Med. Genet. 45, 207–211 (1993).

    Google Scholar 

  222. 222

    Ashournia, H., Johansen, F. T., Folkestad, L., Diederichsen, A. C. & Brixen, K. Heart disease in patients with osteogenesis imperfecta — a systematic review. Int. J. Cardiol. 196, 149–157 (2015).

    Google Scholar 

  223. 223

    Radunovic, Z. & Steine, K. Prevalence of cardiovascular disease and cardiac symptoms: left and right ventricular function in adults with osteogenesis imperfecta. Can. J. Cardiol. 31, 1386–1392 (2015).

    Google Scholar 

  224. 224

    van der Kley, F., Delgado, V., Ajmone Marsan, N. & Schalij, M. J. Transcatheter mitral valve repair in osteogenesis imperfecta associated mitral valve regurgitation. Heart Lung Circ. 23, e169–e171 (2014).

    Google Scholar 

  225. 225

    Gebken, J. et al. Increased cell surface expression of receptors for transforming growth factor-beta on osteoblasts from patients with osteogenesis imperfecta. Pathobiology 68, 106–112 (2000).

    Google Scholar 

  226. 226

    Grafe, I. et al. Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta. Nat. Med. 20, 670–675 (2014).

    Google Scholar 

  227. 227

    Cosman, F. et al. Romosozumab treatment in postmenopausal women with osteoporosis. N. Engl. J. Med. 375, 1532–1543 (2016).

    Google Scholar 

  228. 228

    Sinder, B. P. et al. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. J. Bone Miner. Res. 28, 73–80 (2013).

    Google Scholar 

  229. 229

    Sinder, B. P. et al. Rapidly growing Brtl/+ mouse model of osteogenesis imperfecta improves bone mass and strength with sclerostin antibody treatment. Bone 71, 115–123 (2015).

    Google Scholar 

  230. 230

    Jacobsen, C. M. et al. Targeting the LRP5 pathway improves bone properties in a mouse model of osteogenesis imperfecta. J. Bone Miner. Res. 29, 2297–2306 (2014).

    Google Scholar 

  231. 231

    Roschger, A. et al. Effect of sclerostin antibody treatment in a mouse model of severe osteogenesis imperfecta. Bone 66, 182–188 (2014).

    Google Scholar 

  232. 232

    Perosky, J. E. et al. Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model. Bone 93, 79–85 (2016).

    Google Scholar 

  233. 233

    Willing, M. C. et al. Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. Am. J. Hum. Genet. 55, 638–647 (1994).

    Google Scholar 

  234. 234

    Besio, R. & Forlino, A. Treatment options for osteogenesis imperfecta. Expert Opin. Orphan Drugs 3, 165–181 (2015).

    Google Scholar 

  235. 235

    Otsuru, S. et al. Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms. Blood 120, 1933–1941 (2012).

    Google Scholar 

  236. 236

    Jones, G. N. et al. Potential of human fetal chorionic stem cells for the treatment of osteogenesis imperfecta. Stem Cells Dev. 23, 262–276 (2014).

    Google Scholar 

  237. 237

    Besio, R. & Forlino, A. New frontiers for dominant osteogenesis imperfecta treatment: gene/cellular therapy approaches. Adv. Regen. Biol. 2, 27964 (2015).

    Google Scholar 

  238. 238

    Chitty, L. S. et al. EP21.04: BOOSTB4: a clinical study to determine safety and efficacy of pre- and/or postnatal stem cell transplantation for treatment of osteogenesis imperfecta. Ultrasound Obstet. Gynecol. 48 (Suppl. 1), 356 (2016).

    Google Scholar 

  239. 239

    Colige, A. et al. Human Ehlers–Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am. J. Hum. Genet. 65, 308–317 (1999).

    Google Scholar 

  240. 240

    Li, S. W. et al. Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. Biochem. J. 355, 271–278 (2001).

    Google Scholar 

  241. 241

    Weintrob, J. C. Orthotic management for children with osteogenesis imperfecta. Connect. Tissue Res. 31, S41–S43 (1995).

    Google Scholar 

  242. 242

    Colige, A. et al. cDNA cloning and expression of bovine procollagen I N-proteinase: a new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components. Proc. Natl Acad. Sci. USA 94, 2374–2379 (1997).

    Google Scholar 

  243. 243

    Bachinger, H. P., Mizuno, K., Vranka, J. & Boudko, S. P. in Comprehensive Natural Products II: Chemistry and Biology (eds Mander, L. & Liu, H.-W. ) 469–530 (Elsevier Ltd, 2010).

    Google Scholar 

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Acknowledgements

The authors thank M. Balasubramanian (Department of Oncology & Metabolism, University of Sheffield, Sheffield Children's NHS Foundation, UK) for providing the images shown in Figure 1.

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Contributions

Introduction (J.C.M.); Epidemiology (P.H.B.); Mechanisms/pathophysiology (H.P.B., A.F., O.S., A.D.P., N.F.-Z., P.H.B. and J.C.M.); Diagnosis, screening and prevention (P.H.B.); Management (K.M., D.K., F.F., N.J.B. and J.C.M.); Quality of life (K.M.); Outlook (O.S., K.M.K. and A.F.); Overview of Primer (A.F. and J.C.M.).

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Correspondence to Joan C. Marini.

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Competing interests

K.M.K. received support from Amgen (sclerostin antibody) and Mereo BioPharma (grant; sclerostin antibody) for research studies. N.J.B. received honoraria from Internis and Alexion, consultation fees (paid to the University) from Alexion, Ultragenyx, Mereo and Amgen, and research grants (paid to Sheffield Childrens NHS Foundation) from Amgen, Alexion and Merck. F.F. received royalties from PegaMedical. All other authors declare no competing interest.

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Marini, J., Forlino, A., Bächinger, H. et al. Osteogenesis imperfecta. Nat Rev Dis Primers 3, 17052 (2017). https://doi.org/10.1038/nrdp.2017.52

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