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Sections Genetics of Osteogenesis Imperfecta
Overview
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- Physical
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References

Workup

Laboratory Studies

Results from routine laboratory studies in patients with osteogenesis imperfecta (OI) are usually within reference ranges, and they are useful in ruling out other metabolic bone diseases, such as hypophosphatasia or inherited forms of rickets.

Collagen synthesis analysis has historically been performed by culturing dermal fibroblasts obtained during skin biopsy. This testing modality has fallen out of favor, given that molecular diagnostic techniques are more accurate, have increased in availability, and have decreased in cost. Widespread adoption of next-generation sequencing (NGS) technology has allowed for parallel sequencing of many genes. Thus, there is little or no difference in cost or turnaround time for multigene panels compared with limiting investigation to the two procollagen I genes.

Prenatal DNA mutation analysis can be performed in pregnancies with risk of osteogenesis imperfecta to analyze uncultured chorionic villus cells. Samples are obtained during chorionic villus sampling performed under ultrasonographic guidance when a mutation in another member of the family is already known.

Bone mineral density, as measured with dual-energy radiographic absorptiometry (DRA), is generally low in children and adults with osteogenesis imperfecta. However, there is wide variation in the bone density of patients with OI. Still, normal bone density in a patient in whom osteogenesis imperfecta is being evaluated should prompt consideration of alternate diagnoses.

Imaging Studies

Obtain a radiographic skeletal survey after birth.

In mild (type I) osteogenesis imperfecta, images may reveal thinning of the long bones with thin cortices. Several wormian bones may be present. No deformity of long bones is observed.
In extremely severe (type II) osteogenesis imperfecta, the survey may reveal beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be revealed.
In moderate and severe (types III and IV) osteogenesis imperfecta, imaging may reveal cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are revealed early, with thin bones revealed later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.

Prenatal ultrasonography can be used to detect limb-length abnormalities at 15-18 weeks' gestation.

Mild forms may result in normal sonogram findings.
Features include supervisualization of intracranial contents caused by decreased mineralization of calvaria (also calvarial compressibility), bowing or fracture of the long bones, decreased bone length (especially of the femur), and multiple rib fractures.

Histologic Findings

The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are decreased in all types of osteogenesis imperfecta. The number and thickness of trabeculae are reduced.

Samples may show evidence of defects in modeling of external bone in terms of the size and shape, the production of secondary trabeculae by endochondral ossification, and the thickening of secondary trabeculae by remodeling. Therefore, osteogenesis imperfecta might be regarded as a disease of the osteoblast.^[52]

Bone formation is quantitatively decreased, but the quality of the bone material is probably most important in the pathogenesis of the disease.

Treatment & Management

Marini JC, Dang Do AN, Feingold KR, et al. Osteogenesis Imperfecta. Endotext. 2020 Jul 26. [QxMD MEDLINE Link]. [Full Text].
Subramanian S, Viswanathan VK. Osteogenesis Imperfecta. StatPearls. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
Ralston SH, Gaston MS. Management of Osteogenesis Imperfecta. Front Endocrinol (Lausanne). 2019. 10:924. [QxMD MEDLINE Link]. [Full Text].
Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979 Apr. 16(2):101-16. [QxMD MEDLINE Link].
Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011 May. 155A(5):943-68. [QxMD MEDLINE Link].
Shaker JL, Albert C, Fritz J, Harris G. Recent developments in osteogenesis imperfecta. F1000Res. 2015. 4 (F1000 Faculty Rev):681. [QxMD MEDLINE Link]. [Full Text].
Rauch F, Munns C, Land C, Glorieux FH. Pamidronate in Children and Adolescents with Osteogenesis Imperfecta: Effect of Treatment Discontinuation. J Clin Endocrinol Metab. 2006. 91:1268-74. [QxMD MEDLINE Link].
Otaify GA, Aglan MS, Ibrahim MM, Elnashar M, El Banna RA, Temtamy SA. Zoledronic acid in children with osteogenesis imperfecta and Bruck syndrome: a 2-year prospective observational study. Osteoporos Int. 2016 Jan. 27 (1):81-92. [QxMD MEDLINE Link].
Lindahl K, Langdahl B, Ljunggren O, Kindmark A. Treatment of osteogenesis imperfecta in adults. Eur J Endocrinol. 2014 Aug. 171 (2):R79-90. [QxMD MEDLINE Link].
Castillo H, Samson-Fang L,. Effects of bisphosphonates in children with osteogenesis imperfecta: an AACPDM systematic review. Dev Med Child Neurol. 2009 Jan. 51(1):17-29. [QxMD MEDLINE Link].
Esposito P, Plotkin H. Surgical treatment of osteogenesis imperfecta: current concepts. Curr Opin Pediatr. 2008 Feb. 20(1):52-7. [QxMD MEDLINE Link].
Van Dijk FS, Sillence DO. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014 Apr 8. [QxMD MEDLINE Link].
Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016 Apr 16. 387 (10028):1657-71. [QxMD MEDLINE Link].
Balasubramanian M Md, Sobey GJ FCDerm, Wagner BE BSc Hons, et al. Osteogenesis imperfecta: Ultrastructural and histological findings on examination of skin revealing novel insights into genotype-phenotype correlation. Ultrastruct Pathol. 2016 Feb 10. 1-6. [QxMD MEDLINE Link].
Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000 Sep. 15(9):1650-8. [QxMD MEDLINE Link].
Cho TJ, Lee KE, Lee SK, Song SJ, Kim KJ, Jeon D, et al. A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet. 2012 Aug 10. 91(2):343-8. [QxMD MEDLINE Link]. [Full Text].
Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res. 2002 Jan. 17(1):30-8. [QxMD MEDLINE Link].
Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2011 Mar 11. 88(3):362-71. [QxMD MEDLINE Link]. [Full Text].
Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006 Dec 28. 355(26):2757-64. [QxMD MEDLINE Link].
Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, 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. 2010 Mar 12. 86(3):389-98. [QxMD MEDLINE Link]. [Full Text].
Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, Aktas D, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010 Apr 9. 86(4):551-9. [QxMD MEDLINE Link]. [Full Text].
Kelley BP, Malfait F, Bonafe L, Baldridge D, Homan E, Symoens S, et al. Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J Bone Miner Res. 2011 Mar. 26(3):666-72. [QxMD MEDLINE Link]. [Full Text].
Barnes AM, Cabral WA, Weis M, Makareeva E, Mertz EL, Leikin S, et al. Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix. Hum Mutat. 2012 Nov. 33(11):1589-98. [QxMD MEDLINE Link]. [Full Text].
Lapunzina P, Aglan M, Temtamy S, Caparrós-Martín JA, Valencia M, Letón R, et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet. 2010 Jul 9. 87(1):110-4. [QxMD MEDLINE Link]. [Full Text].
Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002 Jan 11. 108(1):17-29. [QxMD MEDLINE Link].
Martínez-Glez V, Valencia M, Caparrós-Martín JA, Aglan M, Temtamy S, Tenorio J, et al. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat. 2012 Feb. 33(2):343-50. [QxMD MEDLINE Link]. [Full Text].
Asharani PV, Keupp K, Semler O, Wang W, Li Y, Thiele H, et al. Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish. Am J Hum Genet. 2012 Apr 6. 90(4):661-74. [QxMD MEDLINE Link]. [Full Text].
Shaheen R, Alazami AM, Alshammari MJ, Faqeih E, Alhashmi N, Mousa N, et al. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J Med Genet. 2012 Oct. 49(10):630-5. [QxMD MEDLINE Link].
Volodarsky M, Markus B, Cohen I, Staretz-Chacham O, Flusser H, Landau D, et al. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum Mutat. 2013 Apr. 34(4):582-6. [QxMD MEDLINE Link].
Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet. 2013 Apr 4. 92(4):565-74. [QxMD MEDLINE Link]. [Full Text].
Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, Temme RT, et al. WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet. 2013 Apr 4. 92(4):590-7. [QxMD MEDLINE Link]. [Full Text].
Symoens S, Malfait F, D'hondt S, et al. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J Rare Dis. 2013 Sep 30. 8:154. [QxMD MEDLINE Link].
Mendoza-Londono R, Fahiminiya S, Majewski J, et al. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet. 2015 Jun 4. 96 (6):979-85. [QxMD MEDLINE Link].
Doyard M, Bacrot S, Huber C, et al. FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. J Med Genet. 2018 Apr. 55 (4):278-84. [QxMD MEDLINE Link].
Lindert U, Cabral WA, Ausavarat S, et al. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun. 2016 Jul 6. 7:11920. [QxMD MEDLINE Link]. [Full Text].
Hsieh JC, Lee L, Zhang L, et al. Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell. 2003 Feb 7. 112 (3):355-67. [QxMD MEDLINE Link]. [Full Text].
Moosa S, Yamamoto GL, Garbes L, et al. Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta. Am J Hum Genet. 2019 Oct 3. 105 (4):836-43. [QxMD MEDLINE Link]. [Full Text].
Hsu VW, Shah N, Klausner RD. A brefeldin A-like phenotype is induced by the overexpression of a human ERD-2-like protein, ELP-1. Cell. 1992 May 15. 69 (4):625-35. [QxMD MEDLINE Link].
van Dijk FS, Semler O, Etich J, et al. Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2. Am J Hum Genet. 2020 Nov 5. 107 (5):989-99. [QxMD MEDLINE Link]. [Full Text].
Efthymiou S, Herman I, Rahman F, et al. Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features. Am J Med Genet A. 2021 Jul. 185 (7):2241-9. [QxMD MEDLINE Link]. [Full Text].
Shaheen R, Al-Owain M, Faqeih E, Al-Hashmi N, Awaji A, Al-Zayed Z, et al. Mutations in FKBP10 cause both Bruck syndrome and isolated osteogenesis imperfecta in humans. Am J Med Genet A. 2011 Jun. 155A(6):1448-52. [QxMD MEDLINE Link].
Puig-Hervás MT, Temtamy S, Aglan M, Valencia M, Martínez-Glez V, Ballesta-Martínez MJ, et al. Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome--osteogenesis imperfecta phenotypic spectrum. Hum Mutat. 2012 Oct. 33(10):1444-9. [QxMD MEDLINE Link].
Bank RA, Robins SP, Wijmenga C, Breslau-Siderius LJ, Bardoel AF, van der Sluijs HA, et al. Defective collagen crosslinking in bone, but not in ligament or cartilage, in Bruck syndrome: indications for a bone-specific telopeptide lysyl hydroxylase on chromosome 17. Proc Natl Acad Sci U S A. 1999 Feb 2. 96(3):1054-8. [QxMD MEDLINE Link]. [Full Text].
Rush ET, Li L, Goodwin JL, et al. Echocardiographic phenotype in osteogenesis imperfecta varies with disease severity. Heart. 2017 Mar. 103 (6):443-8. [QxMD MEDLINE Link].
Kuurila K, Kaitila I, Johansson R, Grénman R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol. 2002 Oct. 111(10):939-46. [QxMD MEDLINE Link].
Darba J, Marsa A. Hospital incidence, management and direct cost of osteogenesis imperfecta in Spain: a retrospective database analysis. J Med Econ. 2020 Dec. 23 (12):1435-40. [QxMD MEDLINE Link]. [Full Text].
Santos F, McCall AA, Chien W, Merchant S. Otopathology in Osteogenesis Imperfecta. Otol Neurotol. 2012 Dec. 33(9):1562-6. [QxMD MEDLINE Link]. [Full Text].
Machol K, Hadley TD, Schmidt J, et al. Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study. Am J Med Genet A. 2020 Apr. 182 (4):697-704. [QxMD MEDLINE Link].
Jain M, Tam A, Shapiro JR, et al. Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. Genet Med. 2018 Jul 4. [QxMD MEDLINE Link].
Pillion JP, Shapiro J. Audiological findings in osteogenesis imperfecta. J Am Acad Audiol. 2008 Sep. 19(8):595-601. [QxMD MEDLINE Link].
Basal S, Ozgok Y, Tahmaz L, Atim A, Zor M, Bilgic S, et al. Extraperitoneal laparoscopy-assisted percutaneous nephrolithotomy in a patient with osteogenesis imperfecta. Urol Res. 2011 Feb. 39(1):73-6. [QxMD MEDLINE Link].
Rauch F, Travers R, Parfitt AM, Glorieux FH. Static and dynamic bone hystomorphometry in children with osteogenesis imperfecta. Bone. 2000. 26:581-9. [QxMD MEDLINE Link].
Bargman R, Huang A, Boskey AL, Raggio C, Pleshko N. RANKL Inhibition Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta. Connect Tissue Res. 2010 Jan 6. [QxMD MEDLINE Link].
Semler O, Netzer C, Hoyer-Kuhn H, Becker J, Eysel P, Schoenau E. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact. 2012 Sep. 12 (3):183-8. [QxMD MEDLINE Link].
Hoyer-Kuhn H, Netzer C, Koerber F, Schoenau E, Semler O. Two years' experience with denosumab for children with osteogenesis imperfecta type VI. Orphanet J Rare Dis. 2014 Sep 26. 9:145. [QxMD MEDLINE Link].
Janus GJ, Finidori G, Engelbert RH, Pouliquen M, Pruijs JE. Operative treatment of severe scoliosis in osteogenesis imperfecta: results of 20 patients after halo traction and posterior spondylodesis with instrumentation. Eur Spine J. 2000 Dec. 9(6):486-91. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Mueller B, Engelbert R, Baratta-Ziska F, et al. Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J Rare Dis. 2018 Sep 10. 13 (1):158. [QxMD MEDLINE Link]. [Full Text].
Sasaki-Adams D, Kulkarni A, Rutka J, Dirks P, Taylor M, Drake JM. Neurosurgical implications of osteogenesis imperfecta in children. Report of 4 cases. J Neurosurg Pediatr. 2008 Mar. 1(3):229-36. [QxMD MEDLINE Link].
Paterson CR, Ogston SA, Henry RM. Life expectancy in osteogenesis imperfecta. BMJ. 1996 Feb 10. 312 (7027):351. [QxMD MEDLINE Link]. [Full Text].
McAllion SJ, Paterson CR. Causes of death in osteogenesis imperfecta. J Clin Pathol. 1996 Aug. 49 (8):627-30. [QxMD MEDLINE Link]. [Full Text].
Folkestad L, Hald JD, Canudas-Romo V, et al. Mortality and Causes of Death in Patients With Osteogenesis Imperfecta: A Register-Based Nationwide Cohort Study. J Bone Miner Res. 2016 Dec. 31 (12):2159-66. [QxMD MEDLINE Link]. [Full Text].
Folkestad L. Mortality and morbidity in patients with osteogenesis imperfecta in Denmark. Dan Med J. 2018 Apr. 65 (4):[QxMD MEDLINE Link].

Media Gallery

Acute fractures are observed in the radius and ulna. Multiple fractures can be seen in the ribs. Old healing humeral fracture with callus formation is observed.
Beaded ribs. Multiple fractures are seen in the long bones of the upper extremities.
Wormian bones are present in the skull.
This newborn has bilateral femoral fractures.

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Author

Eric T Rush, MD, FAAP Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Geneticist, Children's Mercy Hospital of Kansas City

Eric T Rush, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alexion Pharmaceuticals, Ultragenyx Pharmaceutical, Biomarin Pharmaceuticals, ObsEva, Inozyme Pharma, Ascendis Pharma<br/>Serve(d) as a speaker or a member of a speakers bureau for: Alexion Pharmaceuticals, Ultragenyx Pharmaceutical, and Biomarin Pharmaceuticals<br/>Received research grant from: Alexion Pharmaceuticals, Ultragenyx Pharmaceuticals.

Coauthor(s)

Horacio B Plotkin, MD, FAAP Chief Medical Officer, Retrophin, Inc; Adjunct Associate Professor of Pediatrics and Orthopedic Surgery, University of Nebraska College of Medicine

Horacio B Plotkin, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Received salary from PPD, Inc for: PPD.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Horatio Plotkin, MD, FAAP, to the development and writing of this article.

Erawati V Bawle, MD, FAAP, FACMG Retired Professor, Department of Pediatrics, Wayne State University School of Medicine

Erawati V Bawle, MD, FAAP, FACMG is a member of the following medical societies: American College of Medical Genetics and American Society of Human Genetics

Disclosure: Nothing to disclose.

Alexander A Cacciarelli, MD, FACR Consulting Staff, Department of Radiology, St Joseph's Hospital and Medical Center of Phoenix

Disclosure: Nothing to disclose.

Mandar A Pattekar, MD, MS Consulting Staff, Department of Radiology, Methodist Hospital

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Sections Genetics of Osteogenesis Imperfecta
Overview
Presentation
- History
- Physical
- Causes
- Show All
DDx
Workup
Treatment
Guidelines
Medication
Follow-up
Questions & Answers
Media Gallery
References

Genetics of Osteogenesis Imperfecta Workup

Laboratory Studies

Imaging Studies

Histologic Findings

References

Tables

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