Osteogenesis imperfecta: Clinical features and diagnosis
- John F Beary, III, MD
John F Beary, III, MD
- Clinical Professor of Medicine
- University of Cincinnati
- Arkadi A Chines, MD
Arkadi A Chines, MD
- Clinical Professor of Medicine
- University of California, Los Angeles
Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. It is often called "brittle bone disease." Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may manifest with only premature osteoporosis or severe postmenopausal bone mineral loss.
The pathogenesis, clinical features, diagnosis, and differential diagnosis of OI are presented here. The management and prognosis of OI are discussed separately. (See "Osteogenesis imperfecta: Management and prognosis".)
The estimated incidence of OI is approximately 1 per 20,000 births . This qualifies it as an orphan disease, which is defined in the United States as a disease affecting 200,000 patients or less.
The cause of OI is established in most cases. In patients with identified molecular defects, OI is most commonly caused by mutations in genes encoding the alpha-1 and alpha-2 chains of type I collagen  or proteins involved in posttranslational modification of type I collagen. Type I collagen fibers are polymers of tropocollagen molecules, each of which is a triple helix that contains portions of one alpha 2 and two alpha 1 polypeptide chains. The composition of tropocollagen is shown in the figure (figure 1). Type I collagen is an important structural protein for bone, tendon, ligament, skin, and sclerae. Defective bone quality explains many clinical aspects of OI. (See "Bone physiology and biochemical markers of bone turnover", section on 'Bone formation'.)
Most patients with OI have an autosomal dominant mutation in COL1A1 (located at 17q21.31-q22) or COL1A2 (located at 7q22.1) that affects the structure of one of the two alpha chains of type I collagen. The severity of the clinical presentation depends upon the effect of the mutation (table 1 and table 2) [3-7]. As an example, mutations in COL1A1 or COL1A2 that lead to decreased amounts of normal collagen cause the mild phenotype seen in type I OI. In contrast, mutations that disrupt the formation of the normal type I collagen triple helix cause the lethal phenotype seen in type IIA OI. Other COL1A1 and COL1A2 mutations that result in structural protein defects cause moderate (type IV) and severe, but not lethal (type III), forms of OI.
- Marini JC. Osteogenesis imperfecta: comprehensive management. Adv Pediatr 1988; 35:391.
- Prockop DJ, Kivirikko KI. Heritable diseases of collagen. N Engl J Med 1984; 311:376.
- Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979; 16:101.
- Cohn DH, Byers PH, Steinmann B, Gelinas RE. Lethal osteogenesis imperfecta resulting from a single nucleotide change in one human pro alpha 1(I) collagen allele. Proc Natl Acad Sci U S A 1986; 83:6045.
- Byers PH, Starman BJ, Cohn DH, Horwitz AL. A novel mutation causes a perinatal lethal form of osteogenesis imperfecta. An insertion in one alpha 1(I) collagen allele (COL1A1). J Biol Chem 1988; 263:7855.
- Cohn DH, Apone S, Eyre DR, et al. Substitution of cysteine for glycine within the carboxyl-terminal telopeptide of the alpha 1 chain of type I collagen produces mild osteogenesis imperfecta. J Biol Chem 1988; 263:14605.
- Gajko-Galicka A. Mutations in type I collagen genes resulting in osteogenesis imperfecta in humans. Acta Biochim Pol 2002; 49:433.
- Cho TJ, Lee KE, Lee SK, et al. A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet 2012; 91:343.
- Semler O, Garbes L, Keupp K, 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 2012; 91:349.
- Alanay Y, Avaygan H, Camacho N, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 2010; 86:551.
- Tonachini L, Morello R, Monticone M, et al. cDNA cloning, characterization and chromosome mapping of the gene encoding human cartilage associated protein (CRTAP). Cytogenet Cell Genet 1999; 87:191.
- Baldridge D, Schwarze U, Morello R, et al. CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta. Hum Mutat 2008; 29:1435.
- Barnes AM, Chang W, Morello R, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 2006; 355:2757.
- Ward LM, Rauch F, Travers R, et al. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 2002; 31:12.
- Labuda M, Morissette J, Ward LM, et al. Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone 2002; 31:19.
- Vranka JA, Sakai LY, Bächinger HP. Prolyl 3-hydroxylase 1, enzyme characterization and identification of a novel family of enzymes. J Biol Chem 2004; 279:23615.
- Cabral WA, Chang W, Barnes AM, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 2007; 39:359.
- Osteogenesis imperfecta, type VIII. In: Online Mendelian Inheritance in Man. Johns Hopkins University Press, Baltimore. www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610915 (Accessed on April 10, 2007).
- van Dijk FS, Nikkels PG, den Hollander NS, et al. Lethal/severe osteogenesis imperfecta in a large family: a novel homozygous LEPRE1 mutation and bone histological findings. Pediatr Dev Pathol 2011; 14:228.
- van Dijk FS, Nesbitt IM, Zwikstra EH, et al. PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet 2009; 85:521.
- Barnes AM, Carter EM, Cabral WA, et al. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. N Engl J Med 2010; 362:521.
- Pyott SM, Schwarze U, Christiansen HE, 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 2011; 20:1595.
- Christiansen HE, Schwarze U, Pyott SM, 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; 86:389.
- Becker J, Semler O, Gilissen C, et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 2011; 88:362.
- Lapunzina P, Aglan M, Temtamy S, et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet 2010; 87:110.
- Laine CM, Joeng KS, Campeau PM, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 2013; 368:1809.
- Keupp K, Beleggia F, Kayserili H, et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 2013; 92:565.
- Fahiminiya S, Majewski J, Mort J, et al. Mutations in WNT1 are a cause of osteogenesis imperfecta. J Med Genet 2013; 50:345.
- Pyott SM, Tran TT, Leistritz DF, et al. WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet 2013; 92:590.
- Glorieux FH, Ward LM, Rauch F, et al. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res 2002; 17:30.
- Glorieux FH, Rauch F, Plotkin H, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res 2000; 15:1650.
- Antoniazzi F, Mottes M, Fraschini P, et al. Osteogenesis imperfecta: practical treatment guidelines. Paediatr Drugs 2000; 2:465.
- Byers PH. Disorders of collagen biosynthesis and structure. In: The metabolic and molecular bases of inherited disease, 8th ed, Scriver C, Beaudet AL, Valle D, Sly W (Eds), McGraw-Hill, New York 2001. p.5241.
- Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004; 363:1377.
- Osteogenesis imperfecta. In: Preventive management of children with congenital anomalies and syndromes, Wilson GN, Cooley WC (Eds), Cambridge University Press, Cambridge, UK 2000. p.256.
- Cremin B, Goodman H, Spranger J, Beighton P. Wormian bones in osteogenesis imperfecta and other disorders. Skeletal Radiol 1982; 8:35.
- Greeley CS, Donaruma-Kwoh M, Vettimattam M, et al. Fractures at diagnosis in infants and children with osteogenesis imperfecta. J Pediatr Orthop 2013; 33:32.
- Semler O, Cheung MS, Glorieux FH, Rauch F. Wormian bones in osteogenesis imperfecta: Correlation to clinical findings and genotype. Am J Med Genet A 2010; 152A:1681.
- Plotkin H. Syndromes with congenital brittle bones. BMC Pediatr 2004; 4:16.
- Smith R. Osteogenesis imperfecta. Clin Rheum Dis 1986; 12:655.
- Carty H. Brittle or battered. Arch Dis Child 1988; 63:350.
- Kuurila K, Kaitila I, Johansson R, Grénman R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol 2002; 111:939.
- Radunovic Z, Wekre LL, Diep LM, Steine K. Cardiovascular abnormalities in adults with osteogenesis imperfecta. Am Heart J 2011; 161:523.
- Chines A, Petersen DJ, Schranck FW, Whyte MP. Hypercalciuria in children severely affected with osteogenesis imperfecta. J Pediatr 1991; 119:51.
- Chines A, Boniface A, McAlister W, Whyte M. Hypercalciuria in osteogenesis imperfecta: a follow-up study to assess renal effects. Bone 1995; 16:333.
- Lund AM, Hansen M, Kollerup G, et al. Collagen-derived markers of bone metabolism in osteogenesis imperfecta. Acta Paediatr 1998; 87:1131.
- Rauch F, Travers R, Parfitt AM, Glorieux FH. Static and dynamic bone histomorphometry in children with osteogenesis imperfecta. Bone 2000; 26:581.
- Pedersen U. Hearing loss in patients with osteogenesis imperfecta. A clinical and audiological study of 201 patients. Scand Audiol 1984; 13:67.
- Kuurila K, Grénman R, Johansson R, Kaitila I. Hearing loss in children with osteogenesis imperfecta. Eur J Pediatr 2000; 159:515.
- Paterson CR, Monk EA, McAllion SJ. How common is hearing impairment in osteogenesis imperfecta? J Laryngol Otol 2001; 115:280.
- Petersen K, Wetzel WE. Recent findings in classification of osteogenesis imperfecta by means of existing dental symptoms. ASDC J Dent Child 1998; 65:305.
- Wenstrup RJ, Willing MC, Starman BJ, Byers PH. Distinct biochemical phenotypes predict clinical severity in nonlethal variants of osteogenesis imperfecta. Am J Hum Genet 1990; 46:975.
- Körkkö J, Ala-Kokko L, De Paepe A, et al. Analysis of the COL1A1 and COL1A2 genes by PCR amplification and scanning by conformation-sensitive gel electrophoresis identifies only COL1A1 mutations in 15 patients with osteogenesis imperfecta type I: identification of common sequences of null-allele mutations. Am J Hum Genet 1998; 62:98.
- McPherson E, Clemens M. Bruck syndrome (osteogenesis imperfecta with congenital joint contractures): review and report on the first North American case. Am J Med Genet 1997; 70:28.
- Beighton P, Winship I, Behari D. The ocular form of osteogenesis imperfecta: a new autosomal recessive syndrome. Clin Genet 1985; 28:69.
- Capoen J, De Paepe A, Lauwers H. The osteoporosis pseudoglioma syndrome. J Belge Radiol 1993; 76:224.
- Beighton P. Osteoporosis-pseudoglioma syndrome. Clin Genet 1986; 29:263.
- Frontali M, Stomeo C, Dallapiccola B. Osteoporosis-pseudoglioma syndrome: report of three affected sibs and an overview. Am J Med Genet 1985; 22:35.
- Osteoporosis-pseudoglioma syndrome; OPPG. In: Online Mendelian Inheritance in Man. Johns Hopkins University Press, Baltimore. http://www.ncbi.nlm.nih.gov/omim/259770 (Accessed on April 25, 2005).
- Cole DE, Fraser FC, Glorieux FH, et al. Panostotic fibrous dysplasia: a congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia. Am J Med Genet 1983; 14:725.
- Whyte MP, Obrecht SE, Finnegan PM, et al. Osteoprotegerin deficiency and juvenile Paget's disease. N Engl J Med 2002; 347:175.
- Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev 1994; 15:439.
- Cole DE, Carpenter TO. Bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features: a newly recognized type of osteogenesis imperfecta. J Pediatr 1987; 110:76.
- Smith R. Idiopathic juvenile osteoporosis: experience of twenty-one patients. Br J Rheumatol 1995; 34:68.