Osteogenesis Imperfecta
- Author: Manoj Ramachandran, MBBS, MRCS, FRCS; Chief Editor: Harris Gellman, MD more...
Background
The earliest known case of osteogenesis imperfecta is in a partially mummified infant's skeleton from ancient Egypt now housed in the British Museum in London. In 1835, Lobstein coined the term osteogenesis imperfecta and was one of the first to correctly understand the etiology of the condition. Other names for osteogenesis imperfecta are Lobstein disease, brittle-bone disease, blue-sclera syndrome, and fragile-bone disease.
Osteogenesis imperfecta is one of the most common skeletal dysplasias. It is a generalized disease of connective tissue that may manifest itself with one or more of the following findings: blue sclerae, triangular facies, macrocephaly, hearing loss, defective dentition, barrel chest, scoliosis, limb deformities, fractures, joint laxity, and growth retardation. Additional features, such as constipation and sweating, may also occur. A multidisciplinary approach is required to manage the disease.[1, 2]
Pathophysiology
In osteogenesis imperfecta, pathologic changes are seen in all tissues in which type 1 collagen is an important constituent, such as bone, ligament, dentin, and sclera. The basic defect is one of a qualitative or quantitative reduction in type 1 collagen. Mutations in genes encoding type 1 collagen affect the coding of 1 of the 2 genes, accounting for approximately 80% of cases of osteogenesis imperfecta.[3, 4, 5, 6]
Most cases of osteogenesis imperfecta, previously thought to be either autosomal dominant or autosomal recessive, are now known to arise from autosomal dominant mutations. These mutations are either genetically inherited or new. The inherited mutations have a recurrence risk in subsequent pregnancies of 50% if a parent is affected, whereas the new mutations have an unpredictable recurrence risk. A small number of cases previously thought to be autosomal recessive have now been proven by molecular and linkage analysis to be secondary to gonadal mosaicism. The recurrence risk for these cases is also unpredictable.
In bone, the degree of histologic change is well correlated with the clinical severity of the disease. The disease affects both endochondral and intramembranous ossification. In osteogenesis imperfecta due to quantitative defects of type 1 collagen, a mild form of the disease occurs. On light microscopy, osteoporotic bone is present, with thick osteoid seams and reduced intercellular matrix. The numbers of osteoclasts and osteocytes are normal. Bone trabeculae are thin and disorganized. Lamellar bone is seen in the diaphysis and metaphysis. On electron microscopy, osteoblasts show distended rough endoplasmic reticulum (possibly because of accumulation of incomplete procollagen molecules), and collagen fibers are of reduced diameter.
In osteogenesis imperfecta that results from qualitative defects of type 1 collagen, a severe form of the disease occurs. Light microscopy reveals hyperosteocytosis and increased vascular channels. Other findings are a reduction in cortical bone thickness, lack of normal cortical bone formation, and disorganization of the growth plate. Woven bone is seen, with minimal osteoid bone and no lamellar bone. Electron microscopy shows poorly preserved osteoblasts and collagen bundles of variable diameter, particularly in the more lethal forms of osteogenesis imperfecta.
The epiphysis and physis tend to be broad and irregular, with disorganization of the proliferative and hypertrophic zones and loss of the typical columnar arrangement. Thinning of the zone of calcified cartilage is evident, along with deficiency of the primary spongiosa of the metaphysis and delay of the secondary centers of ossification in the epiphysis.
With respect to the axial skeleton, scoliosis and kyphosis are common. Vertebral bodies tend to be wedged, translucent, and shallow. Thinning of the skull and multiple ossification centers (wormian bones) are present, particularly in the occiput.
Epidemiology
Frequency
International
The birth incidence is approximately 1 case in 20,000 births.
Mortality/Morbidity
Morbidity and mortality associated with osteogenesis imperfecta vary widely depending on the genotype. In addition, variability occurs between individuals with different mutations, and variability has also been observed between unrelated individuals with the same mutations, between members of the same family, and even between identical twins on occasion.
- At one extreme, early stillbirths occur, and virtually every bone in the body has multiple fractures. The severe perinatal form (type II) is usually fatal within hours after birth, although some babies survive for several months.
- At the other extreme is osteogenesis imperfecta in its mildest form. In this setting, adults who have never had a fracture come to medical attention only because their family members are affected.
- Between these extremes is a smooth continuum of severity.
Race
Osteogenesis imperfecta has been described in every human population in which skeletal dysplasias have been studied. The disease appears to have no predilection for a particular race.
Sex
Osteogenesis imperfecta is equally common in males and females.
Age
Osteogenesis imperfecta can present at any age, although the more severe forms tend to become evident at a younger age.
Smith R, Francis MJ, Houghton GR. The brittle bone syndrome. In: Osteogenesis Imperfecta. London: Butterworth. 1983.
Brusin JH. Osteogenesis imperfecta. Radiol Technol. Jul-Aug 2008;79(6):535-48. [Medline].
Cole WG. The Nicholas Andry Award-1996. The molecular pathology of osteogenesis imperfecta. Clin Orthop. Oct 1997;235-48. [Medline].
Cole WG. Advances in osteogenesis imperfecta. Clin Orthop. Aug 2002;6-16. [Medline].
Cole WG. Bone, cartilage and fibrous tissue disorders. In: Benson MKD, Fixsen JA, MacNicol MF, Parch K, eds. Children's Orthopaedics. 2002: 67-92.
Baujat G, Lebre AS, Cormier-Daire V, Le Merrer M. [Osteogenesis imperfecta, diagnosis information (clinical and genetic classification)]. Arch Pediatr. Jun 2008;15(5):789-91. [Medline].
Sillence D. Osteogenesis imperfecta: an expanding panorama of variants. Clin Orthop. Sep 1981;11-25. [Medline].
Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. Apr 1979;16(2):101-16. [Medline].
Labuda M, Morissette J, Ward LM. Osteogenesis imperfecta type VII maps to the short arm of chromosome 3. Bone. Jul 2002;31(1):19-25. [Medline].
Ward LM, Rauch F, Travers R. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone. Jul 2002;31(1):12-8. [Medline].
Duro Friedl EA, Ferrari Mayans L, Desalvo Portal LN, Ferrari Ruiz P, Bidondo Horno MP, Astraldi Tellechea MM. [Bruck syndrome: Osteogenesis imperfecta with congenital joint contractures.]. An Pediatr (Barc). Jul 2008;69(1):90-1. [Medline].
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. Apr 9 2010;86(4):551-9. [Medline]. [Full Text].
Francis MJ, Smith R, Bauze RJ. Instability of polymeric skin collagen in osteogenesis imperfecta. Br Med J. Mar 9 1974;1(905):421-4. [Medline].
Jones D, Hosalkar H, Jones S. The orthopaedic management of osteogenesis imperfecta. Clin Orthop. 2002;16:374-88.
Zeitlin L, Fassier F, Glorieux FH. Modern approach to children with osteogenesis imperfecta. J Pediatr Orthop B. Mar 2003;12(2):77-87. [Medline].
Forin V. [Paediatric osteogenesis imperfecta: medical and physical treatment]. Arch Pediatr. Jun 2008;15(5):792-3. [Medline].
Sofield HA, Page MA, Mead NC. Multiple osteotomies and metal-rod fixation for osteogenesis imperfecta. J Bone Joint Surg. 1952;34A:500-2.
Wekre LL, Frøslie KF, Haugen L, Falch JA. A population-based study of demographical variables and ability to perform activities of daily living in adults with osteogenesis imperfecta. Disabil Rehabil. 2010;32(7):579-87. [Medline].
Glorieux FH, Bishop NJ, Plotkin H, et al. Cyclic administration of pamidronate in children with severe osteogenesis imperfecta. N Engl J Med. Oct 1 1998;339(14):947-52. [Medline].
Shapiro JR, Thompson CB, Wu Y, Nunes M, Gillen C. Bone Mineral Density and Fracture Rate in Response to Intravenous and Oral Bisphosphonates in Adult Osteogenesis Imperfecta. Calcif Tissue Int. Jun 11 2010;[Medline].
Gallego L, Junquera L, Pelaz A, Costilla S. Pathological mandibular fracture after simple molar extraction in a patient with osteogenesis imperfecta treated with alendronate. Med Oral Patol Oral Cir Bucal. Jun 1 2010;[Medline].
Salehpour S, Tavakkoli S. Cyclic pamidronate therapy in children with osteogenesis imperfecta. J Pediatr Endocrinol Metab. Jan-Feb 2010;23(1-2):73-80. [Medline].
| Type | Genetic | Teeth | Bone Fragility | Bone Deformity | Sclera | Spine | Skull | Prognosis |
| IA | AD* | Normal | Variable but less severe than other types | Moderate | Blue | 20% Scoliosis and kyphosis | Wormian bones | Fair |
| IB | AD | Dentinogenesis imperfecta | NA† | NA | NA | NA | NA | NA |
| II | AD | Unknown | Very severe | Multiple fractures | Blue | NA | Wormian bones with absence of ossification | Perinatal death |
| III | AD | Dentinogenesis imperfecta | Severe | Progressive bowing of long bones and spine | Bluish at birth but white in adults | Kyphoscoliosis | Hypoplastic wormian bones | Wheelchair-bound, nonambulatory |
| IVA | AD | Normal | Moderate | Moderate | White | Kyphoscoliosis | Hypoplastic wormian bones | Fair |
| IVB | AD | Dentinogenesis imperfecta | NA | NA | NA | NA | NA | NA |
| * AD indicates autosomal dominant. † NA indicates not applicable. | ||||||||

