Osteogenesis Imperfecta

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PatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

See also: Bisphosphonates written for patients

Synonyms: brittle bone syndrome, Adair-Dighton syndrome, Van der Hoeve's syndrome, Ekman-Lobstein syndrome

Osteogenesis imperfecta (OI) is an inherited condition causing increased fragility of bone. It principally affects those tissues containing the main fibrilla collagen type I - eg, bone and teeth. It also affects sclerae, joints, tendons, heart valves and skin.

OI had been thought to be an autosomal dominant bone dysplasia caused by defects in type I collagen. However, in the past 10 years discoveries of further (mainly recessive) causative genes have lent support to a predominantly collagen-related pathophysiology[1].

There are seven different types:

  • Type I - mildest form: this causes reduction in the amount of bone and defective bone formation. Due to abnormal or decreased pro-alpha 1 or pro-alpha 2 collagen polypeptides. There is osteoporotic bone with an excess of osteoblasts and osteocytes. It also causes thin sclerae, slender weak tendons, thin heart valves and dilated aortic root.
  • Type II - lethal form: cases arising due to new dominant mutations result in multiple fractures (frequently occurring in utero) and short limbs due to faulty conversion of normal mineralised cartilage to defective bone matrix. The result is completely disorganised and structurally incompetent bone structure.
  • Type III - severely progressive: this is a deforming subtype. This has variable amounts of woven immature bone, disorganised trabeculae and multiple islands of cartilage in the epiphyses and metaphyses. The child may be born with fractures. It is characterised by deformity of bones increasing with age and by extreme short stature due to repeated childhood fractures. There is commonly impaired dentition, 'dentinogenesis imperfecta' (DI), with blue-yellow, small mis-shapen teeth, secondary to the type 1 collagen defect.
  • Type IV - moderately severe form: this is differentiated from type 1 by having white sclerae and, from type III, by autosomal dominant inheritance.

Several other types have recently been described (types V, VI, VII). The same genetic mutations are not present as in types I-IV.

  • Type V: this is moderately deforming and patients exhibit moderate-to-severe bone fragility of long bones and vertebral bodies[3]. There are normal-coloured sclerae and ligament laxity. There is no DI. Typically, patients have ossification of interosseous membrane of the forearm with radial head dislocation, hyperplastic callus formation and an abnormal histopathological pattern.
  • Type VI: this is a moderate-to-severe form of brittle bone disease with accumulation of osteoid due to a mineralisation defect, in the absence of a disturbance of mineral metabolism[4]. Patients with OI type VI sustain more frequent fractures than patients with OI type IV. Fractures are first documented between 4 and 18 months of age. Sclerae are white or faintly blue and DI is uniformly absent. All patients have vertebral compression fractures. The underlying genetic defect is not yet known.
  • Type VII: this is a moderate-to-severe recessive form, characterised by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara and osteopenia[5]. Rhizomelia (proximal limb shortening) is a prominent clinical feature. The disease has been localised to chromosome 3p22-24.1, which is outside the loci for type I collagen genes.

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In almost all cases, the mode of inheritance is dominant or involves a new dominant mutation, regardless of the clinical form of OI observed. About 90% of patients have mutations in type I collagen genes (COL1A1 and COL1A2). However, many other genes have now been described[2].

Further mutations have been identified in the CRTAP, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1 and TMEM38B genes, associated with recessive OI, and mutation in the IFITM5 gene associated with dominant OI. In addition to the genetic complexity of the molecular basis of OI, there is also extensive phenotype variation[6].

Incidence is approximately 1/15,000-1/20,000 live births but this may be underestimated, as milder forms can evade diagnosis[7].

It is the leading cause of lethal short-limbed dwarfism and skeletal dysplasia.

Type I

  • This accounts for 60% of all cases.
  • Fractures can occur at any time from the perinatal period onwards.
  • There is a 7 x greater incidence of overall fracture rate than normal, with reduced vertebral bone mineral content in adults.
  • In childhood, fractures may be numerous but rarely lead to deformity.
  • Any type of fracture can occur and these become less frequent with age - most commonly affected are the lower limbs.
  • The skull shows multiple Wormian bones and the vault may overhang the base, causing basilar compression needing surgical correction.
  • When teeth are affected, some may be more affected than others. There is discolouration with enamel fracturing easily from the dentine, causing rapid erosion in both sets.
  • Blue sclerae is an important sign caused by scleral thinness allowing the pigmented coat of the choroid to become visible.
  • Frequently there is early arcus unrelated to hypercholesterolaemia.
  • Cardiac effects are important; they include aortic incompetence, aortic root widening and mitral valve prolapse.
  • Often there is hypermobility of joints, with flat feet, hyper-extensible large joints and dislocations.
  • Hearing can be affected by changes in the middle ear.

Type II

  • These are often diagnosed prenatally at the 20-week ultrasound.
  • Not all infants die immediately with multiple fractures.
  • The infant is short, limbs are short and deformed, the skull is soft and deformed and sclerae are deep grey-blue.
  • There are crumpled long bones and beaded ribs.

Type III

  • The child may be born with fractures and the skull is well ossified.
  • There is progressive deformity of the skull, long bones, spine, chest and pelvis during early years.
  • The face appears triangular with a large vault, prominent eyes and a small jaw.
  • Sclera is blue in infancy but normal colour in childhood.
  • Patients rarely walk, even after multiple surgical procedures and they have very short stature.
  • Early death can occur from respiratory infections predisposed to by reduction in vital capacity associated with severe kyphoscoliosis.

Type IV

  • This may be apparent at birth with fractures or bowing of leg bones or recurrent fractures on walking.
  • The sclera is normal colour in childhood with reduced stature and variable disability.
  • Patients may have the complication of hyperplastic callus appearing as swollen, painful vascular swelling over the long bones.

Types VI-VII
See 'Classification', above.

  • Other forms of lethal, short-limbed dwarfism including:
    • Achondrogenesis
    • Thanatophoric dwarfism
    • Asphyxiating thoracic dystrophy
  • Non-accidental injury is the main differential diagnosis in childhood.
  • During late childhood and adolescence: idiopathic juvenile osteoporosis.

Prenatal diagnosis, in the second trimester, by ultrasound in the most severe forms. Routine scanning shows shortness and deformity of limbs and abnormal skull shape. There is also absence of mineralisation, and deformity of ribs causing a 'champagne cork' appearance on AP projection.

Investigations after birth include X-rays, bone densitometry and genetic testing. There is currently no method of biochemical screening.

  • Multidisciplinary care including physiotherapy, rehabilitation, bracing and surgical interventions.
  • Bisphosphonates are widely used in patients with OI[8].
  • Bisphosphonates bind to and stabilise bone by inhibiting osteoclast activity, whilst stimulating osteoblast activity[9][10].
  • Cyclical administration of intravenous pamidronate reduces the incidence of fracture and increases bone mineral density, while reducing pain and increasing energy levels.

Surgery

  • Surgical interventions include intramedullary rod placement, surgery to manage basilar compression and correction of scoliosis.
  • Painful bony deformities and recurrent fractures are usually treated with intramedullary rods, with or without corrective osteotomies.
  • Soft tissue surgery may be required, such as for lower-limb contractures - eg, Achilles tendon.
  • Anaesthetic-related problems may occur due to the patient's relatively large head and tongue, and for those patients with short necks. Chest deformities may cause respiratory complications. Fractures may occur as a result of the blood pressure cuff or a tourniquet, or may occur when moving the patient. Hyperthermia and increased sweating may also be a problem.
  • Mortality and morbidity are very variable.
  • There is normal life expectancy in type I and it is only slightly reduced in type IV.
  • Where deformity is severe - eg, type III - the patient may lose mobility and become wheelchair-bound.
  • In families with known collagen mutations, fetal DNA analysis from chorionic villus biopsy in the first trimester, may be possible.
  • The design of potential gene therapy is complicated by the genetic heterogeneity of the disease and by the fact that most of the OI mutations are dominant negative, where the mutant allele product interferes with the function of the normal allele[11]

Charles Adair-Dighton was an English otorhinolaryngologist, born in Liverpool in 1885. It was he who, in 1912, first described the autosomal dominant transmission of blue sclerae and its association with adult-onset deafness.

In 1918, van der Hoeve and de Kleyn of Utrecht described a syndrome where brittle bones were associated with blue sclerae and deafness, in osteogenesis tarda. This was also noted by the Swedish physician, Olof Ekman.

Further reading & references

  1. Forlino A, Marini JC; Osteogenesis imperfecta. Lancet. 2016 Apr 16;387(10028):1657-71. doi: 10.1016/S0140-6736(15)00728-X. Epub 2015 Nov 3.
  2. Shaker JL, Albert C, Fritz J, et al; Recent developments in osteogenesis imperfecta. F1000Res. 2015 Sep 7;4(F1000 Faculty Rev):681. doi: 10.12688/f1000research.6398.1. eCollection 2015.
  3. Osteogenesis Imperfecta (Types); Online Mendelian Inheritance in Man (OMIM)
  4. 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 Jan;17(1):30-8.
  5. Ward LM, Rauch F, Travers R, et al; Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone. 2002 Jul;31(1):12-8.
  6. Valadares ER, Carneiro TB, Santos PM, et al; What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J). 2014 Nov-Dec;90(6):536-41. doi: 10.1016/j.jped.2014.05.003. Epub 2014 Jul 18.
  7. Marini J, Smith SM; Osteogenesis Imperfecta.
  8. Cundy T; Recent advances in osteogenesis imperfecta. Calcif Tissue Int. 2012 Jun;90(6):439-49. doi: 10.1007/s00223-012-9588-3. Epub 2012 Mar 27.
  9. 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.
  10. Dwan K, Phillipi CA, Steiner RD, et al; Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2014 Jul 23;(7):CD005088. doi: 10.1002/14651858.CD005088.pub3.
  11. Niyibizi C, Wang S, Mi Z, et al; Gene therapy approaches for osteogenesis imperfecta. Gene Ther. 2004 Feb;11(4):408-16.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Hayley Willacy
Current Version:
Peer Reviewer:
Dr Anjum Gandhi
Document ID:
1612 (v26)
Last Checked:
24/08/2016
Next Review:
23/08/2021

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