Osteogenesis Imperfecta

Author: francesca rumbolo
Date: 19/11/2010



Osteogenesis imperfecta is an autosomal dominant collagen disease resulting from defective biosynthesis of collagen type I and characterized by brittle, osteoporotic, and easily fractured bones.
Severity varies widely, ranging from intrauterine fractures and perinatal lethality to very mild forms without fractures.
Typical extraskeletal manifestations can be associated variably with the disorder.
These include blue sclera, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, hearing impairment, and presence of wormian bones on skull radiographs. Most patients with a clinical diagnosis of osteogenesis imperfecta have a mutation in one of the two genes that encode the chains of collagen type 1 (COL1A1 and COL1A2).

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OI is a rare disease and can affect males and females of all races. Accurate incidence and prevalence data are not available because mild phenotype is often not identified. It was reported to range from one per 10000 to one per 20000 live births.



The majority (80-90%) of OI causing mutations occur in the genes COL1A1 or COL1A2, that code for the two chains that comprise type I collagen , the major protein of the extracellular matrix of bone, skin and tendon. Type I collagen is a heterotrimer composed of two copies of the α1 chain, encoded by the COL1A1 gene on chromosome 17, and one copy of the α2 chain, encoded by COL1A2 on chromosome 7. The two alpha chains are similar in sequence organization; they are composed of 338 uninterrupted repeats of the sequence Gly-X-Y, where gly is glycine, X is often proline and Y is often hydroxyproline. A glycine residue in every third position along the chain is crucial for helix formation; glycine’s small size allows it to be tucked into the sterically constricted internal aspect of the helix. The collagen genes are organized with each exon coding for the helical region beginning with a glycine codon and ending with codon for a Y position; therefore the skipping of a helical exon does not cause a frameshift in the collagen transcript.
832 independent mutations in both chains of type I collagen have been described in OI patients and a general correlation between genotype and phenotype has emerged. Type I OI, the mild form, is caused by quantitative defects in collagen. On the other hand, types II, III and IV OI, the clinically significant forms, are caused by structural defects in either of the type I collagen chains. About 80% of these structural mutations cause the substitution of another aminoacid for glycine that temporarily block helix formation and cause overmodification (glycosylation) of the chains of the trimer. About 20% of structural mutations are single exon skipping defects, which are incorporated into the trimer because the frame of the transcript remains intact. Essentially all of the collagen mutations are dominant negative mutations. They excrete their effects by being secreted and incorporate into the matrix, causing a weakened higher order structure. Cells with such a mutation produce a mixture of normal and abnormal collagen. The resulting phenotype can vary from very mild to lethal depending on which of the two chains in affected, the position in the triple elix at which the substitution occurs and which aminoacid is substituted for glycine.
Approximately 10-15% of individuals who have a phenotype characteristic of OI do not have a defect in the collagen genes COL1A1 or COL1A2. Molecular and biochemical defects have recently been identified; specifically, each type has a defect which causes deficiency of one the components of the collagen prolyl 3-hydroxylation complex. The new understanding of recessive OI as a deficiency of this ER-resident collagen modification complex shifted the paradigm for collagen-related bone dysplasias.
OI is usually inherited in an autosomal dominant pattern. Recently, dysregulation of hydroxylation of a single proline residue at position 986, in the absence of mutations in type I collagen genes, has been implicated in the pathogenesis of recessive forms of OI. In those instances, mutations in CRTAP, LEPRE1 and PPIB, which encodes the protein prolyl 3-hydroxylase-1, abbreviated P3H1, and the protein leprecan) can cause recessively inherited OI.
LEPRE1,CRTAP and PPIB are the three genes that encode the components of the collagen prolyl 3-hydroxylation complex, prolyl 3-hydroxylase 1 (P3H1), cartilage–associated protein (CRTAP) and cyclophilin B (CyPB), respectively. The proteins form a 1:1:1 complex in the endoplasmic reticulum. The complex binds collagen post-translationally and hydroxylates a single residue, proline 986, on each α1(I) chain.In normal collagen, over 90% of Pro 986 residues are 3- hydroxilated.
In some families, clinically unaffected parents will have more than one child with dominant OI. This occurs because one parent is a mosaic carrier of the mutation. Presumably, the mutation occurred during the parent’s fetal development; that parent then has both a normal and a mutant cell population. The proportion of mutant cells and their distribution in somatic and germline tissues depends on the timing of the mutation and the distribution of cells arising from the first mutant cell.


Symptoms of osteogenesis imperfecta vary greatly from person to person, even among people with the same type of disorder. Symptoms tipically include:

  • brittle bones
  • fractures
  • short stature and growth deficiency
  • skeletal deformities of limbs, chest and skull
  • scoliosis or kyphosis
  • loose joints and ligaments

Other symptoms may include:

  • blue-gray sclera
  • hearing loss
  • weak muscles
  • respiratory difficulties
  • thin skin
  • fragile and transparent teeth
  • high-pitched voice

These symptoms are caused by the defective formation of bone and connective tissue and only few people with OI exhibit all of these symptoms.


Clinical diagnosis

The clinical diagnosis of OI is based mainly on the signs and symptoms. Crucial elements of the diagnostic work-up focus on the skeletal system. The physical exam includes measurements of length and head circumference, as well as notations on body proportions, including upper segment: lower segment ratio and arm span. In addition, the segmental lengths of each limb are measured to detect asymmetry. Individuals with OI frequently have relatively long arm span for length and a shortened lower segment (pubis to floor). Sclerae may be blue or blue-gray and teeth may have dentinogenesis imperfecta, with opalescent or yellow-brown enamel. In the thorax, the spine should be examined for scoliosis and the rib cage for flare and/or pectus carinatum or excavatum. In an infant, the size of the fontanels should be noted. Also essential is a careful family pedigree, with inquiries about fractures, hearing loss, dentinogenesis imperfecta, adult height,racial background and consanguinity. Radiographic examination consists of a selective skeletal survey. This practice still holds true, but some limitations should be recognized. Diagnosis is staightforward in individuals with a positive family history or in whom several typical features are present, but can be difficult in the absence of affected family members and when bone fragility is not associated with obvious extraskeletal abnormalities. The uncertainty in such cases is compounded by the fact that are no agreed minimum criteria that establish a clinical diagnosis of the disorder. In this situation, analysis of the collagen genes can provide helpful informations.

Collagen analysis

Collagen analysis from a skin sample may confirm a clinical diagnosis. The collagen biopsy test looks for mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes.

Genetic tests

DNA can be extracted from white blood cells and the coding region of the genes can than be screened for mutations to confirm a clinical diagnosis. A positive type I collagen genetic test confirms the diagnosis of autosomal dominant OI, but a negative result does not rule out OI. When a type I collagen mutation is not found, other DNA tests are used to check for other types of OI. Due to the fact that so many different mutations can cause OI and that many mutations have not been identified, some forms cannot be diagnosed with a genetic test.

Prenatal diagnosis

Severe forms can sometimes be diagnosed prenatally (or while the fetus develops in the womb). If there is a family history of OI, chorionic villus sampling or amniocentesis may be done during pregnancy to determine if the baby has mutations that could cause the condition. In some cases, an ultrasound can identify bone abnormalities at 18 to24 weeks' gestation.


Because osteogenesis imperfecta (OI) is inherited, the only known risk factor is a family history of the disorder. Evidence that OI preferentially affects any particular gender, ethnicity, or age group, is lacking in the available literature.


Complications are based on the type of osteogenesis imperfecta (OI) present.
Short stature is the most prevalent secondary feature of OI. Children with type III and IV OI fall off normal growth curves and final adult stature is typically in the range of a prepubertal child and can be that of a 5-7 year old. Individuals with type I OI grow parallel to the normal growth curve and final height is usually a few inches shorter than same gender relatives. The cause of short stature in OI is not clear. Short stature is not caused by fractures or premature closure of growth plates. The recessive types of OI, with extreme short stature caused by deficiency of proteins that function in both cartilage and bone, have called attention to OI as a chondrosseus dysplasia. Short stature in dominant types of OI may be related to defective transitioning at the junction of the growth plate and bone, although this remains to be demonstrated.
Hearing Loss
A majority of adults with osteogenesis imperfecta have functionally significant hearing loss related to combined conductive and sensorineural deficits. Molecular studies have revealed that hearing loss is not related to OI types or to location of mutation in COL1A1 or COL1A2. In most cases, deficits are detectable only on audiology examination in childhood and the teen years; functional loss does not occur until the twenties.
When hearing loss exceeds the compensation of hearing aids, surgical interventions may be used. Stapedectomy can give satisfactory long-term results; however, this surgery should not be undertaken routinely. The fragility of the small bones of the ear results in a significant percentage of unsatisfactory long term hearing restoration. Given the rarity of OI and surgical complications in OI (i.e., middle ear anatomic anomalies and tendency for profuse bleeding), surgical outcomes may be better at medical facilities experienced with stapes surgery and hearing loss due to OI. Insertion of cochlear implants has been reported in a few case studies; however, this data is limited. The implants have resulted in a short-term improvement in hearing ability, but long term hearing restoration remains unknown.
Pulmonary Complications
Cardiopulmonary complications of osteogenesis imperfecta are the major cause of mortality directly related to the disorder. Infants with type II OI die of respiratory insufficiency or pneumonias. Children with type III OI develop vertebral collapse and kyphoscoliosis, which contribute to restrictive lung disease. These skeletal features, as well as the inactivity associated with wheelchair mobility, predispose them to multiple pneumonias. Lung disease may progress to cor pulmonale in middle age. Pulmonary function should be evaluated every few years, starting in childhood, to facilitate early management with bronchodilators. The need for chronic oxygen may arise as early as adolescence but most frequently occurs in the forties and fifties.
Neurological Complications
Osteogenesis imperfecta is frequently associated with either relative or absolute macrocephaly. Between ages 2-3 years, the child’s head circumference may rapidly cross percentile lines for age. Prominence of sulci and ventriculomegaly are not associated with intellectual deficit. Favorable outcomes have been obtained by delaying surgical intervention until the patient experiences severe headaches as well as long tract signs. Typical clinical features of BI include headaches, dysphagia, ataxia and changes in facial sensation that, if not treated, can progress to rapid neurologic decline and/or respiratory distress. As patients become symptomatic they should be followed in centers with experience in performing anterior ventral decompression with occipitocervical fusion in OI patients.


• Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase, are typically normal; however, the latter is often elevated in response to fracture;
• Infants and children with OI are often described as having a triangular-shaped face. The skull is relatively large compared to body size;
• Although complaints of constipation are common in adults with OI who are mobile in wheelchairs, it is not clear if this is a complication of OI itself or of the mode of transport;
• Life expectancy for those with mild forms of OI is normal, whereas the most severely affected children with type II OI typically do not survive the neonatal period. The natural history of types of OI other than type II is not well understood or documented. Little has been published about adults with OI. Although mean life expectancy in the intermediate forms of OI (type III) may be shortened because of severe kyphoscoliosis and abnormal thoracic shape with attendant restrictive pulmonary disease and cardiac insufficiency, some individuals with these complications have a nearly normal life span;
• Fertility is normal in OI. Pregnancy in women with OI, especially those with OI type III, can be complicated because of a small pelvis, which may necessitate delivery by cesarian section. The role of pregnancy in later fractures, loss of bone mineralization, progression of hearing loss, or any other physical consideration has not been examined in detail.For most women who have OI, pregnancy is uncomplicated. The exception is in those women with OI who are very small and require pre-term cesarean section because of respiratory compromise.


Management focuses on supportive therapy to minimize fractures and maximize function, minimize disability, foster independence, and maintain overall health. Ideally, OI is managed by a multidisciplinary team including specialists in medical therapy of OI, orthopedics, and rehabilitation medicine. Supportive therapy is individualized depending upon the severity, the degree of impairment, and the age of the patient.
Physical medicine treatment
• Instruction of parents and other caregivers in safe handling techniques
• Bracing of limbs with such devices as vacuum pants that are rigid
• Orthotics to stabilize lax joints
• Promotion of appropriate physical activity
• Physical and occupational therapy for increased stability of bone, improved mobility, prevention of contractures, prevention of head and spinal deformity, aerobic fitness, and muscle strengthening
• Endurance training
• Mobility devices such as scooters and chairs for children and modified automobiles for adults
• Analgesics for pain
Orthopedic treatment
• Fractures are treated as they would be in unaffected children and adults with attention to the following:
• The period of immobility in children with OI should be shortened as much as is practical.
• Casts should be small and lightweight.
• Physical therapy should begin as soon as the cast is removed to promote mobility and enhance muscle strength and bone mass.
• At this time, intramedullary rodding remains a mainstay of orthopedic care to provide anatomic positioning of limbs that permits more normal function. It is not yet clear if treatment with bisphosphonates will change the natural history of bone deformity and diminish the use of surgical intervention (see discussion of bisphosphonate treatment below).
• Progressive spinal deformities are particularly difficult because of the poor quality of bone in severely affected children. Progressive scoliosis in severe OI does not respond to conservative management and response to surgical intervention may be limited.
Basilar impression
Basilar impression is best evaluated by CT or MRI scanning with views across the base of the skull. Criteria for surgical intervention are not well defined. If surgery is undertaken, it should be done in a center experienced in the procedures used.
Dental treatment
The goals are the maintenance of both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Pediatric dentists are the most knowledgeable about DI in children. Some consensus exists that early dental restorative coverage of the primary molars, and if possible, aesthetic coverage of the upper anterior teeth is optimal. Plastic polymers are sometimes used to coat teeth. As anxiety can be an issue with children, pre-medication for anxiolysis, such as nitrous oxide analgesia or midazolam, can be used for treatment in a clinic setting. If warranted, orthodontic treatment can be initiated, but care must be taken not to fracture teeth with orthodontic appliances because of the brittleness of the teeth. Dental restorations in adults may best be done by a general dentist knowledgeable about OI or a specialist in prosthetic dentistry.
Treatment of hearing loss
Initial hearing loss in OI is usually conductive as a result of fractures of the bones of the middle ear or contracture and scarring of the incus. Surgical repair of the bones and creation of a prosthetic incus can improve unaided hearing.
Later hearing loss appears to have a significant sensorineural component that does not respond to middle ear surgery. Cochlear implantation has been used in a small number of individuals; outcome data are limited.

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