Approach

Consider a diagnosis of OI in people (most commonly children/adolescents) presenting with one or more of the following features:[1][27][28]

  • recurrent fragility fractures

  • unusually low bone mass

  • bone deformities

  • kyphoscoliosis

  • short stature

  • blue-gray sclera

  • dentinogenesis imperfecta

  • craniofacial deformity

  • progressive hearing loss

  • joint laxity

  • chronic pain

  • muscle weakness.

Other manifestations of OI may include cardiovascular complications, respiratory problems, and skin fragility/bruising.[1][28]

OI demonstrates significant phenotypic variability and the extent and severity of skeletal and extraskeletal manifestations can differ even among affected members of a family. Therefore, absence of any particular clinical feature does not rule out a diagnosis of OI.

Some clinical features may help to narrow down the genetic type of OI; for example, radial head dislocation, calcification of the interosseous membrane, and hypertrophic calluses are typical of OI type V.[1] Severe rhizomelia (disproportionate shortening of the proximal segment of the limbs) is common in OI type VII. Severe skeletal abnormalities and structural brain malformations (e.g., hypoplasia of pons, cerebellum, optic chiasm, and mesencephalic tectum) are suggestive of OI type XV. See Classification.

When considering a diagnosis of OI, it is important to exclude other clinical conditions that can present with unusually low bone mass and recurrent fractures. These vary depending on patient age and severity of the condition; the list of such conditions is extensive. Examples of key differentials to consider include:

  • Genetic or hormonal conditions that may be associated with short stature or bony deformities and conditions associated with nutritional deficiencies.

  • Non-accidental injury, which is a major differential for types I and IV OI, and must be ruled out in children who present with multiple fractures.[11] Metaphyseal corner fractures, bucket handle fractures, multiple fractures in various forms of healing, and complex skull fractures are suggestive of non-accidental trauma. Perform a thorough evaluation of the child and consider accompanying social circumstances by taking a detailed patient and family history, alongside tailored physical exam, radiographic imaging, and assessment of social circumstances to ensure non-accidental injury is not overlooked.

For more detail on important differential diagnoses, see Differentials.

History

As the severity of OI ranges widely from perinatal lethality to short stature and severe skeletal deformities to a near asymptomatic presentation with few fractures and near-normal stature, a detailed history should be taken encompassing a full systems review. The history should focus on the following clinical features.

Growth

Ask about the history of growth and weight gain throughout childhood.

  • Short stature is a common feature of OI.[29]

  • Median weight in OI is well below that of age-matched peers.[29]

  • Decrease in growth velocity and blunting of the growth spurt with puberty are also common in severe forms of OI; however, the final height is also affected in people with mild forms of OI.[29][30]

Fractures

Ask about a history of fractures.

  • Perinatal lethal and severe forms of OI present with in utero fractures and fractures during the newborn and infantile periods.

  • Recurrent fractures with minimal or even no trauma and bone deformities are typical in severe forms of OI.

  • In the mild form of OI (type I), fractures may become apparent as children start to walk or any time during childhood (note that individuals with OI type I may not fracture until adolescence or sometimes even until adulthood).

  • The incidence of fractures in OI shows a bimodal distribution with a peak during early childhood and a second peak after the age of 40 years.[31]

  • Although no particular fracture is characteristic of OI, fractures of long bones after minimal trauma, vertebral fractures, multiple fractures in the setting of bone deformities, and olecranon fractures should raise the suspicion of OI.[32]

  • A history of radial head dislocation is typical for OI type V.[1]

One study of 959 adults with OI noted that 64% self-reported a history of fractures.[28] A Danish population-based cohort study demonstrated that the risk of fracture in adults with OI between ages 20 and 54 years was almost 6 times higher than that of the general population.[31]

Spinal anomalies

Ask about a history of back problems/confirmed spinal conditions.

  • Spinal manifestations of OI include kyphosis, scoliosis, craniocervical junction abnormalities (platybasia, basilar impression, and basilar invagination), and spondylolisthesis.[33]

  • The incidence of kyphoscoliosis is dependent on the severity of OI and can range from 30% in people with mild OI (type I) to 90% in those with severe OI (type III).[34] Single thoracic curves are the most frequent type of scoliosis in mild OI, whereas S-shaped curves and severe scoliosis with Cobb angles >30 degrees are typically observed in severe forms of OI. Scoliosis may rapidly increase during periods of growth and the spinal curvature may worsen until adulthood.[35]

  • Spondylolisthesis typically presents with chronic back pain, which gets worse with age.

Joint abnormalities

Ask about a history of joint pain or hypermobility.

  • Most types of OI are caused by abnormal structure or function of type I collagen.[8][9][10] As this is a major component of the ligaments and tendons, joint hypermobility and ligamentous laxity are common in OI.

  • Joint hypermobility and ligamentous laxity can manifest as chronic pain and increased fatigability/muscle weakness, which may interfere with normal daily activities.

Pain

Take a pain history to quantify pain and assess functional status using a quantifiable scale, such as the Numerical Rating Pain Scale.

  • Chronic pain is prevalent in all OI types and may affect mobility and interfere with activities of daily living.

  • A multicenter, cross-sectional analysis of chronic pain prevalence in 861 people with OI found that chronic pain was present in 41.8% of individuals with OI, with back pain being the most commonly reported pain.[36]

  • Increasing age, history of rodding surgery, scoliosis, use of assistive devices, lower standardized height, and higher body mass index are predictors for pain in OI.[36]

Dental abnormalities

Ask about a history of dental abnormalities, which may include:[37][38][39]

  • Dentinogenesis imperfecta (characterized by gray-brown or opalescent bluish-gray tooth discoloration, bulbous crowns, altered root morphology, and premature obliteration of the pulp)

  • Missing or unerupted teeth

  • Dental malocclusion (significant malocclusion, posterior open bites, and cross bites most commonly seen in OI type III; less severe forms of malocclusion may be seen in types I, II, and IV).

Hearing loss

Ask about hearing loss.

  • Conductive, sensorineural, and mixed hearing loss are well known features of OI.

    • Otosclerosis of the temporal bones including at the oval window, fixation of footplate of stapes, and fracture of the small middle ear bones are underlying causes.

  • Approximately 50% of people with OI develop hearing loss during adulthood and the prevalence of hearing loss increases with age.[40][41]

  • Hearing loss is most commonly found in people with OI type I.[42][43]

  • Hearing loss can also be observed in a subset of children with OI, especially in those with types III and IV.[43]

Cardiopulmonary system

Ask about cardiorespiratory symptoms (which may include chest pain, palpitations, fatigue, syncope, dyspnea, and cough) and a past or current history of cardiopulmonary disease (which may include mitral and aortic valve disease, restrictive pulmonary disease, pulmonary hypertension, cor pulmonale, and mitral valve prolapse).

  • Pulmonary disease is a significant contributor to mortality and morbidity in OI and is multifactorial.[44]

  • Although contributions of factors extrinsic to the lung such as immobility, scoliosis, recurrent rib fractures, muscle weakness, and chest wall abnormalities have been well known for decades, contemporary data in humans and preclinical animal models demonstrate intrinsic lung abnormalities.[44][45][46][47][48]

  • Cardiac abnormalities including mitral valve regurgitation, aortic regurgitation, atrial fibrillation/flutter, and heart failure have been reported at higher frequencies in people with OI compared with the general population.[49][50]

  • Although vascular aneurysms, vascular dissections, aortic root dilatation, and ventricular dysfunction have also been reported in patients with OI, systematic controlled studies to support an association are lacking.[50][51][52][53]

Central nervous system

Ask about central nervous system symptoms, which may include headache, burning pain in extremities, numbness of extremities, or muscle weakness.

  • Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull and can present with headache and symptoms suggestive of spinal cord and spinal nerve root compression (such as numbness, cramping, or weakness in the arms, hands, or legs).[54]

Physical exam

Focus on performing a detailed physical exam to assess for features and severity of OI, and conduct an assessment of the functional status of the patient.

General

Assess height, weight, and vital signs.

  • Be aware that automated blood pressure devices can exert significant pressure on the humerus, which can be painful in those with severe forms of OI, and precautions need to be taken to prevent fractures while taking blood pressure. If available, use a manual device.

  • Note that body mass index may not be an accurate measure of overweight and obesity in individuals with significant short stature.

Head/ENT

Look for facial features and blue-gray sclera. Conduct a detailed oral examination with attention to dentinogenesis imperfecta and dental malocclusion.

  • Craniofacial features, especially in people with severe forms of OI, may include:[11]

    • triangular face

    • frontal bossing

    • broad forehead

    • deep-set eyes

    • beaked nose.

  • Blue-gray scleral discoloration is a classic finding in individuals with OI types I-IV.

    • This is due to increased translucency of the sclera secondary to thinning of collagen, which reveals the underlying choroid.[55]

  • Dental features, including dentinogenesis imperfecta, are typical in people with OI types I-IV, and are not observed in all subtypes of OI.

    • Dentinogenesis imperfecta is characterized by gray-brown or opalescent bluish-gray tooth discoloration, bulbous crowns, altered root morphology, and premature obliteration of the pulp.

    • People with OI type III can also have significant malocclusion, posterior open bites, and cross bites.[37][38][39]

[Figure caption and citation for the preceding image starts]: Gross facial phenotype of child with osteogenesis imperfecta depicting triangular faciesSukumar SP, et al. Case Reports 2013; 2013: bcr2012008536; used with permission [Citation ends].com.bmj.content.model.Caption@4c0e2828

Musculoskeletal system

Assess for bone deformities, spinal anomalies, and joint hypermobility, with a focus on functional limitations caused by musculoskeletal abnormalities.

Cardiovascular system

Assess the heart rhythm and rate, and for murmurs. Assess for signs of arrhythmia, such as atrial fibrillation, and for signs of heart failure, as indicated by symptoms.

  • Cardiac valvular insufficiency, especially involving mitral and aortic valves, are well recognized features.[50][56]

  • One observational cohort study reported higher frequencies of heart failure, and atrial fibrillation or flutter in adults with OI compared with the general population.[50]

Respiratory system

Assess for intrinsic and extrinsic causes of reduced pulmonary function, including assessment of:

  • Breath sounds

  • Chest wall appearance and expansion (e.g., assess for pectus excavatum and pectus carinatum)

  • Chest wall tenderness (may be indicative of rib fractures)

  • Spine curvature (scoliosis)

  • General mobility/immobility.

Skin

Assess for signs of skin fragility and easy bruising, which can commonly occur in OI.

  • In one study of 959 adults with OI, 42% self-reported a history of bruising.[28]

Central nervous system

  • Assess for signs suggestive of basilar impression (sensory and motor deficits that suggest a cervical cord or cervical spinal root involvement).

  • Assess thoracic, lumbar, and sacral nerve root functions.

Initial investigations

A skeletal survey is recommended in most patients when establishing care and to assess the extent of fractures and bone deformities. A skeletal survey includes radiographs of skull; bilateral upper limbs including wrists and hands; bilateral lower limbs including pelvis and feet; anterior-posterior and lateral views of chest; and anterior-posterior and lateral views of cervical, thoracis, and lumbar spine.

Radiographic features will vary according to the type and severity of OI:[57][58][59]

  • People with OI type I and OI type IV may have wormian bones (small, irregular bones/ossicles that develop from extra ossification centers within the cranium) on the skull, vertebral wedging, and thin cortices of long bones

  • Children with OI type III may have flared metaphyses with popcorn calcification (radiologic appearance of calcification with irregular rings and arc, resembling popcorn)

  • People with OI type V may have hyperplastic callus and calcification of interosseous membranes

  • Most people with severe forms of OI have evidence of multiple bone deformities and kyphoscoliosis.

Consider referring all patients in whom diagnosis is to be established for genetic testing. Pretest counseling and interpretation of genetic test results should be done by medical geneticists and/or genetic counselors. Genetic tests available for testing include:

  • Massively parallel (also known as next generation) sequencing-based gene panel testing for OI or skeletal dysplasia

  • Sanger sequencing for COL1A1 and COL1A2 (limited availability as this test has been largely superseded by massively parallel sequencing-based gene panel testing)

  • Exome sequencing

  • Whole genome sequencing.

Genetic testing can detect variants that are categorized by diagnostic laboratories into the following categories:

  • Benign

  • Likely benign

  • Variant of uncertain significance

  • Likely pathogenic and pathogenic (i.e., disease causing variants).

Note that a negative test may not always exclude OI; seek specialist input if there is diagnostic doubt.

Request dual-energy x-ray absorptiometry (DXA) in all (age-appropriate) patients when establishing care to help quantify changes in bone mineral density over time as well as to assess response to treatment.[60][61]

  • This imaging modality is used to measure a 2-dimensional (areal) bone mineral content and bone mineral density.

  • People with OI typically have very low areal bone mineral density compared with age-matched peers in children and young adults and compared with peak bone mass in older adults.[8][62]

  • DXA should not be performed in a child if safe and appropriate positioning cannot be assured.[60]

Other investigations

It is recommended, based on experience in practice, that:

  • Baseline audiology evaluation is performed in all patients at diagnosis; the frequency of further audiologic evaluations should be based on the severity of hearing loss, with particular consideration given to the impact of hearing loss on quality of life for the patient.

  • Hearing evaluation is performed in children with OI before they start school and repeated every 3 years; annual evaluation should be carried out if abnormalities in hearing are detected.

    • Children with issues with speech, recurrent ear infections, or whose parents suspect a hearing loss should have a formal audiologic assessment regardless of age.

  • Adults with reported hearing loss should have annual testing and follow-up appointments similar to the schedule for children.

    • If hearing loss is identified, regular ENT/audiology follow-up is recommended, with further review if hearing changes.

    • Adults experiencing tinnitus or symptoms of hearing loss should also have an audiologic assessment to determine if hearing loss is conductive or sensorineural.

One study carried out in 133 patients with OI found that 57.9% had hearing loss on audiometry; hearing loss was progressive, often of mixed type, mostly bilateral, and began in the second to fourth decades of life.[40]

Consider spirometry examination in patients when establishing care, to evaluate lung function in OI, and especially in patients with severe OI and those with scoliosis and chest deformities.[45]

  • On spirometry, forced vital capacity and FEV₁ are reduced in people with OI, with significantly reduced lung volumes in those with OI type III.[63]

  • Standing height is commonly used to estimate predictive values for many indices used in evaluating pulmonary function; be aware, however, that people with OI typically have a lower than average standing height, which may result in overestimation of pulmonary function status.[64]

Periodic evaluations are recommended in individuals with compromised lung functions.[63]

Request an echocardiogram in people with symptoms suggestive of cardiovascular disease and in those with physical findings suggestive of valvular disease.

  • Practices vary as to when and in which subset of patients this test should be ordered. The author's personal preference is that at least a baseline echocardiogram be considered in most patients.

Use of this content is subject to our disclaimer