eMedicine Specialties > Radiology > Pediatrics

Osteogenesis Imperfecta

Author: Anish Kirpalani, MD, Consulting Radiologist, Texas Radiology Associates, LLP
Coauthor(s): Paul S Babyn, MD, Associate Professor, Department of Medical Imaging, University of Toronto; Radiologist-in-Chief, Department of Diagnostic Imaging, The Hospital for Sick Children
Contributor Information and Disclosures

Updated: Aug 5, 2008

Introduction

Background

Osteogenesis imperfecta (OI) is a common heritable disorder of collagen synthesis that results in weak bones that are easily fractured and are often deformed. Several distinct subtypes have been identified. All of them lead to micromelic (short-limbed) dwarfism of varying degree. Depending on severity, the bone fragility may lead to perinatal death or cause severe deformities that persist into adulthood. A wide array of clinical manifestations of the disease may be seen. These partly depend on the genetic subtype of OI.^1,2,3,4,5,6

In OI, the modes of inheritance, family history, clinical features, and radiologic findings vary. This variability forms the basis for the current accepted classification system, which Sillence et al first proposed in 1979.

Four distinct types are identified: type I, which is the dominantly inherited form with blue sclerae; type II, which is the perinatal lethal form; type III, which is the progressively deforming form with normal sclerae; and type IV, which is the dominantly inherited form with normal sclerae.

In general, type I is the mildest form of disease; type IV, type III, and type II, respectively, increase in severity. These types are discussed in Clinical Details.

Key imaging hallmarks help distinguish OI from child abuse (ie, nonaccidental injury), which is the major disorder in the differential diagnosis. The multiplicity of fractures seen in OI commonly raises a concern about child abuse. Because the radiologist plays a central role in distinguishing between these 2 entities, he or she must have an understanding of OI, its genetic variability, and its imaging appearance.^7,8,9

Related eMedicine topics:
Osteogenesis Imperfecta (from Pediatrics: Genetics and Metabolic Disease)
Osteogenesis Imperfecta (from Orthopedic Surgery)

Pathophysiology

The primary pathology in osteogenesis imperfecta (OI) is a disturbance in the synthesis of type I collagen, which is the predominant protein of the extracellular matrix of most tissues. In bone, this defect of extracellular matrix causes osteoporosis, which leads to an increase in the tendency to fracture. Besides bone, type I collagen is also a major constituent of dentin, sclerae, ligaments, blood vessels, and skin; therefore, individuals with OI may also have abnormalities of these structures.

The process of collagen molecule formation starts with the synthesis of procollagen. This precursor consists of a long triple-helix protein flanked by 2 propeptides at its 2 terminals. Procollagen is synthesized and then secreted into the extracellular compartment, where the amino- and carboxy-terminal propeptides are cleaved; thus, the functional collagen molecule is formed. These molecules then assemble into an ordered fibril. Mutations that interfere with expression of the collagen gene, formation of the triple helix (amino acid sequencing), or procollagen secretion affect the structure and function of collagen fibrils, resulting in a form of OI. Electron microscopic studies of OI demonstrate a decrease in the diameter of the collagen fibril, relative to the collagen fibril of healthy persons, and smaller-than-normal apatite crystals.

A number of genetic defects cause the abnormal type I collagen synthesis that leads to OI. OI generally arises from mutations in 1 of 2 genes that encode for the synthesis and/or structure of type I collagen: the COL1A1 gene on chromosome 17, and the COL1A2 gene on chromosome 7. Mutations in these genes may cause abnormal collagen to be produced and may lead to a decrease in the production of normal collagen. The varying degree to which these 2 factors manifest themselves results in the different phenotypic expressions of OI (see Clinical Details). Milder forms of OI are caused primarily by a decrease in production of normal collagen, whereas more severe forms are caused primarily by the production of abnormal collagen. These abnormalities may be dominantly inherited, or they may be the result of sporadic mutation.

Frequency

United States

The frequency of osteogenesis imperfecta in Canada and the United States is believed to be similar to that reported in Australia (see International, below).

International

Knowledge of the incidence of osteogenesis imperfecta (OI) derives primarily from data regarding patients in Australia reported by Sillence et al.¹⁰ Type I, the most common form of OI, occurs in 1 of 28,500 births. Type II, a rare, lethal form of OI, occurs in 1 of 62,500 births. Type III OI occurs in 1 of 68,800 births. No reliable data exist regarding the frequency of occurrence of type IV OI.

Mortality/Morbidity

Common causes of nonorthopedic morbidity in type I and type IV osteogenesis imperfecta (OI) are joint hypermobility, which causes chronic joint pain; hearing impairment; and brainstem compression.

Children with type III OI often require orthopedic care because of their progressive deformities. Standing and walking are often impossible because of spinal compression fractures and scoliosis. Progressive thoracic deformities are associated with recurrent pneumonias that often limit the patient's lifespan.

• Type I: The life expectancy of patients with all forms of OI other than type III is often assumed to be shortened. However, according to Paterson et al, the life expectancy of patients with OI type IA is the same as that of the general population.¹¹ Type IA is a subtype of type I OI in which dentinogenesis imperfecta (tooth abnormalities) does not occur. Type IB is a rare form of type I OI in which dentinogenesis imperfecta does occur (see Clinical Details for further information).¹² In types IB and IV, mortality is modestly increased in comparison with that of the general population; there is no statistically significant difference in life expectancy.
• Type II: This form of OI is fatal in the perinatal period.
• Type III: Only in type III OI is life expectancy affected. However, patients with type III OI who survive beyond the age of 10 years have a better outlook than other patients with OI.

Race

Osteogenesis imperfecta does not seem to have a predilection for any particular race.

Sex

No known sex predilection is reported for osteogenesis imperfecta.

Age

The onset of fractures and deformities varies according to the type of osteogenesis imperfecta (OI) that is present.

For type I, the age of onset is variable. This form most commonly appears during the preschool years when the child is starting to stand. Onset after puberty is uncommon, although fractures may recur in adulthood after menopause or after periods of inactivity, such as after childbirth.

Type II occurs in utero.

In type III, abnormalities are present at birth (ie, abnormalities develop in utero) in more than 50% of patients. Fractures are frequent during the first 2 years of life.

Type IV abnormalities are present at birth in approximately 30% of patients. The onset of this form is during infancy or the preschool years.

Presentation

The major presenting signs and symptoms of OI include blue sclerae, hearing loss, tooth abnormalities (dentinogenesis imperfecta¹² ), joint laxity, and abnormal skin texture (smooth and thin skin). Other features that are common to multiple OI types include bleeding diathesis (easy bruising) and respiratory distress.

OI is classified into 4 distinct types: I-IV. Some cases of OI do not fit easily into any of the 4 types. A type V category has been added to include patients with osteoporosis or interosseous membrane ossification of the forearms and legs, as well as patients who are prone to the development of hypertrophic calluses.^9,13,14

Type I

This prototypical and most common form of OI is associated with the best prognosis. The mode of inheritance is autosomal dominant. The distinguishing clinical features of type I are blue sclerae, which occurs in patients of all ages, and presenile conductive hearing loss; in addition, most patients with type I OI have a family history of hearing loss. Bone fragility is mild, and there are minimal bony deformities. The stature of patients with type I OI is often normal or near normal. Ligamentous hyperlaxity, resulting in joint hypermobility or subluxation, is common. Approximately 20% of patients have kyphoscoliosis.

Dentinogenesis imperfecta is present in some families but not in others.¹² Therefore, type I OI is subclassified to distinguish patients without dentinogenesis imperfecta (type IA, more common) from those with dentinogenesis imperfecta (type IB, rare). Some investigators have suggested that these 2 subgroups are biochemically distinct and that individuals with OI type IB, whose bodies make structurally abnormal collagen, are more similar to those with OI type IV than to those with other types of OI, including type IA.

Type II

Type II is the most severe form of OI. It is characterized by extreme bone fragility that almost invariably leads to intrauterine or early infant death. The cause of death is most often respiratory failure. The mode of inheritance is autosomal recessive. The sclerae are blue and occasionally dark blue or black. Clinically distinguishing features include intrauterine growth retardation, thin and beaded ribs, crumpled long bones, and limited cranial and/or facial bone ossification. Limbs are short, curved, and angulated.

Type II OI can be further subdivided into types IIA, IIB, and IIC on the basis of the radiographic features of the long bones and ribs. See Radiograph below for details. Patients with type IIA or IIC inevitably die in the perinatal period; rarely, patients with type IIB survive into early childhood.

Type III

Type III is the next most severe form of OI after type II. It is the most severe form in which survival extends beyond the perinatal period. Its hallmark feature is severe bone fragility and osteopenia, which is progressively deforming. The mode of inheritance is thought to be autosomal recessive. Multiple fractures and progressive deformity affect the long bones, skull, and spine and are often present at birth. Postnatal growth failure is severe. Kyphoscoliosis is common. Sclerae are either normal from birth, or they progress from pale blue in infancy to a normal appearance by adolescence.

Type III OI is probably the form that is best known to radiologists and orthopedic surgeons. Children with type II OI tend to have severe dwarfism caused by spinal compression fractures, limb deformities, and disruption of growth plates.

Type IV

Type IV OI is distinguished from type I OI by the slightly increased, though still variable, severity of bone fragility and by the presence of normal sclerae. The mode of inheritance is autosomal dominant. Mild to moderate bony deformity of the long bones and spine is present; the incidence of fracture is variable. Basilar impression of the skull, with consequent brainstem compression, is common; it is reported in 70% of patients.

Hearing loss or a family history of hearing loss is noted in patients with this type of OI, as is dentinogenesis imperfecta. Type IV OI is also subclassified to distinguish patients without dentinogenesis imperfecta (type IVA) from those with it (type IVB). Compared with type I OI, hearing loss is less common in type IV, and dentinogenesis imperfecta (type IVB) is more common.

Some authors have distinguished a self-limiting variant of OI, known as temporary brittle-bone disease. Its clinical features are identical with those found in cases of child abuse. This variant of OI is further discussed in Medical/Legal Pitfalls.

Preferred Examination

The preferred examination for the initial investigation of osteogenesis imperfecta (OI) is plain radiography. Indeed, most of the imaging characteristics of OI are apparent on plain radiographs.

Prenatal ultrasonography plays a role in the diagnosis of OI; OI is one of the more common skeletal dysplasias detected with prenatal ultrasonography. Most cases of OI are found incidentally on sonographic examinations performed for other reasons; typical incidental findings include fractures, decreased calvarial ossification, or calvaria that are compressible with transducer pressure. Most cases of OI that are recognized in this way are of type II, and the patients have no family history of the disease.

MRI plays an adjunct problem-solving role in assessing for associated complications, such as basilar invagination.^15,16

Differential Diagnoses

Child Abuse

Other Problems to Be Considered

Because osteoporosis and multiple fractures are hallmark features of osteogenesis imperfecta (OI), other disorders that cause multiple fractures or decreased bone mineralization may be considered in the differential diagnosis. Such disorders include the following: 

Juvenile osteoporosis
Steroid-induced osteoporosis
Menkes (kinky-hair) syndrome
Hypophosphatasia
Battered child syndrome (syndrome X)
Temporary brittle-bone disease

• Search for CME/CE on This Topic »

• Osteogenesis Imperfecta (Pediatrics: Genetics and Metabolic Disease)
• Osteogenesis Imperfecta (Orthopedic Surgery)
• Intraosseous Access (Pediatrics: Surgery)
• Abdominal Hernias (General Surgery)

• Cyclic Pamidronate Benefits Infants With Osteogenesis Imperfecta
• Bone Mineral Density Identifies Young Lupus Patients at Risk of Bone Problems

• Bisphosphonate Nephrotoxicity
• Suspicious Fracture in a Toddler
• Osteoporosis in Chronic Obstructive Pulmonary Disease Patients