You are in: eMedicine Specialties > Radiology > PEDIATRICS Osteogenesis ImperfectaArticle Last Updated: Aug 5, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Anish Kirpalani, MD, Consulting Radiologist, Texas Radiology Associates, LLP Anish Kirpalani is a member of the following medical societies: American Roentgen Ray Society, Canadian Association of Radiologists, International Society for Magnetic Resonance in Medicine, and Radiological Society of North America 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 Editors: Harris L Cohen, MD, FACR, Vice Chairman/Associate Chairman (Research Activities), Director, Division of Body Imaging, Professor of Radiology, Stony Brook School of Medicine; Visiting Professor of Radiology, Johns Hopkins School of Medicine; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Marta Hernanz-Schulman, MD, FAAP, Professor, Radiology, Radiological Sciences, and Pediatrics, Director, Department of Pediatric Radiology, Radiologist-in-Chief, Director, Department of Diagnostic Imaging, Vanderbilt University Medical Center, Vanderbilt Children's Hospital; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Felix S Chew, MD, MBA, EdM, Professor, Department of Radiology, Vice Chairman for Radiology Informatics, Section Head of Musculoskeletal Radiology, University of Washington Author and Editor Disclosure Synonyms and related keywords: osteogenesis imperfecta, OI, collagen disease, bone disease, inborn genetic disease, Lobstein disease, Lobstein's disease, Ekman syndrome, Ekman's syndrome, osteochondrodysplasia, osteopsathyrosis, van der Hoeve syndrome, an der Hoeve's syndrome, Bruck syndrome, Bruck's syndrome, temporary brittle-bone disease, weak bones, COL1A1, COL1A2, dentinogenesis imperfecta INTRODUCTIONSection 2 of 11
  BackgroundOsteogenesis 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 Medscape topics: Specialty Site Radiology Specialty Site Orthopaedics Resource Center Fracture Resource Center Resource Center Genomic Medicine Resource Center PathophysiologyThe 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. FrequencyUnited StatesThe frequency of osteogenesis imperfecta in Canada and the United States is believed to be similar to that reported in Australia (see International, below). InternationalKnowledge 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/MorbidityCommon 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.
RaceOsteogenesis imperfecta does not seem to have a predilection for any particular race. SexNo known sex predilection is reported for osteogenesis imperfecta. AgeThe 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. Clinical DetailsThe clinical features of osteogenesis imperfecta (OI) depend on the type, but bone fragility with multiple fractures and bony deformities are the common hallmark of all types. 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 ExaminationThe 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 DIFFERENTIALSSection 3 of 11
Child Abuse Other Problems To Be ConsideredBecause 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 RADIOGRAPHSection 4 of 11
FindingsIn cases of suspected osteogenesis imperfecta (OI), postnatal radiographs should include views of the long bones, skull, chest, pelvis, and thoracolumbar spine. Radiographic features are related to the type of OI and the severity of disease. Some findings, however, may be seen in all subtypes. General radiographic features of OIThe radiologic sine qua non of OI is generalized osteoporosis of both the axial and appendicular skeleton. Milder forms of OI result in thin, overtubulated (gracile) bones with thin cortices and relatively few fractures (see Images 1-2). The short tubular bones are also affected, though they are less frequently fractured. More severe forms of OI, such as types II and III, feature thickened, shortened long bones with multiple fractures; these forms are often complicated by hyperplastic callus formation (see Image 3). The callus is most often found around the femur and is often large, appearing as a dense, irregular mass arising from the cortex of bone. This callus is associated with thickened periosteum. Its presence causes other differential diagnostic considerations, including the following: osteosarcoma, myositis ossificans, chronic osteomyelitis, and osteochondroma. In milder forms of disease, radiographs of the skull may reveal normal skull development. With increasing disease severity, the skull demonstrates poor mineralization and multiple wormian, or intrasutural, bones (see Images 4-5). The chest may be small. Multiple rib fractures are often found; these can cause the ribs to become broad and deformed. Spinal abnormalities in all subtypes include platyspondyly and scoliosis (see Type III findings, below). Recent advances in the treatment of OI with bisphosphonates have resulted in specific imaging findings. Cyclical pamidronate treatment produces sclerotic growth recovery lines in the long bones (see Image 1 and Image 6). The amount of bone growth between doses of pamidronate may be measured by the distance between these growth lines. Type-specific radiographic features of OISome radiographic findings are more specific to certain subtypes of OI than others. Type II Type II OI is further categorized into 3 subtypes on the basis of radiologic features of the long bones and ribs. In types IIA and IIB, the long bones are short and broad because of undermodeling; the bones are also crumpled. In type IIC, the long bones are thinner (cylindrical) and longer than in the other subtypes, though they are still undermodeled. The ribs in type IIA are short and broad with continuous beading. In type IIB, beading is absent or minimal and discontinuous. In type IIC, the ribs are thin and beaded. Type III The following radiographic findings are specific to type III OI. Scoliosis of the thoracolumbar spine: As many as 25% of patients with OI have scoliosis, and the association is even higher in patients with type III OI (see Image 7). Most have an S-shaped scoliosis. Severe platyspondyly with vertebral compression fractures and codfish vertebrae are more common in this type than in other types (see Image 8). Popcorn calcifications occur commonly in the metaphyseal-epiphyseal region of long bones, most commonly at the knee and ankle. This results from repeated microfractures at the growth plate. Soft craniofacial bones with a large, thin calvarium cause triangular facies. Type IV Radiographic findings of this type are similar to the general findings and findings specific to type I OI. One feature more commonly associated with type IV than other types is basilar invagination (impression), with or without brainstem compression. This may be detected on plain radiography of the skull or cervical spine. The McGregor line may be used to assess for this complication. This is defined as the straight line connecting the upper surface of the posterior edge of the hard palate to the most caudal point of the occipital curve. Projection of the tip of the odontoid process above the McGregor line suggests the presence of basilar invagination (see Images 9-10). The presence of a large, thin cranium with platybasia and cranial settling may lead to the appearance of the Tam O'Shanter skull. Degree of ConfidenceUpon the detection of hallmark bone findings of osteogenesis imperfecta on plain radiographs, the diagnosis may be made with a high degree of confidence; confirmation with other imaging modalities is not needed. CT SCANSection 5 of 11
FindingsCurrently, the major role of CT is in adjunctive problem-solving. CT may be used to further assess for basilar impression (see Image 9 and MRI below), to evaluate the petrous bone for narrowing of the middle ear or otosclerosis, and to support bone mineral densitometry (BMD) (see Nuclear Medicine below). MRISection 6 of 11
FindingsThe major role of MRI in osteogenesis imperfecta (OI) is in problem-solving. MRI is also used to image complications of OI, such as basilar impression. Although cervical spinal radiography and CT may demonstrate this abnormality well, MRI has the advantage of detecting associated compression of the spinal cord (see Image 10). Basilar impression is frequently associated with type IV OI. In particular, in type IVB OI, the incidence of neurologic symptoms is increased. Other associated conditions that may be imaged better with MRI than with plain radiography include syringohydromyelia and communicating hydrocephalus, especially if these conditions develop after fontanelle closure. ULTRASOUNDSection 7 of 11
FindingsOsteogenesis imperfecta (OI) is one of the most common skeletal dysplasias detected on prenatal ultrasonography. Most cases involve type II OI and are found incidentally. The diagnosis of OI may be made reliably by week 17 of gestation. The diagnosis may be made by detecting morphologic abnormalities on sonograms or by analyzing collagen synthesized by chorionic villus cells after sonography-guided chorionic villus sampling. Sonographic findings of OI during the second trimester scanning include decreased echoes from the calvarium with supervisualized (too easily seen) intracranial structures; bowing and angulation of the long bones, implying platic deformities and fractures; decreased length of the long bones; and multiple rib fractures.17 NUCLEAR MEDICINESection 8 of 11
FindingsBone mineral densitometry (BMD) results may confirm the severity of osteoporosis in patients with osteogenesis imperfecta (OI); it may also confirm the presence of demineralization in mild cases of type I or type IV OI. Currently accepted BMD measurement techniques include the following: (1) cortical radial BMD measured by use of single-photon absorptiometry (SPA); (2) BMD of the lumbar spine (in children older than 1 y) and femoral neck (in children older than 6 y), in which BMD is obtained by use of dual-energy x-ray absorptiometry (DXA); and (3) lumbar spinal BMD measured by means of CT in children older than 4 years. Degree of ConfidenceThere are only a few reported cases in which bone mineral densitometry measurements were made in young children with osteogenesis imperfecta; as such, the reliability of these measurements is unknown. INTERVENTIONSection 9 of 11
Approaches to the treatment of osteogenesis imperfecta (OI) are aimed at improving bone mass. Such treatments include the use of bisphosphonates to decrease bone resorption and to increase bone formation. Intravenous pamidronate is effective in promoting bone growth and relieving chronic pain when given cyclically (eg, every 4-6 mo).18, 19, 20, 21 Medical/Legal Pitfalls
MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
Osteogenesis Imperfecta excerpt Article Last Updated: Aug 5, 2008 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
