History
Patients often have a family history of osteogenesis imperfecta (OI), but most cases are due to new mutations.
Patients most commonly present with fractures after minor trauma. In severe cases, antenatal screening ultrasonography (US) performed during the second trimester may show bowing of long bones, fractures, limb shortening, and decreased skull echogenicity. Lethal OI cannot be diagnosed with certainty in utero.
Patients may bruise easily. They may have repeated fractures after mild trauma. However, these fractures heal readily. Deafness is another feature. About 50% of patients with type I OI (see Physical Examination) have deafness by age 40 years.
Physical Examination
The clinical presentation of OI is dependent on the phenotype. The most widely used classification has been that of Sillence, [18, 1] which classified OI into four types on the basis of clinical and radiologic features (see Table 1 below). In addition, dentinogenesis imperfecta was denoted as subtype B, whereas OI without dentinogenesis imperfecta was denoted as subtype A.
Table 1. Adapted Sillence Classification of Osteogenesis Imperfecta (OI) (Open Table in a new window)
Type of OI |
Inheritance |
Teeth |
Bone Fragility |
Bone Deformity |
Sclera |
Spine |
Skull |
Prognosis |
IA |
AD |
Normal |
Variable but less severe than other types |
Moderate |
Blue |
20% scoliosis and kyphosis |
Wormian bones |
Fair |
IB |
AD |
Dentinogenesis imperfecta |
NA |
NA |
NA |
NA |
NA |
NA |
II |
AD |
Unknown |
Very severe |
Multiple fractures |
Blue |
NA |
Wormian bones with absence of ossification |
Perinatal death |
III |
AD |
Dentinogenesis imperfecta |
Severe |
Progressive bowing of long bones and spine |
Bluish at birth but white in adults |
Kyphoscoliosis |
Hypoplastic wormian bones |
Wheelchair-bound, not ambulatory |
IVA |
AD |
Normal |
Moderate |
Moderate |
White |
Kyphoscoliosis |
Hypoplastic wormian bones |
Fair |
IVB |
AD |
Dentinogenesis imperfecta |
NA |
NA |
NA |
NA |
NA |
NA |
AD = autosomal dominant; NA = not applicable. |
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More than 10 additional types of OI have since been described, [19] including types V, VI, VII, and VIII. The Nosology Committee of the International Skeletal Dysplasia Society has cited 18 different OMIM (Online Mendelian Inheritance in Man) types of OI, grouped under the four major types. [2] The International Classification of the Osteochondrodysplasias (INCO) has continued to use the Sillence classification. Types I-VIII are described further below.
Type I
Type I OI is the mildest and most common form. Patients present with blue sclerae (often described as dark blue with a gray tinge), variable degrees of bone fragility, moderate bone deformity, and premature deafness. Height is usually normal. Exercise tolerance and muscle strength are significantly reduced, even with mild OI. Birth weight tends to be normal, though one or more bones may be fractured.
Fractures may occur for the first time at a later age (eg, when the child starts to walk). These fractures tend to heal well, though sometimes a hypertrophic callus response is seen. Fractures tend to decrease in frequency after puberty, but their frequency may increase later in life when age- and sex-related osteoporosis is superimposed. Over a lifetime, numbers of fractures can range from one to 60 or more.
People with OI have a high tolerance for pain. Old fractures can be discovered in infants only after radiographs are obtained for other reasons other than an assessment of OI, and they can occur without any signs of pain.
Involvement of the axial skeleton, in the form of scoliosis and kyphosis, is seen in 20% of cases. Dentinogenesis imperfecta is characteristic of OI type IB.
Type II
Severely affected babies with type II OI are born with dwarfism, blue sclerae, and short, bowed limbs. Patients may have a small nose, micrognathia, or both. The disease is usually fatal at birth, but some babies survive for several months. All patients have in-utero fractures, which may involve the skull, long bones, or vertebrae. The ribs are beaded, and the long bones are severely deformed. Causes of death include extreme fragility of the ribs, pulmonary hypoplasia, and malformations or hemorrhages of the central nervous system (CNS).
Type III
Of all types of OI, type III is the one that orthopedic surgeons see most often. Babies with type III OI are born with severe bone fragility and suffer multiple fractures at birth, though birth weight tends to be normal. The bone fragility may lead to joint hyperlaxity, muscle weakness, chronic unremitting bone pain, and skull deformities (eg, posterior flattening). In utero fractures are common.
The sclerae are bluish at birth but fade over the years, becoming white in adulthood. Dentinogenesis imperfecta is frequently seen. The presence of dentinogenesis imperfecta is independent of the severity of the OI. Patients may have a triangular face with frontal bossing. Malocclusion is common.
The chest and rib cage are usually spared, with few or no fractures of the ribs. Bowing of the limbs is common with growth, and multiple fractures may be seen later in life. The result is a short skeleton and a relatively less affected barrel-shaped chest, with a pectus carinatum deformity. Deformities of upper limbs may compromise function and mobility. Affected children tend to become wheelchair-bound and nonambulatory.
The classic radiographic appearance is that of popcorn bones, in which fractures of the physes in several locations result in several islands of endochondral ossification. With age, these ossifications tend to disappear, leaving an enlarged radiolucent epiphysis. The axial skeletal is also involved, with progressive platyspondyly and kyphoscoliosis. Eventually, the wide rib cage overlaps the narrow pelvis.
Basilar invagination is an uncommon but potentially fatal occurrence in OI. Vertigo is common in patients with severe OI. The incidence of congenital malformations of the heart in children with OI is probably similar to that in the healthy population. Hypercalciuria may be present in about 36% of patients with OI but does not appear to affect renal function. Constipation and hernias are also common in people with OI.
Type IV
Children with type IV OI have white sclerae with moderate bone fragility and deformity. Fractures usually begin in infancy, but some may occur in utero. The long bones are usually bowed. The clinical picture may be similar to that of type I disease, except for the presence of white sclerae. Axial skeletal involvement, in the form of kyphoscoliosis, is also common. Dentinogenesis imperfecta is seen in type IVB disease.
Type V
Type V OI is an autosomal dominant condition with a severity similar to that of type IV disease but a predisposition to hyperplastic callus formation. Characteristic features include ossification of the interosseous membrane of the forearms and legs, leading to limited pronation and supination and a radiopaque metaphyseal band in growing patients.
Type VI
OI type VI is clinically similar to types II and IV, but it has distinctive histology, including hyperosteoid bone due to a mineralization defect, and does not have a disturbance of bone mineral metabolism.
Type VII
OI type VII has been described in an isolated First Nations community in northern Quebec. [20, 21] It is clinically similar to OI types II and IV but has rhizomelia as a distinctive feature. The gene mutation has been mapped to region 3p22-24.1.
Type VIII
OI type VIII is a recessive form of lethal or severe OI. It is caused by null mutations in P3H1, which encodes prolyl 3-hydroxylase 1. [22] With respect to appearance and symptoms, type VIII resembles types II and III, except for white sclerae. Severe growth deficiency and extreme under-mineralization of the skeleton are noted.
Other types of osteogenesis imperfecta
Many cases of OI do not fit into the aforementioned categories; such variants include the following:
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Osteoporosis-pseudoglioma syndrome - This is caused by mutations in the gene encoding for the low-density-lipoprotein receptor-related protein 5 (LRP5), with clinical features including blindness and bone fragility; LRP5 is thought to mediate the proliferation and differentiation of osteoblasts
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Bruck syndrome - This is an autosomal recessive condition caused by mutations in the bone-specific collagen type 1 telopeptide lysyl hydroxylase enzyme, with clinical features that include congenital joint contractures and bone fragility [23]
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Cole-Carpenter syndrome - This is a severe progressive form of OI, with associated multisutural craniosynostosis and growth failure
Complications
Repeated respiratory infections are complications of severe OI. Basilar impression caused by a large head, which causes brainstem compression, is the major neurologic complication in a child with OI. This is most commonly observed in children with very severe OI. Cerebral hemorrhage caused by birth trauma is another possible complication.
Patients with OI should be considered to be at high risk for complications of anesthesia, though they are not particularly prone to malignant hyperthermia. Patients with OI have a high basal metabolism that may cause hyperthermia during anesthesia, but the hyperthermia is almost never malignant. In fact, only one case of malignant hyperthermia in a child with OI has been described in the literature, and that particular patient had a family history of malignant hyperthermia.
Pregnant women with OI are at increased risk for complications. Births to women with OI have been associated with a higher likelihood of antepartum hemorrhage, abruptio placentae, intrauterine growth restriction and small-for-gestational-age infants, congenital malformation, and preterm birth. [24]
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Osteogenesis imperfecta. Acute fractures are observed in radius and ulna. Multiple fractures can be seen in ribs. Old healing humeral fracture with callus formation is observed.
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Osteogenesis imperfecta. Beaded ribs. Multiple fractures are seen in long bones of upper extremities.
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Osteogenesis imperfecta. Wormian bones are present in skull.
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Osteogenesis imperfecta. Newborn has bilateral femoral fractures.
Tables
Type of OI |
Inheritance |
Teeth |
Bone Fragility |
Bone Deformity |
Sclera |
Spine |
Skull |
Prognosis |
IA |
AD |
Normal |
Variable but less severe than other types |
Moderate |
Blue |
20% scoliosis and kyphosis |
Wormian bones |
Fair |
IB |
AD |
Dentinogenesis imperfecta |
NA |
NA |
NA |
NA |
NA |
NA |
II |
AD |
Unknown |
Very severe |
Multiple fractures |
Blue |
NA |
Wormian bones with absence of ossification |
Perinatal death |
III |
AD |
Dentinogenesis imperfecta |
Severe |
Progressive bowing of long bones and spine |
Bluish at birth but white in adults |
Kyphoscoliosis |
Hypoplastic wormian bones |
Wheelchair-bound, not ambulatory |
IVA |
AD |
Normal |
Moderate |
Moderate |
White |
Kyphoscoliosis |
Hypoplastic wormian bones |
Fair |
IVB |
AD |
Dentinogenesis imperfecta |
NA |
NA |
NA |
NA |
NA |
NA |
AD = autosomal dominant; NA = not applicable. |
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