Osteogenesis Imperfecta Clinical Presentation

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, prenatal screening ultrasonography 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 below) have deafness by age 40 years.

The clinical presentation of OI is dependent on the phenotype. The most widely used classification is that of Sillence,^{[8, 9]} which classifies OI into 4 types on the basis of clinical and radiologic features (see Table below). In addition, dentinogenesis imperfecta is denoted as subtype B, whereas OI without dentinogenesis imperfecta is denoted as subtype A.

Table. Adapted Sillence Classification of Osteogenesis Imperfecta (Open Table in a new window)

Three more types of OI (types V, VI, and VII) have been described, though they have not yet been incorporated into the International Classification of the Osteochondrodysplasias (INCO), which uses the Sillence classification. These 7 forms are described in more detail 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 1 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 1 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 of 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 in utero fractures may occur. 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.^{[10, 11]} 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.

Other types of osteogenesis imperfecta

Many cases of OI do not fit into the aforementioned categories; such variants include osteoporosis-pseudoglioma, Bruck syndrome, and Cole-Carpenter syndrome.

Osteoporosis-pseudoglioma syndrome 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.

Bruck syndrome 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.^[12]

Cole-Carpenter syndrome is a severe progressive form of OI, with associated multisutural craniosynostosis and growth failure.

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, although they are not particularly prone to have 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 1 case of malignant hyperthermia in a child with OI is described in the literature, and that particular patient had a family history of malignant hyperthermia.