Osteogenesis imperfecta (OI) is a clinically heterogeneous, heritable disorder characterized by increased bone fragility with a predisposition to fractures, low bone mass, bone deformities and short stature. It affects an estimate 1 in 10,000 to 1 in 20,000 live births.

“There are highly variable presentations and a spectrum of severity that are present in osteogenesis imperfecta,” said Prasanthi Pasala Gandham, M.D., a pediatric endocrinologist with Norton Children’s Endocrinology, affiliated with the UofL School of Medicine.

Dr. Gandham sees patients at the multidisciplinary Norton Children’s Metabolic Bone Clinic.

About 1,500 mutations have been identified that cause OI; 90% of them are autosomal dominant mutations in genes encoding Type 1 collagen, specifically the COL1A1 and COL1A2 genes. These genes encode for chains involved in forming the collagen molecule’s triple helix.

Over the past 10 to 15 years, a number of non-collagenous, OI-causing mutations have been discovered. The vast majority of these will cause recessive forms of osteogenesis imperfecta.

OI is divided into four types using the Sillence classification, developed by Australian geneticist David Sillence, M.D.

• Type 1 OI is the mildest form. The collagen defect is quantitative, not qualitative. Those with OI Type 1 have a variable fracture risk. They have femoral bowing, can have some mild scoliosis and typically have normal stature, though they are often shorter than would be expected based on parental height. In Type 1 OI, risk of fracture decreases after puberty.
• Type 2 OI is the perinatal lethal form. There are anomalies present at birth, including beaded ribs, compressed or crumpled femurs and marked long bone deformity. Prognosis is very poor, and mortality is generally associated with pulmonary hypoplasia or failure.
• Type 3 OI is the most severe form in surviving patients. Fractures are often present at birth, with markedly decreased stature and triangular faces. Dentinogenesis imperfecta may be seen in about 40% to 80% of children who have Type 3 OI. They also may have pulmonary disease, though it is usually not as severe as in children with Type 2 OI.
• Type 4 OI is a moderate to severe form of OI, milder than Type 3. Children typically don’t have fractures until they begin walking. They do have short stature, which is moderate to severe, and there also can be mild to moderate scoliosis. As with Type 3 OI, dentinogenesis imperfecta may be seen in about 40% to 80% of children with Type 4.

Extraskeletal manifestations of OI include hearing loss, which can affect people with all Sillence types of OI. Hearing loss can be either conductive or sensorineural in nature. Treatment for hearing loss in those with OI consists in either stapedectomy or, in those who have sensorineural loss, a cochlear implant.

Cardiac manifestations also occur with OI. These include valvular disease, most commonly valvular regurgitation, and aortic root dilatation. Echocardiograms often will reveal impaired diastolic functions, which are thought to be the result of increased stiffness of the myocardium.

In addition to dentinogenesis imperfecta, OI results in high incidence of malocclusion, impaction of the teeth and delayed or accelerated tooth eruption.

Treatment of osteogenesis imperfecta requires a multidisciplinary approach. Physical therapy (PT) and rehabilitation are cornerstones of treatment for these children, with the goal being to maximize gross motor function and activities of daily living. Individual places will be created based on a child’s capacity and abilities at any given point in time.

Orthopedic surgery is the mainstay of therapy, especially in children who have severe forms of OI — such as those who have fractures either at birth or in the early stages of infancy. These children often will require either osteotomies or placement of intramedullary rods to improve quality of life and mobility. Complications from surgery include either migration or nonunion of osteotomies.

OI-related scoliosis doesn’t respond well to bracing, but halo traction followed by spine stabilization has shown some success.

The primary medical intervention utilized in OI is bisphosphonate therapy. Observational and retrospective studies have demonstrated pronounced decreases in pain and increases in mobility, activity and ability to complete activities of daily living.

“We see improved vertebral geometry and increases in total-body bone mineral density, as well as lumbar spine bone mineral density,” Dr. Gandham said.

While more randomized  controlled trials are needed in this patient population, the improved mobility, decreased pain and the effect that bisphosphonate therapy has had on ability to complete physical therapy have significantly improved the quality of life in children with osteogenesis imperfecta.