COL1A1/2 Osteogenesis Imperfecta

Clinical characteristics: COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows:

1. Classic non-deforming OI with blue sclerae (previously OI type I)

2. Perinatally lethal OI (previously OI type II)

3. Progressively deforming OI (previously OI type III)

4. Common variable OI with normal sclerae (previously OI type IV)

Diagnosis/testing: The diagnosis of COL1A1/2-OI is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in COL1A1 or COL1A2 by molecular genetic testing.

Management: Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in medical management of OI, clinical genetics, orthopedics, rehabilitation medicine, pediatric dentistry, otology/otolaryngology, and mental health. Parents / other caregivers must practice safe handling techniques. Mainstays of treatment include: bracing of limbs depending on OI severity; orthotics to stabilize lax joints; physical activity; physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, prevent head and spine deformity, and improve muscle strengthening; mobility devices as needed; and pain management. Fractures are treated with: as short a period of immobility as is practical; small and lightweight casts; physical therapy as soon as casts are removed; and intramedullary rodding when indicated to provide anatomic positioning of limbs. Progressive scoliosis in severe OI may not respond well to conservative or surgical management. Bisphosphonates continue to be used most extensively in severely affected children with OI. Surgical treatment for basilar impression should be done in a center experienced in the necessary procedures. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as when caused by other conditions. Mental health support through psychiatry/psychology and appropriate social worker intervention can improve quality of life.

Prevention of secondary complications: During general anesthesia, proper positioning on the operating room table and use of cushioning such as egg crate foam can help avoid fractures.

Surveillance: Orthopedic evaluation with ancillary therapy services (physical and rehabilitation medicine) as indicated every three months until age one year, every six months from ages one to three years, and then annually or with any new fractures. Physical therapy evaluation in infancy for those with motor delays and as needed to improve mobility and function. CT and/or MRI examination with views across the base of the skull to evaluate for basilar impression if concerning signs or symptoms are present. Cervical spine flexion and extension radiographs in children able to cooperate with the examination or before participating in sporting activities in more mildly affected individuals. Twice-yearly dental visits beginning in early childhood or even infancy for those with (or at risk for) DI. Hearing evaluation at three- to five-year intervals from age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions.

Agents/circumstances to be avoided: Contact sports should be avoided.

Genetic counseling: COL1A1/2-OI is inherited in an autosomal dominant manner. The proportion of affected individuals who represent simplex cases (i.e., a single occurrence of the disorder in a family) varies by the severity of disease. Approximately 60% of probands with mild OI represent simplex cases. Virtually 100% of probands with progressively deforming or perinatally lethal OI represent simplex cases and have a de novo pathogenic variant or a pathogenic variant inherited from a parent with somatic and/or germline mosaicism. Parental somatic and/or germline mosaicism is present in up to 16% of families. Each child of an individual with a dominantly inherited form of COL1A1/2-OI has a 50% chance of inheriting the causative variant and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by molecular genetic testing if the COL1A1 or COL1A2 causative variant has been identified in an affected relative. Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur.