COL1A1- and COL1A2-Related Osteogenesis Imperfecta

Excerpt

Included types:

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

2. Perinatally lethal OI (OI type II)

3. Progressively deforming OI (OI type III)

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

Clinical characteristics: COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) is characterized by fractures (often with minimal or absent trauma), variable dentinogenesis imperfecta (DI), and hearing loss (typically in adult years). The severity of COL1A1/COL1A2-OI ranges from perinatal lethality; individuals with severe skeletal deformities, mobility impairments, and very short stature; to individuals with a slight predisposition to fractures and normal dentition, stature, and 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 and wear down or break easily. COL1A1/COL1A2-OI is classified into four types based on clinical presentation and radiographic findings. This classification system, although imperfect, 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: classic non-deforming OI with blue sclerae (previously OI type I), perinatally lethal OI (previously OI type II), progressively deforming OI (previously OI type III), common variable OI with normal sclerae (previously OI type IV).

Diagnosis/testing: The diagnosis of COL1A1/COL1A2-OI is established in a proband with clinical and radiographic manifestations of OI by identification of a heterozygous in COL1A1 or COL1A2 by molecular genetic testing.

Management: Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in the medical management of OI. Educate parents/caregivers of safe handling techniques. Alternate position to minimize deformity. Initiate upright sitting only once the infant has adequate head and trunk control. Physical and occupational therapy to increase bone stability, improve mobility, prevent contractures and head and spine deformity, and improve muscle strength; physical activity guided by therapists. Mobility aids including orthotics to stabilize lax joints. Pain management combines pharmacologic and non-pharmacologic strategies. Fractures are treated with as short a period of immobility as is practical, small and lightweight casts, and physical therapy as soon as casts are removed; intramedullary rodding when indicated to provide anatomic positioning of limbs; bracing of limbs depending on OI severity. Anesthesia requires special attention including proper positioning, intraoperative management, and postoperative analgesia. Progressive scoliosis in severe OI may not respond well to conservative or surgical management. Bisphosphonates continue to be used most extensively in those with vertebral fractures, frequent long bone fractures, or more severe OI. Surgical treatment for symptomatic basilar impression should be done in an experienced center. Dental care 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; standard treatments for later-onset sensorineural hearing loss. Protective glasses to prevent eye injury; ocular surgery should be approached with caution. Nutrition education to support maintaining healthy weight for height. Standard treatments for other gastrointestinal issues and cardiovascular and pulmonary issues. Standard pediatric and adult vaccinations to prevent respiratory disease. Mental health support through psychiatry, psychology, and social work can improve quality of life.

Surveillance: Orthopedic evaluation every three months until age one year, every six months from ages one to three years, and then annually or with any new fractures or other musculoskeletal concerns. Assess growth at each visit throughout childhood and adolescence. Physical and rehabilitation medicine and physical and occupational therapy evaluation in infancy for those with motor delays and as needed in older individuals. Assessment of pain at each visit. Evaluation by bone disease specialist including vitamin D level; frequency will depend on age and OI severity. DXA scans beginning at age five years with follow-up scan based on severity of OI, initial results, and pharmacologic treatment status. CT and/or MRI with views across the base of the skull to evaluate for basilar impression in those with platybasia, moderate-to-severe OI, or concerning signs or symptoms. 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. Dental examination every six months beginning in early childhood or infancy for those with (or at risk for) DI. Annual dental exams in those without DI. Hearing evaluation every three years from age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions. Eye exam every two to three years in adults or more frequently as needed. Nutrition and feeding evaluation annually or as needed. Assess for gastrointestinal issues each visit. Assess for symptoms of cardiovascular disease as needed. Assess for pulmonary issues at each visit; consider pulmonary evaluation in those with lung disease; pulmonary function tests every one to two years in adults; sleep study in those with symptoms of sleep apnea. Mental health evaluation and follow-up genetic counseling as needed. Assess family and social work needs at each visit.

Agents/circumstances to be avoided: In young children, avoid sudden acceleration/deceleration movements; avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering. Contact sports and other physical activities with significant risks of falls or high-impact collision should be avoided. Avoid smoking and secondhand smoke to decrease risk of pulmonary disease; avoid excessive alcohol and caffeine consumption. Consider avoiding or limiting any substance or medication that may affect bone health (e.g., steroids).

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from spine examination and ophthalmic, dental, and audiology evaluations.

Pregnancy management: Women with OI and significant skeletal deformities and short stature should be followed closely during pregnancy at a high-risk prenatal care center.

Genetic counseling: COL1A1-OI and COL1A2-OI are inherited in an autosomal dominant manner. Many individuals diagnosed with the milder forms of COL1A1/COL1A2-OI have the disorder as the result of a pathogenic variant inherited from an affected parent. The proportion of affected individuals who represent simplex cases varies by the severity of disease: ~60% of probands with mild OI represent simplex cases; virtually 100% of probands with progressively deforming or perinatally lethal OI represent simplex cases. A proband who appears to be the only affected family member may have COL1A1/COL1A2-OI as the result of a pathogenic variant that occurred de novo in the proband or as a postzygotic de novo event in a parent with gonadal (or somatic and gonadal) mosaicism. The overall rate of mosaicism is up to 16% in the parents of children with COL1A1/COL1A2-OI. Each child of an individual with COL1A1/COL1A2-OI has a 50% chance of inheriting the causative variant. Once the OI-causing variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. 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 are present.