Clinical Guidance

In general, quantitative impacts on type I collagen tend to result in a milder phenotype when compared to qualitative changes that result in a dominant-negative effect . There are exceptions (e.g., glycine-to-serine substitutions in COL1A1 may lead to a more severe phenotype than a similar change in COL1A2). A large multicenter study reported that splice site and truncating pathogenic variants and COL1A1 whole-gene deletions strongly predicted a milder phenotype of classic non-deforming OI with blue sclerae. Non-glycine missense variants and in-frame COL1A2 deletions or duplications predicted progressively deforming OI.

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"

Penetrance

The penetrance in individuals heterozygous for a COL1A1 or COL1A2 pathogenic variant is 100%, although expression may vary considerably, even in the same family.

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"

Diagnostic Criteria

Suggestive Findings COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) should be suspected in individuals with the following clinical, radiographic, and laboratory findings and family history. Clinical findings (See .) • Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known bone disorders • Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity • Blue/gray scleral hue • Dentinogenesis imperfecta (DI) • Progressive, postpubertal hearing loss • Ligamentous laxity and other signs of connective tissue abnormality Table 1. COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Clinical Findings by Type

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"

Differential Diagnosis

Other Types of Osteogenesis Imperfecta The primary differential diagnoses for individuals with features of COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) are non-collagen-associated forms of OI. There are both dominant and recessive types, which can be phenotypically indistinct from COL1A1/COL1A2-OI. In a small subset of individuals, specific causative variants have not yet been identified. summarizes the molecular basis of these subtypes of OI, the mode of inheritance, the corresponding clinical OI type, and typical clinical and radiographic features. Table 6. Differential Diagnosis of COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Other Types of Osteogenesis Imperfecta

Management Guidelines

No clinical practice guidelines for COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with COL1A1/COL1A2-OI, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 9.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Musculoskeletal

| • Physical exam

• Growth assessment (length/height, weight, head circumference)

• Pain assessment

| • To assess deformities, scoliosis, presence of joint laxity

• Growth parameters should be plotted on OI growth charts (see height weight charts).1

• Referral to PT OT to assess motor development mobility issues

• Referral for surgical intervention to experienced orthopedist as needed

| As indicated by clinical presentation

• Referral to bone disease specialist

• Bone biomarkers (calcium, phosphorus, alkaline phosphatase, parathyroid hormone)

• Vitamin D level to assess for deficiency

|

DXA scan | Beginning at age ~5 yrs

Neurologic

| CT /or MRI exam w/views across base of skull to evaluate for basilar impression | If concerning signs or symptoms are present2

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"

Clinical Guidance

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 or activities with increased fall or high-impact collision risk 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).

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"

Therapies Under Investigation

Several medications are being investigated for use in OI . Some of the medications under investigation are already being used as off-label treatment for OI. Teriparatide is a human 1-34 parathyroid hormone (PTH) with osteoanabolic effect. Three studies examined the use of teriparatide in OI (another large clinical trial is still ongoing) . A double-blind, placebo-controlled trial that included 79 individuals with classic non-deforming OI with blue sclerae, progressively deforming OI, and common variable OI with normal sclerae demonstrated that 18 months of teriparatide treatment was associated with increases in areal BMD (aBMD) at the lumbar spine (6.1% ± 1.0% vs 2.8% ± 1.0% change) and total hip aBMD (2.6% ± 1.0% vs 2.4% ± 1.0% change) compared to placebo .

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, a multidisciplinary approach is recommended . Health care needs change with age and based on individual circumstances, so each individual might have different needs across their life span. Comorbidities are more common in adults than in children, so adults might require more extensive and frequent follow up .

Table 10.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Recommended Surveillance

System/Concern | Evaluation | Frequency

Musculoskeletal

| Orthopedic eval to assess for fractures, scoliosis, other musculoskeletal manifestations | • Every 3 mos until age 1 yr

• Every 6 mos from age 1-3 yrs

• Then annually or w/any new fractures or other musculoskeletal concerns (e.g., long bone deformity, flat feet, leg discrepancy, osteoarthritis)

Assessment of growth | At each visit throughout childhood adolescence

Physical rehab medicine, PT/OT eval to assess mobility other motor skills | In infancy for persons w/motor delays as needed in older persons

Assessment of pain | At each visit

• Eval by bone disease specialist

• Vitamin D level to assess for deficiency

| As recommended by bone disease specialist or as needed based on age OI severity

DXA scan | Beginning at age 5 yrs; frequency depends on severity of OI, results of initial DXA scan, pharmacologic treatment status1

Source: GeneReviews — "COL1A1- and COL1A2-Related Osteogenesis Imperfecta"