Included types

• Classic non-deforming OI with blue sclerae (OI type I)
• Perinatally lethal OI (OI type II)
• Progressively deforming OI (OI type III)
• 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.

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 Table 1.)

• 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

Radiographic findings change with age. The major findings include the following (see Table 2):

• Fractures of varying ages and stages of healing, often of the long bones but also rarely involving ribs and skull. Metaphyseal fractures are rarely seen in a very small number of children with OI. Rib fractures are much more common in NAT than in OI.
• "Codfish" vertebrae, which are the consequence of spinal compression fractures, seen more commonly in adults
• Wormian bones, defined as "sutural bones which are 6 mm by 4 mm (in diameter) or larger, in excess of ten in number, with a tendency to arrangement in a mosaic pattern" [Cremin et al 1982]. Wormian bones are suggestive of but not pathognomonic for OI.
• Protrusio acetabuli, in which the socket of the hip joint is too deep and the acetabulum bulges into the cavity of the pelvis, causing intrapelvic protrusion of the acetabulum
• Low bone mass or osteoporosis detected by dual-energy x-ray absorptiometry (DXA). Bone mineral density (BMD) is significantly lower in more severe forms of OI but occasionally can be normal, especially in individuals with classic non-deforming OI with blue sclerae [Patel et al 2015].

Laboratory findings. Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, alkaline phosphatase may be elevated acutely in response to fracture.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis, as approximately 60% of probands with mild OI and 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 gonadal mosaicism.

Establishing the Diagnosis

The diagnosis of COL1A1/COL1A2-OI is established in a proband with suggestive clinical and radiographic findings by identification of a heterozygous pathogenic (or likely pathogenic) variant in COL1A1 or COL1A2 by molecular genetic testing (see Table 3).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous COL1A1 or COL1A2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

The severity of COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) ranges from perinatal lethality; individuals with severe skeletal deformities, mobility impairments, and very short stature; to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal life span.

COL1A1/COL1A2-OI has been historically classified into four more common types based on clinical presentation, radiographic features, family history, and natural history [Sillence et al 1979]. An update of the Sillence classification has been proposed and has gained some acceptance [Van Dijk & Sillence 2014, Sillence 2024]. Although this classification of COL1A1/COL1A2-OI into types is helpful in providing information about prognosis and management of a given individual, the features of different types of COL1A1/COL1A2-OI overlap and it is not always easy to categorize the extent of the clinical disorder. It is helpful to remember that the severity of clinical and radiographic features lies on a continuum and that the "types" are defined using characteristics that appear to form clinical "nodes." Interfamilial variability is apparent among individuals with the same OI type, and intrafamilial variability is apparent among individuals with the same causative variant. Nonetheless, it is reasonable to continue to think of COL1A1/COL1A2-OI in terms of these types in order to provide information about the expected natural history of the disorder.

Classic non-deforming OI with blue sclerae (previously OI type I) is characterized by blue sclerae and normal stature. A small proportion of infants with classic non-deforming OI with blue sclerae have femoral bowing at birth. The first fractures may occur at birth or with diapering, but more often, the first fractures occur when the infant begins to walk and, more importantly, to fall. In general, in OI the highest fracture rate occurs in infancy and childhood; fractures generally occur at a rate of a few to several per year and then decrease in frequency after puberty. Fracture frequency often increases again in adulthood, especially in postmenopausal women [Folkestad et al 2017]. Affected individuals may have anywhere from a few fractures to more than 100, but the fractures usually heal normally with no resulting deformity.

Most affected individuals have normal or near-normal stature but are often shorter than other members of their families and shorter than predicted based on parental heights. A large longitudinal study of individuals with COL1A1/COL1A2-OI found that the median adult height for women with classic non-deforming OI with blue sclerae was 155.14 cm, and for men it was 163.34 cm [Robinson et al 2023].

Joint hypermobility predisposes to a number of minor comorbidities. The primary clinical concern is early-onset degenerative joint disease due to malalignment of articular surfaces.

Progressive hearing loss occurs in more than 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss, but often sensorineural hearing loss develops over time. Hearing loss was rarely noted in children with this OI type.

Scoliosis affects less than one third of the individuals in this group and if present is usually mild (Cobb angle <30 degrees in all individuals) [Ben Amor et al 2013].

In their classification of OI, Sillence et al [1979] designated a subset of classic non-deforming OI with dentinogenesis imperfecta (DI) (OI type IB). DI is due to dysplastic dentin and can give rise to dental discoloration, pulp calcification, tooth fracture, and attrition. DI is also an independent risk factor for developing caries. Genotype-phenotype correlation studies showed that a small minority of individuals with classic non-deforming OI with blue sclerae caused by COL1A1 haploinsufficiency variants have DI [Ma et al 2019, Marulanda et al 2024b].

Perinatally lethal OI (previously OI type II). Abnormalities characteristic of perinatally lethal OI are evident at birth. Weight and length are small for gestational age. The sclerae are dark blue and connective tissue is extremely fragile. The skull is large for the body size and soft to palpation. Callus formation on the ribs may be palpable. Extremities are short and bowed. Hips are usually flexed and abducted in a "frog-leg" position. Although some fetuses with perinatally lethal OI die in utero or are spontaneously aborted, more typically infants die in the immediate perinatal period. Prior published data indicated that more than 60% of affected infants die on the first day and 80% die within the first week; survival beyond one year is exceedingly rare and usually involves intensive support such as continuous assisted ventilation [Byers et al 1988]. Death usually results from pulmonary insufficiency related to a small thorax, rib fractures, or flail chest because of unstable ribs. Those who survive the first few days of life may not be able to ingest sufficient calories because of respiratory distress. However, in a cohort of 18 infants with a prenatal diagnosis of OI and predicted poor prognosis followed in a specialized center, the majority survived the neonatal period and were discharged home. Twelve of these infants were prenatally predicted to have perinatally lethal OI following results of genetic testing and/or ultrasound findings. Many required respiratory and/or feeding support. The study demonstrated a lack of correlation between prenatal assessment and postnatal survival including requirement of respiratory and feeding support. The authors emphasized the need for caution during prenatal counseling, as COL1A1/COL1A2-OI can present with a variable severity that is difficult to predict prenatally [Carroll et al 2025]. Improved neonatal outcomes most likely correlate with advances in perinatal and neonatal intensive care, which has similarly impacted many skeletal disorders previously determined to be lethal.

Histologic evaluation of bone from infants with perinatally lethal OI shows marked reduction in collagen in secondary trabeculae and cortical bone [Horton et al 1980]. Cortical bone is hypercellular with large osteocytes. Trabeculae contain woven bone with large immature osteoblasts [Cole et al 1992, Cole & Dalgleish 1995].

Progressively deforming OI (previously OI type III). The diagnosis of progressively deforming OI is readily apparent at birth. Fractures are common in the newborn period, simply with handling of the infant. In some affected infants, the number and severity of rib fractures lead to death from pulmonary failure in the first few weeks or months of life.

Infants who survive this period generally fare well, although most do not walk without assistance and usually use a wheelchair or other assistance for mobility because of severe bone fragility and marked bone deformity. Affected individuals have as many as 200 fractures and progressive deformity even in the absence of obvious fracture. Progressively deforming OI is often difficult to manage orthopedically, even with intramedullary rod placement.

Growth velocity is extremely diminished and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter. A large longitudinal study of individuals with COL1A1/COL1A2-OI found that the median adult height for women with progressively deforming OI was 97.94 cm, and for men it was 118.06 cm [Robinson et al 2023].

Intellect is normal except in those with intracerebral hemorrhage (ICH), which is extremely rare. An increased risk for ICH was reported in a "small number" of individuals with COL1A2 pathogenic variants affecting exon 49, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen alpha-2(I) chain [Faqeih et al 2009].

Considerable clinical variability occurs in individuals with progressively deforming OI. Some individuals have normal-appearing teeth and facies, whereas the large majority of individuals with progressively deforming OI caused by glycine substitutions in the triple-helical domain of type I collagen alpha chains have characteristic craniofacial features including frontal bossing, triangular face, smaller and retro-positioned midface, and mandible positioned forward in relation to the cranial base, resulting in a concave facial profile [Rauch et al 2010, Andersson et al 2017, Marulanda et al 2024a]. DI and malocclusion are more common than in milder OI forms and can be associated with clinical impact and severe cosmetic concerns. Relative macrocephaly, enlarged ventricles that reflect the soft calvarium, and barrel chest deformity are observed. Usually, sclerae are blue in infancy but lighten with age. Hearing loss generally begins in the teenage years.

Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal cerebrospinal fluid flow [Cheung et al 2011, Reznikov et al 2019]. Symptoms of basilar impression become apparent with neck flexion. Findings include posterior skull or neck pain, C2 sensory deficit, tingling in the fourth and fifth digits, and numbness in the medial forearm. When swimming, affected individuals may perceive that water temperature differs below and above the umbilicus. Lhermitte sign (tingling on neck flexion) can be demonstrated at any stage. Basilar impression can cause headache with coughing, trigeminal neuralgia, loss of function of the extremities, or paresthesias. At its most severe involvement, sleep apnea and death can occur. The reported prevalence of basilar impression in individuals with OI varies between 25% and 37%. The factors reported to be associated with basilar impression were the severity of OI phenotype (more common in progressively deforming OI), presence of DI, and magnitude of short stature; platybasia was also significantly associated with basilar impression and invagination [Marulanda et al 2024a].

Common variable OI with normal sclerae (previously OI type IV) is characterized by mild-to-moderate short stature, DI, adolescent- or adult-onset hearing loss, and normal white or gray sclerae. This is the most variable form of OI, ranging from moderately severe to so mild that the diagnosis may be unrecognized.

Stature is variable and may vary markedly within the family. A large longitudinal study of individuals with COL1A1/COL1A2-OI found that the median adult height for women with common variable OI with normal sclerae was 136.95 cm, and for men it was 148.04 cm [Robinson et al 2023]. DI is common but may be mild. Sclerae are typically light blue or gray at birth but quickly lighten to near normal. Hearing loss can occur earlier than in milder forms of the disease, and basilar impression can occur rarely.

Genotype-Phenotype Correlations

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 [Ben Amor et al 2011, Zhytnik et al 2019, Sałacińska et al 2023]. 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. Similarly, COL1A2 glycine substitutions in the helical domain almost reached statistical significance for predicting common variable OI with normal sclerae, accounting for 48.1% of all pathogenic variants in this subtype of OI. All other variants were not correlated with a specific phenotype [Patel et al 2015]. Smaller studies have supported correlations between type of collagen I defect and phenotypic severity [Zhytnik et al 2019, Sałacińska et al 2023], but a clear genotype-phenotype correlation does not exist.

Classic non-deforming OI with blue sclerae almost always results from a nonsense, frameshift, or splice site COL1A1 or COL1A2 pathogenic variant that results in premature termination, decreased mRNA stability, and quantitative reduction of either pro-alpha-1(I) or pro-alpha-2(I) chains, and reduced assembly of the collagen fibril.

Perinatally lethal OI, progressively deforming OI, and common variable OI with normal sclerae almost always result from pathogenic variants that alter the structure of either pro-alpha-1(I) or pro-alpha-2(I) chains. This causes a dominant-negative effect whereby the abnormal protein is integrated into the triple helix and collagen fibril, which undergoes continuous remodeling, resulting in significantly compromised structural integrity of the bone matrix. However, there are exceptions, and phenotype should always be considered for classification of OI type and predicted outcome.

The most common pathogenic variants result in substitution of another amino acid for glycine in the triple-helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon, and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon. Glycine is the least bulky amino acid, and other substituting amino acids do not fit well into the collagen triple helix.

• Substitutions in the pro-alpha-1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain.
• For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized.
• Much more variability occurs with pathogenic variants that affect glycine residues in the pro-alpha-2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship.

The other common disease-causing variants affect splice sites. Variants that lead to exon skipping in the pro-alpha-1(I) chain beyond exon 14 and in the pro-alpha-2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from pathogenic variants in the upstream region are more variable and may lead to significant joint hypermobility.

A relatively small number of pathogenic variants that alter amino acid sequences in the carboxyl-terminal regions of both chains have been identified. These domains are used for chain association, and pathogenic variants have the capacity to destroy this property or lead to abnormalities in chain association. The phenotypic effects of pathogenic variants that affect this domain appear to be milder when they result in exclusion rather than inclusion of the chain.

Somatic mosaicism for dominant pathogenic variants has been recognized in perinatally lethal OI, progressively deforming OI, and common variable OI with normal sclerae. The phenotype of the individual with somatic mosaicism can range from no identifiable characteristics of OI to one of the mild forms. The current estimate for the incidence of somatic/gonadal mosaicism is up to 16% of families.

• Individuals with somatic mosaicism for variants that result in non-lethal forms of OI generally have no phenotypic features of OI, even when the variant is present in a majority of somatic cells.
• Somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype if the variant is present in the majority of somatic cells; otherwise, the mosaicism is generally asymptomatic.

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.

Nomenclature

Current OI nomenclature and classification systems are listed in Table 4.

The historical classification scheme of "OI congenita" and "OI tarda" was discarded because fractures at birth can be noted in mild OI and infants with severe OI may not have fractures at birth.

In classifications of genetic conditions, OI may be considered a skeletal dysplasia, a connective tissue disorder, a disorder of collagen or extracellular matrix, or a disorder of bone fragility. In the latest revision of the Nosology of Genetic Skeletal Disorders, OI is included in the osteogenesis imperfecta and bone fragility group [Unger et al 2023].

Prevalence

Considering all types, OI has a prevalence of approximately 6-7:100,000. COL1A1/COL1A2-OI comprises the largest proportion of OI, representing about 80%-85% of affected individuals in Western countries and about 60% of those in countries with a high prevalence of consanguinity [Jovanovic & Marini 2024].

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. Table 6 summarizes the molecular basis of these subtypes of OI, the mode of inheritance, the corresponding clinical OI type, and typical clinical and radiographic features.

Other Disorders and Non-Accidental Trauma

The differential diagnosis of OI depends largely on the age at which the individual is assessed [Plotkin 2004]. Clinical features that help to differentiate COL1A1/COL1A2-OI from other conditions include characteristic triangular facies, blue sclerae, joint hypermobility, dental abnormalities, and hearing loss (in adults).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with COL1A1/COL1A2-OI, the evaluations summarized in Table 9 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management focuses on supportive therapy to minimize fractures and disability, maximize function, foster independence and participation, and maintain overall health. A multidisciplinary approach to management is most beneficial, with care centered on maximizing quality of life [Marini & Dang Do 2000]. The multidisciplinary team includes specialists in the medical management of COL1A1/COL1A2-OI, clinical genetics, genetic counselor, orthopedics, rehabilitation medicine, physical therapy, occupational therapy, dentistry, otology/otolaryngology, pain management, pulmonology, gastroenterology, and mental health as needed. Current treatments for OI are symptomatically supportive and primarily focus on preventing and/or treating fractures, as well as increasing bone mass. Individuals with moderate and severe forms of OI may require surgery to correct bone deformities and fractures. In addition, bisphosphonates are commonly used for treatment of OI [Chaugule et al 2025].

Supportive therapy is individualized depending on the severity, degree of impairment, and age of the affected individual. Considerable support from medical personnel is generally required by parents caring for infants with perinatally lethal COL1A1/COL1A2-OI.

Physical medicine treatment. Physical therapy is one of the most significant therapeutic modalities for individuals with OI. An expert panel developed a consensus statement on physical rehabilitation in children and adolescents with OI to assist physical therapists, occupational therapists, and other health care professionals establish treatment goals and develop treatment plans for individuals with OI [Mueller et al 2018]. Some of the more relevant statements among other useful recommendations are listed below:

• Physical rehabilitation of infants with OI includes assessment, therapy, and caregiver education. Therapists educate caregivers on optimal and safe positioning and handling that facilitates nurturing and development while minimizing risk of fractures and deformities. Despite the most careful handling, infants and children with OI continue to fracture during infancy. Therapists and caregivers should use wide hand support, slow and gentle movements, and avoid twisting the limbs to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck, and lower body; avoid increased pressure on a single point on any long bone; when assisting to stand, do not pull excessively on an extended arm but bend down and brace a greater surface area (e.g., placing a hand behind the back and pulling gently from the front – using the arm – while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. To minimize point pressure, avoid lifting an infant by the ankle when diapering.
• Alternating positions (supine, prone, side-lying) can minimize skull and limb deformities. It is important to initiate upright sitting only once the infant has adequate head and trunk control.
• Physical and occupational therapy should be initiated to increase bone stability, improve mobility, prevent contractures and head and spinal deformity, and improve aerobic fitness and muscle strength. Physical activity provides gravitational stressors required for bone growth and remodeling. Optimal muscle function can contribute to improving motor development, mobility, functional independence, and participation. The muscles' supporting joints are strengthened by activity, and as an overall benefit, improved joint stability aids in overall well-being as pain levels are reduced and mobility is increased. Strengthening trunk muscles and extremities may decrease back pain and improve breathing capacity and trunk stability.
• Children with OI should have access to a range of mobility aids to promote participation and independence, such as orthotics for ankle instability to maximize mobility, optimize muscle function, and minimize pain and fatigue. Wheelchairs should be adjusted to meet the child's participation needs and should not replace standing and walking activities. Wheelchairs should be chosen carefully to match the size of the child. Modified automobiles for adults should be considered.

Pain management. Chronic pain requires a multidisciplinary approach, and individuals with OI report combining pharmacologic and non-pharmacologic strategies for pain relief. Nonsteroidal anti-inflammatory drugs followed by bisphosphonates are the most common treatment used, and individuals with OI report combining these treatments with physical therapy among other non-pharmacologic options [Rodriguez Celin et al 2023].

Orthopedic treatment

• Fractures are treated as they would be in unaffected children and adults (with reduction and realignment, as needed, to prevent loss of function and to interrupt refracturing cycle) [Marini & Dang Do 2000] with attention to the following:
  • The period of immobility in children with COL1A1/COL1A2-OI should be shortened as much as is practical.
  • Casts should be small and lightweight.
  • Physical therapy should begin as soon as the cast is removed to evaluate the functional impact of the fracture, promote mobility, and enhance muscle strength and bone mass.
• Long bone deformity. Intramedullary rodding remains a mainstay of orthopedic care to provide anatomic positioning of limbs to permit more normal function. Internal rods or external braces to support and stabilize deforming limbs are more successful in the milder subtypes of COL1A1/COL1A2-OI. The goal of rodding surgery is to correct long bone deformity and to reduce the fracture rate in bowed limbs. Intramedullary rodding is indicated in individuals with moderate-to-severe OI and a subset with mild OI who develop disability from recurrent fractures or progressive deformity [Rodriguez Celin et al 2020]. Well-coordinated, multidisciplinary management pre- and postoperatively, incorporating rehabilitation goals and equipment needs, ensures a quick return to functional activities and participation [Mueller et al 2018]. Progressively deforming OI may progress despite external or internal bracing.

Anesthesia requires special attention in individuals with OI, including proper positioning on the operating room table, intraoperative management, and postoperative analgesia [Liang et al 2022]. A study that evaluated 205 anesthetic procedures at a center of excellence for treating children with OI reported that anesthetic challenges (e.g., difficult airway, failure to place peripheral nerve blocks, and neuraxial anesthesia) were overall uncommon. However, some issues were more common in children with severe OI (e.g., significant blood loss, difficulty placing intravenous catheters). The reported predilection for fractures due to positioning and blood pressure cuff use was not validated [Rothschild et al 2018]. A smaller study showed similar results, with no fractures during surgical procedures associated with pressure cuff or tourniquet use, but one fracture occurred during body positioning. Due to bone fragility, care should be used during the perioperative period to prevent fractures during body positioning [Sullivan et al 2019].

Scoliosis. Although bracing can slow progression, severe COL1A1/COL1A2-OI may not respond well to conservative management and response to surgical intervention may be limited. Surgical management of severe scoliosis in individuals with OI is challenging because of early onset, curve magnitude, small stature, and bone fragility. Individuals may have complex comorbidities including respiratory and cardiac involvement. Modern medical treatment of OI, including bisphosphonates, has allowed more children to receive scoliosis treatment. When surgery for deformity correction is indicated, preoperative and intraoperative traction, osteotomy to alleviate rigid curves, and segmental pedicle screw fixation has resulted in improved results compared to other methods. The use of bone morphogenetic protein-2 to improve fusion rates has been reported; midterm outcomes of a multimodal approach in 30 individuals with different OI types showed that the surgical intervention led to a notable improvement in the major curve magnitude from 76 degrees to 36 degrees, with minimal correction loss [Hori et al 2024].

Pharmacologic treatment. Bisphosphonates do not provide a cure for OI but are the most commonly used treatment to improve bone density, especially in individuals with vertebral fractures, frequent long bone fractures, or more severe OI. In a Cochrane Collaboration review of OI treatment, bisphosphonate therapy did not appear to reduce fracture incidence, but it did affect bone density and adult height [Dwan et al 2016; RD Steiner, M Rodriguez Celin, D Basel, unpublished data].

Results from a multicenter study that used data from the Osteogenesis Imperfecta Foundation's linked clinical research centers (LCRCs) on 466 individuals with different forms of OI showed increased lumbar vertebral body density and reduced probability of fracture and scoliosis in individuals treated with bisphosphonates compared to those untreated [Bains et al 2019]. Although remodeling abnormalities are poorly characterized in adults with OI of any clinical type, the antiresorptive properties of bisphosphonate may still confer skeletal benefits, and bone density appears to be improved with bisphosphonate therapy in adults with OI. Although this is likely to be beneficial, the effect of bisphosphonates on fracture incidence cannot be confidently derived from the available data, primarily because clinical trials lack adequate power to detect an effect on fracture risk and/or the study designs lack adequate controls [Liu et al 2023].

Nitrogenous bisphosphonates (e.g., alendronate, pamidronate, zoledronic acid, and neridronate) are the most frequently used. Bisphosphonates can be administered either orally or intravenously and are generally well tolerated. The most common side effects include gastrointestinal problems when taken orally and flu-like symptoms that typically occur during the first infusion. Transient hypocalcemia may also occur. Osteonecrosis of the jaw is a rare side effect in adults but has never been reported in children. Long-term safety of bisphosphonates is under investigation but may include delayed bone union after fracture or osteotomy.

A randomized controlled clinical trial found that treatment with oral alendronate for two years in children with OI significantly decreased bone turnover and increased spine areal bone mineral density (BMD; bone mineral content measured by DXA divided by bone area in square centimeters) but was not associated with improved fracture outcomes [Ward et al 2011]. In a second study, oral risedronate increased areal BMD and reduced first and recurrent fractures in children with OI [Bishop et al 2010]. Zoledronic acid, a bisphosphonate with a longer half-life, greater potency, and more convenient dosing, has been studied in children with OI. Annual zoledronic acid infusion was compared to weekly oral alendronate; these treatments showed similar increases in vertebral BMD and were well tolerated [Lv et al 2018].

Basilar impression. Surgical treatment is only considered when symptomatic. Surgery is typically undertaken before persistent/permanent neurologic features are present. If surgery is undertaken, it should be done in a center experienced in the procedure.

Dental treatment. Given the higher risk for dental problems in individuals with OI (e.g., tooth fracture, attrition, caries, and malocclusion), the goals are maintenance of primary and permanent dentition, functional bite or occlusion, optimal gingival health, and overall appearance. However, a prudent approach is recommended, as individuals affected by OI present with specific dentoalveolar problems that may prove difficult to address. Pediatric dentists are the most knowledgeable about dentinogenesis imperfecta (DI) in children. As anxiety can be an issue with children, pre-medication for anxiolysis (e.g., nitrous oxide analgesia or midazolam) can be used in a clinic setting. Dental restorations in adults may best be done by a dentist knowledgeable about OI or a specialist in prosthetic dentistry.

Although there is no clear guideline, experts in OI dental health recommend treatments for damaged or decayed teeth in the primary dentition, such as full-coverage restorations, including stainless steel or zirconia crowns. Full-coverage restorations are recommended for the permanent dentition. Intracoronal restorations should be avoided, as they promote structural tooth loss. Simple extractions can be performed but should not be done immediately before or after intravenous bisphosphonate infusions. Individuals with OI who are taking bisphosphonates should be closely monitored by a dentist. When possible, required dental surgery should be scheduled before starting bisphosphonate treatment or after the treatment has finished. Bisphosphonate treatment should not be resumed until the surgical area has healed.

In severe OI types, orthognathic surgery is discouraged, despite the significant skeletal dysplasia present.

If warranted, orthodontic treatment can be initiated, but care must be taken with the use of orthodontic appliances due to the brittleness of the teeth. Clear aligners are a promising option for orthodontic treatment [Rousseau et al 2018].

Hearing loss. A systematic review evaluated treatment to ameliorate hearing loss in OI. Hearing aids, cochlear implants, and stapes implants are widely used. Nevertheless, their efficacy is limited, and their success rate is impacted by bone fragility and high vascularity. Middle ear surgery is currently the treatment of choice for conductive hearing loss in OI when hearing aids are no longer beneficial. However, the success rate of stapes surgery has shown variable results. The number of publications on cochlear implantation in OI is limited. However, cochlear implantation has proven mostly feasible and successful in ameliorating hearing loss in individuals with OI. While bisphosphonates are used to increase bone density in OI, it is not clear whether they reduce hearing loss [Ugarteburu et al 2022].

Ocular manifestations. Protective glasses are advised to prevent eye injury when necessary. Ocular surgery should be approached with caution [Treurniet et al 2022].

Gastrointestinal and nutrition. Provide nutrition education to support maintaining healthy weight for height and promoting bone health. Standard treatments for other gastrointestinal issues. There is a higher incidence of functional gastrointestinal symptoms, which can be challenging to manage.

Cardiovascular. Generally, standard treatments per specialist service are recommended with no additional or specific cardiovascular disease screening. There is a subset of individuals who are at higher risk, and clinical signs suggesting valvular disease, chest pain, dyspnea, or symptoms indicative of heart failure require prompt cardiovascular evaluation [Folkestad et al 2025].

Pulmonary. Cardiopulmonary complications are the leading cause of morbidity and mortality in adults with OI. Therefore, maintaining pulmonary health should be a priority, regardless of the type or severity of OI. Pulmonary lung disease can develop early in life, so children and adults with pulmonary issues may benefit from pulmonary treatment when necessary for dyspnea, chronic cough, frequent respiratory infections, and sleep apnea. Standard pediatric and adult vaccinations are recommended to prevent respiratory disease (e.g., influenzae, COVID-19, diphtheria, pneumococcal).

Mental health support through psychiatry, psychology, and social work is recommended to address potential negative effects and disease-related distress, fears, and concerns specific to the uncertainty of future bone fractures. Providers should be aware of the relationship between fracture and mood and assess mood after fractures as well as through the course of the injury to provide support as needed [Rork et al 2023].

Healthy lifestyle. People with OI benefit from a healthy lifestyle that includes safe exercise and a nutritious diet. Adequate intake of nutrients such as vitamin D and calcium is necessary to maintain bone health; however, extra-large doses of these nutrients are not recommended. Maintaining a healthy weight is important, since extra weight adds stress to the skeleton, heart, and lungs and reduces the ability to move easily. In addition, people with OI should avoid smoking, secondhand smoke, excessive alcohol, or caffeine consumption and if possible steroid medications, all of which reduce bone density [Osteogenesis Imperfecta Foundation 2013].

Management of lethal OI. Depending on the severity of the clinical presentation and family wishes, it may be appropriate to offer parents the option of allowing the infant to expire without attempting heroic interventions such as assisted ventilation. However, given that infants formerly diagnosed with perinatally lethal OI have been shown to survive the immediate perinatal period and be discharged home, it is recommended that all families be given the option to pursue medical interventions if desired. An individualized approach to neonatal care can optimize outcomes and should begin with a multidisciplinary prenatal assessment. Plans for the mode of delivery and neonatal care are developed with shared decision making and based on individualized goals of care. Neonatal management focuses on respiratory support and pain control. Nursing care should aim to minimize handling by clustering assessment and care activities and limiting unnecessary interventions. Early initiation of bisphosphonate therapy, as soon as is practical, is often recommended. Families should be supported in early parental engagement in care and education and ongoing psychosocial support. Counseling should acknowledge the inherent uncertainty of clinical outcome and remain nondirective [Carroll et al 2025].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, a multidisciplinary approach is recommended (see Table 10). 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 [Osteogenesis Imperfecta Foundation 2023].

Agents/Circumstances to Avoid

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).

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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Fertility is normal in individuals with OI. Maternal hospitalization and cesarean rates were higher in individuals with moderate or severe OI compared to women who reported mild OI. Neonates born to women with OI had a higher risk of being low birth weight and a higher rate of neonatal intensive care unit admissions. In addition, higher neonatal mortality at 28 days of life has been reported, regardless of neonatal OI status [Rao et al 2021]. In contrast, a Danish registry study reported no increased complications relative to the general population aside from an increased likelihood for cesarean section [Lykking et al 2024].

Cesarean section compared to vaginal delivery was not associated with decreased fracture rate in individuals with OI; strong predictors for choosing cesarean section were in utero fracture, maternal history of OI, and breech presentation [Bellur et al 2016]. In general, decisions about the best mode of delivery should be made on an individual basis. There are no definitive research data showing that cesarean delivery is safer than vaginal delivery in women with OI who have normal pelvic dimensions and no other significant complications.

A retrospective multicenter study concluded that both the state of pregnancy and breastfeeding increased the risk of fracture in individuals with OI in addition to a reduction in BMD [Koumakis et al 2022].

Women with OI and significant skeletal deformities and short stature should be followed closely during pregnancy at a high-risk prenatal care center. Most data support that women with OI have successful pregnancies but are at increased risk for complications. Awareness of these complications allows for adequate preconception counseling and proactive measures to reduce potential harm, as well as to recognize modifiable risk factors related to pregnancy and the postpartum period [Rao et al 2021].

Therapies Under Investigation

Several medications are being investigated for use in OI (see Figure 1). Some of the medications under investigation are already being used as off-label treatment for OI.

Figure 1.

Representation of bone remodeling and the targets for therapeutic intervention. Bisphosphonates are the archetypal treatments to increase bone density by reducing osteoclastic activity. There are several new medications that target alternate physiologic (more...)

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) [Liu et al 2024]. 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 [Orwoll et al 2014]. Teriparatide therapy was associated with increase in volumetric BMD (vBMD) at the spine and an increase in estimated vertebral strength as assessed by finite element analysis. A post-hoc evaluation of OI subgroups suggested that there were positive skeletal effects in those with classic non-deforming OI with blue sclerae but not in individuals with more severe forms of OI [Orwoll et al 2014]. Another study included 13 postmenopausal women with classic non-deforming OI with blue sclerae who had vertebral fractures during neridronate treatment [Gatti et al 2013]. The study reported a mean spine aBMD increase of 3.5% during teriparatide therapy but no changes in total hip aBMD [Gatti et al 2013]. Moreover, a larger multicenter randomized double-blind study examined the effects of teriparatide vs neridronate treatment in 98 individuals with classic non-deforming OI with blue sclerae. The mean lumbar spine aBMD change at two years was 5.1% in the teriparatide group and −1.6% in the neridronate group. The number of new fragility fractures in teriparatide and neridronate groups were not significantly different (16% and 27%, respectively) [Leali et al 2017]. Lastly, a prospective randomized controlled trial (TOPAZ, Treatment of Osteogenesis Imperfecta with Parathyroid Hormone and Zoledronic Acid; NCT03735537) is examining fracture rates in adults with a clinical diagnosis of OI, who are treated for two years with teriparatide followed by a single infusion of zoledronic acid. Participants are randomized in a 1:1 ratio to receive teriparatide and zoledronic acid or standard care. The study has completed enrollment to its target of 350 participants and is projected to report results in 2025 [Hald et al 2023].

Anti-sclerostin antibodies (e.g., romosozumab). Sclerostin is a monomeric glycoprotein secreted primarily by osteocytes and some chondrocytes. Sclerostin binds to LRP5/6 receptors and inhibits the Wnt signaling pathway, leading to a decrease in bone formation by osteoblasts [Muñoz-Garcia et al 2023]. Romosozumab is a humanized immunoglobulin G2 monoclonal antibody, FDA approved for the treatment of osteoporosis, that binds to sclerostin and prevents the inhibition of the Wnt signaling pathway. Consequently, romosozumab may promote osteogenesis and, to a lesser extent, reduce bone resorption, resulting in an increase in bone mass in cortical and trabecular bones [Miller et al 2021]. In the first report of romosozumab treatment in an osteoporotic adult with OI, improvements in BMD and bone turnover markers were reported [Uehara et al 2022]. Romosozumab is potentially an effective therapy for individuals with OI, but additional studies are needed to confirm its efficacy and safety.

Setrusumab is another monoclonal antibody that inhibits sclerostin activity. Setrusumab was evaluated in a 12-month randomized double-blind Phase IIb study in adults with OI. Ninety participants were treated with one of three available doses of setrusumab (2, 8, or 20 mg/kg). The study did not meet the primary endpoint of increasing radial trabecular vBMD measured by high-resolution peripheral CT, but total radial vBMD was increased in a dose-dependent manner. At the highest dose, spine aBMD increases for classic non-deforming OI with blue sclerae and progressively deforming / common variable OI with normal sclerae were 8.81% and 10.38%, respectively. At the highest dose, total hip and femoral neck aBMD increased in all OI types (2.48% and 3.37%, respectively). Moreover, the study showed significant increases in aBMD in the spine and total hip in all dose groups. Setrusumab injections were overall well tolerated. Two participants in the setrusumab 20 mg/kg group (anaphylaxis in 1 participant; headache and hydrocephalus in 1 participant) and two participants in the 20 mg/kg open-label group (headache and chills in 1 participant; pulmonary hypertension in 1 participant) had serious treatment-emergent adverse events considered to be related to treatment by the study investigator. Together, these positive outcomes of setrusumab in adults with OI have led to the commencement of a Phase III trial [Glorieux et al 2024]. Other clinical trials with setrusumab for adults and children with OI are also under development or in progress (see NCT05125809).

Transforming growth factor beta (TGF-β) Inhibitors (fresolimumab). In preclinical studies, excess TGF-β has been implicated as a key player in remodeling abnormalities observed in the more severe forms of OI. The inhibition of TGF-β signaling with the use of a blocking antibody was associated with improvements in bone mass, certain bone biomechanical properties, and correction of abnormal alveolar pattern of the lungs. A small Phase II trial of fresolimumab, a TGF-β neutralizing antibody, was associated with decreases in bone remodeling as assessed by plasma levels of osteocalcin. In this study, a positive effect on lumbar spine aBMD was seen in participants with common variable OI with normal sclerae but not in other more severe forms [Song et al 2022]. Larger studies are under way to further evaluate the usefulness of this approach [Liu et al 2023].

RANK ligand antibodies inhibit osteoclast maturation, and studies have shown an increase in vertebral body BMD, normalization of vertebral shape, and a reduction in vertebral compression fractures while on therapy. However, rebound hypercalcemia is a concern, and denosumab, an anti-RANKL antibody, is currently not recommended for the treatment of pediatric OI patients [Stasek et al 2024]. The therapeutic role of denosumab in adults with OI remains unclear.

Other. Investigational agents that have not advanced beyond clinical trials include cathepsin K inhibitors and human growth hormone.

Bone marrow stem cell transplantation to introduce normal mesenchymal stem cells that have the capacity to differentiate into normal osteoblasts as well as transplanted mesenchymal stromal cells, which produce factors that stimulate endogenous bone growth in individuals with OI, have been evaluated in many small trials. This therapeutic approach is under investigation and is a promising therapy for OI [Dinulescu et al 2024]. The TERCELOI clinical trial, conducted over a 2.5-year period, included two children with moderate and severe forms of OI with repeated infusions of their sib's bone marrow stem cells. Both children showed an increase in BMD and a decrease in fracture rates and chronic pain. Also, the benefits were observed at a two-year follow up after halting the therapy [Infante et al 2021]. Human fetal mesenchymal stems cells (hfMSCs) have also been used, as they might have a higher level of osteogenic upregulation and produce more calcium. The trial Boost Brittle Bones Before Birth (BOOSTB4), conducted in Sweden at the Karolinska Institute between 1 January 2016 and 31 December 2022, administered hfMSCs pre- and postnatally in children with progressively deforming OI and common variable OI with normal sclerae, has no published results; however, no complications were reported with the preliminary results on 17 participants receiving one to four doses of hfMSCs. The efficacy was yet to be evaluated [Lindgren et al 2022] (see NCT03706482).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with the milder forms of COL1A1/COL1A2-OI (classic non-deforming OI with blue sclerae and some probands with common variable OI with normal sclerae) have the disorder as the result of a pathogenic variant inherited from an affected parent.
• The proportion of individuals with COL1A1/COL1A2-OI 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 OI 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 an apparently unaffected 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, although the rate of very low levels of parental mosaicism, which can be difficult to detect in leukocyte DNA using standard molecular genetic techniques, may be higher [Pyott et al 2011, Frederiksen et al 2016].
• If the proband appears to be the only affected family member, clinical examination for features suggestive of COL1A1/COL1A2-OI (e.g., short stature, blue/gray sclerae, dentinogenesis imperfecta, joint hypermobility) and molecular genetic testing are recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members. Therefore, de novo occurrence of a COL1A1 or COL1A2 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the COL1A1 or COL1A2 pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for a COL1A1 or COL1A2 pathogenic variant may have no phenotypic features of OI or be mildly/minimally affected (see Genotype-Phenotype Correlations).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. If a parent of the proband is known to be mosaic for the pathogenic variant, the risk to the sibs is up to 50%. The penetrance in individuals heterozygous for an OI-related COL1A1 or COL1A2 pathogenic variant is 100%, although expression may vary considerably among family members with the same pathogenic variant.
• If the proband represents a simplex case and the COL1A1 or COL1A2 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to the sibs of a proband is about 1%-3% because of the significant possibility of parental gonadal (or somatic and gonadal) mosaicism [Pyott et al 2011, Chen et al 2013].
• If the parents have not been tested for the COL1A1 or COL1A2 pathogenic variant but do not have signs of COL1A1/COL1A2-OI on clinical exam, sibs of the proband are presumed to be at increased risk for COL1A1/COL1A2-OI because of the significant possibility of parental mosaicism (see Genotype-Phenotype Correlations).

Offspring of a proband. Each child of an individual with COL1A1/COL1A2-OI has a 50% chance of inheriting the COL1A1 or COL1A2 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

High-risk pregnancies

• Molecular genetic testing. Once the OI-causing variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
• Prenatal ultrasound examination performed in a center with experience in diagnosing OI, done at the appropriate gestational age, can be a valuable tool in the prenatal diagnosis of OI. Normally, ultrasound examination detects only the perinatally lethal and most severe forms of OI prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformity are present.
• Perinatally lethal OI. The bony abnormalities can first be seen by ultrasound examination by about 13 to 14 weeks' gestation. By 16 weeks' gestation, femoral length is typically delayed by two or more weeks, calvarial mineralization is essentially absent, and ribs generally have identified fractures.
• Progressively deforming OI. Limb length generally begins to fall below the growth curve at about 17 to 18 weeks' gestation; serial ultrasound examinations are required to confirm the trend.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancies. Routine prenatal ultrasound examination may identify a fetus not known to be at risk for COL1A1/COL1A2-OI with findings suggestive of OI (perinatally lethal OI or progressively deforming OI) including reduced echogenicity of fetal bones, bowed, crumpled femurs, beaded ribs, evidence of fractures, and markedly diminished calvarial mineralization. As a part of the evaluation of such findings, molecular genetic testing of COL1A1 and COL1A2 may be considered; however, inability to identify a pathogenic variant does not rule out the diagnosis of OI in the fetus.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

COL1A1 and COL1A2 encode the alpha-1 and alpha-2 chains of collagen type I, a fibril-forming collagen found in most connective tissues and abundant in bone, cornea, dermis, and tendon. Collagen type I is a heterotrimer consisting of two α-1 chains and one α-2 chain. It is initially synthesized as a pro-α chain with a propeptide at each end (N propeptide and C propeptide). The propeptides are necessary for pro-α chain association and triple-helix formation, which starts at the C-terminal propeptide and extends to the N-terminal propeptide.

Collagen type I contains a triple-helical segment of 1,014 amino acids in which glycine is in every third position and prolines preceding glycine residues are generally hydroxylated, as are some lysyl residues in the Y-position of the Gly-X-Y triplet. Glycine, the smallest amino acid, must be in the third position to allow proper chain folding.

The pathogenic variants in most families are unique; only a few recurrent variants (mostly CpG dinucleotides) are seen in more than one family.

Mechanism of disease causation. In general, the primary mechanism for disease can be viewed as either quantitative or qualitative impacts on type I collagen. Quantitative changes, which lead to loss of function, tend to have a milder phenotype when compared to qualitative changes, which impart a dominant-negative effect.

Classic non-deforming osteogenesis imperfecta (OI; quantitative, loss of function):

• Decreased production of structurally normal type I procollagen results in a reduction in the amount of bone that can be made, leading to brittle bones.
• The vast majority of disease-causing variants are premature termination codons (e.g., frameshift, nonsense, splice site variants) that result in the reduction of COL1A1 mRNA by half.

Perinatally lethal OI, progressively deforming OI, and common variable OI (qualitative, gain of function):

• Substitutions for glycine within the triple-helical domain of the pro-α chain delay triple helix formation, resulting in additional post-translation modification that prevents secretion of the assembled trimers.
• Small in-frame deletions or duplications of single amino acids or Gly-X-Y triplets and exon-skipping events may disrupt trimer assembly.
• Diminished amount of type I procollagen is secreted.
• Some of the protein in the matrix has an abnormal structure.
• Clinical consequence is influenced by the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid.
• Pathogenic variants closer to the 5' end of the protein are likely to result in milder clinical phenotypes due to chain association occurring at the C-terminal end of the chain.

Author Notes

Dr Rodriguez Celin is a pediatrician currently completing her training in Medical Genetics and Genomics at Medical College of Wisconsin. Prior, she served as an attending physician at the Skeletal Dysplasia Clinic at Garrahan Pediatric Referral Hospital in Buenos Aires and worked as a clinician-researcher at Shriners Hospital for Children, Chicago. Over the last 15 years she has been working and collaborating on several projects trying to address how osteogenesis imperfecta (OI) affects function, mobility, and quality of life. She has a special interest in pain in individuals with OI and how to address and improve management.

Dr Steiner is a pediatrician, clinical geneticist, and clinical biochemical geneticist. He trained under Dr Peter Byers at the University of Washington. Dr Steiner specializes in general genetics, inherited metabolic diseases, metabolic bone diseases, and OI. He participates in a multidisciplinary OI clinic at American Family Children's Hospital in Madison, Wisconsin, for evaluation of children who have or are suspected of having OI. Dr Steiner and the clinic are actively involved in clinical trials evaluating potential therapies for OI and other bone diseases. Dr Steiner has been caring for patients with OI and conducting research in the field for more than three decades.

Dr Basel is the Medical Director for the Clinical Genetics services for Children's Wisconsin. He is a Professor at the Medical College of Wisconsin and Chief of the Division of Genetics within the Department of Pediatrics. He is the Associate Director for the Undiagnosed and Rare Disease Program within the Mellowes Center for Genome Sciences and Precision Medicine Center. He trained under Peter Beighton at the University of Cape Town and worked as a research fellow at University of Connecticut Health Center, studying connective tissue disorders with a focus on fibrillin and type I collagen disorders.

Acknowledgments

Dr Steiner participates in a clinical trial funded by Utragenyx. He acknowledges the outstanding work of Drs Neil Paloian, Blaise Nemeth, and Lindsey Boyke and genetic counselor Peggy Modaff in the UW/AFCH OI Clinic.

Dr Rodriguez Celin appreciates the critical review of the information regarding spine surgical treatment by Dr Peter A Smith from Shriners Hospital for Children, Chicago, and the valuable review of the recommended surveillance table by Drs Fano Virginia and Ramos Mejía Rosario from Garrahan Pediatric Hospital, Buenos Aires.

Author History

Jessica Adsit, MS, CGC; Legacy Center for Maternal Fetal Medicine (2013-2019)
Donald Basel, MD (2013-present)
Peter H Byers, MD; University of Washington Health Sciences Center (2003-2013)
Melanie G Pepin, MS, CGC; University of Washington Health Sciences Center (2003-2013)
Mercedes Rodriguez Celin, MD (2025-present)
Robert D Steiner, MD (2003-present)

Revision History

• 29 May 2025 (sw) Comprehensive update posted live
• 19 September 2019 (sw) Comprehensive update posted live
• 14 February 2013 (me) Comprehensive update posted live
• 28 January 2005 (me) Review posted live
• 14 June 2003 (rs) Original submission

Literature Cited

• Anderesen CK, Al-Najami I, Liu W, Orwoll E, Folkestad L. Risk of Gastrointestinal Diseases in Osteogenesis Imperfecta: A Nationwide, Register-Based Cohort Study. Calcif Tissue Int. 2025;116:15. [PubMed: 39751887]
• Andersson K, Dahllof G, Lindahl K, Kindmark A, Grigelioniene G, Astrom E, Malmgren B. Mutations in COL1A1 and COL1A2 and dental aberrations in children and adolescents with osteogenesis imperfecta - A retrospective cohort study. PLoS One. 2017;12:e0176466. [PMC free article: PMC5428910] [PubMed: 28498836]
• Ashournia H, Johansen FT, Folkestad L, Diederichsen AC, Brixen K. Heart disease in patients with osteogenesis imperfecta - a systematic review. Int J Cardiol. 2015;196:149-57. [PubMed: 26100571]
• Bains JS, Carter EM, Citron KP, Boskey AL, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sliepka JM, Sutton VR, Lee B, Nagamani SC, Raggio CL, et al. A multicenter observational cohort study to evaluate the effects of bisphosphonate exposure on bone mineral density and other health outcomes in osteogenesis imperfecta. JBMR Plus. 2019;3:e10118. [PMC free article: PMC6524673] [PubMed: 31131341]
• Balasubramanian M, Verschueren A, Kleevens S, Luyckx I, Perik M, Schirwani S, Mortier G, Morisaki H, Rodrigus I, Van Laer L, Verstraeten A, Loeys B. Aortic aneurysm/dissection and osteogenesis imperfecta: four new families and review of the literature. Bone. 2019;121:191-5. [PubMed: 30684648]
• Bellur S, Jain M, Cuthbertson D, Krakow D, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Krischer J, Mullins M, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Sutton VR, Lee B; Members of the BBD Consortium; Nagamani SC. Cesarean delivery is not associated with decreased at-birth fracture rates in osteogenesis imperfecta. Genet Med. 2016;18:570-6. [PMC free article: PMC4818203] [PubMed: 26426884]
• Ben Amor IM, Glorieux FH, Rauch F. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011;2011:540178. [PMC free article: PMC3170785] [PubMed: 21912751]
• Ben Amor IM, Roughley P, Glorieux FH, Rauch F. Skeletal clinical characteristics of osteogenesis imperfecta caused by haploinsufficiency mutations in COL1A1. J Bone Miner Res. 2013;28:2001-7. [PubMed: 23529829]
• Bishop N, Harrison R, Ahmed F, Shaw N, Eastell R, Campbell M, Knowles E, Hill C, Hall C, Chapman S, Sprigg A, Rigby A. A randomized, controlled dose-ranging study of risedronate in children with moderate and severe osteogenesis imperfecta. J Bone Miner Res. 2010;25:32-40. [PubMed: 19580461]
• Byers PH, Tsipouras P, Bonadio JF, Starman BJ, Schwartz RC. Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet. 1988;42:237-48. [PMC free article: PMC1715253] [PubMed: 3341380]
• Carroll RS, Donenfeld P, McGreal C, Franzone JM, Kruse RW, Preedy C, Costa J, Dirnberger DR, Bober MB. Comprehensive pain management strategy for infants with moderate to severe osteogenesis imperfecta in the perinatal period. Paediatr Neonatal Pain. 2021;3:156-62. [PMC free article: PMC8975205] [PubMed: 35548555]
• Carroll RS, Little S, McGreal T, Bonner S, Willis D, Franzone JM, Campbell J, Chou M, Raymond MB, Schelhaas A, Costa J, Jain M. Most infants with prenatal osteogenesis imperfecta diagnosis and poor prognosis survive: experience of a quaternary care osteogenesis imperfecta center. JBMR Plus. 2025;9:ziaf022. [PMC free article: PMC11894799] [PubMed: 40070560]
• Chaugule S, Constantinou CK, John AA, Micha D, Eekhoff M, Gravallese E, Gao G, Shim JH. Comprehensive review of osteogenesis imperfecta: current treatments and future innovations. Hum Gene Ther. 2025;36:597-617. [PMC free article: PMC11971546] [PubMed: 39932815]
• Chen CP, Lin SP, Su YN, Chern SR, Su JW, Wang W. Prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta associated with unaffected parents and paternal gonadal mosaicism. Taiwan J Obstet Gynecol. 2013;52:106-9. [PubMed: 23548228]
• Cheung MS, Arponen H, Roughley P, Azouz ME, Glorieux FH, Waltimo-Siren J, Rauch F. Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants. J Bone Miner Res. 2011;26:405-13. [PubMed: 20721936]
• Cole WG, Dalgleish R. Perinatal lethal osteogenesis imperfecta. J Med Genet. 1995.32:284-9. [PMC free article: PMC1050377] [PubMed: 7643358]
• Cole WG, Patterson E, Bonadio J, Campbell PE, Fortune DW. The clinicopathological features of three babies with osteogenesis imperfecta resulting from the substitution of glycine by valine in the pro alpha 1 (I) chain of type I procollagen. J Med Genet. 1992;29:112-8. [PMC free article: PMC1015850] [PubMed: 1613761]
• Cremin B, Goodman H, Spranger J, Beighton P. Wormian bones in osteogenesis imperfecta and other disorders. Skeletal Radiol. 1982;8:35-8. [PubMed: 7079781]
• Dinulescu A, Pasarica AS, Carp M, Dusca A, Dijmarescu I, Pavelescu ML, Pacurar D, Ulici A. New perspectives of therapies in osteogenesis imperfecta-a literature review. J Clin Med. 2024;13:1065. [PMC free article: PMC10888533] [PubMed: 38398378]
• Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2016;10:CD005088. [PMC free article: PMC6611487] [PubMed: 27760454]
• Faqeih E, Roughley P, Glorieux FH, Rauch F. Osteogenesis imperfecta type III with intracranial hemorrhage and brachydactyly associated with mutations in exon 49 of COL1A2. Am J Med Genet A. 2009;149A:461-5. [PubMed: 19208385]
• Folkestad L, Hald JD, Canudas-Romo V, Gram J, Hermann AP, Langdahl B, Abrahamsen B, Brixen K. Mortality and causes of death in patients with osteogenesis imperfecta: a register-based nationwide cohort study. J Bone Miner Res. 2016;31:2159-66. [PubMed: 27345018]
• Folkestad L, Hald JD, Ersboll AK, Gram J, Hermann AP, Langdahl B, Abrahamsen B, Brixen K. Fracture rates and fracture sites in patients with osteogenesis imperfecta: a nationwide register-based cohort study. J Bone Miner Res. 2017;32:125-34. [PubMed: 27448250]
• Folkestad L, Prakash SK, Nagamani SCS, Andersen NH, Carter E, Hald JD, Johnson RJ, Langdahl B, Perfetto EM, Raggio C, Ralston SH, Sandhaus RA, Semler O, Tosi L, Orwoll E. Cardiovascular disease in adults with osteogenesis imperfecta: clinical characteristics, care recommendations, and research priorities identified using a modified Delphi technique. J Bone Miner Res. 2025;40:211-21. [PMC free article: PMC11789389] [PubMed: 39665364]
• Frederiksen AL, Duno M, Johnsen IB, Nielsen MF, Krøigård AB. Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2. Clin Case Rep. 2016;4:972-8. [PMC free article: PMC5054473] [PubMed: 27761249]
• Gatti D, Rossini M, Viapiana O, Povino MR, Liuzza S, Fracassi E, Idolazzi L, Adami S. Teriparatide treatment in adult patients with osteogenesis imperfecta type I. Calcif Tissue Int. 2013;93:448-52. [PubMed: 23907723]
• Glorieux FH, Langdahl B, Chapurlat R, De Beur SJ, Sutton VR, Poole KES, Dahir KM, Orwoll ES, Willie BM, Mikolajewicz N, Zimmermann E, Hosseinitabatabaei S, Ominsky MS, Saville C, Clancy J, MacKinnon A, Mistry A, Javaid MK. Setrusumab for the treatment of osteogenesis imperfecta: 12-month results from the phase 2b asteroid study. J Bone Miner Res. 2024;39:1215-28. [PMC free article: PMC11371902] [PubMed: 39012717]
• Hald JD, Keerie C, Weir CJ, Javaid MK, Lam W, Osborne P, Walsh J, Langdahl BL, Ralston SH. Protocol of a randomised trial of teriparatide followed by zoledronic acid to reduce fracture risk in adults with osteogenesis imperfecta. BMJ Open. 2023;13:e078164. [PMC free article: PMC10668140] [PubMed: 37993151]
• Hori Y, McDonald TC, Thornley P, Almeida da Silva LC, Kaymaz B, Rogers KJ, Yorgova PK, Bober MB, Carroll R, Kruse RW, Franzone JM, Shah SA. Midterm outcomes of multimodal approach to treating severe scoliosis in patients with osteogenesis imperfecta. J Am Acad Orthop Surg. 2024;32:e951-e960. [PubMed: 38996209]
• Horton WA, Dockery N, Sillence D, Rimoin DL. An embedding method for histochemical studies of undecalcified skeletal growth plate. Stain Technol. 1980;55:19-29. [PubMed: 6158142]
• Infante A, Gener B, Vazquez M, Olivares N, Arrieta A, Grau G, Llano I, Madero L, Bueno AM, Sagastizabal B, Gerovska D, Arauzo-Bravo MJ, Astigarraga I, Rodriguez CI. Reiterative infusions of MSCs improve pediatric osteogenesis imperfecta eliciting a pro-osteogenic paracrine response: TERCELOI clinical trial. Clin Transl Med. 2021;11:e265. [PMC free article: PMC7805402] [PubMed: 33463067]
• Jovanovic M, Marini JC. Update on the Genetics of Osteogenesis Imperfecta. Calcif Tissue Int. 2024;115:891-914. [PMC free article: PMC11607015] [PubMed: 39127989]
• Khan SI, Yonko EA, Carter EM, Dyer D, Sandhaus RA, Raggio CL. Cardiopulmonary Status in Adults with Osteogenesis Imperfecta: Intrinsic Lung Disease May Contribute More Than Scoliosis. Clin Orthop Relat Res. 2020;478:2833-43. [PMC free article: PMC7899416] [PubMed: 32649370]
• Koumakis E, Cormier-Daire V, Dellal A, Debernardi M, Cortet B, Debiais F, Javier RM, Thomas T, Mehsen-Cetre N, Cohen-Solal M, Fontanges E, Laroche M, Porquet-Bordes V, Marcelli C, Benachi A, Briot K, Roux C, Cormier C. Osteogenesis Imperfecta: characterization of fractures during pregnancy and post-partum. Orphanet J Rare Dis. 2022;17:22. [PMC free article: PMC8796450] [PubMed: 35090500]
• Kruger KM, Caudill A, Rodriguez Celin M, Nagamani SCS, Shapiro JR, Steiner RD, Bober MB, Hart T, Cuthbertson D, Krischer J, Byers PH, Durigova M, Glorieux FH, Rauch F, Sutton VR, Lee B, Rush ET, Smith PA, Harris GF. Mobility in osteogenesis imperfecta: a multicenter North American study. Genet Med. 2019;21:2311-8. [PMC free article: PMC7401984] [PubMed: 30918359]
• Leali PT, Balsano M, Maestretti G, Brusoni M, Amorese V, Ciurlia E, Andreozzi M, Caggiari G, Doria C. Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study. Clin Cases Miner Bone Metab. 2017;14:153-6. [PMC free article: PMC5726200] [PubMed: 29263724]
• Legare JM, Basel D. What the pediatric endocrinologist needs to know about skeletal dysplasia, a primer. Front Pediatr. 2023;11:1229666. [PMC free article: PMC10477785] [PubMed: 37675393]
• Liang X, Chen P, Chen C, Che W, Yang Y, Tan Z, Li H, Zhou Y, Yin S, To MK, Niu Q. Comprehensive risk assessments and anesthetic management for children with osteogenesis imperfecta: A retrospective review of 252 orthopedic procedures over 5 years. Paediatr Anaesth. 2022;32:851-61. [PubMed: 35384138]
• Lindgren P, Chitty LS, David A, Ek S, Ekblad Nordberg A, Goos A, Kublickas M, Oepkes D, Sagar R, Verweij J, Walther-Jallow L, Westgren M, Astrom E, Götherström C, Consortium B. OC09.07: Boost brittle bones before birth (BOOSTB4): a clinical trial of prenatal stem cell transplantation for treatment of osteogenesis imperfecta. Ultrasound Obstet Gynecol. 2022;60:28-9.
• Liu W, Lee B, Nagamani SCS, Nicol L, Rauch F, Rush ET, Sutton VR, Orwoll E. Approach to the Patient: Pharmacological Therapies for Fracture Risk Reduction in Adults With Osteogenesis Imperfecta. J Clin Endocrinol Metab. 2023;108:1787-96. [PMC free article: PMC10271227] [PubMed: 36658750]
• Liu W, Nicol L, Orwoll E. Current and Developing Pharmacologic Agents for Improving Skeletal Health in Adults with Osteogenesis Imperfecta. Calcif Tissue Int. 2024;115:805-11. [PubMed: 38472351]
• LoTurco HM, Carter EM, McInerney DE, Raggio CL. Patient-reported prevalence of gastrointestinal issues in the adult skeletal dysplasia population with a concentration on osteogenesis imperfecta. Am J Med Genet A. 2022;188:1435-42. [PubMed: 35106923]
• Lv F, Liu Y, Xu X, Song Y, Li L, Jiang Y, Wang O, Xia W, Xing X. Zoledronic acid versus alendronate in the treatment of children with osteogenesis imperfecta: a 2-year clinical study. Endocr Pract. 2018;24:179-88. [PubMed: 29466057]
• Lykking EK, Damkier P, Kammerlander H, Broe A, Folkestad L. Pregnancy complications and birth outcome in patients with osteogenesis imperfecta - A population-based register study. Bone. 2024;187:117202. [PubMed: 39002839]
• Lyster ML, Hald JD, Rasmussen ML, Grauslund J, Folkestad L. Risk of eye diseases in osteogenesis imperfecta - A nationwide, register-based cohort study. Bone. 2022;154:116249. [PubMed: 34728432]
• Ma MS, Najirad M, Taqi D, Retrouvey JM, Tamimi F, Dagdeviren D, Glorieux FH, Lee B, Sutton VR, Rauch F, Esfandiari S. Caries prevalence and experience in individuals with osteogenesis imperfecta: A cross-sectional multicenter study. Spec Care Dentist. 2019;39:214-9. [PMC free article: PMC6402806] [PubMed: 30758072]
• Machol K, Hadley TD, Schmidt J, Cuthbertson D, Traboulsi H, Silva RC, Citron C, Khan S, Citron K, Carter E, Brookler K, Shapiro JR, Steiner RD, Byers PH, Glorieux FH, Durigova M, Smith P, Bober MB, Sutton VR, Lee BH; Members of the BBD Consortium; Nagamani SCS, Raggio C. Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study. Am J Med Genet A. 2020;182:697-704. [PMC free article: PMC7385724] [PubMed: 31876392]
• Marini JC, Dang Do AN. Osteogenesis Imperfecta. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrere B, Levy M, McGee EA, McLachlan R, Muzumdar R, Purnell J, Sahay R, Shah AS, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, eds. Endotext. South Dartmouth (MA). 2000.
• Marlowe A, Pepin MG, Byers PH. Testing for osteogenesis imperfecta in cases of suspected non- accidental injury. J Med Genet. 2002;39:382-6. [PMC free article: PMC1735162] [PubMed: 12070242]
• Martins G, Siedlikowski M, Coelho AKS, Rauch F, Tsimicalis A. Bladder and bowel symptoms experienced by children with osteogenesis imperfecta. J Pediatr (Rio J). 2020;96:472-8. [PMC free article: PMC9432044] [PubMed: 30802423]
• Marulanda J, Retrouvey JM, Lee B, Sutton VR, Members of the B, Rauch F, Briner M. Cranio-cervical abnormalities in moderate-to-severe osteogenesis imperfecta - Genotypic and phenotypic determinants. Orthod Craniofac Res. 2024a;27:237-43. [PMC free article: PMC11198608] [PubMed: 37642979]
• Marulanda J, Retrouvey JM, Rauch F. Skeletal and Non-skeletal Phenotypes in Children with Osteogenesis Imperfecta. Calcif Tissue Int. 2024b;115:923-30. [PubMed: 39167113]
• Miller SA, St Onge EL, Whalen KL. Romosozumab: A Novel Agent in the Treatment for Postmenopausal Osteoporosis. J Pharm Technol. 2021;37:45-52. [PMC free article: PMC7809324] [PubMed: 34752536]
• Moussa S, Rocci J, Hamdy R, Grauslund J, Lyster ML, Tsimicalis A. Ophthalmological screening guidelines for individuals with Osteogenesis Imperfecta: a scoping review. Orphanet J Rare Dis. 2024;19:316. [PMC free article: PMC11363591] [PubMed: 39215363]
• Mueller B, Engelbert R, Baratta-Ziska F, Bartels B, Blanc N, Brizola E, Fraschini P, Hill C, Marr C, Mills L, Montpetit K, Pacey V, Molina MR, Schuuring M, Verhille C, de Vries O, Yeung EHK, Semler O. Consensus statement on physical rehabilitation in children and adolescents with osteogenesis imperfecta. Orphanet J Rare Dis. 2018;13:158. [PMC free article: PMC6131938] [PubMed: 30201006]
• Muñoz-Garcia J, Heymann D, Giurgea I, Legendre M, Amselem S, Castañeda B, Lézot F, William Vargas-Franco J. Pharmacological options in the treatment of osteogenesis imperfecta: A comprehensive review of clinical and potential alternatives. Biochem Pharmacol. 2023;213:115584. [PubMed: 37148979]
• Murali CN, Cuthbertson D, Slater B, Nguyen D, Turner A, Harris G, Sutton VR, Lee B; Members of the BBD Consortium; Nagamani SCS. Pediatric Outcomes Data Collection Instrument is a Useful Patient-Reported Outcome Measure for Physical Function in Children with Osteogenesis Imperfecta. Genet Med. 2020;22:581-9. [PMC free article: PMC7060104] [PubMed: 31772349]
• Nishimura G, Handa A, Miyazaki O, Tsujioka Y, Murotsuki J, Sawai H, Yamada T, Kozuma Y, Takahashi Y, Ozawa K, Pooh R, Sase M. Prenatal diagnosis of bone dysplasias. Br J Radiol. 2023;96:20221025. [PMC free article: PMC10321247] [PubMed: 37351952]
• Orwoll ES, Shapiro J, Veith S, Wang Y, Lapidus J, Vanek C, Reeder JL, Keaveny TM, Lee DC, Mullins MA, Nagamani SC, Lee B. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest. 2014;124:491-8. [PMC free article: PMC3904621] [PubMed: 24463451]
• Osteogenesis Imperfecta Foundation. Adult health toolkit: information for adults living OI, their families, and medical professionals. 2023. Available online. Accessed 5-20-25.
• Osteogenesis Imperfecta Foundation. Introduction to osteogenesis imperfecta: a guide for medical professionals, individuals and families affected by OI. Reviewed by Bober MB; Thomas Jefferson Medical College; AI duPont Hospital for Children. 2013. Available online. Accessed 5-20-25.
• Patel RM, Nagamani SC, Cuthbertson D, Campeau PM, Krischer JP, Shapiro JR, Steiner RD, Smith PA, Bober MB, Byers PH, Pepin M, Durigova M, Glorieux FH, Rauch F, Lee BH, Hart T, Sutton VR. A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers. Clin Genet. 2015;87:133-40. [PMC free article: PMC5529599] [PubMed: 24754836]
• Pepin MG, Byers PH. What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases. Am J Med Genet C Semin Med Genet. 2015;169:307-13. [PubMed: 26566591]
• Plotkin H. Syndromes with congenital brittle bones. BMC Pediatr. 2004;4:16. [PMC free article: PMC516444] [PubMed: 15339338]
• Pyott SM, Pepin MG, Schwarze U, Yang K, Smith G, Byers PH. Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. Genet Med. 2011;13:125-30. [PubMed: 21239989]
• Rao R, Cuthbertson D, Nagamani SCS, Sutton VR, Lee BH, Krischer J, Krakow D. Pregnancy in women with osteogenesis imperfecta: pregnancy characteristics, maternal, and neonatal outcomes. Am J Obstet Gynecol MFM. 2021;3:100362. [PMC free article: PMC9448563] [PubMed: 33781976]
• Rauch F, Lalic L, Roughley P, Glorieux FH. Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfecta. J Bone Miner Res. 2010;25:1367–74. [PubMed: 19929435]
• Reznikov N, Dagdeviren D, Tamimi F, Glorieux F, Rauch F, Retrouvey JM. Cone-beam computed tomography of osteogenesis imperfecta types III and IV: Three-dimensional evaluation of craniofacial features and upper airways. JBMR Plus. 2019;3:e10124. [PMC free article: PMC6636768] [PubMed: 31346560]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Robinson ME, Rauch F. Mendelian bone fragility disorders. Bone. 2019;126:11-17. [PubMed: 31039433]
• Robinson ME, Rauch D, Glorieux FH, Rauch F. Standardized growth charts for children with osteogenesis imperfecta. Pediatr Res. 2023;94:1075-82. [PubMed: 36922619]
• Rodriguez Celin M, Kruger KM, Caudill A, Murali CN, Nagamani SCS; Members of the Brittle Bone Disorders Consortium (BBDC); Smith PA, Harris GF. A multicenter study to evaluate pain characteristics in osteogenesis imperfecta. Am J Med Genet A. 2023;191:160-72. [PMC free article: PMC10399129] [PubMed: 36271817]
• Rodriguez Celin M, Kruger KM, Caudill A, Nagamani SCS; Brittle Bone Disorders Consortium (BBDC); Linked Clinical Research Centers (LCRC); Harris GF, Smith PA. A Multicenter Study of Intramedullary Rodding in Osteogenesis Imperfecta. JB JS Open Access. 2020;5:e20.00031. [PMC free article: PMC7489747] [PubMed: 32984750]
• Rork WC, Hertz AG, Wiese AD, Kostick KM, Nguyen D, Schneider SC, Shepherd WS, Cho H, Murali CN, Lee B, Sutton VR, Storch EA, et al. A qualitative exploration of patient perspectives on psychosocial burdens and positive factors in adults with osteogenesis imperfecta. Am J Med Genet A. 2023;191:2267-75. [PMC free article: PMC10525007] [PubMed: 37317786]
• Rothschild L, Goeller JK, Voronov P, Barabanova A, Smith P. Anesthesia in children with osteogenesis imperfecta: retrospective chart review of 83 patients and 205 anesthetics over 7 years. Paediatr Anaesth. 2018;28:1050-8. [PubMed: 30295359]
• Rousseau M, Retrouvey JM; Members of the Brittle Bone Disease Consortium. Osteogenesis imperfecta: potential therapeutic approaches. PeerJ. 2018;6:e5464. [PMC free article: PMC6100848] [PubMed: 30128210]
• Sałacińska K, Pinkier I, Rutkowska L, Chlebna-Sokół D, Jakubowska-Pietkiewicz E, Michałus I, Kępczyński Ł, Salachna D, Wieczorek-Cichecka N, Piotrowicz M, Chilarska T, Jamsheer A, Matusik P, Wilk M, Petriczko E, Giżewska M, Stecewicz I, Walczak M, Rybak-Krzyszkowska M, Lewiński A, Gach A. NGS analysis of collagen type I genes in Polish patients with Osteogenesis imperfecta: a nationwide multicenter study. Front Endocrinol (Lausanne). 2023;14:1149982. [PMC free article: PMC10556695] [PubMed: 37810882]
• Santos F, McCall AA, Chien W, Merchant S. Otopathology in Osteogenesis Imperfecta. Otol Neurotol. 2012;33:1562-6. [PMC free article: PMC3498599] [PubMed: 22996160]
• Semler O, Cheung MS, Glorieux FH, Rauch F. Wormian bones in osteogenesis imperfecta: Correlation to clinical findings and genotype. Am J Med Genet A. 2010;152A:1681-7. [PubMed: 20583157]
• Sillence DO. A Dyadic Nosology for Osteogenesis Imperfecta and Bone Fragility Syndromes 2024. Calcif Tissue Int. 2024;115:873-90. [PMC free article: PMC11607092] [PubMed: 38942908]
• Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16:101-16. [PMC free article: PMC1012733] [PubMed: 458828]
• Song IW, Nagamani SCS, Nguyen D, et al. Targeting TGF-β for treatment of osteogenesis imperfecta. J Clin Invest. 2022;132: e152571. [PMC free article: PMC8970679] [PubMed: 35113812]
• Stasek S, Zaucke F, Hoyer-Kuhn H, Etich J, Reincke S, Arndt I, Rehberg M, Semler O. Osteogenesis imperfecta: shifting paradigms in pathophysiology and care in children. J Pediatr Endocrinol Metab. 2024;38:1-15. [PubMed: 39670712]
• Steiner RD, Pepin M, Byers PH. Studies of collagen synthesis and structure in the differentiation of child abuse from osteogenesis imperfecta. J Pediatr. 1996;128:542-7. [PubMed: 8618190]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sullivan BT, Margalit A, Garg VS, Njoku DB, Sponseller PD. Incidence of Fractures From Perioperative Blood Pressure Cuff Use, Tourniquet Use, and Patient Positioning in Osteogenesis Imperfecta. J Pediatr Orthop. 2019;39:e68-e70. [PubMed: 29189536]
• Swezey T, Reeve BB, Hart TS, Floor MK, Dollar CM, Gillies AP, Tosi LL. Incorporating the patient perspective in the study of rare bone disease: insights from the osteogenesis imperfecta community. Osteoporos Int. 2019;30:507-11. [PMC free article: PMC6449303] [PubMed: 30191258]
• Swinnen FK, Dhooge IJ, Coucke PJ, D'Eufemia P, Zardo F, Garretsen TJ, Cremers CW, De Leenheer EM. Audiologic phenotype of osteogenesis imperfecta: use in clinical differentiation. Otol Neurotol. 2012;33:115-22. [PubMed: 22143304]
• Tam A, Chen S, Schauer E, Grafe I, Bandi V, Shapiro JR, Steiner RD, Smith PA, Bober MB, Hart T, Cuthbertson D, Krischer J, Mullins M, Byers PH, Sandhaus RA, Durigova M, Glorieux FH, Rauch F, Reid Sutton V, Lee B; Members of the Brittle Bone Disorders Consortium; Rush ET, Nagamani SCS. A multicenter study to evaluate pulmonary function in osteogenesis imperfecta. Clin Genet. 2018;94:502-11. [PMC free article: PMC6235719] [PubMed: 30152014]
• Tosi LL, Oetgen ME, Floor MK, Huber MB, Kennelly AM, McCarter RJ, Rak MF, Simmonds BJ, Simpson MD, Tucker CA, McKiernan FE. Initial report of the osteogenesis imperfecta adult natural history initiative. Orphanet J Rare Dis. 2015;10:146. [PMC free article: PMC4650321] [PubMed: 26578084]
• Treurniet S, Burger P, Ghyczy EAE, Verbraak FD, Curro-Tafili KR, Micha D, Bravenboer N, Ralston SH, de Vries R, Moll AC, Eekhoff EMW. Ocular characteristics and complications in patients with osteogenesis imperfecta: a systematic review. Acta Ophthalmol. 2022;100:e16-e28. [PMC free article: PMC9290710] [PubMed: 34009739]
• Turkalj M, Miranović V, Lulić-Jurjević R, Gjergja Juraški R, Primorac D. Cardiorespiratory complications in patients with osteogenesis imperfecta. Paediatria Croatica. 2017;61:106-112
• Uehara M, Y. Nakamura, M. Nakano, A. Miyazaki, T. Suzuki, J. Takahashi. Efficacy of romosozumab for osteoporosis in a patient with osteogenesis imperfecta: A case report. 2022 [PubMed: 34491363]
• Ugarteburu M, Cardoso L, Richter CP, Carriero A. Treatments for hearing loss in osteogenesis imperfecta: a systematic review and meta-analysis on their efficacy. Sci Rep. 2022;12:17125. [PMC free article: PMC9556526] [PubMed: 36224204]
• Unger S, Ferreira CR, Mortier GR, Ali H, Bertola DR, Calder A, Cohn DH, Cormier-Daire V, Girisha KM, Hall C, Krakow D, Makitie O, Mundlos S, Nishimura G, Robertson SP, Savarirayan R, Sillence D, Simon M, Sutton VR, Warman ML, Superti-Furga A. Nosology of genetic skeletal disorders: 2023 revision. Am J Med Genet A. 2023;191:1164-209. [PMC free article: PMC10081954] [PubMed: 36779427]
• van Dijk FS, Huizer M, Kariminejad A, Marcelis CL, Plomp AS, Terhal PA, Meijers-Heijboer H, Weiss MM, van Rijn RR, Cobben JM, Pals G. Complete COL1A1 allele deletions in osteogenesis imperfecta. Genet Med. 2010;12:736-41. [PubMed: 21113976]
• Van Dijk FS, Sillence DO. Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A. 2014;164A:1470-81. [PMC free article: PMC4314691] [PubMed: 24715559]
• Verdonk SJE, Storoni S, Micha D, et al. Is osteogenesis imperfecta associated with cardiovascular abnormalities? A systematic review of the literature. Calcif Tissue Int. 2024;114:210-21. [PMC free article: PMC10902066] [PubMed: 38243143]
• Ward LM, Rauch F, Whyte MP, D'Astous J, Gates PE, Grogan D, Lester EL, McCall RE, Pressly TA, Sanders JO, Smith PA, Steiner RD, Sullivan E, Tyerman G, Smith-Wright DL, Verbruggen N, Heyden N, Lombardi A, Glorieux FH. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab. 2011;96:355-64. [PubMed: 21106710]
• Zarate YA, Clingenpeel R, Sellars EA, Tang X, Kaylor JA, Bosanko K, Linam LE, Byers PH. 2016. COL1A1 and COL1A2 sequencing results in cohort of patients undergoing evaluation for potential child abuse. Am J Med Genet Part A. 170:1858–62. [PubMed: 27090748]
• Zhytnik L, Maasalu K, Pashenko A, Khmyzov S, Reimann E, Prans E, Koks S, Martson A. COL1A1/2 Pathogenic Variants and Phenotype Characteristics in Ukrainian Osteogenesis Imperfecta Patients. Front Genet. 2019;10:722. [PMC free article: PMC6696896] [PubMed: 31447884]