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COL1A1- and COL1A2-Related Osteogenesis Imperfecta

Synonyms: Brittle Bone Disease, OI

, MD, , MD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: May 29, 2025.

Estimated reading time: 1 hour, 16 minutes

Summary

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.

Diagnosis

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

Table 1.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Clinical Findings by Type

TypeSeverityFracturesBone DeformityStatureDIScleraeHearing Loss
Classic non-deforming OI w/blue sclerae
(OI type I)
MildFew to 100UncommonNormal or slightly short for familyRareBlue or grayRare in childhood, frequent in adulthood (more frequent from 3rd decade of life)
Perinatally lethal OI
(OI type II)
Perinatal lethalMultiple rib fractures, minimal calvarial mineralization, platyspondyly, marked compression of long bonesSevereSeverely short+Dark blueNA
Progressively deforming OI
(OI type III)
SevereThin ribs, platyspondyly, thin gracile bones w/many fractures, "popcorn" epiphyses commonModerate to severeVery short+BlueLess frequent but starts earlier
Common variable OI w/normal sclerae
(OI type IV)
Moderate to mildMultipleMild to moderateVariably short±Normal to grayLess frequent but starts earlier

DI = dentinogenesis imperfecta; NA = not applicable; OI = osteogenesis imperfecta

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].

Table 2.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Radiographic Findings by Type

TypeSeveritySkullSpineExtremitiesOther
Classic non-deforming OI w/blue sclerae
(OI type I)
MildVariable presence of wormian bones (35%)Codfish vertebrae (adults)Thin cortices
  • Osteopenia, slender bones
  • Intrauterine long bone fractures or bowing are very rare.
Perinatally lethal OI
(OI type II)
Perinatal lethalUndermineralization, plaques of calcificationPlatyspondyly
  • Severely deformed
  • Broad, crumpled, bent femurs
  • Narrow thorax w/beaded ribs (pathognomonic)
  • Prenatal shortening, bowing, & fractures w/severe undermodeling of long bones (thick & crumpled)
Progressively deforming OI
(OI type III)
Severe
  • Wormian bones present in 96%
  • Platybasia present in 70%
Codfish vertebrae, kyphoscoliosisFlared metaphyses ("popcorn"-like appearance in childhood), bowing, thin cortices
  • Thin ribs, severe osteoporosis w/defective calvarial ossification & bowing of long bones
  • In utero & perinatal fractures frequent
Common variable OI w/normal sclerae
(OI type IV)
Intermediate
  • Wormian bones present in 78%
  • Platybasia present in 20%
Codfish vertebraeThin corticesFractures may occur in 3rd trimester & occasionally in perinatal period

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).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of COL1A1/COL1A2-OI, molecular genetic testing approaches can include concurrent gene testing or use of a multigene panel.

  • Concurrent gene testing. Sequence analysis of COL1A1 and COL1A2 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • A multigene panel that includes COL1A1, COL1A2, and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 3).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by bone fragility and/or skeletal dysplasia, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 3.

Molecular Genetic Testing Used in COL1A1- and COL1A2-Related Osteogenesis Imperfecta

Gene 1, 2Proportion of OI Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 3 Identified by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
COL1A1 ~5%-70% 6>95% 71%-2% 8
COL1A2 ~5%-30 6>95% 71%-2% 8
1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on variants detected in these genes.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

PH Byers, personal communication

7.

Sequence analysis of COL1A1 and COL1A2 complementary DNA to detect pathogenic variants in the coding sequence and sequence analysis of COL1A1 and COL1A2 genomic DNA to detect pathogenic variants that alter either sequence or stability of messenger RNA identify close to 100% of pathogenic variants in these two genes.

8.

Van Dijk et al [2010] and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

Clinical Characteristics

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.

Other Considerations

Low bone mass or osteoporosis. Bone mineral density (BMD) is usually low in individuals with COL1A1/COL1A2-OI but can be normal, especially in individuals with classic non-deforming OI with blue sclerae. A large multicenter study of individuals with OI showed that in those with classic non-deforming OI with blue sclerae, lumbar spine (LS) areal BMD (aBMD) tended to be lower in individuals with more severe forms of COL1A1/COL1A2-OI. Average LS aBMD z score was around −2 to −3, but LS aBMD was relatively similar in age groups including age zero to three years and age four to eight years, which could be secondary to early and widespread use of bisphosphonates, which increases and/or preserves BMD, in progressively deforming OI and common variable OI with normal sclerae. Beyond age eight years the LS aBMD z scores were significantly lower in individuals with progressively deforming OI as compared to those with classic non-deforming OI with blue sclerae and common variable OI with normal sclerae; in the age group nine to 11 years, the mean LS aBMD z scores (one standard deviation [SD]) in classic non-deforming, progressively deforming, and common variable OI types were −1.52 (0.99), −2.79 (1.67), and −1.84 (1.09), respectively. Between ages 12 and 18 years, there was an increase in LS aBMD in those with classic non-deforming OI during puberty, whereas those with progressively deforming OI had a decline. The mean LS aBMD z scores (SD) in the teenage group for classic non-deforming OI with blue sclerae, progressively deforming OI, and common variable OI with normal sclerae were −1.4 (1.35), −4.33 (3.38), and −2.29 (1.37), respectively [Patel et al 2015]. In another study including 192 children and adolescents with COL1A1/COL1A2-OI, compared with individuals with pathogenic substitutions in the helical domain, individuals with COL1A1 haploinsufficiency on average had higher LS aBMD, and in the whole population of affected individuals, the average LS aBMD z score was higher by 0.6 (95% confidence interval: 0.2-1.0) in girls than in boys [Rauch et al 2010].

Growth. In addition to slow linear growth, infants with severe OI may be poor feeders due to low appetite from fractures or pain, breathing difficulties, reflux, or a weak sucking reflex [Robinson et al 2023]. On the other hand, infants with severe forms of OI may have decreased activity, lower caloric demand, and limited skeletal growth compared to age-matched controls. In these instances, weight gain may be appropriate for linear growth [Carroll et al 2021]. However, it can be difficult to differentiate between inadequate caloric intake contributing to growth deficiency and slow linear growth related to OI. A thorough clinical evaluation, nutritional assessment, and observation of longitudinal growth can distinguish slow linear growth related to OI and inadequate weight gain. Standardized OI type- and sex-specific growth charts have been developed [Robinson et al 2023] and should be used to assess the growth of individuals with OI from infancy to adulthood (see height and weight charts).

Chronic pain. In a large multicenter study, more than 40% of individuals with OI reported experiencing chronic pain, with similar frequency across OI types. Chronic pain can be complex and multifactorial and associated with both fractures and nonspecific myofascial pain. Back pain was the most commonly reported, followed by pain in multiple bones and joints. OI-related chronic pain limits ability to walk and to participate in sports and social activities and results in more missed school or work per year compared to those without chronic pain. Pain interference and intensity increase with age; chronic pain is reported in more than 70% of older individuals with OI [Rodriguez Celin et al 2023].

Facial features. Infants and children with OI are often described as having a triangular face. The skull is relatively large compared to body size.

Other skeletal problems. Other than recurrent fractures and long bone deformity, individuals with OI may also have progressive scoliosis, joint hypermobility, flat feet, early-onset arthritis, non-inflammatory arthralgia, and myofascial pain. The incidence of scoliosis is greater in those with severe OI than milder phenotypes. Onset of OI-related scoliosis is earlier and progression is more rapid than idiopathic scoliosis.

Skin. Easy bruising is a frequent observation in individuals with OI. This is believed to be caused by microvascular fragility and poor microstructural support of the connective tissues.

Hearing loss is reported in 28% of individuals with COL1A1/COL1A2-OI. The overall prevalence of hearing loss was not significantly different between OI subtypes (32% in classic non-deforming OI with blue sclerae, 27% in progressively deforming OI, and 21% in common variable OI with normal sclerae). Conductive hearing loss (CHL), sensorineural hearing loss (SNHL), and mixed hearing loss (MHL) are reported. CHL has been attributed to otosclerosis-like lesions in the temporal bones including at the oval window, leading to fixation of the footplate of the stapes. Hearing impairment in some individuals progresses from CHL to MHL [Santos et al 2012, Swinnen et al 2012]. CHL was found in 43% of affected individuals, pure SNHL in 32%, and MHL in 24%. Overall, CHL was the most predominant form in individuals younger than age 20 years and accounted for 85% of hearing loss in this age group. SNHL and MHL were observed after age 20 years. Prevalence of hearing loss increases with age in individuals with classic non-deforming OI with blue sclerae but not in progressively deforming OI and common variable OI with normal sclerae; in these types, the proportion with hearing impairment was significantly higher in the first decade of life. In individuals with hearing loss, 45% had unilateral and 55% had bilateral loss. Most individuals had mild hearing loss (66.6%), followed by moderate (22.7%) and severe or profound (10.6%) [Machol et al 2020].

Ocular manifestations. Alterations in collagen type I affect multiple structural components of the eye. Decreased thickness of the cornea and sclera cause ocular manifestations including blue sclerae. Most eye problems reported in individuals with OI are ruptures, lacerations, other eye problems following minor trauma, and complications from standard surgical procedures. An increased risk for other ocular diseases (e.g., glaucoma, cataracts, refractive errors, and retinal diseases) has been reported in individuals with OI [Lyster et al 2022]. To date, the risk of ocular disease in OI is unknown, and there is lack of consensus on how to screen for eye disease in this population [Treurniet et al 2022, Moussa et al 2024].

Gastrointestinal (GI). Adults with OI frequently report GI issues (e.g., constipation, diarrhea, unspecified abdominal pain, and reflux) that often go unaddressed, which can significantly affect their quality of life [Tosi et al 2015, Swezey et al 2019]. GI issues occur more frequently in adults with OI compared to the general population [Lo Turco et al 2022, Anderesen et al 2025]. In children with OI, bowel and bladder problems, particularly constipation and urinary incontinence, are common issues [Martins et al 2020].

Cardiovascular. Emerging data support an increased risk for cardiovascular disease (CVD) in individuals with OI. A systematic literature review documented a higher prevalence of an array of CVD phenotypes including arterial and aortic dissection [Ashournia et al 2015]. Three additional individuals with COL1A1/COL1A2-OI and aortic aneurysms have been reported [Balasubramanian et al 2019]. However, a more recent systematic review highlighted inconsistencies across studies with regard to aortic root dilatation, alterations in cardiac dimensions and function, and risk of heart failure [Verdonk et al 2024]. Some studies reported no significant differences in cardiac measurements between individuals with OI and healthy controls. Individuals with OI may have a higher likelihood of valvular abnormalities compared to controls. Mitral and aortic valve regurgitation are the most commonly reported. However, many individuals had trivial or mild regurgitation, and only a small percentage were clinically significant. The risks of hypertension, atrial fibrillation, and arteriosclerosis in OI is not well studied.

Pulmonary disease. In individuals with OI, pulmonary disease can be due to factors extrinsic to the lungs, as well as intrinsic lung abnormalities. Extrinsic factors include short stature, immobility, scoliosis, recurrent rib fractures, muscle weakness, and chest wall abnormalities. The extent of intrinsic pulmonary abnormalities (e.g., restrictive lung physiology) are only recently described [Khan et al 2020]. In a multicenter study including different OI types, pulmonary function tests in 217 children and adults showed that individuals with progressively deforming OI had significantly reduced forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). This study also showed that the normalization process used in spirometry analyses can underestimate the pulmonary involvement in severe forms of OI. The authors suggested that clinicians should be aware of the limitations of spirometric measures when evaluating pulmonary function in OI [Tam et al 2018]. Pulmonary complications range from pulmonary hypoplasia with neonatal death to restrictive lung disease and/or pulmonary hypertension. Pulmonary impairment may cause shortness of breath, fatigue, increased susceptibility to lower-respiratory infections, and sleep apnea [Turkalj et al 2017]. Chronic pulmonary insufficiency may progress to cardiac issues. Cardiopulmonary complications are the major cause of morbidity and mortality in adults with OI.

Development. Cognition is expected to be normal, but gross motor development may be hindered by joint hypermobility, repeated immobilizations with fractures, and progressive bone deformity in severe OI. Some infants with OI will follow a typical developmental course, while others develop their own strategies for movement [Mueller et al 2018].

Functional limitations. Individuals with OI may experience functional limitations. Decreased muscle strength, fatigue, and/or pain may limit endurance and involvement in sports [Mueller et al 2018]. In a large multicenter study, individuals with classic non-deforming OI with blue sclerae experienced minor limitations, while those with more severe types showed more significant limitations in all mobility metrics analyzed (e.g., functional mobility scale, six-minute walk test). The age at first steps in children with classic non-deforming OI with blue sclerae was delayed by about three months compared to typically developing children. In contrast, individuals with progressively deforming OI who eventually walked experienced a delay of 33 months on average and did not walk until around age 3.8 years [Kruger et al 2019]. When patient-reported outcome measures were used in a large cohort of children with different OI types, physical function scores were significantly lower in individuals with progressively deforming OI compared to those with classic non-deforming OI with blue sclerae and common variable OI with normal sclerae. However, there were no significant differences in psychosocial well-being among children with different OI types [Murali et al 2020].

Life expectancy. Neonates with "perinatally lethal OI" have improved outcomes with advances in neonatal care. An appropriate multidisciplinary approach and life support may prolong survival to discharge in some infants. Progressively deforming OI is highly variable, and life expectancy may be shortened by severe kyphoscoliosis with restrictive pulmonary disease resulting in cardiac insufficiency. Life expectancy for classic non-deforming OI with blue sclerae and common variable OI with normal sclerae is normal. In a Danish nationwide, population-based, register-based cohort study the median survival time for all males with OI was 72.4 years, compared to 81.9 years in the reference population. The median survival time for females with OI was 77.4 years, compared to 84.5 years in the reference population. Individuals with OI had a higher risk of death from cardiorespiratory diseases, gastrointestinal diseases, and trauma [Folkestad et al 2016].

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.

Table 4.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Nomenclature

Nomenclature Used in this GeneReview *
[Van Dijk & Sillence 2014]
Corresponding Designations
Clinical OI Type
[Sillence et al 1979]
2023 Nosology of Genetic Skeletal Disorders
[Unger et al 2023]
Classic non-deforming OI with blue scleraeOI type I
  • OI, non-deforming (Sillence type 1), COL1A1-related
  • OI, non-deforming (Sillence type 1), COL1A2-related
Perinatally lethal OIOI type II
  • OI, severe perinatal form (Sillence type 2), COL1A1-related
  • OI, severe perinatal form (Sillence type 2), COL1A2-related
Progressively deforming OIOI type III
  • OI, progressively deforming (Sillence type 3), COL1A1-related
  • OI, progressively deforming (Sillence type 3), COL1A2-related
Common variable OI with normal scleraeOI type IV
  • OI, moderate form (Sillence type 4), COL1A1-related
  • OI, moderate form (Sillence type 4), COL1A2-related

OI = osteogenesis imperfecta

* Note: For consistency throughout this GeneReview, the authors have used the OI classification recommended by Van Dijk & Sillence [2014]. References to "OI type I" from the previous version of this GeneReview and referenced publications have been changed to "classic non-deforming OI with blue sclerae." Similarly, "OI type II" has been replaced with "perinatally lethal OI," "OI type III" with "progressively deforming OI," and "OI type IV" with "common variable OI with normal sclerae."

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].

Differential Diagnosis

Other Types of Osteogenesis Imperfecta

The primary differential diagnoses for individuals with features of COL1A1- and COL1A2-related osteogenesis imperfecta (COL1A1/COL1A2-OI) are non-collagen-associated forms of OI. There are both dominant and recessive types, which can be phenotypically indistinct from COL1A1/COL1A2-OI. In a small subset of individuals, specific causative variants have not yet been identified. 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.

Table 6.

Differential Diagnosis of COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Other Types of Osteogenesis Imperfecta

GeneMOIOMIM-Defined Genetic OI TypeClinical OI Type 1Clinical Characteristics
BMP1 AROI type XIII (OMIM 614856)OI-IIIUmbilical hernia; hypertelorism; no DI or HL
CCDC134 AROI type XXII (OMIM 619795)OI-IIISevere OI; IUGR; early & severe bone fragility w/multiple fractures; variable sclerae color; atlantoaxial instability described
CREB3L1 AROI type XVI (OMIM 616229)OI-IIIPrenatal; severe presentation; may be assoc w/tooth agenesis
CRTAP AROI type VII (OMIM 610682)OI-II, III, or IVNormal birth length; proptosis; no DI; pulmonary vasculature malformations; rhizomelia
FKBP10 AROI type XI (OMIM 610968)OI-III or IVBrachycephaly; variable degree of bone fragility ± (congenital) contractures
IFITM5 ADOI w/calcification in interosseous membranes, OI type V (OMIM 610967)OI-III or IVSclerae generally white; DI rare; hypertrophic callus formation; calcification of interosseous membrane between ulna & radius that leads to inability to fully supinate & pronate forearm; no HL. Depending on the pathogenic variant, calcification of intraosseous membranes or hypertrophic callus can be absent w/more severe clinical presentation mimicking OI type III.
KDELR2 AROI type XXI (OMIM 619131)OI-II or IIISevere OI w/perinatal fractures; frequency of neurodevelopmental delay unknown
MBTPS2 XLOI type XIX (OMIM 301014)OI-III or IVNo HL; sclerae generally white; rhizomelia; epiphyseal "popcorn" calcification
MESD AROI type XX (OMIM 618644)OI-III or IVFacial dysmorphisms incl arched eyebrows & tented shape of lips; long fingers w/5th finger camptodactyly; oligodontia
P3H1 AROI type VIII (OMIM 610915)OI-II or IIINo DI; white sclerae; proptosis; long phalanges
P4HB ARCole-Carpenter syndrome 1 (OMIM 112240)OI-IIICraniosynostosis; ocular proptosis; hydrocephalus; distinctive facial features
PPIB AROI type IX (OMIM 259440)OI-II, III, or IVNo DI or HL; white sclerae
SEC24D ARCole-Carpenter syndrome 2 (OMIM 616294)OI-IIITurricephaly; proptosis; hypertelorism; dysplastic ears; no HL; white sclerae; hydrocephalus; high-pitched voice
Note: Most affected persons have large fontanels (not craniosynostosis).
SERPINF1 AROI type VI (OMIM 613982)OI-III or IVNo DI or HL
SERPINH1 AROI type X (OMIM 613848)OI-IIIMacrocephaly; proptosis; renal calculi
SP7 AROI type XII (OMIM 613849)OI-III or IVNo DI; white sclerae
SPARC AROI type XVII (OMIM 616507)OI-IVNo DI or HL; white sclerae; risk for intracranial hemorrhage
TENT5A AROI type XVIII (OMIM 617952)OI-III or IVNo DI or HL; umbilical hernia
TMEM38B AROI type XIV (OMIM 615066)OI-IIINo DI or HL; white sclerae
WNT1 AROI type XV (OMIM 615220)OI-III or IVStructural brain malformations; rhizomelia

AD = autosomal dominant; AR = autosomal recessive; DI = dentinogenesis imperfecta; HL = hearing loss; IUGR = intrauterine growth restriction; MOI = mode of inheritance; OI = osteogenesis imperfecta; XL = X-linked

1.

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).

In Utero Assessment

Early prenatal ultrasound examination or radiographic findings may lead to a consideration of hypophosphatasia, thanatophoric dysplasia, campomelic dysplasia, and achondrogenesis as well as perinatally lethal OI. In some instances, either biochemical or molecular testing can be a useful adjunct. Note: Fetal imaging is critical in establishing a diagnosis; molecular genetic findings must be correlated with imaging findings [Nishimura et al 2023].

Table 7.

Differential Diagnosis of COL1A1- and COL1A2-Related Osteogenesis Imperfecta: In Utero Assessment

GeneDisorderMOIPrenatal Ultrasound & Radiographic Findings in Disorder
ALPL Perinatal hypophosphatasia AR
(typically)
Defective calvarial ossification; defective ossification of vertebral bodies &/or neural arches; bowing of long bones w/metaphyseal mineralization defect
FGFR3 Thanatophoric dysplasia ADFrontal bossing & mid-face hypoplasia; craniosynostosis; platyspondyly; abnormalities in interpediculate distances; short ribs w/long, narrow thorax; trident ilia; proximal femoral scooping; trident hand; severe brachydactyly
SLC26A2 Achondrogenesis type 1B ARSevere spondylar dysplasia w/rudimentary ossification of vertebral bodies; abnormalities in interpediculate distances, short ribs w/short, broad thorax; delayed pubic & ischial ossification; very short & disorganized long bones w/severe brachydactyly
SOX9 Campomelic dysplasia ADMicrognathia &/or cleft palate; cervical kyphosis; hypoplasia of scapular wing; bowing of long bones (sharply bowed)
~75% of affected persons who have a 46,XY karyotype have either ambiguous external genitalia or normal female external genitalia.
COL2A1 Achondrogenesis, COL2A1-related (See Type II Collagen Disorders Overview.)ADMicrognathia & cleft palate; defective ossification of vertebral arches; platyspondyly; short ribs w/short, broad thorax; micromelia; delayed pubic & ischial ossification
COL2A1 Platyspondylic dysplasia, type Torrance, COL2A1-related (See Type II Collagen Disorders Overview.)ADPlatyspondyly; short ribs w/anterior cupping; hypoplasia of lower ilia w/broad ischial & pubic bones; shortening of tubular bones w/splayed & cupped metaphyses

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; OI = osteogenesis imperfecta

Infancy and Childhood Assessment

Non-accidental trauma (NAT; child abuse). COL1A1/COL1A2-OI needs to be distinguished from NAT. The prevalence of NAT is much higher than the prevalence of COL1A1/COL1A2-OI, and on rare occasion, NAT can occur in a child with COL1A1/COL1A2-OI. Medical history, family history, physical examination, radiographic imaging, and the clinical course all contribute to distinguishing COL1A1/COL1A2-OI from NAT. The overlap in clinical features includes multiple or recurrent fractures, fractures that do not match the history of trauma, and the finding of fractures of varying ages and at different stages of healing [Steiner et al 1996, Marlowe et al 2002, Pepin & Byers 2015].

The continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of COL1A1/COL1A2-OI. Metaphyseal and rib fractures, thought to be virtually pathognomonic for NAT, can rarely occur in COL1A1/COL1A2-OI. The presence or absence of blue sclerae is unreliable in distinguishing COL1A1/COL1A2-OI from NAT because blue sclerae are often found in unaffected normal infants until about age 18 months, and children with OI may not have blue sclerae.

Family history is often unrevealing. Families suspected of possible NAT often provide an unverified family history of frequent fractures; conversely, the family history of individuals with COL1A1/COL1A2-OI often does not reveal any other affected individuals because of a de novo pathogenic variant in the proband or the presence of a mild phenotype in relatives.

The use of molecular testing in individuals with suspected NAT and unexplained fractures continues to be controversial. However, with the decreasing cost of molecular testing, increased availability, and constrained workforces of NAT specialists and clinical geneticists, molecular testing has become more common. Determining whether molecular testing is medically necessary can be challenging. Molecular testing has been suggested when there is uncertainty of NAT, given the clinical overlap that might be seen between NAT and mild forms of OI [Pepin & Byers 2015]. Pepin and Byers [2015] recommend sequence and duplication analysis of COL1A1, COL1A2, and IFITM5. If a causative variant is not identified, in the absence of a clinical phenotype that is highly suggestive of OI, no additional molecular testing is recommended. If a variant of uncertain significance is identified, parental segregation studies are recommended. Interpreting results and implications for each child, and considering the diagnosis of NAT versus OI, ultimately involves a number of experts; evaluations are multidisciplinary and may involve medical providers, child protective services, and in some cases law enforcement professionals [Pepin & Byers 2015]. Another study reported COL1A1 and COL1A2 sequence analysis results in a cohort of 43 children in the setting of suspected NAT; when no other suggestive clinical findings were present, COL1A1 and COL1A2 sequence analysis had a low yield. A careful review of the medical history and a detailed clinical evaluation helped identify those at risk for COL1A1/COL1A2-OI. The authors suggested considering genetic evaluation and molecular testing for OI in the setting of NAT only in those with blue sclerae, osteopenia, and/or a positive family history [Zarate et al 2016].

Other Bone Fragility Disorders

Genetic disorders associated with osteoporosis-related bone fragility (rather than inherent bone fragility as in OI) are listed in Table 8. These disorders are included in the OI and bone fragility group of the 2023 Nosology of Genetic Skeletal Disorders [Unger et al 2023, Sillence 2024].

Table 8.

Other Genetic Disorders Associated with Bone Fragility (But Not Considered Osteogenesis Imperfecta)

GeneDisorderMOIClinical Features of Disorder
ANO5 Gnathodiaphyseal dysplasia, ANO5-related (OMIM 166260)ADEnlarged jaw; osteomyelitis
ATP6V0A2 ATP6V0A2-related cutis laxa ARVariable severity of cutis laxa; abnormal growth; DD; skeletal abnormalities
COPB2 Osteoporosis w/DD & microcephaly, COPB2-related (OMIM 619884)ADEvidence of osteopenia or osteoporosis, w/recurrent fractures following minor trauma in some persons; variable DD; mild intellectual or learning disability; wide-based gait &/or gross motor delays; microcephaly in some persons
FKBP10 Bruck syndrome type 1 (BS1), FKBP10-related (OMIM 259450)ARCongenital contractures w/pterygia; onset of fractures in infancy or early childhood; postnatal short stature; severe limb deformity; progressive scoliosis
GORAB Geroderma osteodysplasticum, GORAB-related (OMIM 231070)ARMicrocephaly; bowed long bones & fractures; camptodactyly; skin wrinkling limited to dorsa of hands & feet; premature aged facial appearance; ID
IFIH1 Singleton-Merten dysplasia, IFIH1-related (OMIM 182250)ADCalcifications of aorta & aortic & mitral valves in childhood or puberty; delayed primary tooth exfoliation & permanent tooth eruption; truncated tooth root formation & tooth loss; osteoporosis; distal limb osteolysis; widened medullary cavities; easy tearing of tendons from bone
LRP5 Osteoporosis pseudoglioma syndrome, LRP5-related (OMIM 259770)ARJuvenile-onset osteoporosis w/long bone fractures; vertebral compression fractures; kyphoscoliosis; deformity of extremities; short stature; congenital or early-onset visual disturbances arising from ophthalmologic problems incl retinal detachment & microphthalmia
PLOD2 Bruck syndrome type 2 (BS2), PLOD2-related (OMIM 609220)AROsteoporosis; joint contractures at birth; fragile bones; short stature
PLS3 Osteoporosis-X-linked form, PLS3-related (OMIM 300910)XLIn males, osteoporosis & fractures of axial & appendicular skeleton developing in childhood
Heterozygous females may have normal bone density or early-onset osteoporosis & vertebral compression fractures on radiographs.
POLR3A Wiedemann-Rautenstrauch syndrome, POLR3A-related (OMIM 264090)ARNeonatal progeroid disorder; IUGR, poor growth, short stature, progeroid appearance, hypotonia, & variable ID
PYCR1 Cutis laxa, PYCR1-related (OMIM 612940)ARVariable severity of cutis laxa; abnormal growth; DD; skeletal abnormalities
RIGI (DDX58)Singleton-Merten dysplasia, DDX58-related (OMIM 616298)ADVariable glaucoma; aortic calcification; skeletal abnormalities; not assoc w/dental anomalies
SGMS2 Bone fragility with calvarial "doughnut” lesions," SGSM2-related (OMIM 126550)ADLow bone mineral density; multiple spinal & peripheral fractures beginning in childhood; sclerotic doughnut-shaped lesions in cranial bones
XYLT2 Spondylo-ocular dysplasia, XYLT2-related (OMIM 605822)ARPlatyspondyly; bone fragility; cataract; retinal detachment; hearing impairment; cardiac defects; facial dysmorphism

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked

Management

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

Evaluations Following Initial Diagnosis

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

Table 9.

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

System/ConcernEvaluationComment
Musculoskeletal
  • Physical exam
  • Growth assessment (length/height, weight, & head circumference)
  • Pain assessment
  • To assess deformities, scoliosis, & presence of joint laxity
  • Growth parameters should be plotted on OI growth charts (see height & weight charts). 1
  • Referral to PT & OT to assess motor development & mobility issues
  • Referral for surgical intervention to experienced orthopedist as needed
As indicated by clinical presentation
  • Referral to bone disease specialist
  • Bone biomarkers (calcium, phosphorus, alkaline phosphatase, parathyroid hormone)
  • Vitamin D level to assess for deficiency
DXA scanBeginning at age ~5 yrs
Neurologic CT &/or MRI exam w/views across base of skull to evaluate for basilar impressionIf concerning signs or symptoms are present 2
Cervical spine flexion & extension radiographsIn children able to cooperate w/exam or before participating in sporting activities in more mildly affected persons
Audiologic Formal hearing assessmentIn all persons at diagnosis
Ophthalmology Eye examBeginning in adulthood
Dental Dental exam
  • When teeth erupt in those w/DI or at risk for DI
  • By age 2-3 yrs for all children w/OI
Gastrointestinal Assessment for constipation, diarrhea, unspecified abdominal pain, & reflux
Pulmonary
  • Assessment for pulmonary complications
  • Referral to pulmonologist as needed
Genetic counseling By genetics professionals 3To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of COL1A1/COL1A2-OI to facilitate medical & personal decision making
Family support
& resources
By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

DI = dentinogenesis imperfecta; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OI = osteogenesis imperfecta; OT = occupational therapist; PT = physical therapist

1.
2.

There is no universal agreement on when screening for basilar impression should be performed. A positive Lhermitte sign (tingling in fingers with neck flexion) should prompt neurosurgical referral. Surgery is typically undertaken before persistent/permanent neurologic features are present.

3.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

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].

Table 10.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Recommended Surveillance

System/ConcernEvaluationFrequency
Musculoskeletal Orthopedic eval to assess for fractures, scoliosis, & other musculoskeletal manifestations
  • Every 3 mos until age 1 yr
  • Every 6 mos from age 1-3 yrs
  • Then annually or w/any new fractures or other musculoskeletal concerns (e.g., long bone deformity, flat feet, leg discrepancy, osteoarthritis)
Assessment of growthAt each visit throughout childhood & adolescence
Physical & rehab medicine, PT/OT eval to assess mobility & other motor skillsIn infancy for persons w/motor delays & as needed in older persons
Assessment of painAt each visit
  • Eval by bone disease specialist
  • Vitamin D level to assess for deficiency
As recommended by bone disease specialist or as needed based on age & OI severity
DXA scanBeginning at age 5 yrs; frequency depends on severity of OI, results of initial DXA scan, & pharmacologic treatment status 1
  • If initial DXA scan in childhood is normal, repeat in 5 yrs
  • In initial DXA scan is abnormal, repeat no more than annually; consider every 2-3 yrs
  • Persons on bisphosphonates require more frequent DXA scans
Neurologic CT &/or MRI exam w/views across base of skull to evaluate for basilar impressionIn those w/platybasia, moderate-to-severe OI, or concerning signs or symptoms
Cervical spine flexion & extension radiographsIn children able to cooperate w/exam (~age 6 yrs) or before participating in sporting activities in more mildly affected persons
Dental Dental exam to assess dental health
  • Every 6 mos for those w/DI or at risk for DI beginning in infancy
  • Annually in those w/o DI.
Audiologic Hearing eval
  • Every 3 yrs starting at age 5 yrs in those w/normal hearing
  • Frequency as indicated based on nature & degree of HL & assoc interventions in those w/HL
Ophthalmology Eye exam
  • At least every 2-3 yrs in adults
  • More frequently as needed based on eye findings & risk assessment by ophthalmologist
Nutrition Nutrition & feeding evalAs needed
Gastrointestinal Assessment for symptoms related to GERD, constipation, or other GI concernsAt each visit
GI evalAs needed
Cardiology
  • Clinical assessment for symptoms of cardiovascular disease
  • Referral to cardiologist for further eval in those w/unexplained symptoms (e.g., chest pain, back pain, dyspnea)
As needed
Pulmonology Assessment for pulmonary issues (dyspnea, chronic cough, frequent respiratory infections, sleep apnea) & risks for lung disease (vaccination status, smoking)At each visit
Consider pulmonology eval.In children & adults w/lung disease
Pulmonary function testsEvery 1-2 yrs in adults or in symptomatic children
Sleep studyIn those w/symptoms of sleep apnea
Mental health professional
  • Eval by therapists, social workers, & psychologist (might help develop skills to manage stress)
  • Evaluate for presence of mood disorders.
As needed
Genetic counseling Follow up w/genetics professionals 1 to provide education re MOI, type of OI, severity, & prognosis & assist in family planning decisionsAs needed
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

DI = dentinogenesis imperfecta; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HL = hearing loss; MOI = mode of inheritance; OI = osteogenesis imperfecta

1.

If possible, DXA scan should be done using the same machine each year to avoid variations in test results caused by different equipment [Osteogenesis Imperfecta Foundation 2023].

2.

DXA scans prior to age five years often require sedation, and data regarding normal values is limited.

3.

There is limited consensus regarding frequency of DXA scans in children. The minimum time between DXA scans should be six to 12 months. Consider annual DXA scan in those receiving bisphosphonates. Otherwise, consider DXA scan every two to three years or every five years, depending on severity of OI, results of initial DXA scan, and pharmacologic treatment status.

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.

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

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:

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

COL1A1- and COL1A2-Related Osteogenesis Imperfecta: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for COL1A1- and COL1A2-Related Osteogenesis Imperfecta (View All in OMIM)

120150COLLAGEN, TYPE I, ALPHA-1; COL1A1
120160COLLAGEN, TYPE I, ALPHA-2; COL1A2
166200OSTEOGENESIS IMPERFECTA, TYPE I; OI1
166210OSTEOGENESIS IMPERFECTA, TYPE II; OI2
166220OSTEOGENESIS IMPERFECTA, TYPE IV; OI4
259420OSTEOGENESIS IMPERFECTA, TYPE III; OI3

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.

Chapter Notes

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

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