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.