INTRODUCTION — Osteogenesis imperfecta (OI) is a disease encompassing a group of disorders mainly characterized by bone fragility and is the most common form of heritable bone fragility. There is a broad spectrum of clinical severity in OI, ranging from multiple fractures in utero and perinatal lethality to near-normal adult stature and low fracture incidence . Rare pathogenic or likely pathogenic genetic variants can be identified in most patients with autosomal dominant (AD) OI and in some patients with autosomal recessive (AR) forms of OI or X-linked osteoporosis. This topic discusses the epidemiology, pathogenesis, genetics, classification, clinical features, diagnosis, and differential diagnosis, with particular emphasis on initial evaluation in patients presenting with heritable bone fragility including OI.
EPIDEMIOLOGY — The estimated incidence of OI varies between 1 in 10,000 to 1 in 20,000 live births . The reported population frequency of OI ranges from 2.35 to 4.7 in 10,0000 worldwide . However, it is possible that some mild forms of OI remain undiagnosed, and, as a result, the incidence may be higher than quoted in medical literature. Increased access to genetic testing and identification of rarer forms of OI will probably lead to a refined incidence estimate over time.
PATHOGENESIS — Most OI is due to defects in genes involved in production, folding, stability, processing, and secretion of type 1 collagen, osteoblast function, or bone matrix mineralization (see 'Genetics' below). Interruption of any of these processes may cause a pathologic phenotype with decreased or abnormal type I collagen produced, resulting in OI. Approximately 85 percent of OI is caused by pathogenic variants in genes encoding type 1 collagen (COL1A1/COL1A2), the most common being glycine substitutions in the triple helical domain, which breaks the repetitive (Gly-X-Y)n pattern of either COL1A1 or COL1A2 [4,5]. These can be associated with a range of phenotypes, from mild to severe, dependent on how protein folding and structure are affected . Genetic variants causing lethal forms of OI are generally located at the C-terminal half of the collagen chain, and nonlethal forms occur due to variants at the N-terminus; however, there are exceptions .
Type I collagen forms bones and is encoded for by the COL1A1 and COL1A2 genes, located on chromosomes 17 and 7, respectively . As with all collagens, type I is a heterotrimer, consisting of three chains: two alpha 1 chains (coded for by COL1A1) and one alpha 2 chain (coded for by COL1A2) . Each pro-alpha chain contains a triple helical region, made from Gly-X-Y repeating units, flanked by a propeptide at either side: the C-propeptide and N-propeptide .
Precursor procollagens are pro-alpha chains that have globular extensions (N and C-propeptides). C-propeptides on the pro-alpha chains interact via hydrophobic and electrostatic forces, which direct chain recognition, selection, and alignment. Disulfide bonds stabilize the triple helix structure that forms [10,11]. Procollagen trimers are then converted to collagen by proteolytic cleavage of the N and C-propeptides .
Collagen synthesis begins in the rough endoplasmic reticulum (ER) with the assembly of the three chains . Hydrophobic and electrostatic forces result in the interaction of the C-propeptides, causing the three pro-alpha chains to align. The triple helical regions on the chains begin to form a triple helix structure . Once the triple helix has formed, its stabilization relies on the cartilage-associated protein (CRTAP)/prolyl 3-hydroxylase 1 (P3H1)/cyclophilin B (CyPB) complex. This complex modifies the proline amino acid in the collagen molecules, a process also known as proline 3-hydroxylation. Important for the folding and assembly of collagen, the CRTAP/P3H1/CyPB complex is encoded for by the CRTAP, P3H1 (previously known as leucine proline-enriched proteoglycan (leprecan) 1 [LEPRE1]), and peptidylprolyl isomerase B (PPIB) genes .
The molecular chaperone FK506-binding protein 65 (FKBP65), encoded for by FKBP prolyl isomerase 10 (FKBP10), then aids the assembly of type I procollagen after localizing to the ER .
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) is essential in maintaining the stability of the collagen cross-links as it hydroxylates the amino-terminal lysyl residues involved . Serpin family H member 1 (SERPINH1) encodes heat shock protein 47 (HSP47), a collagen-specific chaperone that stabilizes the folded collagen and marks it for transfer to the Golgi apparatus .
The procollagen molecule is transported through the Golgi apparatus into the extracellular matrix, and procollagen C- and N-proteinases cleave the propeptides. A tropocollagen molecule is formed. These molecules spontaneously group to form collagen fibrils, with covalent cross-links forming within and between the collagen molecules [13,16].
GENETICS — Defects within genes involved in type 1 collagen production and processing result in OI. Most people with OI inherit the condition, typically in an autosomal dominant (AD) form. There is often a positive family history of fractures, short stature, and early-onset osteoporosis in extended family members when this is explored. However, gene defects can also occur sporadically, without any previous affected family members (de novo variant), although, once they occur, they can be transmitted to offspring.
●Autosomal dominant OI – Approximately 85 to 90 percent of patients with AD OI have a pathogenic variant in COL1A1 or COL1A2 (table 1), which encode the pro-alpha 1 and pro-alpha 2 chains of type I collagen [4,17,18]. A recurrent AD pathogenic variant in interferon-induced transmembrane protein 5 (IFITM5) within the noncoding region of the gene has been identified in all patients with type V OI [16,19-21]. Other dominant forms of bone fragility include pathogenic variants in low-density lipoprotein receptor-related protein 5 (LRP5) and the protooncogene (Wnt family member 1 [WNT1]) genes that cause primary osteoporosis. (See 'Differential diagnosis' below.)
In the AD forms of OI, the recurrence risk is one in two (50 percent) if a parent is affected. Persons with milder forms of OI are more likely to have an affected parent. If the parents of the proband are clinically unaffected, then the recurrence risk for future pregnancies is approximately 7 percent due to the possibility of germline mosaicism in a parent [22,23]. However, this risk may be lower considering that some previously presumed de novo forms of OI were indeed recessive forms of OI. Germline mosaicism is when the pathogenic variant is present in a small proportion of germ cells (ie, egg or sperm) without being present in other body tissues. This is particularly relevant in the more severe AD forms of OI, such as type II OI.
●Autosomal recessive (AR) OI – Recessive pathogenic variants typically result in a more severe phenotype. Defects in several different genes involved in type 1 collagen production and processing can result in AR OI (table 1).
In the AR forms of OI, parents are obligate heterozygotes and carry one pathogenic variant each but are generally asymptomatic, healthy "carriers." However, heterozygous carrier parents with LRP5 or WNT1 pathogenic variants may have a milder phenotype with significant fracture history that will need to be monitored.
The recurrence risk for any future pregnancies is one in four (25 percent), with other offspring having a two-in-three chance of being a "carrier" for one of the pathogenic variants identified in the family. Whether the offspring have children with this condition depends upon whether their future partners are carriers of pathogenic variant of the same gene. Most severe, lethal forms of OI follow this pattern of inheritance, and early confirmation of genetic diagnosis is important to provide accurate prognosis and recurrence risk information.
●X-linked bone fragility – In addition to dominant and recessive forms of OI, there are X-linked forms of bone fragility that affect males more than females (table 1). This is often evident on exploring family history and includes genes such as plastin 3 (PLS3) and membrane-bound transcription factor peptidase, site 2 (MBTPS2) [24-26]. It is important to distinguish X-linked forms of bone fragility for provision of accurate recurrence risk information, such as reassurance that affected males are unlikely to have severely affected children (ie, all their daughters would be carriers, but sons will not inherit it) but also to ensure that carrier females (eg, the mother and sisters of an affected male) are monitored for early-onset osteoporosis.
CLASSIFICATION — OI remains a clinical diagnosis, although improvements in imaging and access to genomic testing have allowed refining of the type of OI and genotype-phenotype correlation. OI was originally classified clinically into four different types based on phenotypic presentation of OI patients by Sillence in 1979. Since this original classification system, over 20 types of OI have been defined in Online Mendelian Inheritance in Man (OMIM), which show variance in their causative genes, mode of inheritance, and clinical phenotypes (table 1 and table 2) . There have been various attempts at classifying OI based on underlying genetics, clinical phenotype, and disease mechanism, although the Sillence classification remains widely used as a clinical classification tool.
Overview — Short stature, bone deformities, and recurrent fractures are common features, but there is a wide range of clinical severity, from multiple fractures in utero and perinatal lethality to rare fractures and near-normal adult stature. Extraskeletal features are variable and may include dentine abnormalities, altered scleral hue, facial dysmorphism, hearing loss, skin laxity, joint hypermobility, and cardiovascular, neurologic, or respiratory manifestations.
Fractures — Low-impact fractures with very minimal trauma remain the hallmark feature in OI. A detailed fracture history includes the number, site, nature of injury, and age at first fracture. In the milder forms of OI, fractures tend to first occur once a child begins standing and as they become more adventurous and active in the preschool years, with a series of fractures occurring in the prepubertal years and a decrease in frequency seen in adult life. These patients may have some degree of gross motor delay and short stature due to long bone deformities, but most have normal adult stature (or relative short stature for family). In the more severe forms of OI, fractures and bony deformities may start antenatally and result in significant effects on the skeleton and subsequent growth.
Scleral hue — The color of the sclerae can be subjective depending upon lighting and age of the person amongst other factors and, as such, should be considered an additional clinical feature rather than a defining feature in OI. Blue/bluish-grey/grey scleral hue have all been described in OI but can also be a normal finding in the neonatal period. Autosomal recessive (AR) forms of OI tend to have a more whitish sclerae while more classical forms of OI tend to have a bluish scleral hue (picture 1).
Dentinogenesis imperfecta — Dentinogenesis imperfecta (DI) is an inherited dentine anomaly and can occur as part of a medical condition or as an isolated dental condition. The estimated incidence of DI is 1:8000. The teeth are discolored, chip and wear easily, and have abnormal crown and root development (picture 2) . DI is classified into three types . Type I (DI-I) occurs in association with OI and is due to a collagen defect, whereas types II and III (DI-II and DI-III) are attributed to pathogenic variants in the dentin sialophosphoprotein (DSPP) gene .
Facial features — Although not typical, certain facial features aid in making a diagnosis of OI on initial evaluation, including triangular face, frontal bossing, broad forehead, deep-set eyes, and beaked nose. Persons with OI may also have a distinctive high-pitched voice.
Growth — Short stature is a common but not invariable feature in OI. There are several contributing factors including bony deformities following healing of repeated fractures, especially of the long bones; defects in primary development of long bones; intraosseous calcification at growth plates; and scoliosis. High body mass index (BMI) or obesity is also a prevalent finding in OI that is not always attributable to reduced mobility and activity in these patients.
Hearing loss — Hearing loss in OI does not occur until adulthood, although hearing assessment should be performed at the time of diagnosis to identify and address any hearing deficit early if there is evidence of impairment. The hearing loss in OI is very similar to that found in otosclerosis and is often a mixed sensorineural and conductive hearing loss.
Joint hypermobility and ligament laxity — Joint hypermobility with increased risk of premature joint degeneration, osteoarthritis, and chronic musculoskeletal pain is increasingly recognized as a clinical feature in OI. The effects of joint hypermobility and ligament laxity resulting in increased fatigability and intractable pain are thought to result in more issues with activities of daily living when compared with the consequence of bone deformities and fractures alone.
Skin laxity — Although not a predominant feature in OI, skin laxity and easy bruising have been described and need to be factored in during initial evaluation, especially in the context of nonaccidental injury (NAI), and while considering the differential diagnosis. (See 'Differential diagnosis' below.)
Chest and spine disorders — Respiratory insufficiency, potentially due to a primary effect of OI on lung tissue and pulmonary function, can often result in death in severe forms of OI, especially in the perinatal period. In the milder forms of the condition, there is a risk of restrictive lung disease due to thoracic kyphoscoliosis and vertebral collapse/fractures. Sternal deformities such as pectus carinatum and excavatum can be seen, resulting in respiratory difficulties. Curvature of the spine needs careful monitoring, especially in the rare forms of OI, due to significant risk of rapidly developing scoliosis resulting in respiratory compromise.
Cardiovascular manifestations — While OI-related valvular insufficiencies and aortic dilatation are well documented, information regarding aortic dissection in this population remains scarce, with only nine reported cases of aortic dissection in literature [31-37]. Mechanical weakness due to abnormal type I collagen in the aortic wall is the suspected underlying mechanism.
The increased incidence of valvular heart disease in OI is well established. Aortic and mitral regurgitation are the most commonly described valvular insufficiencies in patients with OI. A review paper that included 70 patients described in case reports and small studies for OI-related cardiovascular abnormalities found that 40 out of 70 (57 percent) had aortic valve insufficiency and 24 out of 70 (34 percent) had mitral valve insufficiency .
An echocardiogram is typically performed as initial cardiovascular screening. If initial screening is normal, regular screening of valve function and aortic diameters is usually performed every three to five years in adults.
Cranial abnormalities and neurologic manifestations — OI is commonly associated with relative macrocephaly. Platybasia (flattening of the skull base), basilar impression (softening of the bone at the foramen magnum), and basilar invagination (BI; upward displacement of the upper cervical spine and clivus into the foramen magnum) are comorbidities seen in association in OI . Typical symptoms of BI, which requires urgent intervention, include headaches, nystagmus, ataxia, and altered facial sensation. There is a high frequency of BI in patients with severe OI. BI can progress slowly in childhood and take years before symptoms develop .
Certain clinical features appear to confer a higher risk of BI, including short stature with height <0.4th centile, presence of multiple wormian bones (see 'Imaging' below), DI, and specific forms of OI such as type V OI and AR forms of the condition.
Screening for BI is advised in the form of lateral foramen magnum-centered skull radiograph every two years of age, especially in the high-risk group, followed by annual magnetic resonance imaging (MRI) if radiographic signs of BI develop. Patients with OI, especially those at risk of developing BI, should be carefully monitored and followed up in centers with neurosurgery and expertise in managing BI.
Antenatal findings on ultrasound — Antenatally, abnormalities on prenatal ultrasound, such as short long bones, bowed femora, and relatively large head circumference, suggest a skeletal dysplasia such as severe OI . Abnormal findings often are picked up in the second trimester of pregnancy (see 'Antenatal presentation' below). Ultimately, survival in a lethal skeletal dysplasia (OI amongst others) is determined by a number of factors including chest capacity and respiratory insufficiency, in addition to the fractures and skeletal deformities.
Postnatal dysplasia skeletal survey — In a postnatal presentation, a skeletal dysplasia survey is usually the cornerstone in imaging in OI. This includes radiographs of the skull; upper limbs bilaterally, including wrist; lower limbs bilaterally, including pelvis; hands and feet; anterior-posterior (AP) and lateral views of the chest; and AP and lateral views of the spine (image 1A-C). The main radiographic features of OI are fractures, bone deformities, and osteopenia (table 2) .
Fractures — Fractures at varying ages and stages of healing affecting both the appendicular and axial skeleton including long bone diaphyses, ribs, and spine are often a hallmark finding in OI, especially in the more severe forms of the condition . In the spine, multiple thoracolumbar compression fractures and vertebral wedging may be seen and need careful evaluation to assess severity.
Bone deformities — Bone deformities include that of the appendicular skeleton, especially the lower limbs, but may also involve the upper limbs and skull . However, radiographic appearances may be within normal limits in mild forms of OI, making diagnosis challenging.
●Wormian bones are present in approximately 60 percent of patients with OI but are not specific to OI. Multiple wormian bones (defined as presence of 10 or more wormian bones arranged in a "mosaic" pattern) are seen in more severe forms of OI .
●In type V OI, there is often hyperplastic callus formation and interosseous membrane ossification with radial head dislocation, which are characteristic features .
●Leg-length discrepancy due to diaphyseal bending or angulation may be evident. Residual angulation of a healed fracture can result in bone deformities affecting both upper and lower limbs.
●Coxa vara (deformity of the femoral neck in which the angle between the head and neck of the femur is <120 degrees) and acetabular protrusion (displacement of the acetabulum and femoral head into the pelvis) have been reported in OI.
●Popcorn calcification of the metaphyses is seen in certain types of OI .
●Persons with OI who are on treatment with bisphosphonates may show dense metaphyseal bands on radiographic imaging .
Osteopenia — Osteopenia presents as cortical bone thinning and increased trabecular bone transparency on radiographs . However, these findings can be subjective and difficult to assess with conventional radiography unless there is at least 30 to 50 percent reduction in bone mineral content.
Dual energy X-ray absorptiometry — Dual energy X-ray absorptiometry (DXA) is a 2D-imaging technology that is used to measure bone mineral content (BMC). It is also a useful tool to measure changes in bone density over time and assess response to interventions or treatment. The modern DXA instruments may provide lateral spine images of sufficient quality in older children to substitute for plain radiographs, with the advantage of delivering a lower radiation dose. However, it is not applicable under five years of age due to lack of normative measurements and inability of most children to lie still to obtain accurate measurements .
LABORATORY FINDINGS — Biochemical parameters in OI tend to be normal. Serum calcium is normal, although hypercalciuria has been reported in some patients with OI with no kidney dysfunction or nephrocalcinosis . Serum 25-OH vitamin D levels may be low but are not typical and are attributable to lack of sunlight exposure, which can be fairly common.
Biochemical markers for bone turnover do not provide information on bone structure but may be useful in monitoring children with OI, especially response to treatment. Measurement of bone production and resorption markers, for example, urine N-terminal telopeptide (urine NTx) corrected for age and sex, may be useful in monitoring response to treatment. However, these parameters are not very sensitive or specific for the diagnosis of OI [46,47].
When to suspect OI — OI should be suspected in a patient with recurrent fractures, bone deformities, and/or short stature or the finding of short long bones in a fetus on in utero ultrasound or in a baby or child with a family history of OI. However, OI encompasses a wide range of presentations, ranging from mild to severe. Thus, a diagnosis is determined when there is a combination of skeletal and extraskeletal manifestations consistent with OI.
Initial evaluation — The clinical evaluation in OI is mainly focused on the skeletal system, although there are several extraskeletal manifestations that provide additional clues to the diagnosis. Imaging in OI in conjunction with clinical evaluation is key to making a diagnosis of OI. The timing of presentation is crucial (ie, antenatal through detection of findings on ultrasound or postnatally). It is also important to obtain a three-generation family pedigree with specific emphasis of any family history of OI and early-onset osteoporosis in the extended family. (See 'Imaging' above.)
Antenatal presentation — The approach to an antenatal presentation with an abnormal ultrasound depends on the timing of such a finding. Ultrasound findings should be reevaluated periodically (typically repeat ultrasound every two to three weeks), especially if there is suspicion of "short" long bones at 20-week scan, with the frequency determined by fetal growth measurements and imaging repeated postnatally if pregnancy is continued to ensure a precise diagnosis is made, especially in the absence of genetic confirmation of diagnosis. (See 'Antenatal findings on ultrasound' above and 'Postnatal dysplasia skeletal survey' above and "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias", section on 'Overview of prenatal diagnosis'.)
Early presentation — Short long bones identified on a 20-week anomaly scan usually suggest a more severe skeletal disorder, especially if seen in association with other findings such as large head circumference, reduced chest capacity, or abnormal brain imaging demonstrating features such as hydranencephaly, ventriculomegaly, and poorly ossified skull. In the context of a severe skeletal dysplasia, it is important where possible to obtain confirmatory genetic diagnosis through prenatal testing to determine prognosis and counselling regarding current pregnancy. (See 'Genetic and other confirmatory testing' below and 'Genetic counseling' below.)
Later presentation — Antenatal imaging may also identify abnormal findings of milder OI at a later gestation such as short long bones, bowing of femora, and fractures. This must be placed in the context of previous ultrasound findings and gestational age, and, again, an attempt should be made to obtain precise genetic diagnosis to inform prognosis. The infant should be evaluated postnatally to confirm antenatal presentation and diagnosis. Some of the severe forms of OI (not lethal) may be diagnosed at a later gestation and need further discussions with metabolic bone specialists to inform mode of delivery, transfer to a specialized clinical service, and institution of early treatment and care when pregnancy is continued.
Postnatal presentation — The initial evaluation in a child or adult presenting with clinical manifestations suggestive of OI is focused on detailed history taking and comprehensive physical examination, with specific emphasis on timing of initial presentation and fracture history.
History — A detailed history of fractures (including number, site, and mechanism of injury), joint dislocations, dental problems, exercise capacity, backache/stiffness, activities of daily living, and neurologic symptoms should be obtained.
Physical examination — A "head-to-toe" examination is recommended, especially in the pediatric age group. The patient is assessed for growth deficits, bone deformities, spine abnormalities, and extraskeletal features of OI. Measurements of length/height, weight, and head circumference and body proportions should be obtained and evidence of asymmetry noted. The color of sclerae (examined best under natural light) should be ascertained and presence of additional features determined, including dentinogenesis imperfecta (DI), triangular face with a high-pitched voice, pectus deformities of the chest (pectus excavatum/carinatum), rib cage flare, spinal tenderness, and scoliosis.
Imaging — Radiologic imaging provides additional clues for the diagnosis of OI. Plain radiographs are useful in imaging the long bones, spine, and skull. (See 'Postnatal dysplasia skeletal survey' above.)
Genetic counseling — Advances in genomic testing and access to such testing due to reducing costs has allowed more informed discussions in reasonable timescales in prenatal setting when genetic diagnosis confirmed. However, it is important to be mindful of patient values and preferences and uncertainty in giving precise prognostic information with skeletal dysplasias due to phenotypic variability and other factors.
When the diagnosis of a lethal skeletal dysplasia such as severe OI is made in the prenatal setting, it should be followed through with a referral to a specialist (fetomaternal/genetics service) to provide genetic counseling, accurate recurrence risk discussions, options regarding current pregnancy, and discussions in the future regarding options available for the next pregnancy .
Genetic and other confirmatory testing — The mainstay in the diagnosis of OI is molecular analysis of the genes associated with OI, most importantly COL1A1/COL1A2. In the majority of instances, the first-line strategy for diagnostic confirmation is testing for COL1A1/COL1A2 followed by testing of other genes known to cause OI (or a combined panel), especially with decreasing costs and improved access to genomic testing. However, in cases where such first-line genetic testing results in identification of a variant of uncertain significance, it is useful to have adjunct investigations (eg, skin biopsy for histology, electron microscopy, collagen species analysis)  and functional studies  to aid in variant interpretation. With more genes discovered in association with OI, it is increasingly important to accurately phenotype patients with OI in order to direct gene testing and variant interpretation. However, it is also important to be aware that a normal genetic result does not exclude a clinical diagnosis of OI. (See 'Classification' above.)
Standard practice is to perform targeted gene panel testing for all genes associated with OI (the United Kingdom National Health Service [NHS] maintains a list of genes included genomic testing for OI) or targeted analyses of whole exome/genome sequencing data for genes associated with OI.
Dosage analysis of COL1A1/COL1A2 can be performed if targeted panel testing is undertaken and is useful because OI occasionally is caused by partial exon deletions involving these genes . In addition, testing beyond OI panels, such as microarrays (detailed chromosome analyses), is indicated if a child with bone fragility has developmental delay since chromosome deletions involving OI genes can sometimes result in a composite phenotype .
Biochemical analysis of type 1 procollagen expression from cultured fibroblasts used to be helpful in directing gene testing . However, with decreasing costs of genetic testing and increased access, it is preferable to proceed directly with genetic testing. Adjunct investigations such as histology and electron microscopy can be helpful in making a diagnosis of OI, but such findings are not specific to the condition .
DIFFERENTIAL DIAGNOSIS — When a child or adolescent presents with a fracture, it is vital that a detailed history is taken. Fractures are common in an active child. However, if there is no reasonable explanation (a nontraumatic cause or a cause that cannot be identified), then further investigations should be undertaken.
The differential diagnosis of "unexplainable" fractures includes:
●Nonaccidental injury (NAI) – NAI is the most common cause of fractures in infancy or in an immobile child . However, radiologic investigations may not explain the underlying pathology. Thus, genetic testing ideally should be undertaken if OI is a possibility. (See "Differential diagnosis of the orthopedic manifestations of child abuse" and 'Genetic and other confirmatory testing' above.)
●Rickets – Features of rickets include bone pain, skeletal deformities, and dental problems. In severe cases, bones can become fragile and fracture in mobile children . There are other radiologic features of rickets that may be seen such as osteopenia and fraying or cupping of the metaphysis. Thus, fractures potentially caused by rickets should be imaged and biochemical tests performed to identify the underlying cause. (See "Overview of rickets in children".)
●Osteoporosis – Osteoporosis, defined as low bone mineral density (BMD), increases the risk of fracture. It is most commonly diagnosed in postmenopausal females and older males . It is rarely seen in a pediatric population.
●Metabolic conditions and syndromic disorders with bone fragility – Other causes of fracture in children and adults include metabolic conditions such as hypophosphatasia (HPP) and osteopetrosis with renal tubular acidosis [54,57]. Biochemical investigations should be performed if these are to be ruled out. In addition, there are certain genetic syndromes where bone fragility is a predominant feature in the clinical phenotype complicated by moderate-severe intellectual disability, meaning these persons may not be able to explain when a fracture has occurred and/or may have a high pain threshold. Awareness of these associations will help ensure a low threshold for further imaging (including that of the spine) and early recognition of a fracture, leading to adequate treatment and prevention of secondary deformities.
•Cole-Carpenter syndrome – Cole-Carpenter syndrome is often categorized as a rare OI disorder [58,59]. Cole-Carpenter syndrome 1 (CLCRP1; OMIM #11240) is due to a heterozygous missense variant in prolyl 4-hydroxylase subunit beta (P4HB) . All patients in this cohort were found to have a recurrent missense variant in P4HB. Cole-Carpenter syndrome 2 (CLCRP2; OMIM #616294) is caused by compound heterozygous variants in SEC24 homolog D, COPII coat complex component (SEC24D) .
•Short stature, optic atrophy, Pelger-Huet anomaly (SOPH) syndrome – Pathogenic variants in the neuroblastoma-amplified sequence subunit of NRZ tethering complex (NBAS) are associated with multisystem phenotypes [62-67]. SOPH syndrome, found in the isolated Yakut Siberian population, is due to homozygous missense variants in NBAS . Compound heterozygous pathogenic variants in NBAS are associated with a multisystem phenotype that includes bone fragility, frequent fractures, short stature, abnormal liver function tests, acute-onset liver failure, immunodeficiency, and developmental delay [63,67].
•Bruck syndrome – Bruck syndrome is an autosomal recessive (AR) condition with bone fragility, congenital talipes, white or blue sclera, wormian bones, and congenital joint contractures [68,69]. It is characterized by intrafamilial variability between OI and contractures. Bruck syndrome type 1 is caused by pathogenic variants in FKBP10, while Bruck syndrome type 2 is due to a defect in the lysyl hydroxylase (PLOD2), which hydroxylates the amino-terminal lysyl residues that are involved in cross-link formation [15,70]. These hydroxylysyl groups serve as sites of attachment for carbohydrate units and are essential to maintain the stability of the intermolecular collagen cross-links [15,70].
•Osteoporosis pseudoglioma syndrome – This AR disorder is characterized by fractures, bone fragility, and pseudoglioma with blindness in infancy. It is due to variants in the gene encoding LRP5 [71,72]. LRP5, located on chromosome 11q13.4, is a coreceptor of Wnt-signaling pathway and is situated in the osteoblast membrane between two other receptors, Frizzled-4 and Kremen. Wnt signaling is involved in cell proliferation, adhesion, migration, and other activities. Binding of Frizzled-4 and LRP5 to Wnt stabilizes beta-catenin and activates bone formation. LRP5 regulates BMD and is important for maintaining skeletal homeostasis. Heterozygous variants in LRP5 are known to cause primary osteoporosis in children .
•Idiopathic juvenile osteoporosis (IJO) – This condition is characterized by fractures and osteoporosis in the preadolescent period. It usually resolves spontaneously but can leave behind long-term sequelae. Some cases of IJO are now attributed to heterozygous pathogenic variants in LRP5 .
•Caffey disease – Caffey disease, also known as infantile cortical hyperostosis, is a form of type 1 collagenopathy with clinical features at the milder end of the spectrum. It is characterized by pain and swelling in the first six months of life and is associated with massive subperiosteal new bone formation that usually involves the diaphyses of the long bones, ribs, mandible, and scapulae. There is spontaneous resolution of clinical and radiologic features by two years of age. Limited follow-up data on families with Caffey disease have suggested that persons who developed the condition as a child may be more prone to joint laxity, skin hyperextensibility, hernias, and multiple fractures in adulthood, possibly due to low BMD [75,76]. (See "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'.)
There are case reports of prenatal onset of Caffey disease with clinical features that have some overlap with OI. Features include hepatomegaly, pulmonary hypoplasia, bowing of the long bones, and still birth or early neonatal death . A recurrent COL1A1 pathogenic variant, c.3040C>T,p.Arg1014Cys in exon 41, was identified in patients with this condition .
•Hypophosphatasia – HPP is a rare, inherited skeletal dysplasia primarily caused by pathogenic variants in alkaline phosphatase, biomineralization associated (ALPL). It is clinically characterized by extreme heterogeneity. The underlying pathology is defective mineralization of bone and/or teeth due to reduced activity of tissue nonspecific isoenzyme of alkaline phosphatase (TNAP), encoded by ALPL. The disease spectrum, although reported to be a continuum, is usually subclassified into six clinical forms based upon severity and age at diagnosis: perinatal severe HPP, perinatal benign HPP, infantile HPP, childhood or juvenile HPP, adult HPP, and odontohypophosphatasia without any obvious skeletal manifestations . (See "Skeletal dysplasias: Specific disorders", section on 'Hypophosphatasia'.)
•Fibrous dysplasia/McCune-Albright syndrome – This is a rare and severe form of polyostotic fibrous dysplasia caused by somatic gain-of-function variant in GNAS complex locus (GNAS) resulting in overactivity in target tissues. It is characterized by skeletal lesions, skin hyperpigmentation (café-au-lait macules), and endocrinopathies (thyroid lesions amongst others) resulting in precocious puberty. Careful clinical and radiologic evaluation helps distinguish it from OI . (See "Definition, etiology, and evaluation of precocious puberty", section on 'Genetics' and "Congenital and inherited hyperpigmentation disorders", section on 'McCune-Albright syndrome'.)
•Hereditary hyperphosphatasia – This rare, AR disorder is caused by pathogenic variants in tumor necrosis factor receptor superfamily member 11b (TNFRSF11B)  that affects bone growth. Bones are deformed and fracture easily, resulting in progressive skeletal malformations. It is sometimes referred to as juvenile Paget disease due to similar radiographic and biochemical findings to Paget disease (a focal adult-onset disorder characterized by increased bone turnover). Markedly increased bone turnover markers such as plasma alkaline phosphatase (ALP) helps distinguish it from OI, in which ALP is usually normal.
•Hajdu-Cheney acroosteolysis – This autosomal dominant (AD) condition is caused by pathogenic variants in notch receptor 2 (NOTCH2)  and is characterized by failure to thrive, hearing loss, early loss of teeth, osteopenia, fractures, wormian bones, scoliosis, acroosteolysis, and hirsutism .
•Isolated dentinogenesis imperfecta – DI can occur as an isolated familial condition due to pathogenic variants in the gene that encodes for dentin sialophosphoprotein (DSPP), located on chromosome 4q21.3 . DSPP is divided into dentin sialoprotein (DSP), dentis glycoprotein (DGP), and dentin phosphoprotein (DPP). These proteins make up dentin, a bone-like substance present in the middle layer of teeth. DPP in particular is essential for teeth mineralization as it is involved in deposition of mineral crystals around collagen fibers in dentin. (See "Developmental defects of the teeth", section on 'Dentinogenesis imperfecta'.)
•Snyder-Robinson syndrome – Snyder-Robinson syndrome is an X-linked intellectual disability syndrome caused by a hemizygous pathogenic variant in spermine synthase (SMS) with features including moderate-to-severe intellectual disability, speech delay, seizures, kyphoscoliosis, and increased risk of fractures . Most patients with this condition develop fractures following minimal trauma and need careful monitoring, particularly in view of their intellectual disability and communication issues. Progressive scoliosis needing intervention is also a well-recognized complication.
•Sodium channelopathies – Pathogenic variants in genes encoding the neuronal voltage-gated sodium channels such as sodium voltage-gated channel alpha subunit 8 (SCN8A) and sodium voltage-gated channel alpha subunit 9 (SCN9A) are associated with a multiple skeletal fractures and seizure phenotype [86-88]. It remains unclear whether the increased fracture risk in these persons is due to a combination of genetic and environmental factors (such as seizure activity, response to antiseizure medication, high sensitivity to pain) or due to underlying effect on bone. (See "Overview of infantile epilepsy syndromes".)
•SATB homeobox 2 (SATB2) associated osteoporosis – SATB2-associated syndrome (SAS), caused by pathogenic variants in SATB2, is characterized by abnormalities of the palate and teeth, severe speech and intellectual disabilities, and behavioral issues. Skeletal abnormalities, including tibial bowing, osteopenia, and low BMD with potential to increased fracture risk, are also reported [89,90]. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Syndromic cases'.)
•Other bone fragility syndromes – Other bone fragility syndromes include SET domain containing 5 (SETD5) related disorder ; intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies (IMAGe) syndrome ; and 3M syndrome 1 (MIM #273750), 2 (MIM #612921), and 3 (MIM #614205) (named for the three physicians with surnames beginning with M who described the disorder, also called dolichospondylic dysplasia), amongst others .
•Other causes of bone fragility/fractures in adults – Other causes of bone fragility and fractures in adults include environmental factors, eating disorders, and/or nutritional deficiencies (eg, Crohn disease, celiac disease).
MANAGEMENT — The mainstay of management in OI is multidisciplinary and consists of physical therapy, surgical interventions, and bone-targeted therapy [94-96]. The emphasis is on not only improving bone health but also improving muscle strength, mobility, function, and quality of life for persons with OI. Bisphosphonates remain the cornerstone for medical therapy and are used commonly in moderate-to-severe forms of OI with a high risk of fractures. Decisions around commencing bone-targeted therapy and ongoing surveillance are most appropriately made by specialists at centers with significant expertise in managing children and adults with OI.
In addition to bone health, it is also important that persons with OI have ongoing monitoring and assessment for extraskeletal features seen in OI, including routine dental examination, early diagnosis of hearing loss, monitoring growth, cardiovascular assessment for valvular abnormalities and aortic root measurements, and neurodevelopmental assessments for hydrocephalus and basilar impression. OI is a multisystemic disorder, and management is aimed at improving both skeletal and extraskeletal health in these persons.
SUMMARY AND RECOMMENDATIONS
●Pathogenesis and genetics – Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation resulting in low bone mass, bone fragility, and an increased propensity to fracture. The majority of OI is caused by pathogenic variants in genes encoding type 1 collagen (ie, collagen type I alpha 1 chain [COL1A1]/collagen type I alpha 2 chain [COL1A2]) with an autosomal dominant (AD) pattern of inheritance. Most other OI is caused by pathogenic variants in genes involved in processing and secretion of type 1 collagen, bone mineralization, and osteoblast differentiation. (See 'Pathogenesis' above and 'Genetics' above.)
●Classification – OI remains a clinical diagnosis, although improvements in imaging and access to genomic testing have allowed refining of the type of OI and genotype-phenotype correlation (table 1). (See 'Classification' above.)
●Clinical manifestations – There is a broad spectrum of clinical severity in OI, ranging from multiple fractures in utero and perinatal lethality to near-normal adult stature and low fracture incidence (table 1 and table 2). Extraskeletal features are also variable and include blue or greyish sclerae (picture 1), hearing loss, skin hyperlaxity, joint hyperextensibility, and dentinogenesis imperfecta (DI) (picture 2). Facial dysmorphism and cardiovascular, neurologic, and respiratory manifestations are also seen in some patients. (See 'Clinical manifestations' above and 'Imaging' above.)
●When to suspect OI – OI should be considered in a person presenting with low-trauma fractures and/or short stature or the finding of short long bones in a fetus on in utero ultrasound. However, it is important to remember that OI is a multisystem disorder affecting other organ systems in addition to the skeleton. (See 'When to suspect OI' above.)
●Initial diagnostic evaluation – Early diagnosis of OI is important to distinguish it from nonaccidental cause of fractures and institute appropriate therapy. The diagnosis can be made clinically in the milder forms of OI when correlated with family history, medical history, and clinical features including imaging. However, the diagnosis can be difficult in the absence of these features, especially in the context of a negative genetic test. (See 'Initial evaluation' above and 'Imaging' above.)
●Confirmatory testing – Improved access to genomic testing with reduced costs allows for confirmatory genetic diagnosis in OI. However, clinical and radiologic correlation remains vital with regards to variant interpretation and providing prognostic information. In addition, it is important to be aware that a normal genetic result does not exclude a clinical diagnosis of OI. (See 'Genetic and other confirmatory testing' above.)
●Differential diagnosis – The differential diagnosis for low-trauma fracture includes nonaccidental injury (NAI), rickets, osteoporosis, metabolic conditions, and syndromic disorders with bone fragility. (See 'Differential diagnosis' above.)
●Management – OI is a multisystemic disorder, and management is aimed at improving both skeletal and extraskeletal health along with quality of life. The mainstay of management in OI is multidisciplinary and consists of physical therapy, surgical interventions, and bone-targeted therapy. Bisphosphonates remain the cornerstone for medical therapy and are used commonly in moderate-to-severe forms of OI with a high risk of fractures. (See 'Management' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Arkadi A Chines, MD and John F Beary III, MD, who contributed to earlier versions of this topic review.
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