Genetics of Osteogenesis Imperfecta 

Updated: Nov 11, 2019
Author: Eric T Rush, MD, FAAP, FACMG; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Practice Essentials

Osteogenesis imperfecta (OI) is a disorder of bone fragility chiefly caused by mutations in the COL1A1 and COL1A2 genes that encode type I procollagen. Four types of osteogenesis imperfecta were originally described by Sillence in 1979 and are now used broadly as the Sillence Criteria.[1] The Nosology and Classification of Genetic Skeletal Disorders provides similar categorization in the 2010 revision.[2] Precise typing is often difficult, and depends in large degree on the experience of the clinician. Severity ranges from mild forms to lethal forms in the perinatal period. Additional genes have been discovered in which mutations can also cause brittle bones. These are typically clinically indistinguishable and are considered by most to be subtypes of osteogenesis imperfecta.[3] Examples of common radiologic findings of osteogenesis imperfecta are shown in the images below.

Acute fractures are observed in the radius and uln Acute fractures are observed in the radius and ulna. Multiple fractures can be seen in the ribs. Old healing humeral fracture with callus formation is observed.
Beaded ribs. Multiple fractures are seen in the lo Beaded ribs. Multiple fractures are seen in the long bones of the upper extremities.
Wormian bones are present in the skull. Wormian bones are present in the skull.
This newborn has bilateral femoral fractures. This newborn has bilateral femoral fractures.

Physical characteristics of osteogenesis imperfecta

Individuals with type III (severe, progressively deforming) OI may have joint hyperlaxity; muscle weakness; chronic, unremitting bone pain; and skull deformities (eg, posterior flattening) due to bone fragility during infancy. Limb shortening and progressive deformities can occur, and patients have a triangular face with frontal and temporal bossing; malocclusion is common. The sclera have variable hues.

Workup in osteogenesis imperfecta

Results from routine laboratory studies in patients with OI are usually within reference ranges, and they are useful in ruling out other metabolic bone diseases, such as hypophosphatasia or inherited forms of rickets.

Collagen synthesis analysis has historically been performed by culturing dermal fibroblasts obtained during skin biopsy. This testing modality has fallen out of favor, given that molecular diagnostic techniques are more accurate, have increased in availability, and have decreased in cost. Widespread adoption of next-generation sequencing (NGS) technology has allowed for parallel sequencing of many genes. Thus, there is little or no difference in cost or turnaround time for multigene panels compared with limiting investigation to the two procollagen I genes.

Obtain a radiographic skeletal survey after birth. Prenatal ultrasonography can be used to detect limb-length abnormalities at 15-18 weeks’ gestation.

The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are decreased in all types of osteogenesis imperfecta. The number and thickness of trabeculae are reduced.

Management

Cyclic administration of intravenous pamidronate reduces the incidence of fracture and increases bone mineral density, while reducing pain and increasing energy levels.[4] Intravenous zoledronate has been increasingly used in children with OI, given its shorter infusion times and longer infusion intervals. Observational studies have shown similar effects to that of pamidronate, with increased bone mineral density, decreased fracture rate, and improvement in pain.[5] There is scant evidence supporting the use of bisphosphonates in adults with OI, although they continue to be widely used; anecdotally, some patients experience a subjective decrease in pain.[6] The bisphosphonate risedronate may have some effect in reducing fractures in patients with OI.[7]

Nutritional evaluation and intervention are paramount to ensure appropriate intake of calcium and vitamin D. Caloric management is important, particularly in adolescents and adults with severe forms of OI.

Orthopedic surgery is one of the pillars of treatment for patients with OI.[8] Surgical interventions include intramedullary rod placement, surgery to manage basilar impression, and correction of scoliosis.

Pathophysiology

The most widely used classification of osteogenesis imperfecta, published by Sillence et al in 1979, does not include additional forms of the disorder, which were discovered as a result of improvements in molecular diagnostics.[9] Rather, these forms of osteogenesis imperfecta are caused by genes that interact with collagen I or in the complex relationship between formation and remodeling of bone. They are molecularly distinct from osteogenesis imperfecta caused by COL1A1 or COL1A2 but form an example of locus heterogeneity. Forlino and Marini, in 2015, offered an alternate way of understanding the genetics of osteogenesis imperfecta, using five functional categories, as follows[10] :

  • Group A: Primary defects in collagen structure or function ( COL1A1, COL1A2, BMP1)
  • Group B: Collagen modification defects ( CRTAP, LEPRE1, PPIB, TMEM38B)
  • Group C: Collagen folding and cross-linking defects ( SERPINH1, FKBP10, PLOD2)
  • Group D: Ossification or mineralization defects ( IFITM5, SERPINF1)
  • Group E: Osteoblast development defects with collagen insufficiency ( WNT1, CREB3L1, SP7)

This classification system has not been integrated into widespread use but offers significant streamlining of categories into intellectually satisfying divisions.

COL1A1/COL1A2 (Types I-IV)

Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body by weight, (90% of the protein within bone) is defective in osteogenesis imperfecta. In structural terms, type I collagen fibers are composed of a left-handed helix formed by intertwining of pro-alpha 1 and pro-alpha 2 chains. Mutations in the genes that encode these chains cause osteogenesis imperfecta (COL1A1 at 17q21 and COL1A2 at 7q22.1, respectively).

Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described. Quantitative defects most frequently result from missense mutations in a glycine-coding codon and cause disease due to a dominant negative effect. There is not a perfect correlation between genotype and phenotype, but a few observations have been made. First, generally speaking mutations in the COL1A1 gene will tend to be more severe than a corresponding mutation in the COL1A2 gene, likely due to the fact that that two alpha 1 chains are required and only one alpha 2 chain is required to make the procollagen I heterotrimer. Second, mutations located at the carboxyl terminal domain of each of the genes are more severe than in other domains. In particular, missense mutations in COL1A1 in this region are frequently (but not always) lethal. Third, size and polarity matter to the severity of the mutation. As an example, a substitution of glycine for alanine, which is only slightly larger, nonpolar, and with similar chemical properties, is likely to result in a milder phenotype. Contrast this with a substitution of glycine for glutamic acid at the same position, which is large, negatively charged, and with different chemical properties and is more likely to be severe or even lethal. Quantitative defects often result from nonsense mutations but can result from larger deletions in one of the procollagen genes and cause disease due to haploinsufficiency effect, as the prematurely truncated mRNA undergoes nonsense-mediated decay (NMD); while the patient is left with structurally normal collagen, he or she makes only half the normal amount. These patients have mild nondeforming (Type I) osteogenesis imperfecta.

A study by Balasubramanian et al indicated that COL1A1/COL1A2 mutations consistently result in collagen fibril diameter variability and collagen flowers.[11]

Osteogenesis Imperfecta with Calcification of the Interosseous Membranes (Type V)

Patients with this form of osteogenesis imperfecta generally have moderate severity disease but frequently develop hyperplastic calluses in long bones after having a fracture or orthopedic surgery that involves osteotomies. The size and shape of the callus may remain stable for many years after a rapid growth period, but in some cases slowly involutes. Patients also frequently develop calcification of the forearm interosseous membrane and dislocation of the radial head, which results in difficulties with supination and pronation. They may also have subphyseal metaphyseal radiodensity seen on radiography.[12] This condition is caused by heterozygous mutations in the IFITM5 gene, and inheritance is autosomal dominant.[13]

Histology of bone showed that the lamellae are arranged in an irregular fashion and in some cases appeared meshlike, as opposed to the typical parallel arrangement in patients with osteogenesis imperfecta.

Other Forms of Osteogenesis Imperfecta

SERPINFI (Type VI)

Patients with this form of osteogenesis imperfecta generally have moderate severity disease. It was observed that many patients with this form of osteogenesis imperfecta do not have fractures at birth and only develop them later in infancy or as toddlers. Patients with this form of osteogenesis imperfecta have been described as having variably blue or white sclerae and have normal teeth.[14] This condition is caused by homozygous mutation in the SERPINF1 gene, and inheritance is autosomal recessive.[15]

Histology of bone showed a characteristic fish-scale appearance to the lamellae and at least one author has commented on the presence of large quantities of unmineralized osteoid on biopsy specimens.

CRTAP/LEPRE1/PPIB (Types VII-IX)

Patients with osteogenesis imperfecta caused by mutations in these three genes generally have severe disease, with examples of lethal disease being noted. Cartilage-associated protein (CRTAP) is a protein required for prolyl 3-hydroxylation, and with the protein products of the LEPRE1 and PPIB genes, forms a heterotrimeric protein that is crucial for proper posttranslational modification of collagen I. Osteogenesis imperfecta caused by mutations in CRTAP have been designated type VII disease, whereas osteogenesis imperfecta caused by mutations in LEPRE1 and PPIB are designated type VIII and type IX disease, respectively.[16] These conditions are caused by homozygous or compound heterozygous mutations and are inherited in an autosomal recessive manner.

SERPINH1 (Type X)

Report of only one patient with this form of osteogenesis imperfecta could be found in the literature. This male patient was born to a consanguineous union of Saudi Arabian origin, and his parents were reported as clinically normal. He was reported to have severe deforming osteogenesis imperfecta with dentinogenesis imperfecta, nephrocalcinosis, and chronic lung disease. He died at age 3 years from respiratory complications. Genetic testing of this child found a previously described homozygous mutation in the SERPINH1 gene.[17] The protein product of SERPINH1 is a chaperone in the ER that appears to function in collagen trafficking.

FKBP10 (Type XI)

A small number of patients with this form of osteogenesis imperfecta have been reported and severity has been moderate to severe. It is caused by homozygous mutations in the FKBP10 gene and is inherited in an autosomal recessive manner.[18] It is understood that some patients with Bruck syndrome, type II also have mutations in this gene, but the full spectrum of clinical findings is not understood, and it has been proposed to designate FKBP10 -related disorders as recessive forms of progressive deforming osteogenesis imperfecta with or without joint contractures.[19] The protein product of FKBP10 is a chaperone that participates in collagen folding and mutation impairs its secretion.[20]

Histology of bone showed a distorted lamellar structure and a fish scale pattern.

SP7 (Type XII)

Only one patient with this form of osteogenesis imperfecta has been reported and had moderate severity disease. This male patient was the product of a second-cousin union and in addition to fractures had delay in tooth eruption, normal hearing, and white sclerae. A sibling was similarly affected, but also died of a presumably unrelated congenital heart defect. The surviving child had homozygous deletions in the SP7 gene, and this form of osteogenesis imperfecta is inherited in an autosomal recessive fashion.[21] The protein product of SP7 is required for osteoblast differentiation and bone formation. In a null mutant animal model, no cortical bone or bone trabeculae were formed through intramembraneous or endochondral ossification.[22]

BMP1 (Type XIII)

A small number of patients with this form of osteogenesis imperfecta have been described and have generally had severe disease with frequent fractures and severe growth deficiency. However, two siblings described had only borderline low bone density. Patients with this form of osteogenesis imperfecta were described with normal teeth and blue sclerae.[23] This form of osteogenesis imperfecta is caused by homozygous mutation in the BMP1 gene, and it is inherited in an autosomal recessive manner. The BMP1 protein product appears to play important roles in osteogenesis, but also is thought to have a role in the removal of C-propeptides from certain procollagens, including type I procollagen.[24]

TMEM38B (Type XIV)

This form of osteogenesis imperfecta has been described in three consanguineous families of Saudi origin, and three different consanguineous families of Israeli Bedouin origin. Affected individuals had osteogenesis imperfecta of variable severity without blue sclerae, dentinogenesis imperfecta, or hearing loss.[25] This form of OI is caused by homozygous mutation in the TMEM38B gene and is inherited in an autosomal recessive manner.[26]

WNT1 (Type XV)

This recently discovered form of osteogenesis imperfecta has now been described in a number of families and causes moderate to severe disease. Patients with this condition have had short stature, blue or white sclerae, and normal hearing. A subset of patients have been seen with brain malformations and developmental delay. This form of OI is caused by homozygous or compound heterozygous mutations in the WNT1 gene and is inherited in an autosomal recessive manner.[27] Canonical WNT/beta-catenin signaling has been shown to be crucial for the differentiation of osteoblasts and further bone development.[28]

CREB3L1 (Type XVI)

CREB3L1 encodes the endoplasmic reticulum stress transducer protein OASIS, which regulates the expression of type 1 procollagen. Biallelic mutation in this gene can be expected to produce insufficiency of type I procollagen. Two siblings have been reported with this form of OI, and both were homozygous for the same deletion. This deletion is some 91 kB in size and renders patients nullisomic for the CREB3L1 locus. The first affected patient was male and was known to be affected by severe OI. This patient was small for gestational age, with multiple fractures in utero. Postnatally, he developed a number of fractures and was described with beaded ribs. He also had several bouts of pneumonia and died at 9 age months, presumably from respiratory complications, although this was not explicitly stated. The second affected sibling was also male and termination was performed at 19 weeks of gestation. The parents and a healthy older sister did not have similar findings of bone fragility but were described with blue sclerae. The mother had velvety skin and small-joint hypermobility. The father also had velvety skin, as well as conductive hearing loss.[29]

SPARC (Type XVII)

SPARC (secreted protein, acidic, cysteine-rich) is a glycoprotein that binds to multiple matrix proteins, including collagen I. Two unrelated patients have been described as homozygous for pathogenic variants in the SPARC gene; both had significant bone fragility and had been previously diagnosed with Type IV OI based on phenotype alone. The first patient was of North African origin and in addition to her fractures, experienced a neonatal intraventricular hemorrhage. At the time of her evaluation by the authors, she had sustained 10 long-bone fractures but was of normal stature. She had joint hypermobility and humeral bowing, and her bone mineral density was low for her age. The second patient was born of a consanguineous union and was of Indian descent. She presented initially with hip dislocation and was subsequently observed to have hypotonia and motor delay. She also had normal stature, as well as joint laxity and soft skin. Her bone mineral density was also low for her age. Molecular diagnosis was obtained in these patients using whole exome sequencing (WES). The first patient was homozygous for the pathogenic variant c.497G>A (p.Arg166His), and the second patient was homozygous for the pathogenic variant c.787G>A (p.Glu263Lys). It was observed that these pathogenic variants were both in highly conserved regions of the protein. Further investigation revealed that each was located in different portions of the extracellular collagen binding portion of the SPARC protein.[30]

TENT5A (FAM46A) (Type XVIII)

TENT5A (terminal nucleotidyltransferase 5A), also called FAM46A, is an example of a class of enzymes that catalyze the transfer of a nucleoside monophosphate molecule from nucleoside triphosphate to a hydroxyl group in a different molecule. Changes in the TENT5A enzyme cause a recessive form of OI, and a small number of patients have been reported with homozygous pathogenic variants in the TENT5A gene. Doyard et al reported a small case series of four patients in three families with this form of OI. All affected patients were known or suspected to be consanguineous. Patients in this series had variable presentation, but consistent features included typical OI traits such as bowing of the limbs, frequent fractures, wormian bones, blue sclerae, and joint hypermobility. One patient died suddenly at age 4 years for unknown reasons that presumably were unrelated to the OI diagnosis.[31]

MBTPS2 (Type XIX)

MBTPS2 (membrane-bound transcription factor protease, site 2) is involved in transcription control and in the endoplasmic reticulum (ER) stress response. Type XIX OI is an X-linked recessive form of the disease that has been seen in several males in two unrelated families, one from Thailand and one from Germany. Patients presented with multiple fractures, bowing of long bones, low bone mineral density, pectus excavatum, and moderate to severe short stature. There is no evidence of a phenotype for carrier females.[32]

Osteogenesis imperfecta with congenital joint contractures, Types 1 and 2 (Bruck syndrome)

Patients with Bruck syndrome have congenital brittle bones prone to fracture, as well as congenital joint contractures and pterygia. They also have short stature, severe limb deformity, wormian bones, and progressive scoliosis which can be severe. Patients have generally been described with normal hearing, no dentinogenesis imperfecta, and white sclerae. Two forms of Bruck syndrome have been delineated with molecular testing, but appear to be clinically indistinguishable. Bruck syndrome 1 is caused by homozygous mutation in the FKBP10 gene[33] , while Bruck syndrome 2 is caused by homozygous mutation in the PLOD2 gene.[34] Both disorders are inherited in an autosomal recessive manner. It has been suggested that the defect underlying Bruck syndrome is a deficiency of bone-specific telopeptide lysyl hydroxylase, which results in aberrant bone collagen crosslinking.[35]

Cardiovascular concerns in osteogenesis imperfecta

A number of published reports have identified patients with OI who have had aortic and other vascular dissections, and there are reasonable concerns about increased risk in this population. A study by Rush et al evaluated 100 children and adolescents with OI and found that patients with Types III and IV had significantly larger aortic diameters compared with size-matched controls. The investigators also determined that patients with Type I OI had normal aortic diameters but larger and thinner left ventricles compared with size-matched controls. No patient in this study had cardiovascular findings that were immediately actionable, but since reports of potentially lethal cardiovascular complications have been described in adult patients, a screening echocardiogram by age 18 in patients with OI is recommended.[36] No truly evidence-based guidelines for surveillance of cardiovascular disease in OI have been published.

Epidemiology

Frequency

United States

The prevalence of OI is estimated to be 1 per 15,000 live births;[37] however, the mild form is underdiagnosed, and the actual prevalence may be higher.

International

Prevalence appears to be similar worldwide, although there may be an increased risk of recessive forms of osteogenesis imperfecta in populations with high degree of consanguinity.

Race

No differences based on race are reported.

Sex

No differences based on sex are reported.

Age

The age when symptoms (ie, fractures) begin widely varies. Patients with mild forms of OI generally do not present at birth, instead often presenting with fracture after incidental trauma. Patients with severe cases typically present with fractures in utero.

 

Presentation

History

Many patients with osteogenesis imperfecta (OI), particularly individuals with the more severe forms, have acquired the disease through de novo pathogenic variants, although some patients, particularly those with mild forms, have inherited the disease from a parent. 

Patients may present with spontaneous fracture or fracture from minor trauma.

In severe cases, prenatal screening ultrasonography performed during the second trimester may show bowing of long bones, fractures, limb shortening, and decreased skull echogenicity. Lethal OI cannot be diagnosed with certainty in utero, and it is important for perinatal providers to understand the clinical variability of disease. .

Patients with OI may have joint hypermobility, especially of the small joints. Skin can also be fragile, and patients may describe easy bruising.

Unlike individuals with some other brittle bone diseases (such as inherited forms of rickets), patients with OI tend to heal avidly. However, because of the sheer number of fractures, nonunion or delayed union is not rare. 

Hearing loss is a variable feature of OI. About 50% of patients with type I OI have hearing loss by age 40 years.[38]

Physical

Physical examination can vary depending on the severity. Degrees of severity may vary to some extent among different affected members of the same family.

Type I - Mild, nondeforming

See the list below:

  • Patients have no long-bone deformity.

  • The sclera can be blue or white. Blue sclera may also occur in other disorders, such as progeria, cleidocranial dysplasia, Menkes syndrome, cutis laxa, Cheney syndrome, and pyknodysostosis.

  • Dentinogenesis imperfecta may be present.

  • Over a lifetime, numbers of fractures can range from 1-60 or more.

  • Height is usually normal in individuals with mild forms of osteogenesis imperfecta, but may be less than unaffected members of their family.[39]

  • People with osteogenesis imperfecta have a high tolerance for pain. Old fractures may be discovered in infants only after radiographs are obtained for other reasons other than an assessment of osteogenesis imperfecta, and they can occur without any signs of pain.

  • Exercise tolerance and muscle strength are frequently reduced in patients with osteogenesis imperfecta, even in the mild forms.

  • Fractures are most common during infancy but may occur at any age.

  • Other possible findings include kyphoscoliosis, hearing loss,[40] premature arcus senilis, and easy bruising.

Type II - Perinatal lethal

See the list below:

  • Some providers who treat large numbers of patients with osteogenesis imperfecta suggest that the diagnosis of Type II OI be made in retrospect for patients who do not survive the perinatal period, and that even patients with very severe forms of OI who nonetheless are long term survivors be classified as Type III.

  • Blue sclera may be present.

  • Patients may have a small nose, micrognathia, or both.

  • All patients have in utero fractures, which may involve the skull, long bones, and/or vertebrae.

  • The ribs are beaded, and the long bones are severely deformed.

  • Causes of death include extreme fragility of the ribs, pulmonary hypoplasia, and malformations or hemorrhages of the CNS.

Type III - Severe, progressively deforming

See the list below:

  • Patients may have joint hyperlaxity; muscle weakness; chronic, unremitting bone pain; and skull deformities (eg, posterior flattening) due to bone fragility during infancy.

  • Deformities of upper limbs may compromise function and mobility.

  • The presence of dentinogenesis imperfecta is independent of the severity of the osteogenesis imperfecta.

  • The sclera have variable hues.

  • In utero fractures are common.

  • Limb shortening and progressive deformities can occur.

  • Patients have a triangular face with frontal and temporal bossing. Malocclusion is common.

  • Basilar invagination is an uncommon but potentially fatal occurrence in osteogenesis imperfecta.

  • Vertigo is common in patients with severe osteogenesis imperfecta.

  • Hypercalciuria may be present in about 36% of patients with osteogenesis imperfecta, and adults may be at higher risk of renal calculi.[41]

  • Respiratory complications secondary to kyphoscoliosis are common in individuals with severe osteogenesis imperfecta.

  • Constipation and hernias are also common in people with osteogenesis imperfecta.

Type IV - Common variable

See the list below:

  • This type of osteogenesis imperfecta is not as clearly defined as other types.

  • Height is extremely variable with some patients having near-normal height and others having significantly short stature.[39]

  • Dentinogenesis imperfecta may be present. Some have suggested that this sign can be used to divide type IV osteogenesis imperfecta into subtypes a and b.

  • Fractures usually begin in infancy, but in utero fractures may occur. The long bones are usually bowed, although typically not as severe as patients with type III.

Causes

Osteogenesis imperfecta is an inherited disorder. In Types I-V osteogenesis imperfecta, the mode of inheritance is autosomal dominant and often involves a new dominant mutation. This accounts for between 90-95% of the total disease burden. The remaining 5-10% of patients show an autosomal recessive inheritance pattern, with both parents generally being asymptomatic carriers.

Some have proposed possible germ-cell mosaicism as an explanation for cases occurring in families with healthy parents that have more than one child with osteogenesis imperfecta. In some cases, somatic mosaicism has been noted in parents who have had multiple children with the same dominant form of osteogenesis imperfecta.

 

DDx

Diagnostic Considerations

The differential diagnosis of osteogenesis imperfecta (OI) is broad and is very different for patients with severe forms of OI compared with those suffering from milder forms. Patients with severe OI may also be evaluated for other potentially lethal skeletal dysplasias. In patients with less severe forms of OI, the disease may be mistaken for nonsyndromic forms of osteoporosis or may not be appreciated. Examples of potential diagnostic considerations across the spectrum of disease include the following:

  • Nonaccidental trauma

  • Campomelic dysplasia

  • Thanatophoric dysplasia

  • Achondrogenesis type I

  • Infantile/perinatal/juvenile hypophosphatasia

  • Brittle cornea Syndrome

  • Steroid-induced osteoporosis

  • Idiopathic juvenile osteoporosis

  • Osteoporosis of disuse

Differential Diagnoses

 

Workup

Laboratory Studies

Results from routine laboratory studies in patients with osteogenesis imperfecta (OI) are usually within reference ranges, and they are useful in ruling out other metabolic bone diseases, such as hypophosphatasia or inherited forms of rickets.

Collagen synthesis analysis has historically been performed by culturing dermal fibroblasts obtained during skin biopsy. This testing modality has fallen out of favor, given that molecular diagnostic techniques are more accurate, have increased in availability, and have decreased in cost. Widespread adoption of next-generation sequencing (NGS) technology has allowed for parallel sequencing of many genes. Thus, there is little or no difference in cost or turnaround time for multigene panels compared with limiting investigation to the two procollagen I genes. 

Prenatal DNA mutation analysis can be performed in pregnancies with risk of osteogenesis imperfecta to analyze uncultured chorionic villus cells. Samples are obtained during chorionic villus sampling performed under ultrasonographic guidance when a mutation in another member of the family is already known.

Bone mineral density, as measured with dual-energy radiographic absorptiometry (DRA), is generally low in children and adults with osteogenesis imperfecta. However, there is wide variation in the bone density of patients with OI. Still, normal bone density in a patient in whom osteogenesis imperfecta is being evaluated should prompt consideration of alternate diagnoses.

Imaging Studies

Obtain a radiographic skeletal survey after birth.

  • In mild (type I) osteogenesis imperfecta, images may reveal thinning of the long bones with thin cortices. Several wormian bones may be present. No deformity of long bones is observed.

  • In extremely severe (type II) osteogenesis imperfecta, the survey may reveal beaded ribs, broad bones, and numerous fractures with deformities of the long bones. Platyspondylia may also be revealed.

  • In moderate and severe (types III and IV) osteogenesis imperfecta, imaging may reveal cystic metaphyses, or a popcorn appearance of the growth cartilage. Normal or broad bones are revealed early, with thin bones revealed later. Fractures may cause deformities of the long bones. Old rib fractures may be present. Vertebral fractures are common.

Prenatal ultrasonography can be used to detect limb-length abnormalities at 15-18 weeks' gestation.

  • Mild forms may result in normal sonogram findings.

  • Features include supervisualization of intracranial contents caused by decreased mineralization of calvaria (also calvarial compressibility), bowing or fracture of the long bones, decreased bone length (especially of the femur), and multiple rib fractures.

Histologic Findings

The width of biopsy cores, the width of the cortex, and the volume of cancellous bone are decreased in all types of osteogenesis imperfecta. The number and thickness of trabeculae are reduced.

Samples may show evidence of defects in modeling of external bone in terms of the size and shape, the production of secondary trabeculae by endochondral ossification, and the thickening of secondary trabeculae by remodeling. Therefore, osteogenesis imperfecta might be regarded as a disease of the osteoblast.[42]

Bone formation is quantitatively decreased, but the quality of the bone material is probably most important in the pathogenesis of the disease.

 

Treatment

Medical Care

Because osteogenesis imperfecta (OI) is a genetic condition, it has no cure.

Cyclic administration of intravenous pamidronate reduces the incidence of fracture and increases bone mineral density, while reducing pain and increasing energy levels.[4]  Intravenous zoledronate has been increasingly used in children with OI, given its shorter infusion times and longer infusion intervals. Observational studies have shown similar effects to that of pamidronate, with increased bone mineral density, decreased fracture rate, and improvement in pain.[5] There is scant evidence supporting the use of bisphosphonates in adults with OI, although they continue to be widely used; anecdotally, some patients experience a subjective decrease in pain.[6]  The bisphosphonate risedronate may have some effect in reducing fractures in patients with osteogenesis imperfecta.[7]

A preclinical study demonstrated that RANKL inhibition improves density and some geometric and biomechanical properties of the oim/oim mouse bone but does not decrease fracture incidence when compared with placebo.[43]  Research into the RANK inhibitor denosumab in patients with type VI OI has produced positive results,[44] although only 2 years of followup have been published.[45]

Nutritional evaluation and intervention are paramount to ensure appropriate intake of calcium and vitamin D. Caloric management is important, particularly in adolescents and adults with severe forms of osteogenesis imperfecta.

In utero transplantation of adult bone marrow has been shown to decrease perinatal lethality in a murine model of osteogenesis imperfecta.

Surgical Care

Orthopedic surgery is one of the pillars of treatment for patients with osteogenesis imperfecta.[8] Surgical interventions include intramedullary rod placement, surgery to manage basilar impression, and correction of scoliosis.

Intramedullary rod placement

In patients with bowed long bones, intramedullary rod placement may improve weight bearing and, thus, enable the child to walk at an earlier age than he or she might otherwise. Use of the extensible Fassier-Duval rod has been very helpful in improving bowing and mobility in patients with osteogenesis imperfecta.

In children appropriately treated with bisphosphonates, the percutaneous technique of multiple osteotomy with intramedullary fixation is safe and effective.

An experienced team can perform as many as 4 rod procedures in the long bones of the lower extremities in one surgical session.

Fractures heal normally in about 85% of patients with osteogenesis imperfecta. Postoperative immobilization is significantly shortened with this technique. Prolonged immobilization after a fracture must be avoided.

Surgery for basilar impression

This procedure is reserved for cases with neurologic deficiencies, especially those caused by compression of brainstem and high cervical cord. A team of orthopedic surgeons and neurosurgeons is required.

Correction of scoliosis

Correction of scoliosis may be difficult because of bone fragility. Spinal fusion surgery can be beneficial in patients with severe disease.[46]

Consultations

See the list below:

  • Care of patients with osteogenesis imperfecta is multidisciplinary. Team members may include an occupational therapist (OT), a physical therapist (PT), nutritionist, an audiologist, an orthopedic surgeon, neurosurgeon, geneticist, endocrinologist, pulmonologist, and nephrologist, among others.

  • Offer genetic counseling to the parents of a child with osteogenesis imperfecta. During genetic counseling, the possibility of germline mosaicism must be discussed, as this mechanism is responsible in some patients with apparent new dominant mutation. Additionally, the possibility of recessive disease must be discussed, as the recurrence risk would be significantly different in this case.

Diet

See the list below:

  • Adequate calcium, vitamin D, and phosphorus intake are paramount.

  • Caloric management is necessary in nonambulatory patients with severe osteogenesis imperfecta.

Activity

Parents need special instructions in handling affected children. They need to know how to position the child in the crib and how hold the child to avoid causing fractures, while maintaining bonding and physical stimulation.

Patients have varying degrees of physical ability but should be encouraged to be as active as they can safely be. 

 

Guidelines

Guidelines Summary

In 2018, an expert panel, convened in association with the 13th International Conference on Osteogenesis Imperfecta, published a consensus statement on physical rehabilitation in pediatric patients with the condition. The following guidelines were included[47] :

  • The overall treatment goal for children with osteogenesis imperfecta is to maximize mobility, function, activities, and participation
  • A fear of fracturing is present in individuals with osteogenesis imperfecta, their families, and the health professionals treating them; this fear can be a limiting factor for patients in terms of reaching their full potential
  • Optimal muscle function can contribute to improvements in motor development, mobility, and functional independence, as well as in societal participation
  • After a fracture, active range of joint motion, muscular strength, and function of the affected limb should always be reevaluated; early start of rehabilitation after a fracture is important to evaluate the functional impact of the fracture, with intervention if necessary and avoidance of immobility
  • Strengthening of the trunk muscles and extremities may be used to decrease back pain and to improve breathing capacity and trunk stability for sitting
  • Soft spinal braces have been used postsurgery to stabilize the trunk, but there is a lack of evidence showing its efficacy in osteogenesis imperfecta; bracing in individuals with osteogenesis imperfecta with spinal deformities is not yet recommended
  • Upper extremity issues in children with osteogenesis imperfecta may limit participation in daily self-care activities
  • Appropriate assistive devices, compensatory strategies, and architectural adaptations can overcome limited upper extremity range of motion and weak muscle strength and thus promote independence in self-care
  • Early physical rehabilitation of infants with osteogenesis imperfecta includes assessment, therapy, and caregiver education; therapists educate caregivers on optimal and safe positioning and handling so that nurturing and development are facilitated, while the risk of fractures and deformities is minimized
  • Despite the most careful of handling, infants and children with osteogenesis will continue to fracture during infancy; therapists and caregivers should use wide hand support, as well as slow and gentle movements, and should avoid twisting the limbs
  • 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
  • Some infants with osteogenesis imperfecta will follow a typical developmental course, while others may follow an individual path, developing their own strategies for movement
  • Most children with mild to moderate osteogenesis imperfecta are able to walk independently with or without ambulation aids; however, decreased muscle strength, fatigue, and/or pain may limit endurance and/or involvement in sports
  • Children with osteogenesis imperfecta should have access to a range of mobility aids to promote participation and independence; orthotics can be considered to maximize mobility, optimize muscle function, and minimize symptoms of pain and fatigue
  • The use of 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
  • Well-coordinated, multidisciplinary management preoperatively and postoperatively, incorporating rehabilitation goals and equipment needs, ensures the patient’s quick return to functional activities and participation
  • Rehabilitation following lower extremity surgery should focus on range of motion, muscle function, gait, and functional reeducation

 

 

Medication

Medication Summary

See Treatment.

 

Follow-up

Further Outpatient Care

Physical therapy in osteogenesis imperfecta (OI)

  • Therapy should be directed toward improving joint mobility and developing muscle strength

  • Overall, emphasize the achievement of functional ability.

  • Independence is the main objective of therapy.

Periodic nutritional evaluation and intervention

Periodic evaluation and intervention by an occupational therapist (OT) and/or a physical therapist (PT)

Patients with osteogenesis imperfecta require scrupulous oral hygiene and frequent follow-up with a pediatric dentist who is familiar with the disorder. Patients with dentinogenesis imperfecta often have chipping and fracturing of their teeth, which can become carious. These patients require capping of the affected teeth to preserve chewing integrity.

Complications

Repeated respiratory infections can be a complication of severe osteogenesis imperfecta.

Basilar impression can cause brainstem compression, and is a major neurologic complication in a child with osteogenesis imperfecta. This is most commonly observed in children with very severe osteogenesis imperfecta.

Hydrocephalus can be seen in patients with osteogenesis imperfecta. It can be communicating or noncommunicating and sometimes requires CSF shunting.[48] Providers should be aware of increasing head size in patients and should also be sensitive to symptoms suggesting increased intracranial pressure.

Cerebral hemorrhage caused by birth trauma is another possible complication.

Patients with osteogenesis imperfecta should be considered to be at high risk for complications of anesthesia, although they are not particularly prone to have malignant hyperthermia. Patients with osteogenesis imperfecta have a high basal metabolism that may cause hyperthermia during anesthesia but is almost never malignant. In fact, only one case of malignant hyperthermia in a child with osteogenesis imperfecta is described in the literature, and that particular patient had a family history of malignant hyperthermia.

Prognosis

The life expectancy of individuals with nonlethal osteogenesis imperfecta has been studied only to a limited extent and, with exception of patients with severe OI, has been assumed to approach that of the general population. An early study, by Paterson et al, which analyzed survival in over 700 patients in England and Wales, found that patients with OI type IA had a life expectancy indistinguishable from that of the general population, while patients with OI type IB and OI type IV had a life expectancy that was modestly lower than that of the general population. However, patients with type III OI had significantly reduced life expectancy compared with the general population and had a notable excess of deaths for patients below age 10 years, presumably due to pulmonary disease.[49]

An investigation by McAllion and Paterson into the causes of death in OI showed an excess of cardiopulmonary disease in patients with Type III OI, which was felt to be related to alteration in thoracic anatomy and kyphoscoliosis. Several deaths due to complications from basilar invagination were also noted in this study cohort.[50]  Subsequent and comprehensive investigations of OI-associated mortality and its causes in Denmark have shown an all-cause mortality ratio of 2.9 compared with the general population. Life expectancy for males with OI was 9.5 years shorter than that for the general population (72.4 years vs 81.9 years), and for females, was 7.1 years shorter than that for the general population (77.4 years vs 84.5 years). Patients with OI had excess mortality from pulmonary and gastrointestinal disease and an increased risk of death from trauma.[51, 52]  Despite such data, it is reasonably anticipated that modern multidisciplinary treatment of patients with OI will result in better outcomes and longer life expectancy.

Patient Education

Parents need special instructions in positioning the child in the crib and in handling the child while minimizing the risk of fractures.

 

Questions & Answers

Overview

What is osteogenesis imperfecta (OI)?

What are the physical manifestations of osteogenesis imperfecta (OI)?

How is osteogenesis imperfecta (OI) diagnosed?

How is osteogenesis imperfecta (OI) treated?

What are the genetic groupings for osteogenesis imperfecta (OI)?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) types I-IV?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type V?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type VI?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type VII-IX?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type X?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XI?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XII?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XIII?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XIV?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XV?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XVI?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XVII?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XVIII?

What is the role of genetics in the pathophysiology of osteogenesis imperfecta (OI) type XIX?

What is the role of genetics in the pathophysiology of Bruck syndrome?

What is the increased risk for cardiovascular disease in osteogenesis imperfecta (OI)?

What is the US prevalence of osteogenesis imperfecta (OI)?

What is the global prevalence of osteogenesis imperfecta (OI)?

What are the racial predilections of osteogenesis imperfecta (OI)?

What are the sexual predilections of osteogenesis imperfecta (OI)?

At what age is osteogenesis imperfecta (OI) typically diagnosed?

Presentation

Which clinical history findings are characteristic of osteogenesis imperfecta (OI)?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type I?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type II?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type III?

Which physical findings are characteristic of osteogenesis imperfecta (OI) type IV?

Which physical findings are characteristic of osteogenesis imperfecta (OI)?

What causes osteogenesis imperfecta (OI)?

DDX

Which conditions are included in the differential diagnoses of osteogenesis imperfecta (OI)?

What are the differential diagnoses for Genetics of Osteogenesis Imperfecta?

Workup

What is the role of lab tests in the workup of osteogenesis imperfecta (OI)?

What is the role of bone mineral density tests in the workup of osteogenesis imperfecta (OI)?

What is the role of radiography in the workup of osteogenesis imperfecta (OI)?

What is the role of ultrasonography in the workup of osteogenesis imperfecta (OI)?

Which histologic findings are characteristic of osteogenesis imperfecta (OI)?

Treatment

How is osteogenesis imperfecta (OI)?

What is the role of surgery in the treatment of osteogenesis imperfecta (OI)?

What is the role of intramedullary rod placement in the treatment of osteogenesis imperfecta (OI)?

What is the role of neurosurgery in the treatment of osteogenesis imperfecta (OI)?

What is the role of spinal fusion in the treatment of osteogenesis imperfecta (OI)?

Which specialist consultations are beneficial to patients with osteogenesis imperfecta (OI)?

Which dietary modifications are used in the treatment of osteogenesis imperfecta (OI)?

Which activity modifications are used in the treatment of osteogenesis imperfecta (OI)?

Guidelines

What are the treatment guidelines for osteogenesis imperfecta (OI)?

Follow-up

What is the role of physical therapy in the treatment of osteogenesis imperfecta (OI)?

What is included in the long-term monitoring of osteogenesis imperfecta (OI)?

What are the possible complications of osteogenesis imperfecta (OI)?

What is the prognosis of osteogenesis imperfecta (OI)?

What is included in patient education about osteogenesis imperfecta (OI)?