Clinical characteristics.

COL1A1/2-related osteogenesis imperfecta (OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-related OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone, but are most common in the extremities. DI is characterized by grey or brown teeth that may appear translucent and wear down and break easily. COL1A1/2-related OI has been classified into four types (I, II, III, and IV) based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four OI types are now referred to as follows:

• OI type I: classic non-deforming OI with blue sclerae
• OI type II: perinatally lethal OI
• OI type III: progressively deforming OI
• OI type IV: common variable OI with normal sclerae

Diagnosis/testing.

The diagnosis of COL1A1/2-related OI is based on:

• Family history, a history of fractures, and characteristic physical findings;
• Radiographic findings (fractures of varying ages and stages of healing, wormian bones, "codfish" vertebrae, and osteopenia); and
• Molecular genetic testing of COL1A1 and COL1A2 and/or biochemical analysis of type 1 collagen.

Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with historically classified OI type II, about 90% with OI type I, about 84% with OI type III, and about 84% with OI type IV. Molecular genetic testing of COL1A1 and COL1A2 detects abnormalities in more than 90% of individuals with historically classified OI types I, II, III, or IV.

Management.

Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in the medical management of OI, orthopedics, rehabilitation medicine, pediatric dentistry, and otology/otolaryngology. Parents/other caregivers must practice safe handling techniques. Mainstays of treatment include: bracing of limbs; orthotics to stabilize lax joints; promotion of appropriate physical activity; muscle strengthening; pain management; and physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, and prevent head and spinal deformity. Mobility devices are used as needed. Fractures are treated with: intramedullary rodding when indicated to provide anatomic positioning of limbs; as short a period of immobility as is practical; small and lightweight casts; and physical therapy as soon as casts are removed. Progressive scoliosis in severe OI does not respond well to conservative or surgical management. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as it is when caused by other conditions.

Prevention of secondary complications: During general anesthesia proper positioning on the operating room table and use of cushioning such as egg crate foam can help avoid fractures.

Surveillance: Twice-yearly dental visits beginning in early childhood or even infancy for those with DI or at risk for DI. Hearing evaluation at three- to five-year intervals perhaps beginning as early as age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions.

Therapies under investigation: The role of treatment with bisphosphonates in changing the natural history of OI is incompletely understood. The Cochrane database contains a detailed meta-analysis of available data and as of the most recent update, bisphosphonate therapy did not appear to reduce fracture incidence but it did impact bone density and adult height. Oral alendronate treatment for two years in children with OI significantly decreased bone turnover and increased spine areal bone mineral density (BMD) but was not associated with improved fracture outcomes. Similarly, risedronate increased BMD and reduced first and recurrent clinical fractures in children with OI. Furthermore, human growth hormone therapy as an adjunct to bisphosphonate therapy correlated with improved linear growth and increased BMD.

Genetic counseling.

COL1A1/2-related OI is inherited in an autosomal dominant manner. The proportion of cases caused by a de novo COL1A1 or COL1A2 mutation varies by the severity of disease: approximately 60% of cases of classic non-deforming OI with blue sclerae or common variable OI with normal sclerae, virtually 100% of perinatally lethal OI, and close to 100% of progressively deforming OI are de novo. Gonadal mosaicism may be present in 3%-5% of cases. Each child of an individual with a dominantly inherited form of COL1A1/2-related OI has a 50% chance of inheriting the mutation and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by molecular genetic testing if the COL1A1 or COL1A2 mutation has been identified in an affected relative. Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur.

Testing

Biochemical

• Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, the latter may be elevated acutely in response to fracture.
• Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained from a small skin biopsy shows the structure and quantity of the collagen. The sensitivity of biochemical testing is approximately 90% in individuals with clinically confirmed OI [Wenstrup et al 1990; Byers PH, personal communication]. Biochemical analysis is helpful in separating individuals with quantitative defects (classic non-deforming OI) from those with qualitative defects (perinatally lethal OI, progressively deforming OI, and common variable OI with normal sclerae).
  The limitation of biochemical analysis is that it will not identify some quantitative defects of type 1 procollagen, variants that alter sequences in some coding regions of COL1A1/COL1A2 [van Dijk et al 2011].

Testing Strategy for a Proband

To confirm/establish the diagnosis in a proband. An approach to the molecular diagnosis of OI has been published [van Dijk et al 2012] See Figure 2.

Figure 2.

Preferred diagnostic flow in OI The approach to diagnosis is designed to maximize the likelihood that causative variants will be identified in all affected individuals or assign those without causative variants to research pools. This flow assumes that (more...)

The sensitivity for identifying COL1A1/2- related OI by molecular genetic testing is similar to the sensitivity of analysis of the structure and quantity of type 1 collagen in cultured fibroblasts from a skin biopsy, but current diagnostic algorithms favor molecular genetic testing as the first-line test for laboratory confirmation of COL1A1/2- related OI [van Dijk et al 2011].

In an individual with suspected OI, the suggested diagnostic work flow is as follows:

1.

Perform sequence analysis of COL1A1/2 (may require follow-up studies to determine whether a variant is causative).

2.

If no pathogenic variant is found by sequence analysis of COL1A1/2, deletion/duplication analysis (which detects an additional 1%-2% of pathogenic variants) can be pursued.

3.

If no causative COL1A1/2 variant is found, re-review clinical data. With clear evidence of moderate to severe OI, further analysis should proceed to screening for the non-COL1A1/2-related genetic disorders (see Differential Diagnosis).

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant(s) in the family.

Clinical Description

The severity of COL1A1/2-related osteogenesis imperfecta (OI) ranges from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal life span. Although COL1A1/2-related OI comprises the largest proportion of OI, recent classifications based on molecular genetic findings have identified additional types of OI (see Differential Diagnosis)

COL1A1/2 related OI is classified into four types based on clinical presentation, radiographic features, family history, and natural history [Sillence et al 1979]. An update of the Sillence classification was recently proposed and has gained some acceptance (see Emery & Rimoin [2012]). Although this classification of COL1A1/2-related OI into types is helpful in providing information about prognosis and management of a given individual, the features of different types of COL1A1/2-related OI overlap and it is not always easy to categorize the extent of the clinical disorder. It is helpful to remember that the severity of clinical and radiographic features lies on a continuum and that the "types" are defined using characteristics that appear to form clinical "nodes." Interfamilial variability is apparent among individuals with the same OI type and intrafamilial variability is apparent among individuals with the same pathogenic variant. Nonetheless, it is reasonable to continue to think of COL1A1/2-related OI in terms of these types in order to provide information about the expected natural history of the disorder.

Classic non-deforming OI with blue sclerae (previously OI type I) is characterized by blue sclerae and normal stature. A small proportion of infants with OI type I have femoral bowing at birth. The first fractures may occur at birth or with diapering. More often, the first fractures occur when the infant begins to walk and, more importantly, to fall. Fractures generally occur at a rate of a few to several per year and then decrease in frequency after puberty. Fracture frequency often increases again in adulthood, especially in postmenopausal women and men beyond the fifth decade [Paterson et al 1984]. Affected individuals may have anywhere from a few fractures to more than 100, but the fractures usually heal normally with no resulting deformity.

Most affected individuals have normal or near normal stature, but may be shorter than other members of their families.

Joint hypermobility predisposes to a number of minor co-morbidities. The primary clinical concern is early-onset degenerative joint disease due to poor alignment of articular surfaces.

In their classification of OI, Sillence et al [1979] designated a subset of classic non-deforming OI with dentinogenesis imperfecta (DI) (OI type IB). In DI, morbidity results not from dental decay but rather from premature wearing down of the teeth, which interferes with chewing. DI can be a significant cosmetic concern. Dental eruption in classic non-deforming OI can sometimes occur early.

Progressive hearing loss occurs in about 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss but with an additional sensorineural hearing loss component in time.

Perinatally lethal OI (previously OI type II). Abnormalities characteristic of perinatally lethal OI are evident at birth. Weight and length are small for gestational age. The sclerae are dark blue and connective tissue is extremely fragile. The skull is large for the body size and soft to palpation. Callus formation on the ribs may be palpable. Extremities are short and bowed. Hips are usually flexed and abducted in a "frog-leg" position. Although some fetuses with perinatally lethal die in utero or are spontaneously aborted, more typically infants die in the immediate perinatal period. More than 60% of affected infants die on the first day; 80% die within the first week; survival beyond one year is exceedingly rare and usually involves intensive support such as continuous assisted ventilation [Byers et al 1988]. Death usually results from pulmonary insufficiency related to the small thorax, rib fractures, or flail chest because of lack of stable ribs. Those who survive the first few days of life may not be able to take in sufficient calories because of respiratory distress.

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

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

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

Growth is extremely slow and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter (3 feet).

Intellect is normal unless there have been intracerebral hemorrhages (extremely rare and apparently limited to a particular genotype). Faqeih et al [2009] published a report identifying increased risk for intracranial hemorrhage in a “small number” of individuals who were identified to have pathogenic variants affecting exon 49 of COL1A2, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen alpha-2(I) chain. They concluded that this pathogenic variant appeared to increase the risk for abnormal limb development and intracranial bleeding.

Even within progressively deforming OI, considerable heterogeneity is observed at the clinical level. Some individuals have normal-appearing teeth and facial appearance while others have DI and a large head and enlarged ventricles that reflect the soft calvarium. Relative macrocephaly and barrel chest deformity are observed. Usually sclerae are blue in infancy but lighten with age. Hearing loss generally begins in the teenage years. As molecular testing of this subgroup further differentiates those with COL1A1/2-related OI from the recessive forms, the clinical profile of this heterogeneous group will become more refined.

Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal CSF flow [Charnas & Marini 1993, Sillence 1994, Hayes et al 1999]. Symptoms of basilar impression become apparent with neck flexion. Findings include posterior skull pain, C2 sensory deficit, tingling in the fourth and fifth digits, and numbness in the medial forearm. When swimming, affected individuals may perceive that water temperature differs below and above the umbilicus. Lhermitte's sign (tingling on neck flexion) can be demonstrated at any stage. Basilar impression can cause headache with coughing, trigeminal neuralgia, loss of function of the extremities, or parasthesias. At its most severe levels of involvement, sleep apnea and death can occur.

Common variable OI with normal sclerae (previously OI type IV) is characterized by mild short stature, DI, adult-onset hearing loss, and normal-to-grey sclerae. This is the most variable form of OI, ranging in severity from moderately severe to so mild that it may be difficult to make the diagnosis.

Stature is variable and may vary markedly within the family. DI is common but may be mild. Sclerae are typically light blue or gray at birth but quickly lighten to near normal. Hearing loss occurs in some. Basilar impression can occur.

Genotype-Phenotype Correlations

In general a clear genotype-phenotype correlation does not exist. General rules for genotype phenotype correlations in COL1A1/2-related OI have been published [Ben Amor et al 2011], but there are exceptions to these rules. It is important to keep these exceptions in mind in providing genetic counseling, particularly in the prenatal setting. Genotyping can be helpful in distinguishing classic non-deforming OI from all other types of OI.

The most common type of COL1 pathogenic variant in OI affects the triple helix domain of the COL1A1/2 chains. Glycine to serine substitutions may lead to a more severe phenotype in COL1A1 than a similar change in COL1A2. Substitutions by arginine, aspartate, glutamate, and valine beyond the first 200 amino acid residues of COL1A1 are usually lethal but may have a variable outcome in COL1A2 [Ben Amor et al 2011].

Classic non-deforming OI almost always results from a pathogenic variant in one COL1A1 allele that introduces premature termination codons and decreases the stability of mRNA. These pathogenic variants may occur by codon changes, by frame shifts, and by splicing that results in use of cryptic splice sites and frame shifts. The type I collagen molecule contains two pro α1(I) chains and a single α2(I) chain. If the number of available pro α1(I) chains decreases, the amount of the trimer manufactured is diminished because no more than one pro α2(I) chain can be accommodated per molecule.

Perinatally lethal OI, progressively deforming OI, and common variable OI all result from pathogenic variants that alter the structure of either pro α1(I) or pro α2(I) chains. This causes a dominant-negative effect whereby the abnormal protein is integrated into the triple helix and collagen fibril, which in turn undergoes continual remodeling, thus resulting in significantly compromised structural integrity of the bone matrix.

The most common pathogenic variants result in substitution of another amino acid for glycine in the triple helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon.

• Substitutions in the pro α1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix, and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain.
• For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized.
• Much more variability occurs with pathogenic variants that affect glycine residues in the pro α 2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship.

The other common pathogenic variants affect splice sites. Pathogenic variants that lead to exon skipping in the pro α1(I) chain beyond exon 14 and in the pro α2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from pathogenic variants in the upstream region are more variable and may lead to significant joint hypermobility.

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

Somatic mosaicism for dominant pathogenic variants has been recognized in perinatally lethal OI, progressively deforming OI, and common variable OI. The phenotype of the individual with somatic mosaicism can range from no identifiable characteristics of OI to one of the mild forms.

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

Penetrance

The penetrance in individuals heterozygous for a COL1A1 or COL1A2 pathogenic variant is 100%, although expression may vary considerably, even in the same family.

Nomenclature

Previously used nomenclature:

• Classic non-deforming OI with blue sclerae: osteogenesis imperfecta type I
• Perinatally lethal OI: osteogenesis imperfecta type II
• Progressively deforming OI: osteogenesisi type III
• Common variable OI with normal sclerae: osteogenesis imperfecta type IV

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

In classifications of genetic conditions, OI may be considered a skeletal dysplasia, a connective tissue disorder, a disorder of collagen or extracellular matrix, or a disorder of bone fragility.

Prevalence

Considering all types, OI has a prevalence of approximately 6-7:100,000. The two mildest forms, classic non-deforming OI and common variable OI, account for considerably more than half of all OI. OI is found in all racial and ethnic groups. The most recent estimates of prevalence come from Finland, where OI is thought to affect about 1:15,000 individuals [Kuurila et al 2002]. If the same prevalence is assumed for the US, an estimated 18,000 people in the US would be affected. The incidence of the various subtypes includes all causes of OI, both-collagen related and the autosomal recessive subtypes.

• Classic non-deforming OI has a prevalence of approximately 3-4:100,000. Sillence et al [1979] reported an incidence in Australia of 3.5 in 100,000.
• Perinatally lethal OI has an incidence of about 1-2:100,000. Sillence et al [1979] reported an incidence in Australia of 1.6 per 100,000, translating to an approximate prevalence of 1:20,000 in those who survive early-childhood mortality. Perinatally lethal OI is often not considered in prevalence data because of early lethality. Increasingly, perinatally lethal OI is recognized in utero as a consequence of early screening by ultrasound examination with resultant elective termination of pregnancy. This has resulted in a reduced incidence in affected live births in developed countries.
• Progressively deforming OI has a prevalence of 1-2:100,000. Sillence et al [1979] reported an incidence in Australia of 1.6 per 100,000 for progressively deforming OI.
• Sillence et al [1979] believed common variable OI to be uncommon. Since then it has been recognized to be a relatively common form of OI, probably about as common as classic non-deforming OI.

COL1A1/2-Related Osteogenesis Imperfecta (OI)

The primary differential diagnosis for individuals with features of COL1A1/2-related OI are autosomal recessive subtypes of OI and those subtypes of OI in which specific pathogenic variants have not yet been identified. Table 4 and Table 5 summarize the clinical and radiographic features of these subtypes of OI.

Histomorphometric evaluation of iliac crest bone from individuals with OI with calcification in interosseous membranes, type VI, and type VII OI shows maintained lamellar structure, reduced cortical width and cancellous bone volume, and increased bone remodeling [Rauch et al 2000]. The distinction of OI type VI from common variable OI and OI with calcification in interosseous membranes rests in part on a characteristic "fish scale" appearance under polarized light.

OI with calcification in interosseous membranes (previously OI type V). This group was initially thought to have either progressively severe OI or common variable OI because of short stature and fractures. Sclerae were generally white. Two features distinguish OI with calcification in interosseous membranes:

• Striking hypertrophic callus formation, usually at the site of fractures and often in the femoral shaft; and
• Calcification of the interosseous membrane between the ulna and the radius that leads to the inability to fully supinate and pronate the forearm

OI with calcification in interosseous membranes accounts for about 5% of OI. OI with calcification in interosseous membranes has recently been found to be caused by pathogenic variants in the 5’ UTR of IFITM5.

OI type VI. The clinical features of OI type VI are similar to those of common variable OI. The defining features of OI with calcification in interosseous membranes are absent. OI type VI accounts for about 5% of OI. Pathogenic variants in SERPINF1 are believed to be causative.

OI type VII is distinguished by rhizomelic shortening of all limbs. OI type VII has been found to date only in a Native Canadian population. It is inherited in an autosomal recessive manner. OI type VII maps to a 4.5-Mb region on the short arm of chromosome 3. Pathogenic variants in CRTAP are causative

OI type VIII is a lethal/severe OI with a phenotype that overlaps that of perinatally lethal OI or progressively deforming OI with severe osteoporosis, shortened long bones, and a soft skull with wide open fontanel. However, individuals with OI type VIII typically have white sclerae, a round face, and a short barrel-shaped chest. Pathogenic variants in LEPRE1 are causative.

OI type IX is an autosomal recessive, severe form of OI. Pathogenic variants in PPIB are causative.

OI type X is an autosomal recessive form of OI characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclerae. Pathogenic variants in SERPINH1 are causative.

OI type XI is an autosomal recessive form of OI. Affected individuals may have joint contractures. Pathogenic variants in FKBP10 can cause OI type XI.

All Forms of OI

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with COL1A1/2-related osteogenesis imperfecta (OI), the following evaluations are recommended:

• Physical examination to assess deformities and presence of joint laxity
• Hearing assessed through formal audiology
• Screening for basilar impression, best performed by CT and/or MRI scanning with views across the base of the skull. There is no universal agreement on when screening for basilar impression should be done; currently, it is recommended on the basis of concerning signs or symptoms on annual physical examination or on reported symptoms by the affected individual.
• Cervical spine flexion and extension radiographs, obtained when children are able to cooperate with the examination or prior to participating in sporting activities in more mildly affected individuals
• Dental evaluation by age two to three years for all children with OI and at the time that teeth erupt in those with DI or at risk for DI
• Clinical genetics consultation

Treatment of Manifestations

Management focuses on supportive therapy to minimize fractures and maximize function, minimize disability, foster independence, and maintain overall health [Marini & Gerber 1997]. Ideally, OI is managed by a multidisciplinary team including specialists in the medical management of OI, orthopedics, rehabilitation medicine, pediatric dentistry, and otology/otolaryngology.

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

Physical medicine treatment

• Parents and other caregivers should be instructed in safe handling techniques. These are mostly common sense practices in order to relieve stress on a single point. For example: lift an affected infant by bracing the torso, neck and lower body; avoid any situation where increased pressure is placed on a single point on any long bone; when assisting an affected child in standing up, do not pull excessively on an extended arm but bend down and brace a greater surface area (such as placing a hand behind the back and pulling gently from the front (using the arm) while applying pressure from the rear); avoid sudden acceleration/deceleration movements; and avoid throwing a child in the air. Older children should not ride on amusement park rides. Caregivers should avoid recreating the circumstances of a fracture, as it is likely to happen again.
• The use of bracing to try to stabilize progressively deforming limbs depends in part on the subtype of OI. Progressively deforming OI has proven to be progressive despite external or internal bracing. The use of internal rods or braces to support and stabilize deforming limbs is more successful in the milder subtypes of OI and is guided by the expertise of the managing orthopedist.
• Orthotics to support ankle instability are used in toddlers with delayed walking secondary to joint hypermobility and in other affected individuals who suffer recurrent subluxations of their ankle joints.
• Physical activity serves a number of purposes. It provides gravitational stressors required for bone growth and remodeling. The muscles supporting joints are strengthened by activity and as an overall benefit, improved joint stability aides in overall well-being as pain levels are reduced and mobility is increased. Physical activity can be self-directed or coordinated through the services of a physical therapist. Each affected individual’s needs are unique and thus both physical and occupational therapy should be initiated for increased stability of bone, improved mobility, prevention of contractures, prevention of head and spinal deformity, aerobic fitness, and muscle strengthening
• Mobility devices, such as scooters and chairs for children, and modified automobiles for adults should be considered.
• Some individuals with OI experience chronic daily pain associated with both fractures and non-specific myofascial pain associated with the generalized connective tissue disorder. Pain management plays an important role in the management of OI. Some affected individuals do well with minimal analgesics, but many benefit from a multidisciplinary pain management service. Analgesics can be used to control pain from fractures.

Orthopedic treatment. Fractures are treated as they would be in unaffected children and adults with attention to the following:

• The period of immobility in children with OI should be shortened as much as is practical.
• Casts should be small and lightweight.
• Physical therapy should begin as soon as the cast is removed to promote mobility and enhance muscle strength and bone mass.
• At this time, intramedullary rodding remains a mainstay of orthopedic care to provide anatomic positioning of limbs that permits more normal function.

Progressive spinal deformities are particularly difficult to treat because of the poor quality of bone in severely affected children. Progressive scoliosis in severe OI does not respond to conservative management and response to surgical intervention may be limited.

Pharmacologic treatment. Bisphosphonates, analogs of pyrophosphate that decrease bone resorption, are being evaluated in both uncontrolled and controlled trials to assess the extent to which they can increase bone mass and bone strength and improve function in children with OI. These studies are still ongoing. Bisphosphonates have been used most extensively in severely affected children with OI; they may be useful in adults with OI as well [Adami et al 2003].

The role of treatment with bisphosphonates in changing the natural history of OI is incompletely understood. The Cochrane Collaboration is an international network which assembles reviews on various management strategies based on randomized controlled clinical trials within its database in order to improve the practice of evidence-based medicine. As of the Cochrane Collaboration’s most recent update of the OI review, bisphosphonate therapy did not appear to reduce fracture incidence but it did impact bone density and adult height [Dwan et al 2014] (full text).

An open-label trial of cyclical intravenous pamidronate (bisphosphonate) was reported by Glorieux et al [1998], and the effects of relatively long-term use in adults by Aström & Soderhall [2002] and Zeitlin et al [2003]. Falk et al [2003] replicated the study of Glorieux et al [1998] in children older than age 22 months, but did report one child with fracture non-union following treatment with pamidronate. No randomized placebo-controlled clinical trial of pamidronate has been published. Bisphosphonate treatment has produced improvements in bone histomorphometry, increased bone mineral density (BMD), decreased some biochemical markers of bone resorption, and possibly reduced fracture risk. In addition, some investigators have reported decreased bone pain in young, but not older, children following treatment.

Pamidronate use is invasive and inconvenient, typically requiring intravenous infusions every three months four hours a day for three days and has real and potential complications. Recently, pamidronate has been offered even to very young children with OI, but complications including transient asymptomatic hypocalcemia [Plotkin et al 2000] and symptomatic hypocalcemia [Chien et al 2002] have been noted. The long-term consequences of lowering bone turnover in children with OI are unknown, but may include delayed bone union after fracture or osteotomy.

A randomized controlled clinical trial using the oral bisphosphonate alendronate was recently completed and the results published. Ward and colleagues found that treatment with oral alendronate for two years in children with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes [Ward et al 2011]. In a second study with a different oral bisphosphonate, Bishop and colleagues found that oral risedronate increased areal BMD and reduced first and recurrent clinical fractures in children with OI [Bishop et al 2010]. There have not been additional large placebo-controlled trials of IV bisphosphonates, and it is unlikely that additional large randomized placebo controlled studies comparing bisphosphonates with placebo to determine the impact of these agents in altering the natural history of OI will be conducted.

Zoledronic acid, a newer bisphosphonate with a longer half life, greater potency, and more convenient dosing, is being studied in children with OI. A study comparing pamidronate to zoledronic acid was completed; to date, the results have not been published.

Basilar impression. Criteria for surgical intervention are not well defined. If surgery is undertaken, it should be done in a center experienced in the procedures used.

Dental treatment. The goals are the maintenance of both primary and permanent dentition, functional bite or occlusion, optimal gingival health, and overall appearance. Pediatric dentists are the most knowledgeable about DI in children. Some consensus exists that early dental restorative coverage of the primary molars and (if possible) aesthetic coverage of the upper anterior teeth is optimal. Plastic polymers are sometimes used to coat teeth. As anxiety can be an issue with children, pre-medication for anxiolysis (e.g., nitrous oxide analgesia or midazolam) can be used for treatment in a clinic setting.

If warranted, orthodontic treatment can be initiated, but care must be taken in the use of orthodontic appliances because of the brittleness of the teeth.

Dental restorations in adults may best be done by a general dentist knowledgeable about OI or a specialist in prosthetic dentistry.

Hearing loss. Surgical repair of the middle-ear bones and creation of a prosthetic incus can improve unaided hearing.

Later hearing loss appears to have a significant sensorineural component that does not respond to middle ear surgery. Cochlear implantation has been used in a small number of individuals; outcome data are limited.

Management of lethal OI. It is appropriate to offer parents the option of allowing the infant to expire without attempting interventions such as assisted ventilation.

Other therapies. Early trials of anabolic steroids, sodium fluoride, testosterone, vitamins C and D, flavinoids, and calcitonin showed minimal or no improvement in bone formation, or too small a sample size was utilized for meaningful conclusions [reviewed in Byers & Steiner 1992].

Prevention of Secondary Complications

Special attention should be paid to anesthesia concerns including proper positioning on the operating room table, for which egg crate foam is recommended.

Surveillance

The following are appropriate:

• Dental examinations twice a year for those with DI or at risk for DI
• Hearing evaluation at three- to five-year intervals perhaps beginning as early as age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions

Agents/Circumstances to Avoid

Contact sports should be avoided.

Evaluation of Relatives at Risk

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

Pregnancy Management

Women with OI who have significant skeletal deformity and short stature should be followed during pregnancy by a high-risk prenatal care center.

Delivery of an infant with OI by cesarean section or by vagina has about the same rate of complications for each type of OI. Delivery of an infant with OI by cesarean section is more frequent than in the general population because a non-vertex presentation cannot be corrected by external manipulation.

Therapies Under Investigation

Human growth hormone has been evaluated as an adjunctive therapy in conjunction with bisphosphonates in a randomized controlled study. In this study, growth hormone therapy was reported to correlate with improved linear growth and increased BMD [Antoniazzi et al 2010]. An additional study presented similar results in 26 children with moderate to severe OI when growth hormone was used in isolation [Marini et al 2003].

Bone marrow transplantation (BMT) to introduce normal mesenchymal stem cells that have the capacity to differentiate into normal osteoblasts as well as transplanted mesenchymal stromal cells which produce factors that stimulate endogenous bone growth in individuals with OI has been evaluated in a pilot clinical trial. Preliminary data was promising and a clinical to evaluate this treatment further has recently concluded [Otsuru et al 2012, www.clinicaltrials.gov].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Classic non-deforming osteogenesis imperfecta (OI), perinatally lethal OI, progressively deforming OI, and common variable OI caused by mutation of COL1A1 or COL1A2 are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with the milder forms of OI (classic non-deforming and some probands with common variable OI) have an affected parent.
• The proportion of cases caused by de novo pathogenic variants varies by the severity of disease. Approximately 60% of individuals with mild OI have de novo variants; virtually 100% of individuals with progressively deforming or perinatally lethal OI have de novo variants.
• Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include clinical examination of the parents and molecular genetic testing if the variant in the proband has been identified.

Sibs of a proband

• If a parent of the proband is affected, the risk to the sibs is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband is about 5% because somatic and/or germline mosaicism in a parent is possible.

Offspring of a proband. Each child of an individual with a dominantly inherited form of OI has a 50% chance of inheriting the pathogenic variant.

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

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant or that one parent has germline mosaicism with or without somatic mosaicism. Other explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

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

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

High-risk pregnancies

• Molecular genetic testing. Analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation is possible if the disease-causing allele of an affected family member has been identified.
• Biochemical analysis of collagen from fetal cells obtained by CVS at about ten to 12 weeks' gestation has been reported. An abnormality of collagen from cultured cells of an affected family member must be identified before this technique can be used for prenatal testing. Note: Biochemical analysis of collagen from amniocytes is not useful because amniocytes do not produce type I collagen.
  Note: Classic non-deforming cannot be identified prenatally even with CVS cells because the proportion of type I procollagen produced by normal cells is reduced compared to control cells and resembles type I procollagen production from individuals with OI; thus, false positive test results can be an issue.
• Prenatal ultrasound examination performed in a center with experience in diagnosing OI, done at the appropriate gestational age, can be a valuable tool in the prenatal diagnosis of OI. Normally, ultrasound examination detects only the lethal and most severe forms of OI prior to 20 weeks' gestation; milder forms may be detected later in pregnancy when fractures or deformity occur:
  • Perinatally lethal OI. The bony abnormalities can first be seen by ultrasound examination by about 13 to 14 weeks' gestation. By 16 weeks, femoral length is typically two or more weeks delayed, calvarial mineralization is essentially absent, and ribs generally have identified fractures.
  • Progressively deforming OI. Limb length generally begins to fall below the growth curve at about 17 to 18 weeks' gestation; serial ultrasound examinations are required to confirm the trend.

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

Low-risk pregnancies. Routine prenatal ultrasound examination may identify a fetus not known to be at risk for COL1A1/2-related OI with findings suggestive of OI (perinatally lethal OI or progressively deforming OI) including reduced echogenicity of fetal bones, bowed, crumpled femurs, beaded ribs, evidence of fractures, and markedly diminished calvarial mineralization. As a part of the evaluation of such findings, molecular genetic testing of COL1A1 or COL1A2 may be considered; however, inability to identify a pathogenic variant does not eliminate the diagnosis of OI in the fetus.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Molecular Genetic Pathogenesis

This review focuses on OI caused by pathogenic variants in either COL1A1 or COL1A2. These two genes encode the α 1 and α 2 chains of collagen type I. Collagen type I is a heterotrimer consisting of two α 1 chains and one α 2 chain. It is initially synthesized as a pro α chain with a propeptide at each end (N-propeptide and C-propeptide). The propeptides are necessary for pro α chain association and triple helix formation that starts at the carboxy-terminal propeptide and extends to the aminoterminal propeptide.

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Suggested Reading

• Byers PH. Disorders of collagen biosynthesis and structure. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 205.

Author Notes

Dr. Steiner is a pediatrician, clinical geneticist, and clinical biochemical geneticist. He specializes in inherited metabolic diseases and osteogenesis imperfecta. Dr. Steiner runs an OI clinic at Shriners Hospital in Portland for evaluation of children with OI.

Linked Clinical Research Centers

A joint initiative from the OI Foundation and the Children’s Brittle Bone Foundation, the Linked Clinical Research Centers (LCRC) constitute a nationwide network designed to provide the highest quality of standardized medical care for people living with osteogenesis imperfecta.

The first five hospitals participating in the LCRC:

• Baylor Medical Center (Houston, TX)
• Kennedy Krieger Institute (Baltimore, MD)
• Oregon Health & Science University/Portland Shriners (Portland, OR)
• Shriners Hospital for Children (Chicago, IL)
• Shriners Hospital for Children (Montreal, Quebec)

Author History

Jessica Adsit, MS, CGC (2013-present)
Donald Basel, MD, MCW (2013-present)
Peter H Byers, MD; University of Washington Health Sciences Center (2003-2013)
Melanie G Pepin, MS, CGC; University of Washington Health Sciences Center (2003-2013)
Robert D Steiner, MD (2003-present)

Revision History

• 14 February 2013 (me) Comprehensive update posted live
• 28 January 2005 (me) Review posted to live Web site
• 14 June 2003 (rs) Original submission