ABSTRACT

Osteogenesis imperfecta (OI, or Brittle Bone Disease) is a clinically and genetically heterogeneous group of heritable disorders of connective tissue. The incidence of forms recognizable at birth is 1:10-20,000. The hallmark feature of OI is bone fragility, with susceptibility to fracture from minimal trauma, as well as bone deformity and growth deficiency. OI has multiple secondary features, including macrocephaly, blue sclerae, dentinogenesis imperfecta, hearing loss, neurological defects (macrocephaly and basilar invagination), and cardiopulmonary complications (the major cause of mortality directly related to OI). The current paradigm of OI is that of a collagen-related disorder. The classical Sillence types of OI (types I-IV) with autosomal dominant inheritance comprise about 80-85% of cases and are caused by mutations in the genes that encode type I collagen, COL1A1 and COL1A2. These types encompass the full spectrum of OI severity, from perinatal lethal type II to progressively deforming type III to mild and diagnostically delayed type I. The rare forms of OI (types V-XVIII) delineated in the last decade have (except for type V and some XV) autosomal recessive inheritance and are caused by mutations in genes whose protein products interact with collagen for post-translational modification or folding. OI, regardless of etiology, requires clinical management and genetic analysis. Most individuals with OI have significant physical disabilities. The diagnostic work-up focuses on the skeletal system, including age-specific physical exam, a thorough family pedigree, radiographic examination, and DEXA. Differential diagnosis (child maltreatment, thanatophoric dysplasia, achondrogenesis type I, campomelic dysplasia, hypophosphatasia, osteoporosis) varies with patient age and OI severity. Genetic counseling, nonsurgical (e.g., rehabilitation, bracing, splinting), surgical, and pharmacological (bisphosphonates, anti-RANK ligand antibody, recombinant human parathyroid hormone analog, growth hormone) management are essential components of complete care for individuals who have OI. Fractures should be evaluated with standard x-rays and managed with reduction and realignment, as needed, to prevent loss of function and to interrupt a cycle of refracturing. Two pharmacologic treatment modalities target osteoclast bone resorption. Bisphosphonates (synthetic analogs of pyrophosphate) induce osteoclast apoptosis. Maximum effects on bone histology and density occur within the first year following treatment. Meta-analyses do not support significant reduction in long bone fractures in bisphosphonate-treated children. Anti-RANK ligand antibody improves bone mineral density in individuals with OI types I, III, IV and VI without accumulating in the bone matrix. Disturbance of calcium homeostasis is a clinically significant side effect. Anabolic therapy with growth hormone to ameliorate short stature in OI is successful for type I and about half of type IV OI children; responders also have improved bone histology, increased bone density and fewer fractures. Two antibody-based drugs with anabolic action on bone: anti-sclerostin, a negative regulator of bone formation in the Wnt pathway, and anti-TGF-β, a coordinator of bone remodeling produced by osteoblasts, have shown promising efficacy in early phase clinical trials and animal studies, respectively. Overall, a multidisciplinary approach to management of this set of disorders is most beneficial, with care centered on maximizing patient quality of life. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Osteogenesis imperfecta (OI), also known as Brittle Bone Disease, is a clinically and genetically heterogeneous group of heritable disorders of connective tissue. The hallmark feature of OI is bone fragility, with a tendency to fracture from minimal trauma or from the work of bearing weight against gravity. In the more severe forms of the disorder, the bones are deformed as well as fragile. Most individuals with OI have significant physical disabilities. Affected persons also exhibit an array of associated features, including short stature, macrocephaly, blue sclerae, dentinogenesis imperfecta, hearing loss and neurological and pulmonary complications. Autosomal dominant OI types occur at comparable frequency in different genders, races, and ethnic groups. Various recessive OI types occur at higher frequency in populations in which founder mutations have been identified: type VII (CRTAP; First Nations in Ontario, Canada) type VIII (P3H1; West Africa), type XI (FKBP10; Turkey), Type XIV (TMEM38B; Bedouins), Type XV (WNT1; Hmong group in Vietnam and China).

Historically, osteogenesis imperfecta has been viewed as an autosomal dominant disorder of type I collagen, the major protein component in the extracellular matrix of bone. In the past decade, the OI paradigm has undergone a major shift with the identification of autosomal recessive forms. The etiology of recessive OI types involves molecules that modify or interact with collagen post-translationally or are involved in osteoblast differentiation. These include proteins involved in bone mineralization, BRIL and PEDF; proteins involved in collagen modification and processing, CRTAP, P3H1 and CyPB (three components of the endoplasmic reticulum-resident collagen prolyl 3-hydroxylation complex), the chaperone HSP47, the foldase FKBP65, and the processing enzyme BMP-1; proteins involved in osteoblast differentiation SP7, WNT1 and Oasis (transcription factors), TRIC-B (a cation channel), the chaperone SPARC and the intramembrane regulatory protease S2P. OI, regardless of etiology, requires clinical management and genetic analysis. The incidence of forms of OI recognizable at birth is 1:10-20,000, with about equal incidence of mild forms that are not recognizable until later in life (1). OI and Marfan Syndrome share the distinction of being the most common heritable connective tissue disorders.

CLINICAL CLASSIFICATION AND PHENOTYPE

David Sillence formulated the classification currently in use for osteogenesis imperfecta in 1979 (2). Since type I collagen defects were not known to cause OI at that time, the Sillence Classification is based on clinical and radiographic features. The clinical spectrum of OI ranges from perinatal lethal to a mild form that can present in middle-aged adults as premature osteoporosis. In the past decade’s discovery of 16 genes other than COL1A1 and COL1A2 have expanded the genotypic and phenotypic spectrum of OI. This spurred the proposal for a new classification system to accommodate the long-standing functional and relevant grouping of OI types and the expanding genotypes (3). Within this new classification scheme (table 1), OI types I-IV retain their clinical descriptions and are associated with autosomal dominant mutations in the two collagen genes. Types V and XV OI are the only other newly discovered types to have an autosomal dominant inheritance pattern. The remaining OI types, typically occurring at much lower frequency, are autosomal recessive with OI type XVIII having an X-linked inheritance pattern.

Patients with type I OI have a distinctly milder form of the disease, which is generally not detectable at birth. Patients with type I OI tend to present with early osteoporosis; DEXA z-scores range from -1 to -3. Patients may have their first fracture in the pre-school years, for example when attaining ambulation. They may also have a series of fractures in the pre-pubertal years due to mild trauma. Fractures generally decrease dramatically in the post-pubertal years. Patients with type I OI have normally modeled bone and may have mild bowing of long bones and minimal central vertebral compressions. They are often a few inches shorter than same gender relatives. Leg length may be disproportionately short. Blue scleral hue is a defining feature in the Sillence classification, though, in actuality, it may be present or absent. These patients are expected to be spontaneous ambulators, but may have some mild delay of gross motor skills. They can be expected to have a full life span, limited only by greater vulnerability to accidental trauma.

Type II OI is the perinatal lethal form. Infants may be stillborn; if they survive birth, they usually die in the first two months of life (4). Some infants with type II OI may live for as long as a year, but eventually do succumb to multiple pneumonias or respiratory insufficiency. The limbs, especially the legs, are short with severe bowing deformities (Figure 1). Most often the legs are abducted into the classic “frog leg position”. The cranium is relatively large for the trunk and is very poorly ossified. The anterior fontanelle is large, and often extends frontally to the forehead and laterally along the sagittal suture. The posterior fontanelle is often open as well. The presence of two enlarged fontanelles frequently results in ossification only along the lateral plates and for a fingertip breadth at the crown. The infants tend to have flat triangular facies with a small beaked nose and dark blue-gray sclerae. The thorax is usually deformed with a narrow apex. Radiographic examination reveals multiple in utero fractures in various stages of healing. There may be beads of callus on the ribs, which are quite gracile. The long bones are very osteoporotic with minimal to no cortex. Upper extremity long bone morphology is better than that of the lower extremities. The lower long bones are crumpled as well as fractured and are abnormally modeled, with a cylindrical shape. Thus, the defect in type I collagen affects the development as well as the mineralization of the skeleton.

Figure 1.

Radiograph of infant with type II OI. Shows severe osteoporosis of skeleton with fractures of upper extremities, crumpled femora, flared rib cage with narrow apex and multiple beads of callus on each rib.

Type III OI, also known as the Progressive Deforming type (1), is the most severe form of OI compatible with survival beyond infancy and is severely disabling. Individuals with type III OI can have a full life span; however, a significant proportion succumb to respiratory or neurological complications, either during childhood or in early to middle adult years. The long bones of individuals with type III OI are soft as well as fragile and can have bowing deformities of 70-90°, caused either by the tension of normal muscle on the bone, or from angulated healing of fractures (Figures 2, 3). Long bones have a cylindrical shape with more modeling of the metaphysis than in type II; by late childhood there is often exaggerated metaphyseal flaring accompanied by a slender diaphysis (5). An additional finding in the metaphysis and epiphysis of lower limb long bones are so called “popcorn” calcifications caused by disorganization around the growth plate. More than half of the individuals with type III OI develop this radiographic change between the ages of 4 to 14 years with resolution of popcorn calcifications when epiphyses close (6). Fractures can occur from activities of daily living; there may be hundreds of fractures in a lifetime. DEXA z-scores are in the range of –5 to –7 SD. Body proportions are better preserved than in type II OI, with less shortening of the extremities relative to the trunk. The calvarium is almost always relatively macrocephalic for the body and frequently measures greater than 95^th centile for age, though occasionally children will have a normal or smaller than average head circumference for age. The midface is flat with frontal bossing and DI is common and its presence correlates with that of basilar invagination (7). Mixed type hearing loss occurs more commonly in adults than children with type III OI. Children with type III OI almost always develop chest wall abnormalities; pectus carinatum is more frequent and less detrimental to pulmonary status than pectus excavatum. Virtually all children with OI type III will also develop significant scoliosis. Even with aggressive intervention, these individuals are most often full-time wheelchair users.

Figure 2.

A, B: Radiographs of lower extremities of type III OI child. Shows osteoporosis, flared metaphyses, and placement of intramedullary Rush rod. C, D: Radiographs of child with type III OI. Shows lower long bones osteoporotic with cystic formation and “popcorn” metaphyses, and placement of telescoping intramedullary rods. Lateral view of spine shows anterior and central compression of multiple vertebrae.

Figure 3.

AP view of spine from type III OI child. Shows severe scoliosis and flared rib cage, as well as gracile and wavy ribs.

Type IV OI is the moderately severe type. The skeletons of these individuals are brittle, not soft. On average, people with type IV OI have dozens of fractures (Figure 4). Most fractures occur either prior to puberty or beyond middle age, with the intervening years relatively protected by sex steroids. Popcorn calcifications have been reported as a radiographic change associated with type IV OI; however, it does not occur as frequently as seen in type III (6). Individuals are significantly osteoporotic, with DEXA z-scores in the range of –3 to –5 SD. With medical intervention these individuals can expect to be community ambulators and have an essentially normal life span. Body proportions approach normal, although the legs are still short for the trunk and the cranium is relatively macrocephalic. As with type I OI, individuals with type IV are divided into types A and B by the Sillence classification, based on the presence or absence of dentinogenesis imperfecta (8). Vertebral compressions in childhood and laxity of paraspinal muscles may lead to significant scoliosis.

Figure 4.

Radiographs of lower extremities of type IV OI child. Shows mild bowing and placement of Rush rod. B: Lateral view of spine shows milder scoliosis and milder compression of vertebrae.

OI types V and above comprise the approximately 15-20% of individuals who have a phenotype characteristic of OI but who do not have a defect in the collagen genes COL1A1 or COL1A2. In many ways, type V OI is clinically indistinguishable from type IV because both types present with frequent fractures, moderate deformity, ligamentous laxity, tendency to bruise easily and periodic fracture-related loss of mobility. Clinical, histological and molecular differences exist, however, that distinguish type V from IV. Individuals with type V do not have blue sclera or DI. In type V, the distinctive bone histology is an irregular arrangement or a mesh-like appearance of the lamellae. Patients also have a triad of hypertrophic callus, dense metaphyseal bands and ossification of the interosseus membranes of the forearm. This causes severely limited pronation/supination of forearms. In addition, the type I collagen protein of these patients has normal electrophoretic mobility (9). In 2012, it was found that all cases of type V OI are caused by the same recurring defect in the IFITM5 gene that encodes the BRIL (Bone-restricted IFITM-like) protein, a known osteoblast marker which is highly expressed in mineralizing osteoblasts (10). The heterozygous mutation adds a 5-residue MALEP extension to the N-terminus of BRIL, disrupting the normal protein with a gain-of-function defect.

Type VI OI is clinically and histologically distinct from type V. Characteristics of individuals with type VI OI include short stature, ligamentous laxity, white or faintly blue sclera and no DI. There are no fractures or other signs of OI at birth. First fractures in type VI OI occur when affected individuals begin standing as infants/toddlers, with progressive deformity clinically similar to type III. Deformity caused by long bone fractures can be moderate to severe, often necessitating support devices for ambulation or wheelchairs to maintain mobility. Type VI OI is distinguished by distinct histologic and molecular criteria (11). Bone histology includes “fish-scale” pattern of the lamellae under polarized light, and decreased mineralized bone volume secondary to increased osteoid volume. This bone mineralization defect is a defining attribute of Type VI OI. Various autosomal recessive null mutations in the SERPINF1 gene, which encodes PEDF (pigment epithelium-derived factor), a potent anti-angiogenic factor that binds to type I collagen and a tumor inhibitor, have been shown to cause OI type VI (12, 13). These patients have negligible serum PEDF levels, as opposed to type V and other types, in which PEDF serum levels are equivalent to controls. Individuals with a point mutation in one copy of the IFITM5 gene, causing a p.S40L substitution in BRIL, present with histomorphologic and biochemical features of type VI OI, further underlining the connection between the two protein products and OI types (14).

Molecular and biochemical defects in types VII, VIII and IX OI were the first of the recessive forms identified; specifically, each type has a defect which causes deficiency of one of the components of the collagen prolyl 3-hydroxylation complex. Although 3-hydroxylation of Pro986 in type I collagen had been known to occur for almost three decades (15), its importance to bone formation had not been appreciated. The initial understanding of recessive OI as being due to a deficiency of this ER-resident collagen modification complex shifted the paradigm for collagen-related bone dysplasias (16). LEPRE1, CRTAP and PPIB are the three genes that encode the components of the collagen prolyl 3-hydroxylation complex, prolyl 3-hydroxylase 1 (P3H1- the enzymatic component of the complex), cartilage–associated protein (CRTAP- the helper-protein in the complex) and cyclophilin B (CyPB), respectively. The proteins form a 1:1:1 complex in the endoplasmic reticulum (17). The complex binds collagen post-translationally and hydroxylates a single residue, Proline 986, on each α1(I) chain. In normal collagen, over 90% of Pro986 residues are 3-hydroxylated. The importance of the collagen prolyl 3-hydroxylation complex for bone development became clear during investigation of the Crtap knock-out mouse. These mice have severe osteopenia, rhizomelia and later develop kyphosis. In addition, these mice lacked 3-hydroxylation of Proline 986 on both α1 (I) and α1(II) collagen chains (18). The type I collagen of CRTAP- or LEPRE1-deficient individuals also lacks Pro986 hydroxylation. Surprisingly, this collagen is, in turn, overmodified by Prolyl 4-hydroxylase (P4H) and lysyl hydroxylases (LH), proteins that modify proline and lysine residues along the length of the helical region of both alpha chains. Excess modification of the helix indicates that folding of the helix has been delayed.

Interestingly, the phenotype as well as the collagen biochemical findings of CRTAP and LEPRE1 null mutations are essentially indistinguishable. The basis of this similarity is the mutual protection of CRTAP and P3H1 in the modification complex (19). Cells with a null mutation in either gene are missing both proteins; restoration of the genetically deficient protein restores both proteins. Thus, null mutations in either gene cause absence of the complex from the cell.

Type VII OI is a lethal/severe recessive chondro-osseous dysplasia caused by null mutations in CRTAP. Fractures and limb deformities are present at birth. Radiographically, long bones are severely under-tubulated. Infants with type VII may develop respiratory insufficiency in the neonatal and postnatal periods and frequently die as a result of the underlying problem (i.e., pulmonary anatomical anomalies or infectious disease) (20). Distinctive features of type VII OI include small or normal head circumference, exophthalmia, white or light blue sclera, and rhizomelia. Deficiency of CRTAP affects post-translational modification of both bone (type I collagen) and cartilage (type II collagen). The index pedigree from Quebec (21) first described for type VII OI has a hypomorphic defect in CRTAP (18) and a correspondingly milder phenotype with rhizomelia, coxa vara and white sclerae, more similar to dominant type IV OI in skeletal severity. These children have moderate growth deficiency. They attain ambulation without assistive devices.

Type VIII OI, caused by defects in LEPRE1 (encoding P3H1) is also a severe/lethal autosomal recessive form of OI (22-24). Phenotypic characteristics overlap the dominant types II (lethal) and III (severe) OI, but have the distinguishing features of white sclerae, under-tubulated long bones and normal to small head circumference. Like type VII OI, rhizomelia is a distinctive feature of type VIII. Some individuals with type VIII OI have lived into their second or third decade (currently, the oldest known individual is mid-20’s). Their physical exam is notable for extreme short stature, severe osteoporosis (DEXA z-scores of -6 or -7), and popcorn calcifications during the growing years. The most frequently identified LEPRE1 mutation is a West African founder mutation (IVS5+2G>T) that also occurs in Afro-Caribbeans and African-Americans (23). Homozygosity for this West African allele has been lethal by 3 months of age.

Mutations causing deficiency of the third component of the collagen prolyl 3-hydroxylation complex, CyPB, are rarer and have been designated as type IX OI (25, 26). In this type, individuals have a distinctive phenotype compared to types VII/VIII in that they do not have rhizomelia. However, they share the white sclera of recessive OI. Total absence of cyclophilin B (CyPB) due to a mutation in the start codon causes moderately severe OI, overlapping dominant type IV OI in skeletal severity (25). Their osteoporosis is also moderately severe, with DEXA z-scores in the -2 to -3 range. They have attained community ambulation after osteotomy procedures. They have moderate short stature and may or may not have vertebral compressions. Biochemically, they have normal 3-hydroxylation of Pro986, consistent with persistence of the CRTAP/P3H1 complex in the absence of CyPB. More surprisingly, they do not have excess modification of their collagen helix, suggesting that CyPB is not the unique peptidyl-prolyl isomerase. In other cases, the presence of truncated CyPB (26) interferes with function of the 3-hydroxylation complex and causes severe or lethal OI. As for types VII and VIII OI, these CyPB mutations are associated with decreased Pro986 hydroxylation and delayed collagen folding.

Type X OI has been traced to a defect in SERPINH1, which encodes HSP47, a critical player in correct intracellular folding and transport of the procollagen triple helix. The only known SERPINH1 mutation causing bone dysplasia in humans caused severe, progressive OI with a myriad of clinical signs, some common and some unusual for OI (27). This patient survived for 3 years (probably due to functionality of the small amount of residual protein) despite the embryonic lethality of the null mutation in mice.

Type XI OI is caused by mutations in the FKBP10 gene, which encodes a known PPIase, FKBP65 (28), another important protein for proper folding of procollagen molecules. The first discovery of FKBP10 mutations was in a moderately severe type of OI (29). FKBP10 mutations have since been shown to be causative in the recessive Bruck syndrome I (severe OI with congenital contractures) (30), and the contractures are now understood to be variable expression of the null FKBP10 allele. Also, an in-frame tyrosine deletion in a PPI’ase domain of FKBP65 (31) was delineated as the cause of Kuskokwim syndrome, an Alaskan Yup’ik Eskimo congenital contracture syndrome with minor skeletal symptoms. Prior to these discoveries, there had been no known link between these three disorders, which represent the phenotypic range of the gene spectrum, encompassing bone dysplasia and congenital contractures of large joints.

Type XII OI is associated with an autosomal recessive inheritance pattern of mutations in BMP1, which encodes the C-propeptidase of type I procollagen (32). Individuals with type XII OI experience recurrent fractures early and, unlike previous OI types, have increased bone mineral density. A high bone mass OI phenotype was also observed in individuals with dominantly inherited mutations at the C-propeptide cleavage site of collagen (33). Conversely, mutations in the N-propeptidase ADAMTS-2, or the N-propeptide cleavage site, the N-anchor domain of the helical region cause combined osteogenesis imperfecta and Ehlers–Danlos syndrome (EDS) (OI/EDS) (34).

The subsequent, more recently identified, OI types are very rare, each with only a few cases described. Causative mutations reside in genes involved in regulation of osteoblast differentiation. Inheritance pattern is autosomal recessive for all except type XVIII OI, which is X-linked.

Type XIII OI has been described in two families with skeletal phenotype similar to that seen in Type IV OI (35, 36). The first report was on an Egyptian male, the second on an Iraqi sibship. Both families reported consanguinity. The associated gene is SP7/Osterix (OSX), which is a transcriptional factor and a regulator of bone function in mouse models and in the human cases (35, 36).

Type XIV OI is caused by null mutations in TMEM38B, encoding TRIC-B, a cation channel also involved in cell differentiation. The mechanism for this disruption involves impaired osteoblast Ca2+ flux from cytoplasm into the ER. Reported cases were first identified among Saudi Arabian and Israeli Bedouins (37, 38), but have since been identified in individuals of other ethnicities (39). Their clinical phenotype is similar to that of Type IV OI, with distinctive histological features of decreased osteoblast number and normal mineralization at the tissue level, in contrast to the elevated mineral content seen in other OI types. Because of the intracellular Ca2+ signaling involvement, cardiac involvement may occur at a higher frequency (39).

Type XV OI has been associated with mutations in WNT1, and reported in individuals of various ethnic backgrounds (40-43). Individuals with homozygous or compound heterozygous mutations in WNT1 have Type IV OI phenotype, while those with heterozygous mutation in WNT1 have osteoporosis (42). In its role as a stimulator of bone formation, WNT1 interacts with LRP5, which is known to cause a juvenile osteoporosis similar to type IV OI (44). Brain malformations have been reported in some individuals with this OI type.

Type XVI OI has a severity similar to that of Type II OI, in that almost all individuals diagnosed with it have died in utero (45). A living 11-yo male with Type XVI OI has severe bone dysplasia similar to that seen in Type III OI (46). Mutations in CREB3L1, encoding OASIS, an ER-stress transducer and regulator of genes in cellular differentiation and maturation, are causative (45). Mice lacking Creb3l1 show spontaneous fractures due to severe osteopenia (47). Individuals with heterozygous mutations in CREB3L1 have been reported to have features of blue sclerae, osteopenia, and mild recurrent fractures history (48).

Type XVII OI is caused by mutations in SPARC, whose protein product is a chaperone for extracellular matrix proteins. Only two individuals have been identified with this OI type (49). The presentation is similar to Type IV OI, with progressive skeletal involvement, including the spine.

Type XVIII OI has been described in male individuals from two families with phenotypes in the severity range of types III and IV OI (50). The gene involved, MBTPS2, codes for S2P, an intramembrane protease in the Golgi apparatus. In concert with S1P, S2P processes and activates transcription factors such as OASIS in the Regulatory Intramembrane Proteolysis (RIP) pathway. Despite the OASIS link, the phenotype for type XVIII is not as severe as that in type XVI. Obligate female carriers of MBTPS2 mutations do not have OI features (50).

SECONDARY FEATURES OF OI

DIAGNOSTIC WORK-UP AND DIFFERENTIAL DIAGNOSIS

Crucial elements of the diagnostic work-up focus on the skeletal system. The physical exam includes measurements of length and head circumference, as well as notations on body proportions, including upper segment: lower segment ratio and arm span. In addition, the segmental lengths of each limb are measured to detect asymmetry. Individuals with OI frequently have relatively long arm span for length and a shortened lower segment (pubis to floor). Sclerae may be blue or blue-gray and teeth may have dentinogenesis imperfecta, with opalescent or yellow-brown enamel. In the thorax, the spine should be examined for scoliosis and the rib cage for flare and/or pectus carinatum or excavatum. In an infant, the size of the fontanels should be noted. Also essential is a careful family pedigree, with inquiries about fractures, hearing loss, dentinogenesis imperfecta, adult height, racial background and consanguinity.

Radiographic examination consists of a selective skeletal survey. AP and lateral views of the long bones are examined for significant osteoporosis, bowing, healing fractures, metaphyseal flare and the sharpness of the growth plate. AP and lateral views of the spine are examined for scoliosis, vertebral compressions, and sharpness of the vertebral endplates. Rhizomelia is suggestive of recessive types of OI, although it occurs more commonly in chondrodystrophies. A lateral view of the skull should also be obtained to detect Wormian bones.

It is essential to obtain a DEXA of the lumbar vertebral bodies for a relatively quantitative assessment of the individual’s osteoporosis. Since the bone matrix in types II-IV, VII-XII OI is qualitatively abnormal, the DEXA z-score reflects the structural arrangement of the mineral as well as the quantity and therefore is not a straightforward quantitative measurement.

Differential diagnosis varies with the severity of OI and age of the patient. On prenatal ultrasound, severe OI may be confused with thanatophoric dysplasia, achondrogenesis type I, or campomelic dysplasia, all of which demonstrate relatively large heads and short limbs. Type III OI may need to be distinguished from infantile hypophosphatasia, which presents with severe osteoporosis and micromelia. Hypophosphatasia results in low serum alkaline phosphatase and increased inorganic pyrophosphate, while in OI, serum alkaline phosphatase is normal or increased. Type IV and more severe type I OI may be confused with primary juvenile osteoporosis or other secondary causes of osteoporosis in childhood, such as hypogonadism of malignancy. The major differential diagnosis with types I and IV OI is non-accidental trauma.

Molecular genetic sequencing, whether via broad-based panels or step-wise testing, has become the common first approach to diagnosis. Step-wise genetic testing applies in areas where access and cost remain challenging, and would include interrogating dominant OI genes first in individuals without family history of OI. This approach would yield informative findings in ~80% of the cases, and if a causal mutation is not identified may be followed by sequencing of recessive OI genes. Biochemical studies of collagen and of the components of the collagen prolyl 3-hydroxylation complex can complement decreased BMD and other skeletal features of OI, in cases of uncertain molecular findings.

COLLAGEN MUTATIONS AND GENOTYPE-PHENOTYPE CORRELATION

The majority (85-90%) of OI causing mutations occur in the genes that code for the two chains that comprise type I collagen, the major protein of the extracellular matrix of bone, skin and tendon (81). Type I collagen is a heterotrimer composed of two copies of the α1 chain, encoded by the COL1A1 gene on chromosome 17, and one copy of the α2 chain, encoded by COL1A2 on chromosome 7. The two alpha chains are similar in sequence organization; they are composed of 338 uninterrupted repeats of the sequence Gly-X-Y, where Gly is glycine, X is often proline and Y is often hydroxyproline. A glycine residue in every third position along the chain is crucial for helix formation; the small size of glycine’s side chain allows it to be tucked into the sterically constricted internal aspect of the helix. The collagen genes are organized with each exon coding for the helical region beginning with a glycine codon and ending with a Y-position codon; therefore the skipping of a helical exon does not cause a frameshift in the collagen transcript.

As of 2019, over 1600 unique pathogenic variants in both chains of type I collagen had been described in OI patients (82-84). One general correlation between genotype and phenotype emerged: Type I OI, the mild form, is caused by quantitative defects in collagen. Only half the normal amount of collagen is produced but all the collagen produced is structurally normal. This is almost always due to a null allele of COL1A1 (85). On the other hand, types II, III and IV OI, the clinically significant forms, are caused by structural defects in either of the type I collagen chains. About 80% of these structural mutations cause the substitution of another amino acid, with a charged, polar or bulky side chain, for one of the obligatory glycine residues occurring in every third position along the chain. Glycine substitution mutations temporarily block helix formation and cause over-modification (glycosylation) of the chains of the trimer. About 20% of structural mutations are single exon skipping defects, which are incorporated into the trimer because the frame of the transcript remains intact (84). Essentially all of the collagen mutations are dominant negative mutations. They exert their effects by being secreted and incorporate into the matrix, causing a weakened higher order structure.

For structural mutations of type I collagen, the relationship between genotype and phenotype has been elusive. A lethal mutation was found to be more likely in the α1 chain, in which about one-third of known glycine substitutions caused lethal OI, than in the α2 chain, in which only ~20% were lethal (84). Nonetheless, both chains contain substantial numbers of mutations causing the full range of the OI phenotype. The two chains have different patterns of lethal and non-lethal mutations along the helical region, supporting different roles for the two chains in matrix. Lethal and non-lethal clusters alternate along the α2(I) chain (86). The clusters are quite evenly spaced, and appear to play a role in regularly repeating interactions of collagen with non-collagenous matrix molecules. When the alignment of cluster boundaries was compared to the clinical outcome of mutations, the cluster boundaries correctly predicted the phenotype of 86% of α2(I) mutations (84). In the α1(I) chain, the mutations may disrupt the stability of the collagen helix itself (84). Two regions of uninterrupted lethal mutations in the carboxyl end of α1(I) coincide with the major ligand binding region (MLBR) for integrins, fibronectin, and COMP (84).

The phenotype-genotype relationship in OI is complicated by multiple examples of variable expression. Individuals with the same genotype have a different phenotype, an interesting feature of many dominant disorders. In the α1(I) chain, there are several dozen sites with examples of extreme variable expression of the same mutation; these glycine substitutions are found in both lethal and non-lethal forms of OI. A more frequent occurrence in both chains is substantial variation in severity between family members or unrelated individuals with the same mutation. For example, phenotype can range from type III to IV OI. One explanation for this interesting feature may be the existence of discrete modifying genes. Understanding modifying factors may provide new approaches to treatment.

Animal models for OI, including the Brtl (brittle), Amish, and Aga2 (abnormal gait 2) mice have shed new light on pathophysiology, modifying factors and treatment of OI. The Brtl mouse is a knock-in model for type IV OI (87). It contains a classic glycine substitution in one allele at α1(I) G349C, which causes dominant negative OI. The Brtl mouse reproduces the phenotype, histology, biochemistry and biomechanics of the disorder. It also has variable phenotypic expression, which may lead to an understanding of modifying factors. Clinically relevant findings elucidated with the Brtl mouse model include post-pubertal improvement in bone matrix material properties (88), the imbalance between decreased osteoblast function and increased osteoclasts precursors as a potential lead to novel OI therapies (89), and the concomitant beneficial and detrimental effects of cumulative bisphosphonates exposure (90). A knock-in mouse model for the α2(I) chain has also been published (91). It recapitulates the mutation found in a large Amish pedigree that causes a Gly610Cys substitution, hence its designation as the Amish mouse. Long bones of the Amish mouse are less fragile than those of Brtl. The human pedigree with the Gly610Cys substitution has a wide range of phenotypic variability. Crossing the murine mutations into different genetic backgrounds demonstrated that whole bone fracture susceptibility was influenced by factors reflected in the size and shape of bone, and will be useful for the identification of genetic modifiers. Finally, the Aga2 mouse has a dominant mutation located in the terminal C-propeptide that was created using an N-ethyl-N-nitrosourea mutagenesis strategy (92). Like the Brtl mouse model, the Aga2 phenotype has a perinatal lethal and a severe surviving form. This mouse will provide important insight into the special mechanism of OI caused by mutations in the C-propeptide. Since the C-propeptide is normally removed before collagen is incorporated into matrix, it is not clear why mutations in this region should cause moderate to lethal OI. In Aga2 osteoblasts, the intracellular retention of abnormal collagen chains has been shown to induce the Unfolded Protein Response (UPR) and result in cellular apoptosis.

In addition, there is a naturally occurring mouse model for type III OI, the oim mouse (93). Although this mouse has been extensively studied, its histomorphometry differs from that seen in classical dominant OI, limiting the utility of this model (94). The oim mouse is also atypical in other ways. First, although it has a collagen defect in COL1A2, the phenotype is recessively inherited vs the dominant inheritance of other type I collagen defects. Second, the collagen chain configuration in oim does not normally occur in bone. The defect in oim in the α2(I) chain prevents the fully synthesized chain from incorporating into heterotrimer and leads to the production of an α1(I) homotrimer. Third, and perhaps most importantly, the mechanism of bone defect in oim is also atypical. Patients with α1(I) homotrimer caused by null-mutations in the amino end of the α2(I) chain have been shown to have Ehlers/Danlos Syndrome but not OI (95, 96). Since the bone dysplasia of oim cannot be directly attributed to the presence of homotrimer, but is likely connected to the cellular effects of degrading unincorporated α2(I) chains, it is impossible to meaningfully interpret oim investigations.

Murine models for types V-XII, XV, and XVII have been developed (97, 98). Canine models for types III and X, and zebrafish models for types I-IV, VII, VIII, and XIII have also been reported (98, Forlino A et al., Matrix Biology, In Press).

GENETIC COUNSELING AND RATIONALE FOR COLLAGEN STUDIES

Genetic counseling is an essential component of complete care for individuals who have OI. More than half of individuals with autosomal dominant OI have a family history of OI. In a Finnish survey (57), about 65 percent of individuals with OI were in families in which a prior generation was affected and the remaining 35 percent represented new mutations in a type 1 collagen gene. In contrast, individuals with autosomal recessive OI seldom have a family history. Collagen studies are useful in cases where the molecular sequencing result is equivocal. Virtually all type I collagen mutations have dominant inheritance. If no collagen mutation is identified, abnormal collagen biochemistry can point to defects in CRTAP or LEPRE1. PPIB defects will rely on sequencing for detection, since collagen biochemistry may be normal or abnormal.

In autosomal dominant OI, a severe presentation is likely to be the result of a spontaneous mutation that occurred at or around conception; the affected individual is likely to be the first affected person in the family. The parents of a child with a de novo mutation are at no increased risk of recurrence compared to the general population. However, genetic testing of both child and parents is required to determine whether the OI is inherited from a mosaic parent (see below), which occurs in 5-10% of new cases and increases the risk of recurrence. Individuals who are affected with dominant OI have a 50% risk of transmission with each pregnancy.

Genetic counseling for autosomal recessive OI is challenging given the limited carrier information about these newly identified OI types. Certainly, parental consanguinity increases the risk that a child may have recessive OI. However, data have shown that the carrier frequency for type VIII OI among contemporary West Africans is over 1%; among African Americans about 1/200-300 individuals are carriers (99). Currently the carrier frequency of other recessive OI types is not known. Because recessive OI types can present as lethal OI and be incorrectly assumed to be type II OI, the genes for type I collagen frequently are not sequenced leading to the missed diagnosis of recessive OI and parental carrier status. The parents of a child with recessive OI have a 25% risk of recurrence. The mother of a son with X-linked OI overall has a 25% risk of recurrence with an unaffected partner.

PRENATAL DIAGNOSIS

For the first case of moderate to severe OI in a family, prenatal diagnosis will probably occur during ultrasound at 18 to 24 weeks’ gestation (101, 102). Given the severity of types VII-IX, XIV-XVI and XVIII OI and their clinical overlap with types II and III OI, the first case of recessive OI in a pedigree can be expected to be diagnosed in the same timeframe by ultrasound.

Detecting recurrence of all OI types prenatally is easiest if the exact mutation in the affected child is known. In that case, a potential mutation in the current pregnancy can be detected early and with confidence. Cultured chorionic villi cells (CVS) can be used for DNA or RNA extraction and detection by either PCR and restriction enzyme digestion or sequencing. CVS can also be used for biochemical analysis if the known mutation causes significant collagen protein over-modification (100). Amniocentesis is only appropriate for molecular diagnosis via RNA or DNA analysis. Biochemical analysis of amniocytes is complicated by the overproduction of α1(I) chains; the excess chains form homotrimers, which are overmodified and co-migrate with overmodified heterotrimers, potentially causing a false-positive test result (100). At this time, there are no data available on expression of the components of the 3-hydroxylation complex in CVS or amniocytes. Thus, analysis of DNA by sequencing or restriction digestion will be required.

Collagen analysis is useful when the diagnosis is equivocal. A positive collagen biochemical study can counteract charges of child abuse in mild cases, although the absence of a positive study still leaves a substantial possibility (about 25%) of a false negative result. False negative biochemical tests occur with most mutations in the amino-quarter of the alpha chains, which is also a region where almost all mutations are non-lethal (103). A positive collagen analysis can also settle subtle distinctions between type IV OI and idiopathic juvenile osteoporosis.

From a research standpoint, each new collagen mutation delineated in OI provides information about genotype-phenotype relationships either directly or by making the cells containing that particular mutation available for studies of mechanism at the level of bone matrix. Further, mutations may vary in response to different therapeutic approaches. Determination of mutations that cause OI may allow investigators to understand which drugs or therapies will be helpful for different individuals.

THERAPEUTIC APPROACHES

A multidisciplinary approach to OI management is most beneficial (104). A combination of nonsurgical treatment (e.g. rehabilitation, bracing, splinting), surgical intervention, and pharmacological management (bisphosphonates or growth hormones) are used.

ACKNOWLEDGMENT

The authors thank Helen Rajpar, PhD and Simone M. Smith, PhD for their work on prior versions of this chapter.

REFERENCES

1.

Sillence DO, Barlow KK, Cole WG, Dietrich S, Garber AP, Rimoin DL. Osteogenesis imperfecta type III. Delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet. 1986;23(3):821–32. [PubMed: 3953678]

2.

Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16(2):101–16. [PMC free article: PMC1012733] [PubMed: 458828]

3.

Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016;387(10028):1657–71. [PMC free article: PMC7384887] [PubMed: 26542481]

4.

Sillence D. Osteogenesis imperfecta: an expanding panorama of variants. Clin Orthop Relat Res. 1981;(159):11–25. [PubMed: 7285446]

5.

Sillence DO, Barlow KK, Garber AP, Hall JG, Rimoin DL. Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity. Am J Med Genet. 1984;17(2):407–23. [PubMed: 6702894]

6.

Obafemi AA, Bulas DI, Troendle J, Marini JC. Popcorn calcification in osteogenesis imperfecta: incidence, progression, and molecular correlation. Am J Med Genet A. 2008;146A(21):2725–32. [PMC free article: PMC6320686] [PubMed: 18798308]

7.

Engelbert RH, Gerver WJ, Breslau-Siderius LJ, van der Graaf Y, Pruijs HE, van Doorne JM, et al. Spinal complications in osteogenesis imperfecta: 47 patients 1-16 years of age. Acta Orthop Scand. 1998;69(3):283–6. [PubMed: 9703404]

8.

Levin LS, Salinas CF, Jorgenson RJ. Classification of osteogenesis imperfecta by dental characteristics. Lancet. 1978;1(8059):332–3. [PubMed: 75372]

9.

Glorieux FH, Rauch F, Plotkin H, Ward L, Travers R, Roughley P, et al. Type V osteogenesis imperfecta: a new form of brittle bone disease. J Bone Miner Res. 2000;15(9):1650–8. [PubMed: 10976985]

10.

Moffatt P, Gaumond MH, Salois P, Sellin K, Bessette MC, Godin E, et al. Bril: a novel bone-specific modulator of mineralization. J Bone Miner Res. 2008;23(9):1497–508. [PubMed: 18442316]

11.

Glorieux FH, Ward LM, Rauch F, Lalic L, Roughley PJ, Travers R. Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect. J Bone Miner Res. 2002;17(1):30–8. [PubMed: 11771667]

12.

Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, et al. Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2011;88(3):362–71. [PMC free article: PMC3059418] [PubMed: 21353196]

13.

Homan EP, Rauch F, Grafe I, Lietman C, Doll JA, Dawson B, et al. Mutations in SERPINF1 cause osteogenesis imperfecta type VI. J Bone Miner Res. 2011;26(12):2798–803. [PMC free article: PMC3214246] [PubMed: 21826736]

14.

Farber CR, Reich A, Barnes AM, Becerra P, Rauch F, Cabral WA, et al. A novel IFITM5 mutation in severe atypical osteogenesis imperfecta type VI impairs osteoblast production of pigment epithelium-derived factor. J Bone Miner Res. 2014;29(6):1402–11. [PMC free article: PMC4352343] [PubMed: 24519609]

15.

Fietzek PP, Rexrodt FW, Wendt P, Stark M, Kuhn K. The covalent structure of collagen. Amino-acid sequence of peptide 1-CB6-C2. Eur J Biochem. 1972;30(1):163–8. [PubMed: 4343807]

16.

Marini JC, Cabral WA, Barnes AM, Chang W. Components of the collagen prolyl 3-hydroxylation complex are crucial for normal bone development. Cell Cycle. 2007;6(14):1675–81. [PubMed: 17630507]

17.

Bachinger HP, Morris NP, Davis JM. Thermal stability and folding of the collagen triple helix and the effects of mutations in osteogenesis imperfecta on the triple helix of type I collagen. Am J Med Genet. 1993;45(2):152–62. [PubMed: 8456797]

18.

Morello R, Bertin TK, Chen Y, Hicks J, Tonachini L, Monticone M, et al. CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006;127(2):291–304. [PubMed: 17055431]

19.

Chang W, Barnes AM, Cabral WA, Bodurtha JN, Marini JC. Prolyl 3-hydroxylase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex. Hum Mol Genet. 2010;19(2):223–34. [PMC free article: PMC2796888] [PubMed: 19846465]

20.

Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, et al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006;355(26):2757–64. [PMC free article: PMC7509984] [PubMed: 17192541]

21.

Ward LM, Rauch F, Travers R, Chabot G, Azouz EM, Lalic L, et al. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone. 2002;31(1):12–8. [PubMed: 12110406]

22.

Baldridge D, Schwarze U, Morello R, Lennington J, Bertin TK, Pace JM, et al. CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta. Hum Mutat. 2008;29(12):1435–42. [PMC free article: PMC2671575] [PubMed: 18566967]

23.

Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, et al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007;39(3):359–65. [PMC free article: PMC7510175] [PubMed: 17277775]

24.

Willaert A, Malfait F, Symoens S, Gevaert K, Kayserili H, Megarbane A, et al. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J Med Genet. 2009;46(4):233–41. [PubMed: 19088120]

25.

Barnes AM, Carter EM, Cabral WA, Weis M, Chang W, Makareeva E, et al. Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. N Engl J Med. 2010;362(6):521–8. [PMC free article: PMC3156560] [PubMed: 20089953]

26.

van Dijk FS, Nesbitt IM, Zwikstra EH, Nikkels PG, Piersma SR, Fratantoni SA, et al. PPIB mutations cause severe osteogenesis imperfecta. Am J Hum Genet. 2009;85(4):521–7. [PMC free article: PMC2756556] [PubMed: 19781681]

27.

Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, et al. Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86(3):389–98. [PMC free article: PMC2833387] [PubMed: 20188343]

28.

Zeng B, MacDonald JR, Bann JG, Beck K, Gambee JE, Boswell BA, et al. Chicken FK506-binding protein, FKBP65, a member of the FKBP family of peptidylprolyl cis-trans isomerases, is only partially inhibited by FK506. Biochem J. 1998;330(Pt 1):109–14. [PMC free article: PMC1219115] [PubMed: 9461498]

29.

Alanay Y, Avaygan H, Camacho N, Utine GE, Boduroglu K, Aktas D, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86(4):551–9. [PMC free article: PMC2850430] [PubMed: 20362275]

30.

Kelley BP, Malfait F, Bonafe L, Baldridge D, Homan E, Symoens S, et al. Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome. J Bone Miner Res. 2011;26(3):666–72. [PMC free article: PMC3179293] [PubMed: 20839288]

31.

Barnes AM, Duncan G, Weis M, Paton W, Cabral WA, Mertz EL, et al. Kuskokwim syndrome, a recessive congenital contracture disorder, extends the phenotype of FKBP10 mutations. Hum Mutat. 2013;34(9):1279–88. [PMC free article: PMC3770534] [PubMed: 23712425]

32.

Martinez-Glez V, Valencia M, Caparros-Martin JA, Aglan M, Temtamy S, Tenorio J, et al. Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta. Hum Mutat. 2012;33(2):343–50. [PMC free article: PMC3725821] [PubMed: 22052668]

33.

Lindahl K, Barnes AM, Fratzl-Zelman N, Whyte MP, Hefferan TE, Makareeva E, et al. COL1 C-propeptide cleavage site mutations cause high bone mass osteogenesis imperfecta. Hum Mutat. 2011;32(6):598–609. [PMC free article: PMC3103631] [PubMed: 21344539]

34.

Cabral WA, Makareeva E, Colige A, Letocha AD, Ty JM, Yeowell HN, et al. Mutations near amino end of alpha1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. J Biol Chem. 2005;280(19):19259–69. [PubMed: 15728585]

35.

Fiscaletti M, Biggin A, Bennetts B, Wong K, Briody J, Pacey V, et al. Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment. Bone. 2018;110:66–75. [PubMed: 29382611]

36.

Lapunzina P, Aglan M, Temtamy S, Caparros-Martin JA, Valencia M, Leton R, et al. Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta. Am J Hum Genet. 2010;87(1):110–4. [PMC free article: PMC2896769] [PubMed: 20579626]

37.

Shaheen R, Alazami AM, Alshammari MJ, Faqeih E, Alhashmi N, Mousa N, et al. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J Med Genet. 2012;49(10):630–5. [PubMed: 23054245]

38.

Volodarsky M, Markus B, Cohen I, Staretz-Chacham O, Flusser H, Landau D, et al. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Hum Mutat. 2013;34(4):582–6. [PubMed: 23316006]

39.

Webb EA, Balasubramanian M, Fratzl-Zelman N, Cabral WA, Titheradge H, Alsaedi A, et al. Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect. J Clin Endocrinol Metab. 2017;102(6):2019–28. [PMC free article: PMC5470761] [PubMed: 28323974]

40.

Fahiminiya S, Majewski J, Mort J, Moffatt P, Glorieux FH, Rauch F. Mutations in WNT1 are a cause of osteogenesis imperfecta. J Med Genet. 2013;50(5):345–8. [PubMed: 23434763]

41.

Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, et al. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet. 2013;92(4):565–74. [PMC free article: PMC3617378] [PubMed: 23499309]

42.

Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, et al. WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med. 2013;368(19):1809–16. [PMC free article: PMC3709450] [PubMed: 23656646]

43.

Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, Temme RT, et al. WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet. 2013;92(4):590–7. [PMC free article: PMC3617391] [PubMed: 23499310]

44.

Monroe DG, McGee-Lawrence ME, Oursler MJ, Westendorf JJ. Update on Wnt signaling in bone cell biology and bone disease. Gene. 2012;492(1):1–18. [PMC free article: PMC3392173] [PubMed: 22079544]

45.

Symoens S, Malfait F, D'Hondt S, Callewaert B, Dheedene A, Steyaert W, et al. Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans. Orphanet J Rare Dis. 2013;8:154. [PMC free article: PMC3850743] [PubMed: 24079343]

46.

Lindahl K, Astrom E, Dragomir A, Symoens S, Coucke P, Larsson S, et al. Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy. Bone. 2018;114:268–77. [PubMed: 29936144]

47.

Murakami T, Saito A, Hino S, Kondo S, Kanemoto S, Chihara K, et al. Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation. Nat Cell Biol. 2009;11(10):1205–11. [PubMed: 19767743]

48.

Keller RB, Tran TT, Pyott SM, Pepin MG, Savarirayan R, McGillivray G, et al. Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. Genet Med. 2018;20(4):411–9. [PMC free article: PMC5816725] [PubMed: 28817112]

49.

Mendoza-Londono R, Fahiminiya S, Majewski J. Recessive osteogenesis imperfecta caused by missense mutations in SPARC. Am J Hum Genet. 2015;96(6):979–85. Care4Rare Canada C, Tetreault M, Nadaf J, et al. [PMC free article: PMC4457955] [PubMed: 26027498]

50.

Lindert U, Cabral WA, Ausavarat S, Tongkobpetch S, Ludin K, Barnes AM, et al. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. Nat Commun. 2016;7:11920. [PMC free article: PMC4935805] [PubMed: 27380894]

51.

Barber LA, Abbott C, Nakhate V, Do AND, Blissett AR, Marini JC. Longitudinal growth curves for children with classical osteogenesis imperfecta (types III and IV) caused by structural pathogenic variants in type I collagen. Genet Med. 2019;21(5):1233–9. [PMC free article: PMC7573860] [PubMed: 30270360]

52.

Marini JC, Bordenick S, Heavner G, Rose S, Chrousos GP. Evaluation of growth hormone axis and responsiveness to growth stimulation of short children with osteogenesis imperfecta. Am J Med Genet. 1993;45(2):261–4. [PubMed: 8456815]

53.

Germain-Lee EL, Brennen FS, Stern D, Kantipuly A, Melvin P, Terkowitz MS, et al. Cross-sectional and longitudinal growth patterns in osteogenesis imperfecta: implications for clinical care. Pediatr Res. 2016;79(3):489–95. [PubMed: 26539664]

54.

Sillence D, Butler B, Latham M, Barlow K. Natural history of blue sclerae in osteogenesis imperfecta. Am J Med Genet. 1993;45(2):183–6. [PubMed: 8456800]

55.

Garretsen AJ, Cremers CW, Huygen PL. Hearing loss (in nonoperated ears) in relation to age in osteogenesis imperfecta type I. Ann Otol Rhinol Laryngol. 1997;106(7 Pt 1):575–82. [PubMed: 9228859]

56.

Hartikka H, Kuurila K, Korkko J, Kaitila I, Grenman R, Pynnonen S, et al. Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients. Hum Mutat. 2004;24(2):147–54. [PubMed: 15241796]

57.

Kuurila K, Grenman R, Johansson R, Kaitila I. Hearing loss in children with osteogenesis imperfecta. Eur J Pediatr. 2000;159(7):515–9. [PubMed: 10923226]

58.

Letocha AD. Hearing loss in children with types III and IV OI: Incidence, progression and correlation with collagen mutations. 8th International Osteogenesis Imperfecta Conference; Annecy, France2002.

59.

Swinnen FK, De Leenheer EM, Coucke PJ, Cremers CW, Dhooge IJ. Audiometric, surgical, and genetic findings in 15 ears of patients with osteogenesis imperfecta. Laryngoscope. 2009;119(6):1171–9. [PubMed: 19358256]

60.

Swinnen FK, De Leenheer EM, Goemaere S, Cremers CW, Coucke PJ, Dhooge IJ. Association between bone mineral density and hearing loss in osteogenesis imperfecta. Laryngoscope. 2012;122(2):401–8. [PubMed: 22252604]

61.

Pedersen U. Hearing loss in patients with osteogenesis imperfecta. A clinical and audiological study of 201 patients. Scand Audiol. 1984;13(2):67–74. [PubMed: 6463554]

62.

Swinnen FK, De Leenheer EM, Coucke PJ, Cremers CW, Dhooge IJ. Stapes surgery in osteogenesis imperfecta: retrospective analysis of 34 operated ears. Audiol Neurootol. 2012;17(3):198–206. [PubMed: 22399015]

63.

Kuurila K, Pynnonen S, Grenman R. Stapes surgery in osteogenesis imperfecta in Finland. Ann Otol Rhinol Laryngol. 2004;113(3 Pt 1):187–93. [PubMed: 15053199]

64.

Rotteveel LJ, Beynon AJ, Mens LH, Snik AF, Mulder JJ, Mylanus EA. Cochlear implantation in 3 patients with osteogenesis imperfecta: imaging, surgery and programming issues. Audiol Neurootol. 2008;13(2):73–85. [PubMed: 18057871]

65.

Streubel SO, Lustig LR. Cochlear implantation in patients with osteogenesis imperfecta. Otolaryngol Head Neck Surg. 2005;132(5):735–40. [PubMed: 15886627]

66.

Folkestad L, Hald JD, Gram J, Langdahl BL, Hermann AP, Diederichsen AC, et al. Cardiovascular disease in patients with osteogenesis imperfecta - a nationwide, register-based cohort study. Int J Cardiol. 2016;225:250–7. [PubMed: 27741483]

67.

Widmann RF, Bitan FD, Laplaza FJ, Burke SW, DiMaio MF, Schneider R. Spinal deformity, pulmonary compromise, and quality of life in osteogenesis imperfecta. Spine (Phila Pa 1976). 1999;24(16):1673–8. [PubMed: 10472101]

68.

LoMauro A, Pochintesta S, Romei M, D'Angelo MG, Pedotti A, Turconi AC, et al. Rib cage deformities alter respiratory muscle action and chest wall function in patients with severe osteogenesis imperfecta. PLoS One. 2012;7(4):e35965. [PMC free article: PMC3338769] [PubMed: 22558284]

69.

Thiele F, Cohrs CM, Flor A, Lisse TS, Przemeck GK, Horsch M, et al. Cardiopulmonary dysfunction in the Osteogenesis imperfecta mouse model Aga2 and human patients are caused by bone-independent mechanisms. Hum Mol Genet. 2012;21(16):3535–45. [PMC free article: PMC3406754] [PubMed: 22589248]

70.

Hortop J, Tsipouras P, Hanley JA, Maron BJ, Shapiro JR. Cardiovascular involvement in osteogenesis imperfecta. Circulation. 1986;73(1):54–61. [PubMed: 3940669]

71.

Radunovic Z, Wekre LL, Diep LM, Steine K. Cardiovascular abnormalities in adults with osteogenesis imperfecta. Am Heart J. 2011;161(3):523–9. [PubMed: 21392607]

72.

Radunovic Z, Wekre LL, Steine K. Right ventricular and pulmonary arterial dimensions in adults with osteogenesis imperfecta. Am J Cardiol. 2012;109(12):1807–13. [PubMed: 22459302]

73.

Lamanna A, Fayers T, Clarke S, Parsonage W. Valvular and aortic diseases in osteogenesis imperfecta. Heart Lung Circ. 2013;22(10):801–10. [PubMed: 23791715]

74.

Arponen H, Makitie O, Haukka J, Ranta H, Ekholm M, Mayranpaa MK, et al. Prevalence and natural course of craniocervical junction anomalies during growth in patients with osteogenesis imperfecta. J Bone Miner Res. 2012;27(5):1142–9. [PubMed: 22258757]

75.

Arponen H, Vuorimies I, Haukka J, Valta H, Waltimo-Siren J, Makitie O. Cranial base pathology in pediatric osteogenesis imperfecta patients treated with bisphosphonates. J Neurosurg Pediatr. 2015;15(3):313–20. [PubMed: 25559924]

76.

Cheung MS, Arponen H, Roughley P, Azouz ME, Glorieux FH, Waltimo-Siren J, et al. Cranial base abnormalities in osteogenesis imperfecta: phenotypic and genotypic determinants. J Bone Miner Res. 2011;26(2):405–13. [PubMed: 20721936]

77.

Menezes AH. Specific entities affecting the craniocervical region: osteogenesis imperfecta and related osteochondrodysplasias: medical and surgical management of basilar impression. Childs Nerv Syst. 2008;24(10):1169–72. [PubMed: 18401562]

78.

Khandanpour N, Connolly DJ, Raghavan A, Griffiths PD, Hoggard N. Craniospinal abnormalities and neurologic complications of osteogenesis imperfecta: imaging overview. Radiographics. 2012;32(7):2101–12. [PubMed: 23150860]

79.

Ibrahim AG, Crockard HA. Basilar impression and osteogenesis imperfecta: a 21-year retrospective review of outcomes in 20 patients. J Neurosurg Spine. 2007;7(6):594–600. [PubMed: 18074683]

80.

Charnas LR, Marini JC. Communicating hydrocephalus, basilar invagination, and other neurologic features in osteogenesis imperfecta. Neurology. 1993;43(12):2603–8. [PubMed: 8255464]

81.

Kuivaniemi H, Tromp G, Prockop DJ. Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels. Hum Mutat. 1997;9(4):300–15. [PubMed: 9101290]

82.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat. 2011;32(5):557–63. [PubMed: 21520333]

83.

Forlino A. Consortium for OI mutations in the helical region of type I collagen: an updated analysis. 11th International Conference on Osteogenesis Imperfecta; Dubrovnik, Croatia2011.

84.

Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, et al. Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat. 2007;28(3):209–21. [PMC free article: PMC4144349] [PubMed: 17078022]

85.

Willing MC, Pruchno CJ, Atkinson M, Byers PH. Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen. Am J Hum Genet. 1992;51(3):508–15. [PMC free article: PMC1682712] [PubMed: 1353940]

86.

Marini JC, Lewis MB, Wang Q, Chen KJ, Orrison BM. Serine for glycine substitutions in type I collagen in two cases of type IV osteogenesis imperfecta (OI). Additional evidence for a regional model of OI pathophysiology. J Biol Chem. 1993;268(4):2667–73. [PubMed: 8094076]

87.

Forlino A, Porter FD, Lee EJ, Westphal H, Marini JC. Use of the Cre/lox recombination system to develop a non-lethal knock-in murine model for osteogenesis imperfecta with an alpha1(I) G349C substitution. Variability in phenotype in BrtlIV mice. J Biol Chem. 1999;274(53):37923–31. [PubMed: 10608859]

88.

Kozloff KM, Carden A, Bergwitz C, Forlino A, Uveges TE, Morris MD, et al. Brittle IV mouse model for osteogenesis imperfecta IV demonstrates postpubertal adaptations to improve whole bone strength. J Bone Miner Res. 2004;19(4):614–22. [PubMed: 15005849]

89.

Uveges TE, Collin-Osdoby P, Cabral WA, Ledgard F, Goldberg L, Bergwitz C, et al. Cellular mechanism of decreased bone in Brtl mouse model of OI: imbalance of decreased osteoblast function and increased osteoclasts and their precursors. J Bone Miner Res. 2008;23(12):1983–94. [PMC free article: PMC2686922] [PubMed: 18684089]

90.

Uveges TE, Kozloff KM, Ty JM, Ledgard F, Raggio CL, Gronowicz G, et al. Alendronate treatment of the brtl osteogenesis imperfecta mouse improves femoral geometry and load response before fracture but decreases predicted material properties and has detrimental effects on osteoblasts and bone formation. J Bone Miner Res. 2009;24(5):849–59. [PMC free article: PMC2672204] [PubMed: 19113917]

91.

Daley E, Streeten EA, Sorkin JD, Kuznetsova N, Shapses SA, Carleton SM, et al. Variable bone fragility associated with an Amish COL1A2 variant and a knock-in mouse model. J Bone Miner Res. 2010;25(2):247–61. [PMC free article: PMC3153383] [PubMed: 19594296]

92.

Lisse TS, Thiele F, Fuchs H, Hans W, Przemeck GK, Abe K, et al. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genet. 2008;4(2):e7. [PMC free article: PMC2222924] [PubMed: 18248096]

93.

Chipman SD, Sweet HO, McBride DJ Jr, Davisson MT, Marks SC Jr, Shuldiner AR, et al. Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta. Proc Natl Acad Sci U S A. 1993;90(5):1701–5. [PMC free article: PMC45947] [PubMed: 8446583]

94.

Kalajzic I, Terzic J, Rumboldt Z, Mack K, Naprta A, Ledgard F, et al. Osteoblastic response to the defective matrix in the osteogenesis imperfecta murine (oim) mouse. Endocrinology. 2002;143(5):1594–601. [PubMed: 11956140]

95.

Malfait F, Symoens S, Coucke P, Nunes L, De Almeida S, De Paepe A. Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems. J Med Genet. 2006;43(7):e36. [PMC free article: PMC2564565] [PubMed: 16816023]

96.

Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet. 2004;74(5):917–30. [PMC free article: PMC1181985] [PubMed: 15077201]

97.

Besio R, Chow CW, Tonelli F, Marini JC, Forlino A. Bone biology: insights from osteogenesis imperfecta and related rare fragility syndromes. FEBS J. 2019;286(15):3033–56. [PMC free article: PMC7384889] [PubMed: 31220415]

98.

Enderli TA, Burtch SR, Templet JN, Carriero A. Animal models of osteogenesis imperfecta: applications in clinical research. Orthop Res Rev. 2016;8:41–55. [PMC free article: PMC6209373] [PubMed: 30774469]

99.

Cabral WA, Barnes AM, Adeyemo A, Cushing K, Chitayat D, Porter FD, et al. A founder mutation in LEPRE1 carried by 1.5% of West Africans and 0.4% of African Americans causes lethal recessive osteogenesis imperfecta. Genet Med. 2012;14(5):543–51. [PMC free article: PMC3393768] [PubMed: 22281939]

100.

Pepin M, Atkinson M, Starman BJ, Byers PH. Strategies and outcomes of prenatal diagnosis for osteogenesis imperfecta: a review of biochemical and molecular studies completed in 129 pregnancies. Prenat Diagn. 1997;17(6):559–70. [PubMed: 9203215]

101.

Krakow D. Osteogenesis imperfecta. In: J. A. Copel DA, M. E., Feltovich, H., Gratacos, E., Krakow, D., Odibo, A. O., Platt, L. D., Tutschek, B., editor. Obstetric Imaging: Fetal Diagnosis and Care. 2nd ed: Elsevier, Inc; 2018. p. 270-3.

102.

Thompson EM. Non-invasive prenatal diagnosis of osteogenesis imperfecta. Am J Med Genet. 1993;45(2):201–6. [PubMed: 8456803]

103.

Cabral WA, Milgrom S, Letocha AD, Moriarty E, Marini JC. Biochemical screening of type I collagen in osteogenesis imperfecta: detection of glycine substitutions in the amino end of the alpha chains requires supplementation by molecular analysis. J Med Genet. 2006;43(8):685–90. [PMC free article: PMC2564593] [PubMed: 16882741]

104.

Tsang KS, Adedapo A. Cannulated screw fixation of fracture neck of femur in children with osteogenesis imperfecta. J Pediatr Orthop B. 2011;20(5):287–90. [PubMed: 21606853]

105.

Gerber LH, Binder H, Weintrob J, Grange DK, Shapiro J, Fromherz W, et al. Rehabilitation of children and infants with osteogenesis imperfecta. A program for ambulation. Clin Orthop Relat Res. 1990;(251):254–62. [PubMed: 2295183]

106.

Marini JC, Gerber NL. Osteogenesis imperfecta. Rehabilitation and prospects for gene therapy. JAMA. 1997;277(9):746–50. [PubMed: 9042848]

107.

Zionts LE, Ebramzadeh E, Stott NS. Complications in the use of the Bailey-Dubow extensible nail. Clin Orthop Relat Res. 1998;(348):186–95. [PubMed: 9553552]

108.

Lee K, Park MS, Yoo WJ, Chung CY, Choi IH, Cho TJ. Proximal migration of femoral telescopic rod in children with osteogenesis imperfecta. J Pediatr Orthop. 2015;35(2):178–84. [PubMed: 24919136]

109.

Fassier F. Experience with the Fassier-Duval rod: Effectiveness and complications. 9th International Conference on Osteogenesis Imperfecta; Annapolis, MD, USA2005.

110.

Ruck J, Dahan-Oliel N, Montpetit K, Rauch F, Fassier F. Fassier-Duval femoral rodding in children with osteogenesis imperfecta receiving bisphosphonates: functional outcomes at one year. J Child Orthop. 2011;5(3):217–24. [PMC free article: PMC3100465] [PubMed: 22654983]

111.

Krishnan H, Patel NK, Skinner JA, Muirhead-Allwood SK, Briggs TW, Carrington RW, et al. Primary and revision total hip arthroplasty in osteogenesis imperfecta. Hip Int. 2013;23(3):303–9. [PubMed: 23329537]

112.

Anissipour AK, Hammerberg KW, Caudill A, Kostiuk T, Tarima S, Zhao HS, et al. Behavior of scoliosis during growth in children with osteogenesis imperfecta. J Bone Joint Surg Am. 2014;96(3):237–43. [PMC free article: PMC6948836] [PubMed: 24500586]

113.

Yilmaz G, Hwang S, Oto M, Kruse R, Rogers KJ, Bober MB, et al. Surgical treatment of scoliosis in osteogenesis imperfecta with cement-augmented pedicle screw instrumentation. J Spinal Disord Tech. 2014;27(3):174–80. [PubMed: 24945295]

114.

Glorieux FH, Rauch F, Shapiro JR. Bisphosphonates in children with bone diseases. N Engl J Med. 2003;349(21):2068-71; author reply -71. [PubMed: 14631922]

115.

Plotkin H, Rauch F, Bishop NJ, Montpetit K, Ruck-Gibis J, Travers R, et al. Pamidronate treatment of severe osteogenesis imperfecta in children under 3 years of age. J Clin Endocrinol Metab. 2000;85(5):1846–50. [PubMed: 10843163]

116.

Gatti D, Antoniazzi F, Prizzi R, Braga V, Rossini M, Tato L, et al. Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study. J Bone Miner Res. 2005;20(5):758–63. [PubMed: 15824848]

117.

Letocha AD, Cintas HL, Troendle JF, Reynolds JC, Cann CE, Chernoff EJ, et al. Controlled trial of pamidronate in children with types III and IV osteogenesis imperfecta confirms vertebral gains but not short-term functional improvement. J Bone Miner Res. 2005;20(6):977–86. [PubMed: 15883638]

118.

Sakkers R, Kok D, Engelbert R, van Dongen A, Jansen M, Pruijs H, et al. Skeletal effects and functional outcome with olpadronate in children with osteogenesis imperfecta: a 2-year randomised placebo-controlled study. Lancet. 2004;363(9419):1427–31. [PubMed: 15121405]

119.

Ward LM, Rauch F, Whyte MP, D'Astous J, Gates PE, Grogan D, et al. Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study. J Clin Endocrinol Metab. 2011;96(2):355–64. [PubMed: 21106710]

120.

Dwan K, Phillipi CA, Steiner RD, Basel D. Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. 2014;(7):CD005088. [PubMed: 25054949]

121.

Li JS, Eisenstein EL, Grabowski HG, Reid ED, Mangum B, Schulman KA, et al. Economic return of clinical trials performed under the pediatric exclusivity program. JAMA. 2007;297(5):480–8. [PMC free article: PMC2773665] [PubMed: 17284698]

122.

Rauch F, Travers R, Glorieux FH. Pamidronate in children with osteogenesis imperfecta: histomorphometric effects of long-term therapy. J Clin Endocrinol Metab. 2006;91(2):511–6. [PubMed: 16291701]

123.

Bishop N, Adami S, Ahmed SF, Anton J, Arundel P, Burren CP, et al. Risedronate in children with osteogenesis imperfecta: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9902):1424–32. [PubMed: 23927913]

124.

Bradbury LA, Barlow S, Geoghegan F, Hannon RA, Stuckey SL, Wass JA, et al. Risedronate in adults with osteogenesis imperfecta type I: increased bone mineral density and decreased bone turnover, but high fracture rate persists. Osteoporos Int. 2012;23(1):285–94. [PubMed: 21739105]

125.

Land C, Rauch F, Travers R, Glorieux FH. Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment. Bone. 2007;40(3):638–44. [PubMed: 17127117]

126.

Semler O, Netzer C, Hoyer-Kuhn H, Becker J, Eysel P, Schoenau E. First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J Musculoskelet Neuronal Interact. 2012;12(3):183–8. [PubMed: 22947550]

127.

Leali PT, Balsano M, Maestretti G, Brusoni M, Amorese V, Ciurlia E, et al. Efficacy of teriparatide vs neridronate in adults with osteogenesis imperfecta type I: a prospective randomized international clinical study. Clin Cases Miner Bone Metab. 2017;14(2):153–6. [PMC free article: PMC5726200] [PubMed: 29263724]

128.

Orwoll ES, Shapiro J, Veith S, Wang Y, Lapidus J, Vanek C, et al. Evaluation of teriparatide treatment in adults with osteogenesis imperfecta. J Clin Invest. 2014;124(2):491–8. [PMC free article: PMC3904621] [PubMed: 24463451]

129.

Marom R, Lee YC, Grafe I, Lee B. Pharmacological and biological therapeutic strategies for osteogenesis imperfecta. Am J Med Genet C Semin Med Genet. 2016;172(4):367–83. [PubMed: 27813341]

130.

Marini JC, Hopkins E, Glorieux FH, Chrousos GP, Reynolds JC, Gundberg CM, et al. Positive linear growth and bone responses to growth hormone treatment in children with types III and IV osteogenesis imperfecta: high predictive value of the carboxyterminal propeptide of type I procollagen. J Bone Miner Res. 2003;18(2):237–43. [PubMed: 12568401]

131.

Antoniazzi F, Monti E, Venturi G, Franceschi R, Doro F, Gatti D, et al. GH in combination with bisphosphonate treatment in osteogenesis imperfecta. Eur J Endocrinol. 2010;163(3):479–87. [PubMed: 20592128]

132.

Sinder BP, Eddy MM, Ominsky MS, Caird MS, Marini JC, Kozloff KM. Sclerostin antibody improves skeletal parameters in a Brtl/+ mouse model of osteogenesis imperfecta. J Bone Miner Res. 2013;28(1):73–80. [PMC free article: PMC3524379] [PubMed: 22836659]

133.

Sinder BP, White LE, Salemi JD, Ominsky MS, Caird MS, Marini JC, et al. Adult Brtl/+ mouse model of osteogenesis imperfecta demonstrates anabolic response to sclerostin antibody treatment with increased bone mass and strength. Osteoporos Int. 2014;25(8):2097–107. [PMC free article: PMC4415164] [PubMed: 24803333]

134.

Kocijan R, Muschitz C, Fahrleitner-Pammer A, Amrein K, Pietschmann P, Haschka J, et al. Serum sclerostin levels are decreased in adult patients with different types of osteogenesis imperfecta. J Clin Endocrinol Metab. 2014;99(2):E311–9. [PubMed: 24203063]

135.

Dawson PA, Marini JC. Hammerhead ribozymes selectively suppress mutant type I collagen mRNA in osteogenesis imperfecta fibroblasts. Nucleic Acids Res. 2000;28(20):4013–20. [PMC free article: PMC110781] [PubMed: 11024182]

136.

Cabral WA, Marini JC. High proportion of mutant osteoblasts is compatible with normal skeletal function in mosaic carriers of osteogenesis imperfecta. Am J Hum Genet. 2004;74(4):752–60. [PMC free article: PMC1181952] [PubMed: 15024692]

137.

Guillot PV, Abass O, Bassett JH, Shefelbine SJ, Bou-Gharios G, Chan J, et al. Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Blood. 2008;111(3):1717–25. [PubMed: 17967940]

138.

Li F, Wang X, Niyibizi C. Distribution of single-cell expanded marrow derived progenitors in a developing mouse model of osteogenesis imperfecta following systemic transplantation. Stem Cells. 2007;25(12):3183–93. [PubMed: 17823236]

139.

Panaroni C, Gioia R, Lupi A, Besio R, Goldstein SA, Kreider J, et al. In utero transplantation of adult bone marrow decreases perinatal lethality and rescues the bone phenotype in the knockin murine model for classical, dominant osteogenesis imperfecta. Blood. 2009;114(2):459–68. [PMC free article: PMC2714216] [PubMed: 19414862]

140.

Dominici M, Marino R, Rasini V, Spano C, Paolucci P, Conte P, et al. Donor cell-derived osteopoiesis originates from a self-renewing stem cell with a limited regenerative contribution after transplantation. Blood. 2008;111(8):4386–91. [PMC free article: PMC2288731] [PubMed: 18182575]

141.

Le Blanc K, Gotherstrom C, Ringden O, Hassan M, McMahon R, Horwitz E, et al. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation. 2005;79(11):1607–14. [PubMed: 15940052]

142.

Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A. 2002;99(13):8932–7. [PMC free article: PMC124401] [PubMed: 12084934]

143.

Marini JC. Osteogenesis imperfecta calls for caution. Nat Med. 1999;5(5):466–7. [PubMed: 10229207]

144.

Chamberlain JR, Deyle DR, Schwarze U, Wang P, Hirata RK, Li Y, et al. Gene targeting of mutant COL1A2 alleles in mesenchymal stem cells from individuals with osteogenesis imperfecta. Mol Ther. 2008;16(1):187–93. [PMC free article: PMC4128632] [PubMed: 17955022]

145.

Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, et al. Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science. 2004;303(5661):1198–201. [PubMed: 14976317]