Osteogenesis imperfecta: Clinical features and diagnosis Authors John F Beary, III, MD Arkadi A Chines, MD Section Editor Helen

V Firth, DM, FRCP, DCH Deputy Editor Elizabeth TePas, MD, MS Disclosures Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu May 26 00:00:00 GMT 2011 (More) INTRODUCTION Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. It is often called "brittle bone disease." Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may manifest with only premature osteoporosis or severe postmenopausal bone mineral loss. The pathogenesis, clinical features, diagnosis, and differential diagnosis of osteogenesis imperfecta are presented here. The management and prognosis of osteogenesis imperfecta are discussed separately. (See "Osteogenesis imperfecta: Management and prognosis".) EPIDEMIOLOGY The estimated incidence of OI is approximately 1 per 20,000 births [1]. This qualifies it as an orphan disease, which is defined in the United States as a disease affecting 200,000 patients or less. PATHOGENESIS The cause of OI is established in most cases. In patients with identified molecular defects, OI is most commonly caused by mutations in genes encoding the alpha-1 and alpha-2 chains of type I collagen [2] or proteins involved in posttranslational modification of type I collagen. Type I collagen fibers are polymers of tropocollagen molecules, each of which is a triple helix that contains portions of one alpha 2 and two alpha 1 polypeptide chains. The composition of tropocollagen is shown in the figure (figure 1). Type I collagen is an important structural protein for bone, tendon, ligament, skin, and sclerae. Defective

bone quality explains many clinical aspects of osteogenesis imperfecta. (See "Bone physiology and biochemical markers of bone turnover", section on 'Bone formation'.) Most patients with OI have an autosomal dominant mutation in COL1A1 (located at 17q21.31-q22) or COL1A2 (located at 7q22.1) that affects the structure of one of the two alpha chains of type I collagen. The severity of the clinical presentation depends upon the effect of the mutation (table 1 and table 2) [37]. As an example, mutations in COL1A1 or COL1A2 that lead to decreased amounts of normal collagen cause the mild phenotype seen in type I OI. In contrast, mutations that disrupt the formation of the normal type I collagen triple helix cause the lethal phenotype seen in type IIA OI. Other COL1A1 and COL1A2 mutations that result in structural protein defects cause moderate (type IV) and severe, but not lethal (type III), forms of OI. COL1A1 and COL1A2 genes are normal in approximately 10 percent of cases. Many of these patients have autosomal recessive genetic defects. Mutations in the FK506-binding protein 10 (FKBP10 or FKBP65) gene, located at 17q21, were identified in a cohort of five consanguineous Turkish families and in a Mexican-American family with recessively inherited, moderately severe OI [8]. FKBP10 encodes a molecular chaperone that interacts with type I collagen and tropoelastin and is involved in the folding of type I procollagen. Mutations in FKBP10 affect type I procollagen secretion. The OI phenotype associated with FKBP10 mutations (designated OI type VI) most closely resembles OI type III, because of its severity and progressive nature. However, histologic findings of distorted lamellar structure and elevated alkaline phosphatase in some of the affected children are consistent with OI type VI. Mutations in FKBP10 can cause a related disorder, Bruck syndrome. (See 'Other skeletal syndromes' below.) Mutations in any of the three components of the 3-prolylhydroxylation complex that modifies type I collagen posttranslation can cause lethal/severe, recessive forms of OI with normal collagen folding. These components include:

 Cartilage-associated protein (CRTAP, gene located at 3p22) [9,10]. CRTAP deficiency was detected in 3 of 10 children with recessively inherited lethal or severe OI who had type I collagen with normal primary structure, but excess posttranslational modification of the alpha chain helical regions [11]. Mutations in CRTAP cause type IIB OI (a perinatal lethal form) and type VII OI (a severe, nonlethal form) [11-13]. Prolyl-3-hydroxylase-1 (P3H1; encoded by leprecan-like 1, LEPRE1 located at 1q34) [14,15]. Mutations in LEPRE1 cause type VIII OI [10,15-17]. Peptidyl-prolyl isomerase B (also called cyclophilin B; PPIB gene located at15q21-q22). Mutations in PPIB cause type IX OI [18-20]. Mutations causing severe, recessive OI resembling type III OI have also been identified in other genes encoding proteins involved in bone formation and homeostasis. These include:

SERPINH1 (located at 11q13.5) that encodes a collagen chaperone-like protein (serpin peptidase inhibitor, clade, H, member 1; also called collagen-binding protein 2, CBP2; and heat-shock protein 47, HSP47) [21]. SERPINF1 (located at 17p13.3) that encodes a multifunctional glycoprotein that is a strong inhibitor of angiogenesis (serpin peptidase inhibitor, clade F, member 1; also called pigment epithelium-derived factor, PEDF) [22]. SP7/OSX (located at 12q13.13) that encodes specificity protein 7 or osterix, a zinc finger transcription factor that is an essential regulator of bone cell differentiation [23]. DISEASE CLASSIFICATION OI is classified into nine major subtypes based on genetic, radiographic, and clinical characteristics (table 1 and table 2) [3,12,24,25]. A more useful clinical classification, based upon the typical problems that manifest in infants, children, and adults with mild, moderate to

severe, and lethal disease [26], is presented below. CLINICAL MANIFESTATIONS Overview The clinical manifestations vary substantially within families [27]. One member may be significantly affected clinically, whereas another member with the same mutation may have normal function. This emphasizes that identifying a mutation in a particular gene does not necessarily result in a clear clinical diagnosis and suggests that it may take defects in other connective tissue components to fully express the genetic syndrome of clinically observable OI. (See 'Diagnosis' below.) Clinical manifestations of OI include (table 1 and table 2) [2730]:

Excess or atypical fractures (brittle bones) Short stature Scoliosis Basilar skull deformities, which may cause nerve compression or other neurologic symptoms Blue sclerae (picture 1) Hearing loss (usually detected in later childhood to early adulthood) Opalescent teeth that wear quickly (dentinogenesis imperfecta) (picture 2) (see "Developmental defects of the teeth", section on 'Dentinogenesis imperfecta') Increased laxity of the ligaments and skin Wormian bones (small, irregular bones along the cranial sutures) [31] Easy bruisability

Mild (type I) Bone fragility is the least severe in type I OI [28]. The fracture rate is variable. Individuals with type I OI may have few or no fractures before puberty or numerous fractures throughout their lives [27,32]. Deformity is minimal and stature is usually normal. Individuals with type I OI occasionally present in the perinatal period with intrauterine femoral bowing or fractures [27,33], but they usually do not begin to have fractures until they begin toddling or walking [34]. The most frequently

involved bones are the long bones of the arms and legs, ribs, and the small bones of the hands and feet. The frequency of fractures declines after puberty [27]. Adults with OI type I may present with premature or accelerated osteoporosis following menopause. In addition, adults may present with premature hearing loss. One study of 133 adults with type I OI found that 58 percent had hearing loss, predominantly mixed conductive and sensorineural, that began in the second to fourth decade of life and was generally progressive [35]. Only 17 percent of these adults had subjective hearing impairment. Moderate to severe (types III-IX) Bone fragility is moderate to severe in patients with OI types III, IV, V, VI, VII VIII, and IX [28]. Those with OI type III are most severely affected. However, children with OI type VII and VIII may also develop a severe lethal type of OI resembling OI type II as described below. Children with OI of these types have an increased number and frequency of fractures, mild to moderate bone deformities, kyphoscoliosis, and variable short stature [15,28]. Some children are immobile and require motorized wheelchairs. In addition, children may develop ossicular dislocation, stapes fixation, or fracture of the ossicles, resulting in conductive hearing loss. (See "Evaluation of hearing impairment in children" and "Treatment of hearing impairment in children".) Adults with moderate OI develop hearing loss and osteoporosis, similar to adults with mild OI. However, the onset may be earlier and the expression more intense. Mothers are prone to accelerated bone loss following pregnancy and breastfeeding. Aging and physical inactivity also accelerate OI-related osteoporosis. Hypermobility of the joints of the hands, wrists, and feet can cause pain and decreased function requiring orthopedic intervention. Cardiovascular abnormalities are more common in patients with OI, particularly type III, compared with the general population [36]. The practical aspect of identifying moderate to severe OI is that bisphosphonate therapy is helpful in these patients. (See

"Osteogenesis imperfecta: Management and prognosis", section on 'Bisphosphonate therapy'.) Lethal perinatal form (type II) Patients with lethal perinatal OI (type II) usually die in utero or in early infancy. Severe fractures and pulmonary failure are typical problems that accelerate death in this group. Genetic counseling is indicated for affected families. Treatment of OI type II is supportive. LABORATORY FINDINGS Although biochemical parameters of bone and mineral metabolism are usually normal in OI, some abnormalities may be noted, including:

Elevated levels of serum alkaline phosphatase have been reported in type VI OI, reflecting impaired bone mineralization [24]. Hypercalciuria is common in OI children, and its magnitude appears to reflect the severity of the skeletal disease. One study found increased urinary excretion of calcium in 36 percent of children with OI [37]. The children with hypercalciuria were of shorter stature and had a greater lifelong fracture rate compared with OI children with normal urinary calcium excretion. However, their renal function was not compromised [38]. Markers of bone formation (C-terminal propeptide of type I procollagen) may be lower, and markers of bone resorption (C-telopeptide of type I collagen) can be higher in OI, particularly in severely affected subjects [39]. PATHOLOGY Bone histology may show disorganized (woven) bone, especially in more severely affected children. A bone biopsy study in 70 children with types I, III, and IV OI demonstrated normal mineralization with significant reductions in cortical width, cancellous bone volume, trabecular number, and trabecular width [40]. This study also found significantly increased bone remodeling (turnover) in all types of OI studied (ie, about a 70 percent increase compared to age-matched controls). The latter observation provides a rationale for the use of bisphosphonates in children with OI. Bone remodeling,

however, is normal in type VI OI, which is characterized by defective mineralization [24], and thus bisphosphonates should not be prescribed to these children. (See "Osteogenesis imperfecta: Management and prognosis".) DIAGNOSIS The clinical diagnosis of OI is based on the signs and symptoms described above. The diagnosis is usually straightforward in individuals with bone fragility and a positive family history or several extraskeletal manifestations [28]. However, in the absence of these features, diagnosis may be difficult. Extraskeletal manifestations can be subclinical (eg, hearing loss [35,41-43]), nonspecific (eg, dark or bluish sclerae are commonly present in infants, limiting the usefulness of this sign in this age group), or more obvious at certain ages (eg, dentinogenesis imperfecta may be more noticeable in the primary than the permanent dentition [44]). (See 'Clinical manifestations' above.) There is no definitive, readily available lab test for OI. However, research labs have made advances in molecular genetic testing that will eventually be more accessible. The types of tests available for the various genetic defects and laboratories that perform them can be found on the GeneTests website (file://www.ncbi.nlm.nih.gov/sites/GeneTests/). The structure and quantity of type I collagen can be determined in vitro from fibroblast culture using a small skin biopsy. Abnormalities either in quantity or quality of type I collagen are present in about 90 percent of OI cases. Sequence analysis of cDNA (which requires skin biopsy for fibroblast culture) or genomic DNA testing of white blood cells for mutations in COL1A1 and COL1A2 can detect 90 percent or more of all collagen type I mutations [28,45,46]. Negative studies do not exclude the diagnosis, because of the OI types that are not associated with type I collagen mutations (types II B and types V through IX) and the false negative rate of about 10 percent DIFFERENTIAL DIAGNOSIS The differential diagnosis of OI includes inflicted injury (child abuse) and a variety of skeletal conditions associated with bone fragility, including rickets and osteomalacia. Child abuse Children with inflicted trauma have multiple

fractures in various stages of healing, similar to children with moderate to severe types of OI. They also may have metaphyseal, rib, and skull fractures. OI is a well-recognized cause of fractures that occur with minimal or no witnessed trauma, but it is a rare disorder and consequently is seldom the cause of such fractures. The differentiation between OI and child abuse is discussed in detail elsewhere. (See "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Osteogenesis imperfecta'.) Rickets Rickets can cause slow growth, bone deformities, elevation of alkaline phosphatase, defective bone mineralization, and in some forms, abnormal tooth formation. However, scleral abnormalities and hearing loss typically do not occur. Radiographic findings in rickets are characteristic and include an increased width of the epiphyseal plate, irregular hazy margins of the distal metaphysis, and marginal metaphyseal overgrowth that results in a ball-in-cup-like appearance. (See "Overview of rickets in children".) Vitamin D-resistant rickets in children, or osteomalacia in adults, may be associated with hypophosphatemia (see "Causes of hypophosphatemia" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia"). Osteomalacia Osteomalacia in adults can cause bone pain, insufficiency fractures, and alkaline phosphatase elevation, but neither hearing loss nor blue sclerae. The most common radiologic finding in osteomalacia is reduced bone density; other abnormalities include Looser's zones or pseudofractures (picture 3), narrow lines of radiolucency at the cortical margins of bones, and the loss of distinctiveness of trabeculae in vertebral bodies. (See "Epidemiology and etiology of osteomalacia" and "Clinical manifestations, diagnosis, and treatment of osteomalacia".) Other skeletal syndromes Other skeletal syndromes with moderate to severe bone fragility and/or deformity include [28]:

Bruck syndrome Bruck syndrome (MIM #312750 and %259450), previously called OI with congenital joint contractures, is an autosomal recessive disorder [28].

Clinical features that distinguish it from OI include congenital contractures of the knees, ankles, and feet; webbing (pterygia) of the elbow and knee; and clubfoot (talipes equinovarus) [47]. Osteoporosis-pseudoglioma syndrome Osteoporosispseudoglioma syndrome (MIM #259770) is an autosomal recessive disorder that was previously called the ocular form of OI [28,48-50]. It is caused by deletion of the gene for low-density-lipoprotein (LDL) receptor-related protein 5 (LRP-5). Other characteristic findings include microcephaly; pseudoglioma (inflammatory changes of the vitreous body, secondary to iridochoroiditis, that mimic retinal glioma); blindness (with onset in infancy); vitreoretinal abnormalities; cataract; absent anterior chamber; iris atrophy; intraocular calcification; and hypotonia [51,52]. Panostotic fibrous dysplasia Panostotic fibrous dysplasia, the extreme form of polyostotic fibrous dysplasia (McCuneAlbright syndrome, MIM #174800), is caused by a somatic mutation in the guanine nucleotide stimulatory protein (GNAS1) gene [28,53]. It is characterized by cystic or ground glass lesions in all bones. (See "Overview of benign bone tumors in children and adolescents", section on 'Fibrous dysplasia'.) Juvenile Paget disease Juvenile Paget disease (MIM #239000), also known as idiopathic hyperphosphatasia, is an autosomal recessive disorder [28,54]. Patients with idiopathic hyperphosphatasia have increased serum alkaline phosphatase, which distinguishes it from OI, in which alkaline phosphatase is usually normal. However, elevated levels of serum alkaline phosphatase have been reported in some patients with type VI OI [24]. (See "Transient hyperphosphatasemia of infancy and early childhood" and "Clinical manifestations and diagnosis of Paget disease of bone".) Hypophosphatasia Hypophosphatasia (MIM #241500) is a rare, autosomal disease caused by a deficiency of tissue nonspecific alkaline phosphatase and characterized by abnormal mineralization of bone and dental tissues [28,55]. Patients with hypophosphatasia have decreased serum concentrations of alkaline phosphatase, which distinguishes it from OI. (See "Systemic conditions associated with

periodontal disease in children", section on 'Hypophosphatasia'.) Cole-Carpenter syndrome The inheritance pattern of ColeCarpenter syndrome (MIM 112240) is unknown. It is characterized by osteoporosis, short stature, craniosynostosis, hydrocephalus, and proptosis [56]. Idiopathic juvenile osteoporosis Idiopathic juvenile osteoporosis is a nonhereditary form of transient, isolated childhood osteoporosis that occurs in prepubertal, previously healthy children [57]. SUMMARY

Osteogenesis imperfecta (OI) is a rare inherited connective tissue disorder with many phenotypic presentations. Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may be manifested by only premature osteoporosis or severe postmenopausal bone mineral loss. (See 'Introduction' above and 'Clinical manifestations' above.) OI is most commonly caused by autosomal dominant mutations in genes encoding the alpha-1 and alpha-2 chains of type I collagen (COL1A1 and COL1A2). The autosomal recessive forms are caused by mutations in genes encoding proteins involved in posttranslational modification of type I collagen (FKBP10, CRTAP, LEPRE1, PPIB) or other mechanisms of bone formation and homeostasis (SERPINH1, SERPINF1, SP7/OSX) (table 1). (See 'Pathogenesis' above.) OI is classified into nine major subtypes based on genetic, radiographic, and clinical characteristics. It can also be classified by clinical severity. (See 'Disease classification' above and 'Clinical manifestations' above.) The diagnosis should be considered in patients who have bone fragility and any of the following clinical manifestations (table 1 and table 2) (see 'Clinical manifestations' above): Short stature Scoliosis Basilar skull deformities

 Blue sclerae (picture 1) Hearing loss Opalescent teeth that wear quickly (dentinogenesis imperfecta) (picture 2) Increased laxity of the ligaments and skin Wormian bones (small, irregular bones along the cranial sutures) Easy bruisability

The differential diagnosis includes child abuse, rickets, osteomalacia, and other rare skeletal syndromes. The diagnosis usually can be made clinically in patients with a positive history and/or several extraskeletal manifestations. However, the diagnosis can be difficult in the absence of these features. Skin biopsy for analysis of type I collagen genes and/or testing of genomic DNA for mutations in COL1A1 and COL1A2 may be helpful. However, normal results of these tests do not exclude the diagnosis. (See 'Diagnosis' above and 'Differential diagnosis' above.) Use of UpToDate is subject to the Subscription and License Agreement.

Osteogenesis imperfecta: Management and prognosis Authors John F Beary, III, MD Arkadi A Chines, MD Section Editor Helen V Firth, DM, FRCP, DCH Deputy Editor Elizabeth TePas, MD, MS Disclosures Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 | This topic last updated: Thu May 26 00:00:00 GMT 2011 (More) INTRODUCTION Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with many phenotypic presentations. It is often called "brittle bone disease." Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may manifest with only premature osteoporosis or severe postmenopausal bone mineral loss. The goals of therapy for patients with OI are to reduce fracture rates, prevent long-bone deformities and scoliosis, minimize chronic pain, and to maximize mobility and other functional capabilities [1-3]. Patients with OI should be referred for evaluation by specialists in genetics and, if clinically indicated, orthopedics with expertise in treating OI at the time of diagnosis [4]. Treatment requires a coordinated multidisciplinary team approach and consists of physical therapy, surgical interventions, medications, and, in some cases, experimental therapies [5-7]. Patients with OI need additional health supervision from their primary care providers and monitoring for potential complications. The management and prognosis of osteogenesis imperfecta are presented here. The pathogenesis, clinical features, diagnosis, and differential diagnosis are discussed separately. (See "Osteogenesis imperfecta: Clinical features and diagnosis".) BISPHOSPHONATE THERAPY Bisphosphonates are the mainstay of pharmacologic fracture-prevention therapy for most forms of OI (except for type VI (table 1) in which bone

mineralization is defective), although none are approved specifically for use in either children or adults with OI. (See "Osteogenesis imperfecta: Clinical features and diagnosis", section on 'Pathology'.) Bisphosphonates are stable analogs of pyrophosphate and are potent inhibitors of bone resorption and bone turnover. They are used widely in treatment of osteoporosis in adults, and have reduced the risk of fractures in women with postmenopausal osteoporosis, men with osteoporosis, and patients with glucocorticoid-induced osteoporosis in multiple clinical trials. Reports of bisphosphonates for children with OI are encouraging, with a reduced fracture frequency of up to 100 percent in observational studies [7,8]. The long-term effects on structural outcomes such as scoliosis and basilar invagination are unclear. Further study, particularly in the form of randomized trials, is needed. IV pamidronate The majority of information about the use of bisphosphonates in OI comes from uncontrolled studies of cyclical infusions of pamidronate in various regimens in children with OI [9]. These reports have noted increased bone mineral density (BMD), decreased fracture rate, and improved functional abilities, mobility, ambulation, and pain, without negative effects on fracture healing or growth rate in most studies, even when used in young children [8,10-18]. A single observational study of 14 prepubertal children with mild forms of OI (types I and IV) treated with pamidronate found a significant increase in height and sitting height standard deviation scores during the first year of treatment. In the only controlled trial, 18 children (age range 4 to 13 years) with types III and IV OI were randomly assigned to treatment with intravenous pamidronate (10 mg/m2 per day for three days every three months) or no treatment for one year; four children in each group also received recombinant growth hormone [19]. After one year, treated patients had significantly increased lumbar spine BMD, midvertebral height, and total vertebral area, compared with controls. Upper extremity fracture rate decreased significantly in the first, but not second, year of treatment compared with the baseline rate (0.89 at baseline, and 0.22 and 0.29 after one and two years of treatment, respectively). There

was a trend toward decreased fracture rate in the lower extremities in the first year of treatment compared with baseline (1.44 versus 0.67 respectively). Growth rate, gross motor function, muscle strength, and pain did not change significantly in treated patients compared to controls. In the seven patients who extended treatment for an additional 6 to 12 months, bone density, midvertebral height, and vertebral area were maintained, but did not increase beyond the 12-month values. EXPERIMENTAL THERAPIES Growth hormone The use of growth hormone (GH) in OI has been studied in small groups of patients since 1975, although it is still viewed as an experimental therapy. The theoretical basis for using GH is to stimulate bone formation and also to increase stature. No studies have extended beyond two years. In a single randomized trial, 30 prepubertal children with OI (types I, III, and IV) were observed for 12 months during ongoing neridronate therapy and then randomized to recombinant GH (rGH) plus neridronate or neridronate alone [51]. Bone mineral density and growth velocity were significantly higher in the group that received GH compared with the control group, although no difference was seen in the fracture risk rate. The increase in bone age was similar in both groups. A summary of experience with GH therapy for OI included one investigator's experience with 22 OI patients [52]. In this series, treatment with GH had beneficial effects on bone turnover, bone mineral density, and height velocity rate. Another series of 26 children with type III or type IV OI (table 1) of moderate severity received GH (0.1 to 0.2 IU/kg per day for six of seven days per week) for one year [53]. Roughly one-half of the children responded with an increase in linear growth rate of 50 percent or more from their pretreatment rate. Those who had such an increase in growth also had increased vertebral bone mineral density and decreased fracture rates. Higher levels of procollagen carboxy terminal propeptides (PICP) were correlated with a growth response to GH. A cut-off level of PICP of 86 microgram/mL was 73 percent predictive of a response to growth hormone administration.

Cell replacement therapies A pilot study of allogeneic hematopoietic cell transplantation (HCT) was performed in five children with OI [54]. Three children had successful engraftment, and in these three, improvements in growth velocity and reduction in fracture rate were noted following transplantation. Engrafting allogeneic mesenchymal cells may provide another avenue to treatment. In one series of six patients with severe OI who received allogeneic bone marrow transplantation, donor-derived mesenchymal cells that incorporated a reporter gene were subsequently recovered from skin, bone, and bone marrow [55]. Linear growth was more rapid following the mesenchymal cell infusions than in the six-month period between the marrow transplantations and the first of two infusions of mesenchymal cells. Although transplantation of mesenchymal stem cells or bone marrow stromal cells have a good theoretical basis for correcting genetic defects of bone and cartilage [56,57], more clinical research is needed before these therapies can be recommended for patients with OI. Gene therapy Antisense therapy and gene targeting have been evaluated in animal models of OI. The goal of antisense therapy in OI is to suppress or silence a particular mutant allele of the type I collagen gene and not interfere with the expression of the normal allele [58]. Thus, a severe form of OI could potentially be turned into a mild form of the disease. Small molecules with complementary sequences are used to bind and sequester the target messenger RNA, thus preventing translation of the defective collagen precursor. Another approach under exploration is gene targeting of the patient's mesenchymal stem cells. In a preliminary study, adenoassociated virus vectors successfully disrupted the mutated allele ex vivo in mesenchymal stem cells [59]. Infusion of these cells into a mouse model resulted in bone formation. There are several potential problems associated with such a gene-targeting approach that need to be addressed before this technique can be applied to patients with OI [60].

PROGNOSIS The prognosis depends upon the type of OI [61]. Patients with mild OI (type I, (table 1)) typically have a few childhood fractures, no long-bone deformity, and a normal life expectancy. Patients with moderate to severe (types III- to IX, (table 1)) have an increased risk of premature death in both childhood and adult life compared with the general population. Shortened life span may be related to immobility and thoracic deformities in a subset of patients with moderately severe disease. These problems create an increased risk of severe pulmonary infections and subsequent loss of lung function. SUMMARY AND RECOMMENDATIONS

The goals of therapy for patients with osteogenesis imperfecta (OI) are to reduce fracture rates, prevent long-bone deformities and scoliosis, minimize pain, and to maximize mobility and other functional capabilities. (See 'Introduction' above.) Bisphosphonates are the mainstay of pharmacologic fractureprevention therapy for most forms of OI (except for type VI (table 1) in which bone mineralization is defective), although none are approved specifically for use in either children or adults with OI. Little information on treatment in adults with OI is available. The optimal dose range, dosing interval, duration of treatment, and the long-term efficacy and safety profile have yet to be established. We suggest treatment with intravenous pamidronate for patients with all forms of OI, except type VI, in whom clinical benefits are likely to outweigh potential long-term risks (ie, those with long-bone deformities, vertebral compression fractures, and three fractures per year) (Grade 2C). The suggested duration of treatment is two to four years. The decision to use these drugs is best made by specialists at medical centers with significant experience in treating OI. Treatment requires a coordinated, multidisciplinary team approach and consists of physical therapy, surgical interventions, medications, and, in some cases, experimental therapies. Patients with OI and parents of patients with OI should be advised to seek care in specialty

medical centers with significant experience in treating OI. A list of clinics specializing in OI is available on the Osteogenesis Imperfecta Foundation website (www.oif.org). (See 'Orthopedic and other surgery' above and 'Physical and occupational therapy' above and 'Psychosocial aspects' above and 'Primary care considerations' above and 'Experimental therapies' above.) Patients with OI should undergo regular surveillance for potential complications so that appropriate intervention can be initiated as soon as possible (See 'Monitoring for complications' above and 'Primary care considerations' above.). This includes:

Regular monitoring of growth and head circumference Hearing test, assessment of bone mineral density, and spirometry every two years, particularly in patients with moderate to severe OI Electrocardiogram and echocardiogram every two years and yearly spirometry in all patients with type III OI and other moderate to severe types (VII to IX) (table 1) Neurologic examination and cranial assessment as indicated by symptoms or behavioral changes Skeletal radiographs at the time of diagnosis and then every one to two years (or sooner if clinically indicated) and coordinated with orthopedic advice

The prognosis depends upon the type of OI, ranging from a normal life expectancy in patients with type I OI to perinatal mortality in patients with type II OI (table 1). (See 'Prognosis' above and "Osteogenesis imperfecta: Clinical features and diagnosis", section on 'Clinical manifestations'.) Use of UpToDate is subject to the Subscription and License Agreement.

What is the official name of the LEPRE1 gene?

The official name of this gene is leucine proline-enriched proteoglycan (leprecan) 1. LEPRE1 is the gene's official symbol. The LEPRE1 gene is also known by other names, listed below. Read more about gene names and symbols on the About page.

What is the normal function of the LEPRE1 gene?

The LEPRE1 gene, which is also known as P3H1, provides instructions for making an enzyme called leprecan or prolyl-3 hydroxylase 1. This enzyme works with two other proteins, cartilage associated protein and cyclophilin B, as part of a complex that helps process certain forms of collagen. Collagens are proteins that provide strength, support, and the ability to stretch (elasticity) to many body tissues. The leprecan-containing complex modifies a protein building block (amino acid) called proline in collagen molecules. This modification, which is known as proline 3-hydroxylation, appears to be critical for the normal folding and assembly of collagen. It also may be important for releasing collagen molecules into the spaces around cells (the extracellular matrix). The secretion of collagen from cells is necessary for the proper formation of connective tissues, such as bones, tendons, and cartilage, that form the body's supportive framework. Studies suggest that leprecan has several additional functions. For example, this enzyme may play a role in interactions between certain types of cells and the extracellular matrix that surrounds them. Other research indicates that leprecan may act as a tumor suppressor, preventing cells from growing and dividing too fast or in an uncontrolled way.

How are changes in the LEPRE1 gene related to health conditions?

osteogenesis imperfecta - caused by mutations in the LEPRE1 gene At least four mutations in the LEPRE1 gene have been identified in

people with a rare, severe form of osteogenesis imperfecta classified as type VIII. These mutations prevent cells from producing any functional leprecan. Without this enzyme, certain forms of collagen are not modified through proline 3hydroxylation. The altered collagen molecules are incorrectly folded, and some abnormal collagen is secreted from cells more slowly than usual. These collagen defects weaken connective tissues, resulting in extremely slow growth and thin, brittle bones that may fracture before birth.

Where is the LEPRE1 gene located?

Cytogenetic Location: 1p34.1 Molecular Location on chromosome 1: base pairs 43,212,005 to 43,232,754

The LEPRE1 gene is located on the short (p) arm of chromosome 1 at position 34.1. More precisely, the LEPRE1 gene is located from base pair 43,212,005 to base pair 43,232,754 on chromosome 1.

What is the official name of the CRTAP gene?

The official name of this gene is cartilage associated protein. CRTAP is the gene's official symbol. The CRTAP gene is also known by other names, listed below. Read more about gene names and symbols on the About page.

What is the normal function of the CRTAP gene?

The CRTAP gene provides instructions for making a protein called

cartilage associated protein. While the specific function of this protein is not known, it plays an important role in normal bone development. Cartilage associated protein works with two other proteins, leprecan and cyclophilin B, as part of a complex that helps process certain forms of collagen. Collagens are proteins that provide strength, support, and the ability to stretch (elasticity) to many body tissues. The complex containing cartilage associated protein modifies a protein building block (amino acid) called proline in collagen molecules. This modification, which is known as proline 3hydroxylation, appears to be critical for the normal folding and assembly of collagen. It also may be important for releasing collagen molecules into the spaces around cells (the extracellular matrix). The secretion of collagen from cells is necessary for the proper formation of connective tissues, such as bones, tendons, and cartilage, that form the body's supportive framework.

How are changes in the CRTAP gene related to health conditions?

osteogenesis imperfecta - caused by mutations in the CRTAP gene At least five mutations in the CRTAP gene are responsible for a rare type of osteogenesis imperfecta that is usually classified as type VII. Several of these mutations prevent cells from producing any cartilage associated protein. Without this protein, bones and other connective tissues do not form properly, leading to a very severe form of the disorder. Another mutation in the CRTAP gene greatly reduces the amount of cartilage associated protein produced, which disrupts the normal formation of collagen. This genetic change causes less severe signs and symptoms of osteogenesis imperfecta.

Where is the CRTAP gene located?

Cytogenetic Location: 3p22.3 Molecular Location on chromosome 3: base pairs 33,155,449 to 33,189,264

The CRTAP gene is located on the short (p) arm of chromosome 3 at position 22.3. More precisely, the CRTAP gene is located from base pair 33,155,449 to base pair 33,189,264 on chromosome 3.