Student Examination into the Causes, Treatment, and Prognosis of Osteogenesis Imperfecta
Anitra Swann
Baltimore City Community College
Professor McNair
AH 130
October 18, 2011

Abstract
Osteogenesis Imperfecta is a heritable disorder of bone formation resulting in low bone mass and a propensity to fracture. It exhibits a broad range of clinical severity, ranging from multiple fracturing in utero and perinatal deaths to normal adult stature and a low fracture incidence. The disorder is currently classified into seven types based on differences in bone architecture. In addition to its primary effect on the skeletal system, the alterations in connective tissue may affect several extra skeletal structures, such as the cardiovascular system, sclera, middle and inner ear, tendons/ligaments, and central nervous system. Patients with Osteogenesis Imperfecta also have a greater incidence of airway anomalies, cardiovascular anomalies, and increased incidence of perioperative bleeding, easily fractured bones and teeth. Treatment of Osteogenesis Imperfecta by bisphosphonate therapy can improve bone mass in all types of the disorder, and while not being a cure for the disorder does improve the quality of life of the patient. This paper will examine the causes, treatment, and prognosis of Osteogenesis Imperfecta.

Student Examination into the Causes, Treatment, and Prognosis of Osteogenesis Imperfecta Osteogenesis Imperfecta (OI) is an abnormally brittle bone disease that is inherited. The term Osteogenesis Imperfecta means “imperfect bone formation.” Individuals who have OI suffer from short stature, scoliosis, thin skin, and hearing loss. Numerous fractures are common, and can occur before birth. This disorder affects six-to-seven per 100 thousand people worldwide. There are seven forms of OI. The types can be distinguished by their signs and symptoms, even though their characteristic features overlap. Types I and IV are the most common form of OI affecting three-to-four per 100 thousand. Type II and III are rarer, affecting one-to-two per 100 thousand. Of these, type II is the most severe and is usually fatal within a short time after birth. Types I, III, and IV share distinctive symptoms, thus overlap, with the hallmark symptom being fragile bones. Types V through VII are the newer forms of the disease (Wilson, 2006). Type I is the most common and mildest form of Osteogenesis Imperfecta (OI). In addition to fragile bones, type I is frequently accompanied by blue sclera, hearing loss, thin skin, loose joints, low muscle tone and brittle teeth. Type I patients may also develop scoliosis, a condition in which spine curvature leads to chronic back pain and difficulty breathing. Triangular faces are also common. Type I patients typically experience most of their fractures, about 40 breaks occur, before they enter puberty (Wilson, 2006). Type II is the most severe form. Infants with type II have bones that appear bent, crumpled, and/or fractured before birth. These infants have short, bowed arms and legs, hips that turn outward, and unusually soft skull bones. Most infants with type II are stillborn or die shortly after birth, usually from respiratory failure (Stynowick, 2007). Type III is the next most severe form, comparable to survival beyond infancy, and is severely handicapping. Individuals with type III OI can have a full life span; however, a significant proportion succumbs to respiratory failure or neurological complications, either during childhood or in early to middle adult years. The long bones of individuals with type III OI patients are soft as well as fragile and can have bowing. It is common for a person with this type to have experienced 100 fractures by the time he/she reaches puberty. There are often fractures present at birth and X-rays may even show healed fractures that occurred before birth. Moreover, children with OI type III will develop significant scoliosis. Lifespan may be normal, albeit with severe physical handicapping. Without aggressive intervention, these individuals will be wheelchair bound. Type IV is moderately severe but worse than type I. Bones fracture easily, but the whites of the eyes are normal. Some people with type IV OI may be shorter than average and may have brittle teeth (Marini, 2011).
Type V is a mild-to-moderately severe form of OI, which does not appear to be associated with collagen type I mutations. There are normal-colored sclera and ligament laxity. There is no DI. Typically patients have ossification of interosseous membrane of the forearm with radial head dislocation, hyperplastic callus formation and an abnormal histopathological pattern.
Type VI OI, like type V, is similar to type IV. Characteristics of individuals with type VI OI include short stature, ligamentous laxity, white or faintly blue sclera. First fractures in type VI OI occur when affected individuals are infants or toddlers and the frequency of fractures is greater than seen in type IV. 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 from type IV solely on histology and molecular criteria. Bone histology includes “fish-scale” pattern of the lamellae, and decreased mineralized bone volume secondary to increased osteoid volume. This bone mineralization defect is a defining attribute of Type VI OI.
Type VII OI is a lethal/severe recessive chondrosseus dysplasia. Fractures and limb deformities are present at birth. Radiographically, long bones are severely undertubulated. 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). Distinctive features of type VII OI include small or normal head circumference, exophthalmia, white or light blue sclera, and rhizomelia. Type I collagen genes are normal in type VII OI. Type VII OI is caused by null mutations in CRTAP. This gene encodes the cartilage-associated protein (CRTAP), which functions as the helper-protein in the collagen prolyl 3-hydroxylation complex. Deficiency of this protein affects post-translational modification of both bone (type I collagen) and cartilage (type II collagen). These children have moderate growth deficiency. They attain ambulation without assistive devices.
Osteogenesis Imperfecta usually begins either in utero or in infancy. Osteogenesis Imperfecta is a result of mutations in the genes that code for type I collagen. Type I is different from the other types in many different ways. Individuals who suffer from Type I OI have generally normal type 1 collagen. Types II, Type III and Type IV have lower levels of type 1 collagen. Mutations in the COL1A1, COL1A2, CRTAP, and LEPRE1 genes cause Osteogenesis Imperfecta. According to Aileen M. Barnes: Type I collagen is the most abundant protein in bone and skin extracellular matrix. It contains two alpha-1 (α1[I]) chains and one alpha-2 (α2[I]) chain, which fold into a triple helix from the carboxyl end to the amino end. These collagen chains contain glycine residues in every third position that are crucial for proper folding of the helix; substitutions for glycines delay helical folding and cause over modification by increasing the length of time these chains are exposed to modifying enzymes in the endoplasmic reticulum. Prolyl 4-hydroxylase (P4H) and lysyl hydroxylase (LH) modify multiple proline and lysine residues, respectively, along the collagen helix, which are important for collagen stability and cross-linking. In contrast, the collagen prolyl 3-hydroxylation complex, consisting of P3H1 (also known as leucine- and proline-enriched proteoglycan 1 [LEPRE1]), CRTAP, and CyPB, modifies the α1(I)Pro986 residue. Although the function of this modification remains unknown, a deficiency of either P3H1 or CRTAP causes severe or lethal autosomal recessive Osteogenesis Imperfecta, which accounts for 5 to 7% of all severe cases of Osteogenesis Imperfecta. Null mutations of CRTAP or LEPRE1 cause severe Osteogenesis Imperfecta with rhizomelia, classified, respectively, as type VII. These mutations lead to a deficiency of these two components of the complex and a reduction in or absence of hydroxylation. Unexpectedly, a lack of the complex causes collagen over modification by P4H and LH. We hypothesized that the delay in helical folding is due to the unavailability of the complex to shuttle CyPB to the carboxyl end of the helix, rather than to the absence of the 3-hydroxylation modification itself. CyPB, a ubiquitous peptidyl-prolyl cis–trans isomerase (PPIase), is currently thought to catalyze the prolyl isomerization that is the rate-limiting step in collagen folding. Most of the mutations that cause Osteogenesis Imperfecta type I occur in the COL1A1 gene. Alanay reports that: These genetic changes reduce the amount of type I collagen produced in the body, which causes bones to be brittle and to fracture easily. The mutations responsible for most cases of OI types II, III, and IV occur in either the COL1A1 or COL1A2 gene. These mutations typically alter the structure of type I collagen molecules. A defect in the structure of type I collagen weakens connective tissues, particularly bone, resulting in the characteristic features of Osteogenesis Imperfecta. Mutations in the CRTAP and LEPRE1 genes are responsible for rare, often severe cases of OI. Cases caused by CRTAP mutations are usually classified as type VII; when LEPRE1 mutations underlie the condition, it is classified as type VIII. The proteins produced from these genes work together to process collagen into its mature form. Mutations in either gene disrupt the normal folding, assembly, and secretion of collagen molecules. These defects weaken connective tissues, leading to severe bone abnormalities and problems with growth. In OI due to quantitative defects of type 1 collagen, mutations are usually found on the COL1A gene. The mutations result in the production of a premature stop codon or a microsense frame shift, which leads to mutant messenger RNA (mRNA) in the nucleus. However, the cytoplasm contains normal alpha1 mRNA; therefore, reduced amounts of structurally normal collagen are produced. In OI due to qualitative defects of type 1 collagen, autosomal dominant mutations are found on either the COL1A or the COL1B gene. The mutations result in the production of a mixture of normal and mutant collagen chains. Substitution of glycine by a larger amino acid (e.g., cysteine, alanine) results in abnormal helix formation, but these chains can combine with normal chains to produce type 1 collagen. The type 1 collagen thus formed is functionally impaired because of the mutant chain; this is the so-called dominant negative mechanism. Most cases of OI have an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the condition. Many people with type I or type IV OI inherit a mutation from a parent who has the disorder. Most infants with more severe forms of OI (such as type II and type III) have no history of the condition in their family. In these infants, the condition is caused by new (sporadic) mutations in the COL1A1 or COL1A2 gene (Morello, 2006). The general risk factor of OI is an inherited in an autosomal dominant pattern. Almost all infants with the severe type II OI are born into families without a family history of the condition. Usually, the cause in these families is a new mutation in the egg or sperm or very early embryo in the COL1A1 or COL1A2 gene. In the milder forms of OI, 25-30 percent of cases occur as a result of new mutations. The other cases are inherited from a parent who has the condition. Whether a person has OI due to a new mutation or an inherited genetic change, an adult with the disorder can pass the condition down to future generations. In autosomal dominant inherited OI, a parent who has OI has one copy of a gene mutation that causes OI. There is no evidence that OI preferentially affects any particular gender, ethnicity, or age group. With each of his/her pregnancies, there is a 1 in 2 (50 percent) chance to pass on the OI gene mutation to a child who would have OI, and a 1 in 2 (50 percent) chance to pass on the normal version of the gene to a child who would not have OI. Occasionally a child may be born with OI despite neither parent having the condition. Rarely, OI can be inherited in an autosomal recessive pattern. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. Autosomal recessive inheritance means two copies of the gene must be altered for a person to be affected by the disorder. The autosomal recessive form of type III OI usually results from mutations in genes other than COL1A1 and COL1A2. All people with OI have weak bones, which makes them susceptible to fractures. Symptoms of OI vary greatly from person to person, even among people with the same type of the disorder. Symptoms include skeletal dysplasia, osteoporosis, increased brittleness and deformity, blue sclera and hearing loss. It is characterized by great differences in clinical reemergence of multiple intrauterine fractures and death, light and school-age who have symptoms and survive to old age. Repeated fracture is characteristic of OI to transverse fractures, spiral fractures of the most common, about 15% of the fractures occurred in the metaphysis. Can have substantial fracture callus proliferation, the majority can be healing, but often residual deformity (Health Study, 2008). Some symptoms of Osteogenesis Imperfecta include: 1) Increase in bone brittleness. Minor injuries can cause fractures, serious fracture patients showed spontaneous. Congenital type that is in the birth has multiple fractures. Green sticks mostly fracture type, displacement of less pain, heal quickly, depend on the completion of subperiosteal osteoblasts, which often go unnoticed and result in abnormal connectivity. Long bones and ribs for the better part of hair. Many of the deformities caused by fractures and further reduce the length of the bone. After puberty, the trends of decreasing fracture. 2) Blue sclera. This is because of the sclera in patients with a translucent; you can see the bottom of the choroid due to the color. Scleral thickness and the structural anomaly, and its semi-transparent are because of the nature of collagen fibers caused by changes happen. 3) Hearing loss. Approximately half of all people with the condition will have impaired hearing. The age of onset is usually during the teens, but in some cases earlier. Early stage hearing problems usually result from poor transmission of sound waves through the middle ear (conductive hearing loss). With increasing age the nerve system may fail to transmit sound impulses (sensorineural hearing loss). If several members of a family have OI, the severity of hearing loss may vary. Tinnitus (ringing in the ears) is common. Adults may experience dizziness and balance problems, often in association with head movements. 4) Head and face deformities. Severe dysplasia of the skull, the skull at birth, there is a sense of bladder. After the broad skull, parietal bone and occipital bone prominent, and the two spherical bulging temporal, frontal bone protrusion, have been pushed below the ears, face down into a triangle. 5) Dental dysplasia. Teeth should not very good quality development. Primary and permanent teeth may be affected. Teeth yellow, or blue-gray, easy caries and early loss. 6) Dwarf. The height and weight growth of children with type III or severe forms of type IV will level out, and unless they receive medical treatment these children usually stop growing around the age of eight, coupled with multiple fractures of the spine and lower limbs caused by malunion. These children will tend to be shorter than other members of their family. Diagnosing OI is primarily a clinical process and based on family history. In addition to a complete medical history and physical examination, diagnostic procedures for OI may include a skin biopsy to evaluate the amount and structure of collagen. The doctor will ask a number of questions about a person's medical history, including current symptoms and family history of any medical problems. The doctor will also perform a physical exam (looking for any signs of Osteogenesis Imperfecta) and order certain tests. Severe forms can sometimes be diagnosed prenatally (or while the fetus develops in the womb). If there is a family history of OI, chorionic villus sampling or amniocentesis may be done during pregnancy to determine if the baby has mutations that could cause the condition. In some cases, an ultrasound can identify bone abnormalities at 18 to 24 weeks gestation. According to Byers: Radiographic findings include fractures of varying ages and stages of healing, wormian bones, "codfish" vertebrae, and osteopenia. Analysis of bone biopsies is an adjunct to the diagnosis of OI type V and OI type VI. Biochemical testing (i.e., analysis of the structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) detects abnormalities in 98% of individuals with OI type II, about 90% with OI type I, about 84% with OI type IV, and about 84% with OI type III. About 90% of individuals with OI types I, II, III, and IV (but none with OI types V, VI and VII) have an identifiable mutation in either COL1A1 or COL1A2. Such testing is clinically available. Osteogenesis Imperfecta type’s I-V is inherited in an autosomal dominant manner. Osteogenesis Imperfecta type VII is inherited in an autosomal recessive manner, and the mode of inheritance of OI type VI is not yet certain. For type’s I-IV, the proportion of cases caused by a de novo mutation in either COL1A1 or COL1A2 varies by the severity of disease. Approximately 60% of individuals with mild OI have de novo mutations; virtually 100% of individuals with lethal (type II) OI or with severe (type III) OI have a de novo mutation. Each child of an individual with a dominantly inherited form of OI has a 50% chance of inheriting the mutation and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by analysis of collagen synthesized by fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation if an abnormality of collagen has been identified in cultured cells from the proband. Biochemical analysis of collagen from amniocytes is not useful because amniocytes do not produce type I collagen. Prenatal testing in high-risk pregnancies can be performed by molecular genetic testing of COL1A1 and COL1A2 if the mutation has been identified in an affected relative. Prenatal ultrasound examination performed in a center with experience in diagnosing OI, and done at the appropriate gestational age, can be valuable in the prenatal diagnosis of the lethal form and most severe forms of OI prior to 20 weeks' gestation; fetuses affected with milder forms may be detected later in pregnancy when fractures or deformities occur. Additional diagnostic tests may include:  X-ray--A diagnostic test which uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film  An examination of the ear, nose, and throat (to detect hearing loss) Tests used to diagnose Osteogenesis Imperfecta generally require several weeks before results are known. Both the collagen biopsy test and DNA test are thought to detect almost 90% of all collagen type 1 mutations. A positive collagen type 1 study confirms the Osteogenesis Imperfecta diagnosis, but a negative result leaves open the possibility that either a collagen type 1 mutation is present but was not detected, or the patient has a form of Osteogenesis Imperfecta that is not associated with collagen type 1 mutations. Currently, there is no known way to prevent OI, even though adults with OI should be carefully counseled regarding the chance of their offspring being born with the disease. In the dominant form of OI, a child who has one parent with the disease has a 50% chance of also having the disease. In the recessive form of OI, a child who has two parents with the disease has a 25% chance of having the disease, a 25% chance of being completely unaffected, and a 50% chance of being a carrier. A carrier is someone who does not have the disease itself, but "carries" the defective gene, and thus can pass it on to future offspring. A child who has only one parent with the recessive form of OI has no chance of actually having the disease, but a 50% chance of being a carrier. Genetic counseling is recommended for couples considering pregnancy if there is a personal or family history of this condition (Marini, 2011). Problems related to OI can be reduced or prevented by a healthy lifestyle with exercise and good nutrition. Avoid smoking and excessive alcohol consumption, which may weaken bond and increase fracture risk. Preventive measures within the area of bone health span all three types. For example, certain measures to achieve optimal bone mass can be considered primary prevention, including encouraging adequate intake of calcium and vitamin D, appropriate physical activity, and other bone-healthy lifestyle behaviors. Other measures that are commonly considered treatments for osteoporosis, such as using antiresorptive and anabolic agents, should also be thought of as secondary prevention, since they are designed to retard the progression of the disease to prevent disability. Fall prevention in this population may also be seen as secondary prevention, since its purpose is to prevent disability in an individual who already has bone disease. Appropriate and comprehensive treatment of a fracture is considered tertiary prevention, because such treatment attempts to prevent a person with a disability from becoming dependent. Drugs prescribed to individuals who have already sustained a fracture are also a part of this tertiary prevention effort. From a public health perspective, physical therapy and other forms of rehabilitation are considered methods of tertiary prevention in this population. Regardless of treatment, fractures will occur. Most fractures heal quickly. Time in a cast should be limited since bone loss (disuse osteoporosis) may occur when you do not use a part of your body for a period of time (Marini, 2011). Problems related to OI can be reduced or prevented by a healthy lifestyle with exercise and good nutrition. Avoid smoking and excessive alcohol consumption, which may weaken bone and increase fracture risk. Problems related to OI can be reduced or prevented by a healthy lifestyle with exercise and good nutrition. Avoid smoking and excessive alcohol consumption, which may weaken bone and increase fracture risk. The prognosis for a person with OI varies greatly depending on the number and severity of symptoms. Respiratory failure is the most frequent cause of death for people with OI, followed by accidental trauma. Despite numerous fractures, restricted activity, and small stature, most adults and children with OI lead productive and successful lives. They attend school, develop friendships and other relationships, have careers, raise families, participate in sports and other recreational activities, and are active members of their communities. Specific therapies can reduce the pain and complications associated with OI. OI is caused by a genetic defect. Overall, any person with OI has a 50% chance of passing the disease to his or her children. Through genetic counseling, OI can be prevented from being passed from one generation to another (Kleigman, 2007). Bisphosphonates are drugs that have been used to treat osteoporosis. They have proven to be very valuable in the treatment of OI symptoms, particularly in children. These drugs can increase the strength and density of bone in persons with OI. They have been shown to greatly reduce bone pain and fracture rate (especially in the bones of the spine). Low impact exercises such as swimming keep muscles strong and help maintain strong bones. Such exercise can be very beneficial for persons with OI and should be encouraged. In more severe cases, surgery to place metal rods into the long bones of the legs may be considered to strength the bone and reduce the risk of fracture. Bracing can also be helpful for some people. Reconstructive surgery may be needed to correct any deformities. Such treatment is important because deformities (such as bowed legs or a spinal problem) can significantly affect a person's ability to move or walk. Bone fractures can and will occur, but the correct preventative measures will minimize them. According to Forin: Until recently, surgical correction of deformities, physiotherapy, and the use of orthotic support and devices to assist mobility (e.g. wheelchairs) were the primary means of treatment for Osteogenesis Imperfecta. With the more recent understanding of the molecular mechanisms of the disease, medical treatment to increase bone mass and strength are gaining popularity, and surgery is reserved for functional improvement. Bisphosphonates, particularly pamidronate, are synthetic analogs of pyrophosphate that inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by binding to hydroxyapatite. As a result, unopposed osteoblastic new bone formation on the periosteal surface results in an increase in cortical thickness. Cyclic intravenous pamidronate is given in a dose of 7.5 mg/kg/y at 4- to six month intervals. Intravenous pamidronate is effective in babies and can be used to relieve pain in severe cases. Good evidence suggests that bisphosphonate therapy may significantly improve the natural history of type III and type IV disease, particularly by decreasing the rate of fracture, increasing bone mineral density, decreasing bone pain, and significantly increasing height (especially with prolonged cyclic therapy up to 4 y). In some cases, crumpled femurs and flattened vertebrae may assume more normal shapes and cortical thickness. Other bisphosphonates, such as risedronate, alendronate, and zoledronic acid, are also being assessed. According to Salehpour: Growth hormone is known to act on the growth plate and also stimulate osteoblast function, possibly via insulinlike growth factor-1 (IGF-1) and IGF–binding protein-3 (IGFBP-3). Growth hormone may be beneficial in patients with a quantitative collagen defect, but its role in the management of Osteogenesis Imperfecta has not been clearly defined. Unfortunately, a higher proportion of engrafted normal cells is required to achieve the level of normal osteoblasts necessary to functionally correct the OI phenotype. Furthermore, the use of immunosuppressive agents to prevent graft rejection and graft versus host reaction can itself damage bone. Future approaches include the autografting of genetically modified mutant osteoblasts, whereby the mutant collagen gene is inactivated. These therapies are several years away from clinical reality. Gene therapy is being explored in animal models, but major obstacles remain because of intrinsic difficulties (as evidenced in attempts to treat conditions such as cystic fibrosis) and because of the dominant negative mechanism of the disease. The recent success in treating X-linked severe combined immunodeficiency disease (X-SCID) by using gene therapy provides some hope that this approach may eventually be successful in conditions such as OI. In conclusion, although there is no cure for OI, individuals with the disease can still lead normal lives. Osteogenesis Imperfecta is the most common genetic disorder of the bone. It occurs in about one-in-twenty thousand live births, is prevalent in all races, and both sexes. All-in-all, it is possible that, in order to dramatically decrease the fracture rate, combined therapies aimed at both circumventing the consequences of the gene defect using stem cells and reinforcing bone strength with bisphosphonates will be considered. Bisphosphonates are the cornerstone therapy and the main response to treatment. Many adults with OI marry and have children, despite the high risk for transmittance of the condition. Financial and employment problems are significant for these individuals due to chronic illness, chronic pain, frequent hospitalizations, and frequent absenteeism. Such problems are particularly true for individuals with milder forms of OI who often do not appear physically disabled yet still experience medical complications. The goal of people with OI is to promote the general physical wellness, reduce risk of fracture, and increase bone density. Medical treatment is not curative, but it improves the patient’s quality of life.

References Alanay. Y, Avaygan, H., Camacho, N., Utine, G. E., Boduroglu, K., Aktas, D., et al. (2010). “Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta.” Am J Hum Genet. 86(4), 551-9. Barnes, A. M., Carter, E. M., Cabral, W. A. (2010). “Lack of Cyclophilin B in osteogenesis imperfecta with Normal Collagen Folding.” New England J Med. 362, 521-528. Byers P. H. (the year of publication goes here). Disorders of collagen biosynthesis and structure. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) “The Metabolic and Molecular Bases of Inherited Disease” (OMMBID). New York: McGraw-Hill. Forin V. (2008). “Paediatric osteogenesis imperfecta: medical and physical treatment”. Arch Pediatric. 15(5), 792-3. Health Study (2008). Retrieved October 30, 2011, from http://www.ahealthstudy.com/diseases/osteogenesis-imperfecta-symptoms Kleigman, R. M., Behrman, R. E., Jenson H. B., Stanton, B. F., (eds). (2007). Nelson Textbook of Pediatrics. 18th ed. Philadelphia, PA: Saunders. Marini J. C. (2011). Osteogenesis imperfecta. In: Kliegman, R. M., Behrman, R. E., Jenson, H. B., Stanton, B. F. (eds). (2011). Nelson Textbook of Pediatrics. 19th ed. Philadelphia, Pa: Saunders Elsevier. Marlowe, A., Pepin, M. G., Byers, P. H. (2006). “Testing for osteogenesis imperfecta in cases of suspected non-accidental injury”. J Med Genet. 39(6), 382–386. Morello, R., Bertin, T. K., Chen, Y., Hicks, J. (2006). “CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta”. Cell. 127(2), 291-304. Salehpour, T. S. (2010). “Cyclic pamidronate therapy in children with osteogenesis imperfecta”. J Pediatric Endocrinol Metab. Jan-Feb 2010;23(1-2):73-80. Stynowick, G. A., Tobias, J. D. (2007). “Perioperative Care of the Patient With osteogenesis imperfecta” ORTHOPEDICS. 30(12), 1043. Wilson, J., Sherk, S. (2004). "Osteogenesis Imperfecta." Gale Encyclopedia of Children's Health: Infancy through Adolescence. Retrieved on November 13, 2011, from Encyclopedia.com http://www.encyclopedia.com/doc/1G2-3447200418.html