OSTEOGENESIS IMPERFECTA

Definition:
Known as Brittle Bone Disease, or "Lobstein syndrome" which is a genetic bone disorder. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of Type-I collagen. This deficiency arises from an amino acid substitution of glycine to bulkier amino acids in the collagen triple helix structure. The larger amino acid side-chains create steric hindrance that creates a "bulge" in the collagen complex. As a result, the body may respond by hydrolyzing the improper collagen structure. If the body does not destroy the improper collagen, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness. Osteogenesis imperfecta (OI) is "a rare genetic disorder of collagen synthesis associated with broad spectrum ofmusculoskeletal problems, most notably bowing and fractures of the extremities, muscle weakness, ligamentous laxity,and spinal deformities." Other collagen-containing extraskeletal tissues, such as the sclerae, the teeth, and the heart valves are also affectedto a variable degree. OI has a "common feature of bony fragility associated with defective formation of collagenby osteoblasts and fibroblasts." (Smith, 1983, 13) This disease, involving defective development of the connective tissues, is usually the result of the autosomal dominant gene, but can also be the result of the autosomal recessive gene. Spontaneous mutations are common and the clinical presentation of the disease remains to be quite broad. ALTERNATIVE NAMES: y Fragilitas ossium, y Hypolasia of the mesenchyme y Osteopsathyrosis.

ETIOLOGY:
It is a congenital disease, meaning it is present at birth. It is frequently caused by defect in the gene that produces type 1 collagen, an important building block of bone. There are many different defects that can affect this gene. The severity of OI depends on the specific gene defect. OI is an autosomal dominant disease. That means if you have one copy of the gene, you will have the disease. Most cases of OI are inherited from a parent, although some cases are the result of new genetic mutations.

ANATOMY & PHYSIOLOGY

seen through an x-ray, this infant's developing skeleton appears to be healthy. However, infants with osteogenesis imperfect frequently experience bone fractures as they develop inside their mother's wombs. The task largely falls to cells called osteoblasts, which create new bone tissue, while cells called osteoclasts break down old bone. This ongoing process is called bone remodeling. Osteoblasts form new bones and increase the size of growing bones. This process is called ossificiation. Think of workers constructing a building -- the process has a lot in common with the way osteoblasts build new bone. First, both need strong building blocks with which to form the finished product. Construction workers use bricks or concrete blocks to form walls. Osteoblasts form bone from inorganic mineral salts, mainly calcium carbonate and calcium phosphate. This is the reason a calcium-rich diet is important to maintain strong bones. But you can't erect a building using only blocks and bricks. You need a metal framework to give it flexibility and tensile strength, the amount of stress a construction can endure without falling apart. An earthquake or strong wind could destroy a skyscraper, no matter the strength of the pieces, without a flexible steel framework. In bones, fibers of collagen, a protein produced by all vertebrates, supply this framework. Osteoblasts secrete these collagen fibers to form the framework and then initiate calcification -- calcium fills the flexible framework, providing strength. In cases of OI, the body either creates poor-quality collagen or doesn't create enough of it. The resulting bones lack flexibility and tensile strength, making them far more susceptible to fracture than normal, healthy bones.

TYPES OF OI:

Type I Collagen is of normal quality but is produced in insufficient quantities:

y y y y y

y y

Bones fracture easily Slight spinal curvature Loose joints Poor muscle tone Discolouration of the sclera (whites of the eyes), usually giving them a blue-gray color. The blue-gray color of the sclera is due to the underlying choroidal veins which show through. This is due to the sclera being thinner than normal because of the defective Type I Collagen not forming correctly. Early loss of hearing in some children Slight protrusion of the eyes

Type II Collagen is not of a sufficient quality or quantity

y y y

Most cases die within the first year of life due to respiratory failure or intracerebral hemorrhage Severe respiratory problems due to underdeveloped lungs Severe bone deformity and small stature

Type III Collagen quantity is sufficient but is not of a high enough quality
y y y y y y y y

Bones fracture easily, sometimes even before birth Bone deformity, often severe Respiratory problems possible Short stature, spinal curvature and sometimes barrel-shaped rib cage Loose joints Poor muscle tone in arms and legs Discolouration of the sclera (the 'whites' of the eyes) Early loss of hearing possible

Type IV Collagen quantity is sufficient but is not of a high enough quality

y y y y

Bones fracture easily, especially before puberty Short stature, spinal curvature and barrel-shaped rib cage Bone deformity is mild to moderate Early loss of hearing

Type V

y y

Same clinical features as Type IV. Distinguished histologically by "mesh-like" bone appearance. Further characterized by the "V Triad" consisting of o a) radio-opaque band adjacent to growth plates, o b) hypertrophic calluses at fracture sites, and o c) calcification of the radio-ulnar interosseous membrane [4]. OI Type V leads to calcification of the membrane between the two forearm bones, making it difficult to turn the wrist. Another symptom is abnormally large amounts of repair tissue (hyperplasic callus) at the site of fractures. At the present time, the cause for Type V is unknown, though doctors have determined that it is inherited.

Type VI y y Same clinical features as Type IV. Distinguished histologically by "fish-scale" bone appearance

Type VII y y A new recessive form was discovered in Quebec @ 2005 Mutations in the gene CRTAP causes this type

Type VIII y OI caused by mutation in the gene LEPRE1 is classified as type VIII

PATHOPHYSIOLOGY
Type I collagen fibers are found in the bones, organ capsules, fascia, cornea, sclera, tendons, meninges, and dermis. Type I collagen, which constitutes approximately 30% of the human body by weight, is the defective protein in OI. In structural terms, type I collagen fibers are composed of a left-handed helix formed by intertwining of pro-alpha 1 and pro-alpha 2 chains. Mutations in the loci that encode these chains cause OI (ie, COL1A1 on band 17q21 and COL1A2 on band 7q22.1, respectively). Other mutations may cause congenital bone fragility associated with distinctive clinical or histologic features (eg, redundant callus formation, pseudoglioma, defective mineralization of bone). These conditions have been grouped as syndromes resembling osteogenesis imperfecta.

Qualitative defects (eg, an abnormal collagen I molecule) and quantitative defects (eg, decreased production of normal collagen I molecules) are described. Of note, recent studies have reported that quantitative defects can cause very severe (even lethal) syndromes resembling osteogenesis imperfecta through posttranslational modifications of collagen.2 Cartilage-associated protein (CRTAP) is a protein required for prolyl 3-hydroxylation. Loss of CRTAP in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. In humans, CRTAP mutations cause excess posttranslational modification of collagen, and may be associated with syndromes resembling osteogenesis imperfecta, including recessive forms of lethal syndromes resembling OI and syndromes resembling osteogenesis imperfecta with redundant callus formation.
PREDISPOSING FACTOR

Mutation of COL1A1 and COL1A2

Absence of Type 1 collagen

Incomplete Bone formation

BRITTLE BONES

DIAGNOSTIC EXAMS:
Family history and characteristic features blue sclerae or deafness Performing collagen biochemical studies of cultured skin fibroblasts Prenatal Dx for the families with identified mutation Prenatal ultrasound @ 16 wks evidence of severe OI X-rays Diagnostic Serial UTZ for future pregnancies for those families with OI history To verify: o to detect limb shortening o utero fractures o polyhydramnios. 7. Children may undergo physical examination show that the whites of their eyes have a blue tint. 8. Skin punch biopsy removal of a piece of skin to diagnose or rule out an illness. 9. Chronic villi sampling for those pregnant mothers with history of OI to determine if the baby has the condition. 1. 2. 3. 4. 5. 6.

TREATMENT
1. Physical therapy *Muscle strength and bone mass can be increased through therapy (though patients can't overcome bone weakness). *exercise can improve mobility and help prevent future fractures. *Swimming is an ideal form of exercise for those with OI since it offers exertion without putting much stress on the limbs. *Maintaining a healthy weight can also cut down on bone stress. 2. Diet *Vitamin D and calcium are very important for ensuring bone strength * avoidance of steroids *avoid large amts of caffeine and alcohol 3. Surgical Management RODDING to help strengthen long bones against fracture and prevent or correct deformities. This involves implanting metal rods to run along the lengths of the bones. To help growing children, these rods can be expanded to keep pace with developing bones. Casting, bracing, or splinting of fractures to immobilize the bone so that healing can occur.

4. Meds/Drugs A. AREDIA  Strengthens the bones and reduces the fracture rate of individual  Usually taken 36 months B. BIPHOSPHONATES (BP)  Nitrogen-containing biphosphonates  Being increasingly administered to increase bone mass and reduces incidence of fracture  Proven efficacy in reducing fracture rates in children C. ICE/HEAT PACKS Cold compress VS. HEAT COMPRESS y Numbs the area * relief to stiffed muscles y reduces inflammation y provides relief D. TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION(TENS) Use of small machine which emits an electrical pulse to block pain signals from being sent to the brain. 5. Physical aids With adaptive equipment such as crutches, wheelchairs, splints, grabbing arms, and/or modifications to the home many individuals with OI can obtain a significant degree of autonomy. 6. PHYSIOTHERAPY Physiotherapy used to strengthen muscles and improve motility in a gentle manner, while minimizing the risk of fracture. This often involves hydrotherapy and the use of support cushions to improve posture. Individuals are encouraged to change positions regularly throughout the day in order to balance the muscles which are being used and the bones which are under pressure. 7. SUPPORTIVE MEASURES Supportive measures include: checking the patient's circulatory, motor, and sensory abilities encouraging the patient to walk when possible (children with osteogenesis imperfecta develop a fear of walking)

 teaching preventive measures, such as avoiding contact sports or strenuous activities or wearing knee pads, helmets, or other protective devices when engaging in sports assessing for and treating scoliosis, a common complication promoting preventive dental care and repair of dental caries.

PROGNOSIS
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.