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OsteogenesisImperfecta:A Guide for

MedicalProfessionals,

Individuals, andFamilies

Affected by OI

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A newborn lets out a sharp cry while he isbeing cleaned and weighed. He screams whenhe is picked up or when someone touches hisleg. An x-ray reveals a fractured femur, as wellas several healed rib fractures.

Parents bring their one-year-olddaughter to the emergency room. She waspulling to a stand, when suddenly the parentsheard a “pop” and the little girl fell to the floor,crying with the pain of a broken leg. This is thetoddler’s third fracture since birth.

A teenager checks into the hospital for thesecond time this year. A few months ago, hehad a metal rod put into his tibia. This time, hewill undergo risky surgery to put a rod in hisspine. Doctors hope that the surgery will halthis progressively worsening scoliosis, which iscrowding his lungs and leading to repeatedrespiratory infections.

At her annual check-up, a 45-year-oldwoman asks her physician for a referral to agood orthopedist. The woman had severaldozen bone fractures in her childhood andteen years. Though she has been fracture-freefor a number of years, she is concerned thatmenopause will weaken her already fragilebones, leading to another cycle of fractures.

The newborn, the toddler, the teenager,and the middle-aged woman all haveosteogenesis imperfecta, or “brittlebone disorder.” Osteogenesis imperfecta (OI) isa genetic disorder that causes fragile bones andother connective tissue symptoms.

This brochure provides the latest informationon osteogenesis imperfecta for health careproviders and people affected by OI.

For more information on OI, contact theOsteogenesis Imperfecta Foundation at1-800-981-2663, or www.oif.org.

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Myths and Facts AboutOsteogenesis Imperfecta

Thanks to the work of dedicated researchersand clinicians, we learn more about osteogenesisimperfecta every day. Most babies born todaywith OI have a good chance of leading indepen-dent, successful, and satisfying lives. Traditionaltreatments are being perfected, and new treat-ments for strengthening OI bone are on thehorizon. Because OI is a rare disorder, manyparents who have a child with OI have neverheard of it, and their health care providers maynever before have treated anyone with OI. Thisbrochure provides families and medical profes-sionals with updated and accurate information.

Myth: A baby with osteogenesis imperfectashould always be carried on a pillow anddiscouraged from moving.

Fact: Though there are handling techniques andprecautions that are useful when caring for aninfant with OI, it is in the child’s best interest tobe held and touched, and to explore indepen-dent movement to the greatest extent possible.Immobility increases bone loss and fragility,leading to more fractures.

Myth: You can easily distinguish fracturescaused by osteogenesis imperfecta from thosecaused by child abuse.

Fact: Children with osteogenesis imperfecta canhave all types of fractures—spiral, rib, skull,incomplete, displaced, etc. Distinguishing OIfrom child abuse requires a thorough assess-ment by a medical professional familiar with thefull range of OI characteristics

Myth: OI affects only the bones.

Fact: Though fragile bones are the hallmark ofOI, people with OI often have other connectivetissue symptoms, including excessive perspira-tion, loose joints, early hearing loss, brittle teeth,respiratory problems, easy bruising, and thin,smooth skin.

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Myth: OI is a childhood disorder; people growout of it by their teens.

Fact: OI is a genetic disorder that is presentthroughout a person’s lifetime. Many peoplewith OI have fewer fractures after puberty whengrowth stops. The genetic defect remains.Fractures and other complications occur through-out the lifespan; especially after menopause.

Myth: Everyone who has OI is shorter thannormal, has blue sclera (whites of the eyes),and uses a wheelchair.

Fact: The appearance of people with OI variescosiderably. Though many people with OI areshort-statured, people with milder forms may beof normal or near-normal height and have noobvious symptoms of OI. About 50 percent ofpeople with OI have tinted sclera that can rangein color from nearly white to dark blue or gray.People with OI also have variable mobility,ranging from independent walking to full-timewheelchair use.

Myth: Everyone who has OI is diagnosed atbirth.

Fact: Though present from conception, OI canbe diagnosed at many different ages. OI Type I,the most common and mildest form of OI, israrely diagnosed at birth. Some very mild casesare only diagnosed when a person has a childwith OI Type I, and a review of the parent’smedical history reveals a pattern of broken bonesand OI features.

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What is OsteogenesisImperfecta?

Osteogenesis imperfecta (OI) is a geneticdisorder. Most cases (90 percent) involve adefect in type 1 collagen— the protein “scaffold-ing” of bone and other connective tissues. Afaulty gene reduces the amount or the quality oftype 1 collagen throughout the body. Other casesof OI are caused by mutations in other genes inthe collagen pathway. The result in all cases(regardless of the cause) is bones that break easilyand other connective tissue symptoms. OI occursequally among males and females and it occurs inall racial and ethnic groups.

Several forms of OI have been described,representing wide variation in appearance andseverity. Types of OI include mild, moderate andsevere forms. It is estimated that approximately50,000 people in the U.S. have OI.

Below are the clinical features of the majortypes of OI. Clinical features vary widelynot only between types, but within types,and even within the same family. Manypeople with OI have only some—not all—of theclinical features. Some features are age depen-dent. Children with milder OI, in particular, mayhave few obvious clinical features.

Type I (Mild)• Most common and mildest type of OI.• Bones predisposed to fracture. Most frac-

tures occur before puberty.• Normal or near-normal stature. Stature may

be average or slightly shorter than average ascompared with unaffected family members,but within the normal range for age.

• Loose joints and muscle weakness.• Sclera (whites of the eyes) often have a blue,

purple, or gray tint.• Triangular face.• Tendency toward spinal curvature.• Bone deformity absent or minimal.• Brittle teeth possible.• Hearing loss possible, often beginning in

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teens.• Collagen structure is normal, but the amount

is reduced.• Dominantly inherited; spontaneous mutations

are common. (It can be passed from parentto child, or occur in a previously unaffectedfamily due to a new mutation.)

Type II (Perinatal Lethal)• Most severe form.• Frequently lethal at or shortly after birth,

often due to respiratory problems.• Numerous fractures and severe bone defor-

mity evident at birth.• Small stature with underdeveloped lungs,

and low birth weight.• Collagen is improperly formed.• Results from new dominant mutations to

type 1 collagen genes, parental mosaicism orrecessive inheritance of a mutation to CRTAPgene.

Type III (Progressive Deforming)• Progressive bone deformity, often severe.• Bones fracture easily. Fractures are often

present at birth, and x-rays may revealhealed fractures that occurred before birth.

• Short stature.• Sclera have a blue, purple, or gray tint.• Loose joints and poor muscle development

in arms and legs.• Barrel-shaped rib cage.• Triangular face.• Spinal curvature and compression fracture of

vertebrae.• Respiratory problems possible.• Brittle teeth are common but not universal.• Hearing loss possible.• Reduced amounts of poor quality type I

collagen.• Results from dominant mutations in type I

collagen genes, (often the result of spontane-ous mutation, parental mosaicism) orrecessive inheritance of a mutation to CRTAPgene.

Type IV (Moderate Severe)• Between Type I and Type III in severity.• Bones fracture easily, most before puberty.• Shorter than average stature for age.

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• Sclera are white or near-white (i.e., normalin color).

• Mild to moderate bone deformity.• Spinal curvature and compression fracture of

vertebrae.• Barrel-shaped rib cage.• Triangular face.• Brittle teeth possible.• Hearing loss possible.• Reduced amounts of poor quality type I

collagen.• Results from dominant mutations in type I

collagen genes, (often the result of spontane-ous mutation, parental mosaicism) orrecessive inheritance of a mutation to CRTAPgene.

Types V

• Similar to Type IV in appearance andsymptoms of OI.

• Large hypertrophic calluses at fracture orsurgical procedure sites.

• Calcification of the membrane between theradius and ulna to restrict forearm rotation.

• Does not have type I collagen mutation.• Dominant inheritance pattern.

Types VI

• Similar to Type IV in appearance andsymptoms of OI.

• Distinguished by a characteristic mineraliza-tion defect seen in biopsied bone.

• Does not have type I collagen mutation.• Mode of inheritance is unknown.

Types VII

• Limited to a set of Canadian Natives.• Short humeri and femora.• Short staure.• Coxa vara.• Results from recessive inheritance of a

mutation to CRTAP gene.

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How Is OI Inherited?Approximately 90 percent of all people with

OI have a dominant genetic mutation in the typeI collage genes. This means that only one copy ofthe OI gene is necessary for the child to have OI.In the majority of cases, the gene is either inher-ited from a parent who has OI or results from amutation at the time of conception. In rare casesdominant OI can occur when a parent is mosaicfor an OI mutation. This means that an OIcausing mutation is present in a percentage ofone parent’s cells; but does not cause anysymptoms in the parent.

Lethal or severe OI similar to Types II, III andIV can also be a recessive form when there is amutation to the CRTAP (cartilage associatedprotein) gene. In this situation, the parents donot have OI, but both carry the mutation intheir genes. For a child to have recessive OI, theCRTAP mutation must be inherited from bothparents.

When a child with OI is born into a previ-ously unaffected family the chance of havinganother child with OI varies depending onwhether the cause is a dominant or recessivemutation. If the cause is a spontaneous dominantmutation, the chance is 2-5 percent. If the cause isparental mosaicism for a dominant mutation,there is a 10-50 percent chance per pregnancy. Ifthe cause is the recessive form of OI, the chance is25 percent per pregnancy. Genetic testing canconfirm whether OI was inherited in a dominantor recessive manner and whether a parent is amosaic carrier.

A person with OI has a 50 percent chance ofpassing on the disorder to each of his or herchildren. An affected child will have the samemutation, and therefore the same type of OI, asthe parent. However, the expression— thedegree of severity, number of fractures— may bedifferent among family members.

Unaffected siblings of a child with dominantOI have no greater risk of having children withOI than the general population. Unaffectedsiblings of a child with recessive OI have a 50percent chance of being a carrier for the recessive

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gene. Genetic testing is available for siblings.

How is OI Diagnosed?Bone fractures that occur with little or no

trauma are often the first indication that an infantor child may have OI. Babies with Types II, III,and IV are often born with broken bones, and/or may show evidence of in utero fractures.Children with Type I often sustain their firstbroken bones as a result of normal activity duringthe first several years of life—during a diaperchange, while being lifted or burped, or whenthey begin standing and walking. Some very mildcases of OI Type I are not diagnosed until theteen or adult years.

OI remains primarily a clinical diagnosis. Aphysician familiar with all types of OI can oftendiagnose the condition based on the presence offractures and other clinical features. The presenceof clinical features varies widely and somefeatures are age or type dependent. A positivefamily history for the disorder can help confirm adiagnosis, although spontaneous or recessivemutations do occur in previously unaffectedfamilies.

There are three types of laboratory testsavailable to help confirm a diagnosis of OI. Thesetests are to be used in conjunction with a clinicalevaluation. DNA-based testing (COL1A1/COL1A2mutation assay) using blood or saliva andprotein-based testing (collagen screening) usingcultured skin cells, detect the types of OI causedby a dominant mutation to type I collagen genes.People who do not show a type I collagenmutation but have symptoms of severe andmoderate OI, may have the recessive form whichinvolves a mutation to the CRTAP gene. A DNAtest using a blood sample is available to test forthis mutation. Because all genetic causes for OIhave not yet been identified, a negative collagenor DNA test does not rule out an OI diagnosis.Additional blood and urine tests are used to ruleout other disorders.

OI can be diagnosed prenatally in somecases. Ultrasound can detect bowing, fractures,

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shortening or other bone abnormalities,particulary in the more severe forms of OI. Evenwhen ultrasound is done by a highly qualifiedtechnician or physician, it may not be possible topinpoint the type of OI or differentiate betweenType II or Type III. Cells obtained throughamniocentesis can be used for DNA analysis. Theparent’s OI mutation must be known beforechorionic villus sampling (CVS) is performed.

How is OI Treated?There is no cure for OI. Currently, OI is

treated primarily by managing fractures, and activephysical rehabilitation to promote as muchmobility and independence as possible. Prolongedimmobility can further weaken bones and lead tomuscle loss, weakness, and more fractures. Manyorthopedists prefer to treat fractures with short-term immobilization in lightweight casts, splints, orbraces to allow some movement as soon as possibleafter the fracture.

Physical Therapy and Exercise. Physicaltherapy should begin as soon as it is evident thatan infant has muscle weakness or motor skilldelay when compared with same-age peers. Thelong-term goal for children with OI is indepen-dence in all life functions (e.g., self-care, locomo-tion, recreation, social interaction, and educa-tion), with adaptive devices as needed. Occupa-tional therapy can help with fine motor skills andadaptive equipment for daily living. As a childwith OI grows older and gains more indepen-dence, he or she will benefit from continuedphysical activity, such as adapted physicaleducation. Adults with OI also benefit from safe,regular exercise to maintain bone and musclemass. Swimming and water therapy are particu-larly well-suited for people with OI of all ages, asthey allow independent movement with littlefracture risk. Walking is also excellent exercise forthose who are able (with or without mobilityaids).

Surgery. Many children with OI undergo asurgical procedure known as rodding, in whichmetal rods are inserted into the long bones to

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control fractures and improve deformities thatinterfere with function. Both non-expandableand expandable rods are available.

Progressive, sometimes severe, scoliosis is aproblem for many people with OI, and mayaggravate respiratory problems. Surgery may berequired to stabilize the spine.

Medications and Other ExperimentalTherapies. Bisphosphonate drugs, which arecurrently approved by the Food and DrugAdministration (FDA) to prevent and treatosteoporosis and bone complications of cancer,are used off label to increase bone density inchildren and adults with moderate and severeOI. Specific guidelines for dose and length oftreatment for both the tablet forms and theintravenous forms are being developed. Longterm effects continue to be studied. Peopleinterested in trying these drugs are encouraged toenroll in a clinical trial and be closely monitored.Other treatments being researched includeteriparatide (a drug based on the parathyroidhormone), growth hormone, and gene thera-pies.

Healthy LIfestyle. People with OI benefitfrom a healthy lifestyle that includes safe exerciseand a nutritious diet. Adequate intake of nutri-ents, such as Vitamin D and calcium to maintainbone density is important. However, extra largedoses of these nutrients are not recommended.Evaluation by a physician or registered dietitianwill help people with OI determine adequatenutrient intake for their body size and age.Maintaining a healthy weight reduces stress onfragile bones. People with OI should avoidsmoking, excessive alcohol or caffeine consump-tion, and steroid medications, which will reducebone density.

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Are There Precautions to TakeWhen Caring for People withOI?

• Never pull or push on a limb, or bend it intoan awkward position.

• Lift a baby with OI by placing one handunder the buttocks and legs, and the otherhand under the shoulders, neck and head. Donot lift the baby from under the armpits, orlift by the ankles to change a diaper. Be awareof where the baby’s arms and legs are at alltimes to avoid awkward positions or gettinga hand or foot caught.

• It is important for babies with OI to be heldand touched by parents and other caregivers,and that they be allowed to explore indepen-dent movement. Supporting infants in avariety of positions (e.g., side lying, stomachlying) develops muscles that will help withsitting and standing later on. Fractures willoccur no matter how careful you are, and thephysical and emotional benefits of touch andmovement outweigh the risks.

• Use caution when inserting IVs, taking bloodpressure, or performing other medicalprocedures on children and adults. Pressureon an arm or leg can lead to bruising orfractures.

• When a fracture is suspected, minimizehandling of the affected limb.

• Respect the opinions, advice, or instructionsprovided by parents, children, and adults withOI. They have dealt with dozens, evenhundreds, of fractures and medical proce-dures, and have a good sense of whether afracture has occurred even before x-rays aretaken. They have learned the best methods(medication, positioning, lifting, etc.) tominimize pain and distress when a fractureoccurs.

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For More Information:

Osteogenesis Imperfecta Foundation804 West Diamond Avenue

Suite 210Gaithersburg, MD 20878

(800) 981-2663 or (301) 947-0083Fax: (301) 947-0456

E-mail: bonelink@oif.orgwww.oif.org

This brochure was produced by theOsteogenesis Imperfecta Foundation, Inc.

Additional support was provided by:

National Institutes of HealthOsteoporosis and Related BoneDiseases~National Resource Center1232 22nd Street NWWashington, DC 20037(800) 624-BONE(202) 223-0344Fax: (202) 293-2356TTY: (202) 466-4315E-mail: orbdnrc@nof.orgwww.osteo.org

The National Resource Center is supported by the NationalInstitute of Arthritis and Musculoskeletal and Skin Diseaseswith contributions from the National Institute of Child Healthand Human Development, National Institute of Dental andCraniofacial Research, National Institute of EnvironmentalHealth Sciences, NIH Office of Research on Women’s Health,Office of Women’s Health, PHS, and the National Institute onAging. The Resource Center is operated by the National Os-teoporosis Foundation, in collaboration with the Paget Foun-dation and the Osteogenesis Imperfecta Foundation.

Revised: 12/06