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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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Osler-Weber-Rendu syndrome

the components of blood, but no ammonia (this liquid is like the water in the water and cola example). Thus, ammonia spreads throughout the blood and the liquid surrounding the hose (the same way cola will spread out throughout water added to the glass) and the amount of ammonia in the blood is reduced. By continuously pumping blood through the hose and changing the liquid around the hose, most of the ammonia can be removed from the blood. All of the really large particles, like red blood cells, are also kept in the blood because the hose has holes that are only large enough to let smaller particles like ammonia out while keeping red blood cells in.

The future

The future treatment of OTC deficiency probably will come from experiments in gene therapy. OTC deficiency is a disorder particularly amenable to gene therapy because only one gene is affected and only one organ, the liver, would need the new gene. However, as of 2001, gene therapy has not been successfully demonstrated in human beings. Many technical problems must still be solved in order to successfully treat OTC deficiency and other disorders like it with gene therapy.

Prognosis

Only 50% of the most severely affected patients live beyond the time they first attend school. Of those receiving liver transplants, 82% of patients survive five years after receiving the transplant. Children with the severe disorder that receive drug therapy are much more likely to experience mental retardation, developmental delay, and a lack of growth. Also, many infants who experience hyperammonemic comas have severe mental damage.

For individuals not identified at birth or soon after, the prognosis varies widely. The consequences of the disorder are affected by the severity of the disorder and how it is managed, although anyone with the disorder may experience life-threatening attacks of acute hyperammonemia. In terms of long-term survival, puberty appears to be a difficult time for those with OTC deficiency, and persons who survive until after puberty have improved outcomes. The prognosis for this disorder can vary from quite hopeful to very distressing based upon its severity and how well the disorder can be controlled. A severe disorder that is well-controlled may still have a positive outcome.

Resources

PERIODICALS

Maestri, Nancy E., et al. “The Phenotype of Ostensibly Healthy Women Who Are Carriers for Ornithine Transcarbamylase Deficiency.” Medicine 77, no. 6 (November 1998): 389.

ORGANIZATIONS

National Urea Cycle Disorders Foundation. 4841 Hill Street, La Canada, CA 91011. (800) 38NUCDF. http://www

.NUCDF.org/ .

WEBSITES

“Ornithine transcarbamylase deficiency.” NORD—National

Organization for Rare Diseases. http://www.rarediseases

.org .

“Ornithine transcarbamylase deficiency.” Aim for Health.http://www.aim4health.com/family/otc.htm .

Michael V. Zuck, Ph D

I Osler-Weber-Rendu

syndrome

Definition

Osler-Weber-Rendu syndrome (OWR), or hereditary hemorrhagic telangiectasia (HHT), is a blood vessel disorder, typically involving recurrent nosebleeds and telangiectases (arteriovenous malformations that result in small red spots on the skin) of the lips, mouth, fingers, and nose. Arteriovenous malformations (AVMs) are abnormal, direct connections between the arteries and veins (blood vessels), causing improper blood flow. AVMs are often present in OWR, and may occur in the lungs, stomach, or brain.

Description

The story of OWR began years ago with a sequence of events between three prominent physicians, Osler, Weber, and Rendu. The earliest report of OWR was compiled by Rendu in 1896. Osler further characterized the condition in 1901, and F. Parkes Weber described many cases of the vascular problems as well. OWR is caused by a genetic defect in the development of blood capillaries. Capillaries are vessels that exist between arteries and veins, connecting them throughout the body. The abnormality causes the capillaries to end bluntly, so they cannot properly connect the arteries and veins. Because of this, AVMs and telangiectases may result in various parts of the body.

Telangiectases on the skin represent a small AVM that has reached the outer surface of skin. Telangiectases usually have thin walls and are quite fragile, so they may burst spontaneously, causing bleeding. This bleeding may occur in the nose, explaining the frequent nosebleeds that result from little trauma. Telangiectases most often occur on the cheeks, lips, tongue, fingers, mouth,

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and toes. Occasionally, larger AVMs may exist in the brain, lungs, or stomach and this may lead to more serious bleeding. It is very rare for an individual to have all the symptoms typically found in OWR.

People with OWR do not have any mental limitations, and therefore have the same academic potential as anyone else. Nosebleeds may begin by age twelve, and may be initially assumed to be a typical childhood experience. However, if fatigue and other symptoms of anemia accompany the nosebleeds, they can pose great stress on a young child. Children with OWR may find it difficult if they play with and are unable to keep up with their peers. OWR has the potential need for continual medical management into adulthood, which can also be quite taxing on the individual and his or her family.

Genetic profile

OWR may be divided into two groups, OWR1 and OWR2. OWR1 is caused by alterations in the endoglin (ENG) gene, located on the q (long) arm of chromosome 9 at band (location) 34. AVMs of the lung may be more common in OWR1 than OWR2. OWR2 is caused by alterations in the activin receptor-like kinase 1 gene (ALK1), located on the q arm of chromosome 12 at band 1. Normally, ENG and ALK1 make proteins that are important in blood vessel formation. Therefore, alterations within these genes would naturally cause problems with blood vessels. The causes of OWR are complex; various alterations in multiple genes, or various alterations within the same gene, generate similar symptoms.

OWR is inherited in an autosomal dominant manner. An affected individual has one copy of an alteration that causes OWR. The individual has a 50% chance to pass the alteration on to each of his or her children, regardless of that child’s gender. As of 2000, nearly all affected people have a family history of OWR, which is typically a parent with the condition.

Demographics

As of 2000, OWR affects about one in 10,000 people. It spans the globe, but a higher prevalence exists in the Danish island of Fyn, the Dutch Antilles, and parts of France. It affects both males and females.

Signs and symptoms

The symptoms in OWR result from several AVMs, which may occur in differing severity and areas of the body. Ultimately, AVMs may lead to mild or severe bleeding in affected areas. As of 1998, about 90% of people with OWR experience frequent nosebleeds. They occur because the layers of mucous membranes in the

K E Y T E R M S

Alteration—Change or mutation in a gene, specifically in the DNA that codes for the gene.

Aneurysm—Widening of an artery, which could eventually bleed.

Arteriovenous malformation (AVM)—Abnormal, direct connection between the arteries and veins (blood vessels). Can range from very small to large in size. Bleeding or an aneurysm may result.

Cauterization—Process of burning tissue either with a laser or electric needle to stop bleeding or destroy damaged tissue.

Echocardiogram—A non-invasive technique, using ultrasonic waves, used to look at the various structures and function of the heart.

Embolization therapy—Introduction of various substances into the circulation to plug up blood vessels in order to stop bleeding.

Endoscopy—A slender, tubular optical instrument used as a viewing system for examining an inner part of the body and, with an attached instrument, for biopsy or surgery.

Magnetic resonance imaging (MRI)—A technique that employs magnetic fields and radio waves to create detailed images of internal body structures and organs, including the brain.

Stroke—A sudden neurological condition related to a block of blood flow in part of the brain, which can lead to a variety of problems, including paralysis, difficulty speaking, difficulty understanding others, or problems with balance.

Telangiectasis—Very small arteriovenous malformations, or connections between the arteries and veins. The result is small red spots on the skin known as “spider veins”.

nose are very sensitive and fragile, and AVMs in this area can easily and spontaneously bleed. Consistent nosebleeds may begin by about twelve years of age, and are not always severe enough to result in medical treatment or consultation. Occasionally, severe nosebleeds can cause mild to severe anemia, sometimes requiring a blood transfusion or iron replacement therapy.

Small AVMs, called telangiectases, commonly occur on the nose, lips, tongue, mouth, and fingers. They may vary in size from a pinpoint to a small pea. Because telangiectases are fragile, sudden bleeding may occur from only slight trauma, and bleeding may not sponta-

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neously stop. Thirty percent of people with OWR report telangiectases first appearing before age 20, and 67% before age 40. Telangiectases and larger AVMs can be found anywhere in the gastrointestinal system, and if large enough they may cause a significant amount of internal bleeding. This bleeding may become more severe with age, but usually does not appear until age forty.

Pulmonary AVMs (AVMs of the lung) may cause bleeding within the lungs. As of 1998, this occurs in about 20% of people with OWR. These are problematic because the abnormal connections between arteries and veins bypass the natural filtering system within the lung, allowing bacteria to enter the system. Low levels of oxygen and infection may result, causing migraine-like headaches. An individual with a pulmonary AVM may experience intolerance to exercise, or may have areas of their skin turn blue (due to low oxygen levels). Complications in the brain may also result, sometimes causing a stroke. Occasionally, AVMs may occur in the spine, liver, and brain. A network of AVMs in the liver can cause blood to be forced away from the normal circulation, increasing the risk of heart failure because the heart becomes overloaded with blood.

Diagnosis

As of 2001, genetic testing is available for OWR, but only on a research basis. The University of Utah offers linkage analysis to determine alterations in either ENG or ALK1, and results are not guaranteed. Linkage analysis is a method of genetic testing that requires several family members, both affected and unaffected, to give a blood sample for DNA analysis. The testing attempts to study family markers on the various chromosomes, in an attempt to find alterations near the proposed gene location. Results are abnormal if an alteration near ENG or ALK1 is found. If a familial alteration is identified, unaffected individuals could be offered testing to see whether or not they have the same alteration. If an individual had the alteration, he or she would be at risk for symptoms of OWR. Currently, no prenatal testing is available for OWR.

Because testing is neither widely available nor useful for diagnostic purposes, most people with OWR are identified by careful physical examination and study of their medical and family histories. Findings suggestive of an OWR diagnosis include nosebleeds (especially at night), multiple telangiectases (especially on the lips, mouth, fingers, and nose), and AVMs of various organs (especially the lungs, brain, liver, spine, and gastrointestinal (GI) tract). The final piece is a family history of OWR, with the affected person having the mentioned symptoms. OWR is considered definite when three or

more findings are present, possible/suspected when two findings are present, and unlikely when fewer than two findings are present.

OWR is difficult to diagnose (and often under-diag- nosed) because bleeding and venous malformations happen in otherwise healthy individuals. For example, isolated nosebleeds are very common in the general population and may occur for a variety of reasons. Because nosebleeds are often the first sign in OWR, they may initially be ignored, until they become so frequent that they are brought to medical attention. Isolated internal bleeding, or aneurysms, are quite common in the brain and GI tract. However, not all aneurysms are caused by AVMs and this needs to be determined, as AVMs are more specific to OWR. Most individuals with a pulmonary AVM actually have OWR.

Telangiectases may sometimes be a sign of other bleeding disorders, such as von Willebrand disease, a problem with blood coagulation (clotting). Telangiectases may also naturally occur in pregnancy or chronic liver disease. A hereditary form of telangiectases exists, and in this they are usually found on the face, upper limbs, and upper trunk of the body. Ataxia telangiectasia, another genetic condition involving telangiectases, should be considered if individuals have ataxia (problems with muscle coordination); movement and walking disorders are often observed with this condition as well.

Treatment and management

Treatment for OWR is based on the specific symptoms an individual experiences. To assess the need for treatment, a review of medical history regarding nosebleeds and other bleeding episodes should be noted. There should be careful inspection of any telangiectases. Stool samples may be analyzed to determine whether there is any blood present that is not obvious to the naked eye; this may indicate anemia. A complete blood count (CBC) can also determine whether anemia is a factor, due to blood loss. Pulse oximetry involves studying a blood sample, and determining whether the amount of oxygen absorption by red blood cells is normal. It can help to determine whether the lungs and heart are functioning properly, because their roles are to help oxygenate blood. Careful imaging of the heart by echocardiogram or chest x rays can assess whether the heart structures are normal. Chest x rays may identify pulmonary AVMs. Magnetic resonance imaging (MRI) of the head can visualize the brain to rule out any bleeding. An ultrasound of the liver and abdomen can help to rule out any AVMs in this area.

There are a few options for those who experience chronic nosebleeds. Generally, sterile sponges and sprays

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may help absorb free-flowing blood. Another option is laser therapy, used for individuals who have mild to moderate nosebleeds. A small laser beam is directed around each telangiectasis, and automatic clotting occurs, sealing them. It is usually done under local anesthesia, and few complications exist. Nearly everyone sees improvements for several months, and the procedure may be repeated as needed. For more severe cases (sometimes requiring transfusions) there is septal dermoplasty, first pioneered in the 1960s. This replaces the normally fragile lining of the nose with a tougher lining, using a skin graft from the thigh area. The procedure can be done with local or general anesthetic, and has minimal complications. Some individuals never have nosebleeds again after the operation, but most of them experience a significant lessening of symptoms. Estrogen and aminocaproic acid (an amino acid) therapies have also been found to help with clotting in the nose. Estrogen improves the smoothness of layers of skin on the telangiectases, making them less fragile. Aminocaproic acid improves the clotting process by magnifying the protein responsible for clotting.

Gastrointestinal bleeding is one of the most difficult symptoms of OWR to treat. Endoscopy can help to identify the location of the AVM. Using an endoscopic probe, treatment can be attempted by laser or through cauteriza- tion—sealing the injury with heat. These help to seal the telangiectasis or AVM. If bleeding is severe, iron therapy is often needed to help build more red blood cells and alleviate anemia. Hormone therapy (with estrogen and progesterone) has been helpful in many patients with chronic GI bleeding. As of 1998, no perfect treatment for liver AVMs has been established, but embolization therapy has been used. For more severe cases (usually in older individuals) liver transplant may be considered.

Pulmonary AVMs are often treated with a procedure known as balloon embolization. A small tube is inserted into a large vein in the groin. It is passed through the blood vessels to the pulmonary AVM. A balloon or coil is placed into the artery leading into the AVM, blocking it off completely, and this stops the bleeding. This usually takes 1–2 hours, with minimal recuperation time. Pulmonary AVMs can almost always be treated very well with this method. Women with OWR who become pregnant and have untreated pulmonary AVMs run a high risk for an internal lung bleed. They should be treated during their second trimester to avoid this complication. Pregnant women with treated pulmonary AVMs appear to be at no higher risk for bleeding than pregnant women without pulmonary AVMs.

For generalized anemia, iron replacement and red blood cell transfusions may become necessary. People with OWR may develop medical problems unrelated to

The distended blood capillaries of this patient are visible on the face. These are referred to as telangiectases and are characterisic of Osler-Rendu-Weber syndrome. (Photo Researchers, Inc.)

the condition, such as ulcers or colon cancer, which may cause additional GI blood loss.

Because telangiectases can occur in the mouth, dental work may be a particular problem for those with OWR. Bleeding in the mouth makes the oral area susceptible to oral bacteria, such as those on the gums. Bacteria can enter the bloodstream and cause infections in other areas of the body. The best preventive measure for this is to take antibiotics before any dental work in order to prevent infection. Additionally, medications such as aspirin and non-steroidal anti-inflammatory agents (such as Advil, Aleve, and Motrin) should be avoided because they can increase bleeding.

Since effective treatment measures are available, unaffected at-risk individuals in a family should be screened for symptoms of OWR, especially for brain, pulmonary, and GI AVMs.

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Prognosis

Prognosis for individuals with OWR is good, assuming they receive appropriate and timely treatments. Because many treatments are effective, proper screening is crucial to prognosis.

Resources

PERIODICALS

Christensen, Gordon J. “Nosebleeds may mean something much more serious: an introduction to HHT” Journal of the American Dental Association 129, no. 5 (May 1998): 635–37.

Garcia-Tsao, Guadalupe, et al. “Liver disease in patients with hereditary hemorrhagic telangiectasia.” The New England Journal of Medicine 343, no. 13 (September 28, 2000): 931–36.

ORGANIZATIONS

HHT Foundation International, Inc. PO Box 8087, New Haven, CT 06530. (800) 448-6389 or (410) 584-7287. Canada: (604) 596-3418. Other countries: (914) 887-5844. Fax: (410) 584-7721 or (604) 596-0138. hhtinfo@hht.org.http://www.hht.org .

WEBSITES

Birth Disorder Information Directory. http://www.bdid.com/ owrs.htm .

Family Village. http://www.familyvillage.wisc.edu/lib_ht

.htm .

“Hereditary Hemorrhagic Telangiectasia (HHT) Syndrome.”

University of Michigan Health System. http://www.med

.umich.edu/1libr/topics/hemo03.htm .

Deepti Babu, MS

I Osteoarthritis

Definition

Osteoarthritis is a degenerative joint disease characterized by the breakdown of the joint’s cartilage.

Description

Osteoarthritis is one of the oldest and most common types of arthritis. With the breakdown of cartilage, the part of the joint that cushions the ends of bones, bones rub against each other, causing pain and loss of movement. Often called “wear-and-tear arthritis” or “old person’s arthritis,” many factors can cause osteoarthritis.

The biologic causes of the disorder are currently unknown. It does not appear to be caused by aging itself, although osteoarthritis generally accompanies aging.

Osteoarthritic cartilage is chemically different from normal aged cartilage.

In many cases, certain conditions seem to trigger osteoarthritis. People with joint injuries from sports, work-related activity, or accidents may be at increased risk, and obesity may lead to osteoarthritis of the knees. Individuals with mismatched surfaces on the joints that could be damaged over time by abnormal stress may be prone to osteoarthritis. One study reported that wearing shoes with 2.5 in (6.3 cm) heels or higher may also be a contributing factor. High heels force women to alter the way they normally maintain balance, putting strain on the areas between the kneecap and thigh bone and on the inside of the knee joint.

Demographics

Osteoarthritis is estimated to affect more than 20 million Americans, mostly after age 45. Women are more commonly affected than men.

In the United States about 6% of adults over 30 have osteoarthritis of the knee and about 3% have osteoarthritis of the hip. Prevalence of osteoarthritis in most joints is higher in men than women before age 50, but after this age, more women are affected by osteoarthritis. The occurrence of the disease increases with age. In men, the hip is affected more often while in women, the hands, fingers, and knees are more problematic.

Some forms of osteoarthritis are more prevalent in African-American men and women than in Caucasians, possibly because they have a higher bone mineral density. In the case of knee osteoarthritis, it may be related to occupational and physical demands. AfricanAmerican women also have a higher risk of developing bilateral knee osteoarthritis and hip osteoarthritis compared to women of other races. This difference may be because African-American women generally have a higher body mass index which puts more stress on the joints.

Osteoarthritis is common worldwide, although risk of osteoarthritis varies among ethnic groups. Caucasians have a higher risk than Asians, and the risk of osteoarthritis in the hips is lower in Asia and some Middle East countries than in the United States. Asians appear to have a higher incidence of osteoarthritis in the knee than Caucasians, however, and an equal risk in the spine. Location of affected joints and inherited forms of the disorder can influence age of onset.

Genetic profile

Genetics plays a role in the development of osteoarthritis, particularly in the hands and hips. One

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study found that heredity may be involved in 30% of people with osteoarthritic hands and 65% of those with osteoarthritic knees. Another study found a higher correlation of osteoarthritis between parents and children and between siblings than between spouses. Other research has shown that a genetic abnormality may promote a breakdown of the protective structure in cartilage.

Abnormal collagen genes have been identified in some families with osteoarthritis. One recent study found that the type IX collagen gene COL9A1 (6q12-q13) may be a susceptibility locus for female hip osteoarthritis. Other research has suggested that mutations in the COL2A1 gene may be associated with osteoarthritis.

Some evidence also suggests that a female-specific susceptibility gene for idiopathic osteoarthritis is located on 11q. There is some evidence of genetic abnormality at the IL1R1 marker on gene 2q12 in individuals with severe osteoarthritis and Heberden nodes (bony lumps on the end joint of fingers).

Signs and symptoms

Although up to 85% of people over 65 show evidence of osteoarthritis on x ray, only 35-50% experience symptoms. Symptoms range from very mild to very severe, affecting hands and weight-bearing joints such as knees, hips, feet, and the back. The pain of osteoarthritis usually begins gradually and progresses slowly over many years.

Osteoarthritis is commonly identified by aching pain in one or more joints, stiffness, and loss of mobility. The disease can cause significant trouble walking and stair climbing. Inflammation may or may not be present. Extensive use of the joint often exacerbates pain in the joints. Osteoarthritis is often more bothersome at night than in the morning and in humid weather than dry weather. Periods of inactivity, such as sleeping or sitting, may result in stiffness, which can be eased by stretching and exercise. Osteoarthritis pain tends to fade within a year of appearing.

Bony lumps on the end joint of the finger, called Herberden’s nodes, and on the middle joint of the finger, called Bouchard’s nodes, may also develop.

Diagnosis

A diagnosis of osteoarthritis is made based on a physical exam and history of symptoms.

X rays are used to confirm diagnosis. In people over 60, the disease can often be observed on x ray. An indication of cartilage loss arises if the normal space between the bones in a joint is narrowed, if there is an abnormal increase in bone density, or if bony projections or ero-

K E Y T E R M S

Cartilage—Supportive connective tissue which cushions bone at the joints or which connects muscle to bone.

Collagen—The main supportive protein of cartilage, connective tissue, tendon, skin, and bone.

Corticosteroids—Anti-inflammatory medications. Related to cortisol, a naturally produced hormone that controls many body functions.

sions are evident. Any cysts that might develop in osteoarthritic joints are also detectable by x ray.

Additional tests can be performed if other conditions are suspected or if the diagnosis is uncertain. Blood tests can rule out rheumatoid arthritis or other forms of arthritis.

It is possible to distinguish osteoarthritis from other joint diseases by considering a number of factors together:

Osteoarthritis usually occurs in older people.

It is usually located in only one or a few joints.

The joints are less inflamed than in other arthritic conditions.

Progression of pain is almost always gradual.

A few of the most common disorders that might be confused with osteoarthritis are rheumatoid arthritis, chondrocalcinosis, and Charcot’s joints.

Treatment and management

There is no known way to prevent osteoarthritis or slow its progression. Some lifestyle changes can reduce or delay symptoms. Treatment often focuses on decreasing pain and improving joint movement. Prevention and treatment measures may include:

Exercises to maintain joint flexibility and improve muscle strength. By strengthening the supporting muscles, tendons, and ligaments, regular weight-bearing exercise helps protect joints, even possibly stimulating growth of the cartilage.

Joint protection, which prevents strain and stress on painful joints.

Heat/cold therapy for temporary pain relief.

Various pain control medications, including corticosteroids and NSAIDs (nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, ibuprofren, and naproxen). For inflamed joints that are not responsive to

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NSAIDS, injectable glucocorticoids may be used. For mild pain without inflammation, acetaminophen may be used.

Weight control, which prevents extra stress on weightbearing joints. One study reported that weight loss seemed to reduce the risk for symptomatic osteoarthritis of the knee in women, and in another, women who lost 11 pounds or more cut their risk for developing osteoarthritis in half.

Surgery may be needed to relieve chronic pain in damaged joints. Osteoarthritis is the most common indication for total joint replacement of the hip and knee.

New treatment findings

Studies have found that estrogen may promote healthy joints in women. Hormone replacement therapy may significantly reduce the risk in postmenopausal women, particularly in the knees.

It has been reported that deficiencies in vitamin D in older people may worsen their condition, so individuals with osteoarthritis should strive to get the recommended 400 IU a day. To protect bones, adults should also consume at least 1,000 mg of calcium daily.

Glucosamine and chondroitin sulfate are popular nutritional supplements that may diminish the symptoms of osteoarthritis. According to some reports, a daily dose of 750–1,500 mg of glucosamine and chondroitin sulfate may result in reduced joint pain, stiffness, and swelling, however these supplements are not approved by the Food and Drug Adminstration as effective treatment of osteoarthritis. A person with osteoarthritis should consult with a doctor before using dietary supplements to treat symptoms.

Prognosis

Osteoarthritis is not life threatening, but quality of life can deteriorate significantly due to the pain and loss of mobility that it causes. Advanced osteoarthritis can force the patient to forgo activities, even walking, unless the condition is alleviated by medication or corrected by surgery.

There is no cure for osteoarthritis, and no treatment alters its progression with any certainty. Only heart disease has a greater impact on work, and 5% of those who leave the work force do so because of osteoarthritis.

Resources

BOOKS

Grelsamer, Ronald P., and Suzanne Loebl, eds. The Columbia

Presbyterian Osteoarthritis Handbook. New York: Macmillan, 1997.

PERIODICALS

Felson, D.T., et al. “Osteoarthritis: New Insights. Part 1: The Disease and Its Risk Factors.” Annals of Internal Medicine 133, no. 8 (2000): 635 .

Felson, D.T., et al. “Osteoarthritis: New Insights. Part 2: Treatment Approaches.” Annals of Internal Medicine 133, no. 9 (2000): 726 .

McAlindon, Tim. “Glucosamine for Osteoarthritis: Dawn of a New Era?” Lancet 357 (January 27, 2001): 247 .

ORGANIZATIONS

Arthritis Foundation. 1330 West Peachtree St., Atlanta, GA 30309. (800) 283-7800. http://www.arthritis.org .

WEBSITES

National Institute of Arthritis and Musculoskeletal and Skin

Diseases. http://www.nih.gov/niams .

The Arthritis Research Institute of America.

http://www.preventarthritis.org .

Jennifer F. Wilson, MS

I Osteogenesis imperfecta

Definition

Osteogenesis imperfecta (OI) is a group of genetic diseases of collagen in which the bones are formed improperly, making them fragile and prone to breaking.

Description

Collagen is a fibrous protein material. It serves as the structural foundation of skin, bone, cartilage, and ligaments. In osteogenesis imperfecta, the collagen produced is abnormal and disorganized. This results in a number of abnormalities throughout the body, the most notable being fragile, easily broken bones.

There are four forms of OI, Types I through IV. Of these, Type II is the most severe, and is usually fatal within a short time after birth. Types I, III, and IV have some overlapping and some distinctive symptoms, particularly weak bones.

Genetic profile

Evidence suggests that OI results from abnormalities in the collagen gene COL1A1 or COL1A2, and possibly abnormalities in other genes. In OI Type I, II, and III, the gene map locus is 17q21.31-q22, 7q22.1, and in OI Type IV, the gene map locus is 17q21.31-q22.

OI is usually inherited as an autosomal dominant condition. In autosomal dominant inheritance, a single

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abnormal gene on one of the autosomal chromosomes (one of the first 22 “non-sex” chromosomes) from either parent can cause the disease. One of the parents will have the disease (since it is dominant) and is the carrier. Only one parent needs to be a carrier in order for the child to inherit the disease. A child who has one parent with the disease has a 50% chance of also being a carrier and having the disease and a 50% chance of not inheriting the dominant gene, and thus not having the disorder.

In OI, the genetic abnormality causes one of two things to occur. It may direct cells to make an altered collagen protein and the presence of this altered collagen causes OI Type II, III, or IV. Alternately, the dominant altered gene may fail to direct cells to make any collagen protein. Although some collagen is produced by instructions from the normal gene, an overall decrease in the total amount of collagen produced results in OI Type I.

If both parents have OI caused by an autosomal dominant gene change, there is a 75% chance that the child will inherit one or both OI genes. In other words, there is a 25% chance the child will inherit only the mother’s OI gene (and the father’s unaffected gene), a 25% chance the child will inherit only the father’s OI gene (and the mother’s unaffected gene), and a 25% chance the child will inherit both parents’ OI genes. Because this situation has been uncommon, the outcome of a child inheriting two OI genes is hard to predict. It is likely that the child would have a severe, possibly lethal, form of the disorder.

About 25% of children with OI are born into a family with no history of the disorder. This occurs when the gene spontaneously mutates in either the sperm or the egg before the child’s conception. No triggers for this type of mutation are known. This is called a new dominant mutation. The child has a 50% chance of passing the disorder on to his or her children. In most cases, when a family with no history of OI has a child with OI, they are not at greater risk than the general population for having a second child with OI, and unaffected siblings of a person with OI are at no greater risk of having children with OI than the general population.

In studies of families into which infants with OI Type II were born, most of the babies had a new dominant mutation in a collagen gene. In some of these families, however, more than one infant was born with OI. Previously, researchers had seen this recurrence as evidence of recessive inheritance of this form of OI. More recently, however, researchers have concluded that the rare recurrence of OI to a couple with a child with autosomal dominant OI is more likely due to gonadal mosaicism. Instead of a mutation occurring in an indi-

K E Y T E R M S

Collagen—The main supportive protein of cartilage, connective tissue, tendon, skin, and bone.

Ligament—A type of connective tissue that connects bones or cartilage and provides support and strength to joints.

Mutation—A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring.

Sclera—The tough white membrane that forms the outer layer of the eyeball.

Scoliosis—An abnormal, side-to-side curvature of the spine.

vidual sperm or egg, it occurs in a percentage of the cells that give rise to a parent’s multiple sperm or eggs. This mutation, present in a percentage of his or her reproductive cells, can result in more than one affected child without affecting the parent with the disorder. An estimated 2–4% of families into which an infant with OI Type II is born are at risk of having another affected child because of gonadal mosaicism.

Demographics

OI affects equal numbers of males and females. It occurs in about one of every 20,000 births.

Signs and symptoms

Type I

This is the most common and mildest type. Among the common features of Type I are the following:

Bones are predisposed to fracture, with most fractures occurring before puberty. People with OI type I typically have about 20–40 fractures before puberty.

Stature is normal or near-normal.

Joints are loose and muscle tone is low.

Usually sclera (whites of the eyes) have blue, purple, or gray tint.

Face shape is triangular.

Tendency toward scoliosis (a curvature of the spine).

Bone deformity is absent or minimal.

Dentinogenesis imperfecta may occur, causing brittle teeth.

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Hearing loss is a possible symptom, often beginning in the early 20s or 30s.

Structure of collagen is normal, but the amount is less than normal.

Type II

Sometimes called the lethal form, Type II is the most severe form of OI. Among the common features of Type II are the following:

Frequently, OI Type II is lethal at or shortly after birth, often as a result of respiratory problems.

Fractures are numerous and bone deformity is severe.

Stature is small with underdeveloped lungs.

Collagen is formed improperly.

Type III

Among the common features of Type III are the following:

Bones fracture easily. Fractures are often present at birth, and x rays may reveal healed fractures that occurred before birth. People with OI Type III may have more than 100 fractures before puberty.

Stature is significantly shorter than normal.

Sclera (whites of the eyes) have blue, purple, or gray tint.

Joints are loose and muscle development is poor in arms and legs.

Rib cage is barrel-shaped.

Face shape is triangular.

Scoliosis (a curvature of the spine) is present.

Respiratory problems are possible.

Bones are deformed and deformity is often severe.

Dentinogenesis imperfecta may occur, causing brittle teeth.

Hearing loss is possible.

Collagen is formed improperly.

Type IV

OI Type IV falls between Type I and Type III in severity. Among the common features of Type IV are the following:

Bones fracture easily, with most fractures occurring before puberty.

Stature is shorter than average.

Sclera (whites of the eyes) are normal in color, appearing white or near-white.

Bone deformity is mild to moderate.

Scoliosis (curvature of the spine) is likely.

Rib cage is barrel-shaped.

Face is triangular in shape.

Dentinogenesis imperfecta may occur, causing brittle teeth.

Hearing loss is possible.

Collagen is formed improperly.

Diagnosis

It is often possible to diagnose OI solely on clinical features and x ray findings. Collagen or DNA tests may help confirm a diagnosis of OI. These tests generally require several weeks before results are known. Approximately 10–15% of individuals with mild OI who have collagen testing, and approximately 5% of those who have genetic testing, test negative for OI despite having the disorder.

Diagnosis is usually suspected when a baby has bone fractures after having suffered no apparent injury. Another indication is small, irregular, isolated bones in the sutures between the bones of the skull (wormian bones). Sometimes the bluish sclera serves as a diagnostic clue. Unfortunately, because of the unusual nature of the fractures occurring in a baby who cannot yet move, some parents have been accused of child abuse before the actual diagnosis of osteogenesis imperfecta was reached.

Prenatal diagnosis

Testing is available to assist in prenatal diagnosis. Women with OI who become pregnant, or women who conceive a child with a man who has OI, may wish to explore prenatal diagnosis. Because of the relatively small risk (2–4%) of recurrence of OI Type II in a family, families may opt for ultrasound studies to determine if a developing fetus has the disorder.

Ultrasound is the least invasive procedure for prenatal diagnosis, and carries the least risk. Using ultrasound, a doctor can examine the fetus’s skeleton for bowing of the leg or arm bones, fractures, shortening, or other bone abnormalities that may indicate OI. Different forms of OI may be detected by ultrasound in the second trimester. The reality is that when it occurs as a new dominant mutation, it is found inadvertantly on ultrasound, and it may be difficult to know the diagnosis until after delivery since other genetic conditions can cause bowing and/or fractures prenatally.

Chorionic villus sampling is a procedure to obtain chorionic villi tissue for testing. Examination of fetal collagen proteins in the tissue can reveal information about the quantitative or qualitative collagen changes that lead

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to OI. When a parent has OI, it is necessary for the affected parent to have the results of his or her own collagen test available. Chorionic villus sampling can be performed at 10–12 weeks of pregnancy.

Amniocentesis is a procedure that involves inserting a thin needle into the uterus, into the amniotic sac, and withdrawing a small amount of amniotic fluid. DNA can be extracted from the fetal cells contained in the amniotic fluid and tested for the specific mutation known to cause OI in that family. This technique is useful only when the mutation causing OI in a particular family has been identified through previous genetic testing of affected family members, including previous pregnancies involving a baby with OI. Amniocentesis is performed at 16–18 weeks of pregnancy.

Treatment and management

There are no treatments available to cure OI, nor to prevent most of its complications. Most treatments are aimed at correcting the fractures and bone abnormalities caused by OI. Splints, casts, braces, and rods are all used. Rodding refers to a surgical procedure in which a metal rod is implanted within a bone (usually the long bones of the thigh and leg). This is done when bowing or repeated fractures of these bones has interfered with a child’s ability to begin to walk.

Other treatments include hearing aids and early capping of teeth. Patients may require the use of a walker or wheelchair. Pain may be treated with a variety of medications. Exercise is encouraged as a means to promote muscle and bone strength. Swimming is a form of exercise that puts a minimal amount of strain on muscles, joints, and bones. Walking is encouraged for those who are able.

Smoking, excessive alcohol and caffeine consumption, and steroid medications may deplete bone and increase bone fragility.

Alternative treatment such as acupuncture, naturopathic therapies, hypnosis, relaxation training, visual imagery, and biofeedback have all been used to try to decrease the constant pain of fractures.

Prognosis

Lifespan for people with OI Type I, III, and IV is not generally shortened. The prognosis for people with these types of OI is quite variable, depending on the severity of the disorder and the number and severity of the fractures and bony abnormalities.

Fifty percent of all babies with OI Type II are stillborn. The rest of these babies usually die within a very short time after birth. In recent years, some people with Type II have lived into young adulthood.

Osteogenesis Imperfecta, radiograph of the left leg. X ray showing light spot and poor bone formation. Photo by Joseph R. Siebert, Ph. D. (Custom Medical Stock Photo, Inc.)

Resources

BOOKS

Hall, Bryan D. “Inherited Osteoporoses.” In Nelson Textbook of

Pediatrics, edited by Richard Behrman. Philadelphia:

W.B. Saunders Co., 1996.

PERIODICALS

Kocher, M. S., and F. Shapiro. “Osteogenesis imperfecta.”

Journal of the American Academy of Orthopedic Surgery

6 (July-August 1998): 225 .

Kocher, M. S., and J. R. Kasser. “Orthopaedic aspects of child abuse.” Journal of the American Academy of Orthopedic

Surgery 8 (January-February 2000):10 .

Marini, Joan C. “Osteogenesis imperfecta: Managing brittle bones.” New England Journal of Medicine 339 (October 1, 1998): 986 .

Niyibizi, C., et al. “Potential of gene therapy for treating osteogenesis imperfecta.” Clinical Orthopedics 379 (October 2000): S126 .

Paterson, Colin, et al. “Life Expectancy in Osteogenesis Imperfecta.” British Medical Journal 312 (February 10, 1997): 351.

Smith, R. “Severe osteogenesis imperfecta: New therapeutic options?” British Medical Journal 322 (January 13, 2001): 63 .

Wacaster, Priscilla. “Osteogenesis Imperfecta.” Exceptional Parent 30 (April 2000): 94 .

ORGANIZATIONS

Children’s Brittle Bone Foundation. 7701 95th St., Pleasant Prairie, WI 53158. (847) 433-498. http://www.cbbf

.org .

WEBSITES

“Osteogenesis Imperfecta.” National Institutes of Health

Osteoporosis and Related Bone Diseases–National

Resource Center. http://www.osteo.org/oi.html .

Jennifer F. Wilson, MS

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