Your connective tissue supports many different parts of your body, such as your skin, eyes, and heart. It is like a "cellular glue" that gives your body parts their shape and helps keep them strong. It also helps some of your tissues do their work. It is made of many kinds of proteins. Cartilage and fat are types of connective tissue.

Over 200 disorders that impact connective tissue. There are different types:

• Genetic disorders, such as Ehlers-Danlos syndrome, Marfan syndrome, and osteogenesis imperfecta
• Autoimmune disorders, such as lupus and scleroderma
• Cancers, like some types of soft tissue sarcoma

Each disorder has its own symptoms and needs different treatment.

Cartilage is the tough but flexible tissue that covers the ends of your bones at a joint. It also gives shape and support to other parts of your body, such as your ears, nose and windpipe. Healthy cartilage helps you move by allowing your bones to glide over each other. It also protects bones by preventing them from rubbing against each other.

Injured, inflamed, or damaged cartilage can cause symptoms such as pain and limited movement. It can also lead to joint damage and deformity. Causes of cartilage problems include

• Tears and injuries, such as sports injuries
• Genetic factors
• Other disorders, such as some types of arthritis

Osteoarthritis results from breakdown of cartilage.

This is a supportive connective tissue with a flexible rubbery matrix. The cells that secrete the matrix are called chondroblasts. The chondroblasts surround themselves with the matrix until they become trapped in little cavities called lacunae. Then they are called chondrocytes.

Cartilages do not have blood vessels except when transforming into bone. Nutrition and waste removal therefore depend on slow diffusion through the matrix from/to blood vessels in the dense irregular connective tissue membrane (perichondrium) surrounding it. Chondrocytes thus have slow rates of metabolism and cell division. Injured cartilages therefore heal slowly.

The matrix contains collagen fibres which give cartilages their flexibility and strength.

Cartilages are divided into three types: hyaline cartilage, elastic cartilage and fibrocartilage.

HYALINE CARTILAGE

Hyaline cartilage has a clear glassy blue-white appearance, arising from the invisible fineness of its collagen fibres. It is the most abundant type of cartilage. It covers the ends of bones where bones form joints (articular surfaces) and forms the cartilage rings of the respiratory tract (larynx, trachea and bronchi). It also forms the costal cartilages which attach the ribs to the sternum and the epiphyseal plates (growth plates) of bones and the embryonic skeleton. The tip of the nose is also supported by hyaline cartilage.

Hyaline cartilage provides support and some flexibility.

ELASTIC CARTILAGE

Elastic cartilage contains conspicuous elastic fibres among bundles of collagen fibres. It provides rigidity with even more flexibility than hyaline cartilage. It is found in the external ear, epiglottis and auditory tube.

FIBROCARTILAGE

Fibrocartilage contains coarse, readily visible bundles of collagen. It has more collagen fibres than hyaline cartilage. It is found in the discs between vertebrae, the symphysis pubis (joint between the public bones). It is somewhat flexible and capable of withstanding considerable pressure. There is no perichondrium around the fibrocartilage.

Cartilage Templates

Bone is a replacement tissue; that is, it uses a model tissue on which to lay down its mineral matrix. For skeletal development, the most common template is cartilage. During fetal development, a framework is laid down that determines where bones will form. This framework is a flexible, semi-solid matrix produced by chondroblasts and consists of hyaluronic acid, chondroitin sulfate, collagen fibers, and water. As the matrix surrounds and isolates chondroblasts, they are called chondrocytes. Unlike most connective tissues, cartilage is avascular, meaning that it has no blood vessels supplying nutrients and removing metabolic wastes. All of these functions are carried on by diffusion through the matrix. This is why damaged cartilage does not repair itself as readily as most tissues do.

Throughout fetal development and into childhood growth and development, bone forms on the cartilaginous matrix. By the time a fetus is born, most of the cartilage has been replaced with bone. Some additional cartilage will be replaced throughout childhood, and some cartilage remains in the adult skeleton.

Intramembranous Ossification

During intramembranous ossification, compact and spongy bone develops directly from sheets of mesenchymal (undifferentiated) connective tissue. The flat bones of the face, most of the cranial bones, and the clavicles (collarbones) are formed via intramembranous ossification.

The process begins when mesenchymal cells in the embryonic skeleton gather together and begin to differentiate into specialized cells (Figure 6.16a). Some of these cells will differentiate into capillaries, while others will become osteogenic cells and then osteoblasts. Although they will ultimately be spread out by the formation of bone tissue, early osteoblasts appear in a cluster called an ossification center.

The osteoblasts secrete osteoid, uncalcified matrix, which calcifies (hardens) within a few days as mineral salts are deposited on it, thereby entrapping the osteoblasts within. Once entrapped, the osteoblasts become osteocytes (Figure 6.16b). As osteoblasts transform into osteocytes, osteogenic cells in the surrounding connective tissue differentiate into new osteoblasts.

Osteoid (unmineralized bone matrix) secreted around the capillaries results in a trabecular matrix, while osteoblasts on the surface of the spongy bone become the periosteum (Figure 6.16c). The periosteum then creates a protective layer of compact bone superficial to the trabecular bone. The trabecular bone crowds nearby blood vessels, which eventually condense into red marrow (Figure 6.16d).

Figure 6.16 Intramembranous Ossification Intramembranous ossification follows four steps. (a) Mesenchymal cells group into clusters, and ossification centers form. (b) Secreted osteoid traps osteoblasts, which then become osteocytes. (c) Trabecular matrix and periosteum form. (d) Compact bone develops superficial to the trabecular bone, and crowded blood vessels condense into red marrow.

Intramembranous ossification begins in utero during fetal development and continues on into adolescence. At birth, the skull and clavicles are not fully ossified nor are the sutures of the skull closed. This allows the skull and shoulders to deform during passage through the birth canal. The last bones to ossify via intramembranous ossification are the flat bones of the face, which reach their adult size at the end of the adolescent growth spurt.

Endochondral Ossification

In endochondral ossification, bone develops by replacing hyaline cartilage. Cartilage does not become bone. Instead, cartilage serves as a template to be completely replaced by new bone. Endochondral ossification takes much longer than intramembranous ossification. Bones at the base of the skull and long bones form via endochondral ossification.

In a long bone, for example, at about 6 to 8 weeks after conception, some of the mesenchymal cells differentiate into chondrocytes (cartilage cells) that form the cartilaginous skeletal precursor of the bones (Figure 6.17a). Soon after, the perichondrium, a membrane that covers the cartilage, appears Figure 6.17b).

Figure 6.17 Endochondral Ossification Endochondral ossification follows five steps. (a) Mesenchymal cells differentiate into chondrocytes. (b) The cartilage model of the future bony skeleton and the perichondrium form. (c) Capillaries penetrate cartilage. Perichondrium transforms into periosteum. Periosteal collar develops. Primary ossification center develops. (d) Cartilage and chondrocytes continue to grow at ends of the bone. (e) Secondary ossification centers develop. (f) Cartilage remains at epiphyseal (growth) plate and at joint surface as articular cartilage.

As more matrix is produced, the chondrocytes in the center of the cartilaginous model grow in size. As the matrix calcifies, nutrients can no longer reach the chondrocytes. This results in their death and the disintegration of the surrounding cartilage. Blood vessels invade the resulting spaces, not only enlarging the cavities but also carrying osteogenic cells with them, many of which will become osteoblasts. These enlarging spaces eventually combine to become the medullary cavity.

As the cartilage grows, capillaries penetrate it. This penetration initiates the transformation of the perichondrium into the bone-producing periosteum. Here, the osteoblasts form a periosteal collar of compact bone around the cartilage of the diaphysis. By the second or third month of fetal life, bone cell development and ossification ramps up and creates the primary ossification center, a region deep in the periosteal collar where ossification begins (Figure 6.17c).

While these deep changes are occurring, chondrocytes and cartilage continue to grow at the ends of the bone (the future epiphyses), which increases the bone’s length at the same time bone is replacing cartilage in the diaphyses. By the time the fetal skeleton is fully formed, cartilage only remains at the joint surface as articular cartilage and between the diaphysis and epiphysis as the epiphyseal plate, the latter of which is responsible for the longitudinal growth of bones. After birth, this same sequence of events (matrix mineralization, death of chondrocytes, invasion of blood vessels from the periosteum, and seeding with osteogenic cells that become osteoblasts) occurs in the epiphyseal regions, and each of these centers of activity is referred to as a secondary ossification center (Figure 6.17e).

How Bones Grow in Length

The epiphyseal plate is the area of growth in a long bone. It is a layer of hyaline cartilage where ossification occurs in immature bones. On the epiphyseal side of the epiphyseal plate, cartilage is formed. On the diaphyseal side, cartilage is ossified, and the diaphysis grows in length. The epiphyseal plate is composed of four zones of cells and activity (Figure 6.18). The reserve zone is the region closest to the epiphyseal end of the plate and contains small chondrocytes within the matrix. These chondrocytes do not participate in bone growth but secure the epiphyseal plate to the osseous tissue of the epiphysis.

Figure 6.18 Longitudinal Bone Growth The epiphyseal plate is responsible for longitudinal bone growth.

The proliferative zone is the next layer toward the diaphysis and contains stacks of slightly larger chondrocytes. It makes new chondrocytes (via mitosis) to replace those that die at the diaphyseal end of the plate. Chondrocytes in the next layer, the zone of maturation and hypertrophy, are older and larger than those in the proliferative zone. The more mature cells are situated closer to the diaphyseal end of the plate. The longitudinal growth of bone is a result of cellular division in the proliferative zone and the maturation of cells in the zone of maturation and hypertrophy.

Most of the chondrocytes in the zone of calcified matrix, the zone closest to the diaphysis, are dead because the matrix around them has calcified. Capillaries and osteoblasts from the diaphysis penetrate this zone, and the osteoblasts secrete bone tissue on the remaining calcified cartilage. Thus, the zone of calcified matrix connects the epiphyseal plate to the diaphysis. A bone grows in length when osseous tissue is added to the diaphysis.

Bones continue to grow in length until early adulthood. The rate of growth is controlled by hormones, which will be discussed later. When the chondrocytes in the epiphyseal plate cease their proliferation and bone replaces the cartilage, longitudinal growth stops. All that remains of the epiphyseal plate is the epiphyseal line (Figure 6.19).

Figure 6.19 Progression from Epiphyseal Plate to Epiphyseal Line As a bone matures, the epiphyseal plate progresses to an epiphyseal line. (a) Epiphyseal plates are visible in a growing bone. (b) Epiphyseal lines are the remnants of epiphyseal plates in a mature bone.

How Bones Grow in Diameter

While bones are increasing in length, they are also increasing in diameter; growth in diameter can continue even after longitudinal growth ceases. This is called appositional growth. Osteoclasts resorb old bone that lines the medullary cavity, while osteoblasts, via intramembranous ossification, produce new bone tissue beneath the periosteum. The erosion of old bone along the medullary cavity and the deposition of new bone beneath the periosteum not only increase the diameter of the diaphysis but also increase the diameter of the medullary cavity. This process is called modeling.

Bone Remodeling

The process in which matrix is resorbed on one surface of a bone and deposited on another is known as bone modeling. Modeling primarily takes place during a bone’s growth. However, in adult life, bone undergoes remodeling, in which resorption of old or damaged bone takes place on the same surface where osteoblasts lay new bone to replace that which is resorbed. Injury, exercise, and other activities lead to remodeling. Those influences are discussed later in the chapter, but even without injury or exercise, about 5 to 10 percent of the skeleton is remodeled annually just by destroying old bone and renewing it with fresh bone.

Ehlers-Danlos syndrome (EDS) is a group of inherited disorders that weaken connective tissues. Connective tissues are proteins that support skin, bones, blood vessels, and other organs.

EDS usually affects your skin, joints and blood vessel walls. Symptoms include

• Loose joints
• Fragile, small blood vessels
• Abnormal scar formation and wound healing
• Soft, velvety, stretchy skin that bruises easily

There are several types of EDS. They can range from mild to life-threatening. About 1 in 5,000 people has EDS. There is no cure. Treatment involves managing symptoms, often with medicines and physical therapy. It also includes learning how to protect your joints and prevent injuries.

What is lupus?

Lupus is an autoimmune disease. This means that your immune system attacks healthy cells and tissues by mistake. This can damage many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels, and brain.

There are several kinds of lupus

• Systemic lupus erythematosus (SLE) is the most common type. It can be mild or severe and can affect many parts of the body.
• Discoid lupus causes a red rash that doesn't go away
• Subacute cutaneous lupus causes sores after being out in the sun
• Drug-induced lupus is caused by certain medicines. It usually goes away when you stop taking the medicine.
• Neonatal lupus, which is rare, affects newborns. It is probably caused by certain antibodies from the mother.

What causes lupus?

The cause of lupus is unknown.

Who is at risk for lupus?

Anyone can get lupus, but women are most at risk. Lupus is two to three times more common in African American women than in Caucasian women. It's also more common in Hispanic, Asian, and Native American women. African American and Hispanic women are more likely to have severe forms of lupus.

What are the symptoms of lupus?

Lupus can have many symptoms, and they differ from person to person. Some of the more common ones are

• Pain or swelling in joints
• Muscle pain
• Fever with no known cause
• Red rashes, most often on the face (also called the "butterfly rash")
• Chest pain when taking a deep breath
• Hair loss
• Pale or purple fingers or toes
• Sensitivity to the sun
• Swelling in legs or around eyes
• Mouth ulcers
• Swollen glands
• Feeling very tired

Symptoms may come and go. When you are having symptoms, it is called a flare. Flares can range from mild to severe. New symptoms may appear at any time.

How is lupus diagnosed?

There is no specific test for lupus, and it's often mistaken for other diseases. So it may take months or years for a doctor to diagnose it. Your doctor may use many tools to make a diagnosis:

• Medical history
• Complete exam
• Blood tests
• Skin biopsy (looking at skin samples under a microscope)
• Kidney biopsy (looking at tissue from your kidney under a microscope)

What are the treatments for lupus?

There is no cure for lupus, but medicines and lifestyle changes can help control it.

People with lupus often need to see different doctors. You will have a primary care doctor and a rheumatologist (a doctor who specializes in the diseases of joints and muscles). Which other specialists you see depends on how lupus affects your body. For example, if lupus damages your heart or blood vessels, you would see a cardiologist.

Your primary care doctor should coordinate care between your different health care providers and treat other problems as they come up. Your doctor will develop a treatment plan to fit your needs. You and your doctor should review the plan often to be sure it is working. You should report new symptoms to your doctor right away so that your treatment plan can be changed if needed.

The goals of the treatment plan are to

• Prevent flares
• Treat flares when they occur
• Reduce organ damage and other problems

Treatments may include drugs to

• Reduce swelling and pain
• Prevent or reduce flares
• Help the immune system
• Reduce or prevent damage to joints
• Balance the hormones

Besides taking medicines for lupus, you may need to take medicines for problems that are related to lupus such as high cholesterol, high blood pressure, or infection.

Alternative treatments are those that are not part of standard treatment. At this time, no research shows that alternative medicine can treat lupus. Some alternative or complementary approaches may help you cope or reduce some of the stress associated with living with a chronic illness. You should talk to your doctor before trying any alternative treatments.

How can I cope with lupus?

It is important to take an active role in your treatment. It helps to learn more about lupus - being able to spot the warning signs of a flare can help you prevent the flare or make the symptoms less severe.

It is also important to find ways to cope with the stress of having lupus. Exercising and finding ways to relax may make it easier for you to cope. A good support system can also help.

Marfan syndrome is a disorder that affects connective tissue. Connective tissues are proteins that support skin, bones, blood vessels, and other organs. One of these proteins is fibrillin. A problem with the fibrillin gene causes Marfan syndrome.

Marfan syndrome can be mild to severe, and the symptoms can vary. People with Marfan syndrome are often very tall, thin, and loose jointed. Most people with Marfan syndrome have heart and blood vessel problems, such as a weakness in the aorta or heart valves that leak. They may also have problems with their bones, eyes, skin, nervous system, and lungs.

There is no single test to diagnose Marfan syndrome. Your doctor may use your medical history, family history, and a physical exam to diagnose it. Marfan syndrome has no cure, but treatments can help delay or prevent complications. Treatments include medicines, surgery, and other therapies.

Osteogenesis imperfecta (OI) is a genetic disorder in which bones break easily. Sometimes the bones break for no known reason. OI can also cause weak muscles, brittle teeth, a curved spine, and hearing loss. OI is caused by one of several genes that aren't working properly. When these genes don't work, it affects how you make collagen, a protein that helps make bones strong.

OI can range from mild to severe, and symptoms vary from person to person. A person may have just a few or as many as several hundred fractures in a lifetime.

No single test can identify OI. Your doctor uses your medical and family history, physical exam, and imaging and lab tests to diagnose it. Your doctor may also test your collagen (from skin) or genes (from blood). There is no cure, but you can manage symptoms. Treatments include exercise, pain medicine, physical therapy, wheelchairs, braces, and surgery.

OI, or “brittle bone disease,” is a condition causing fragile bones that break easily, sometimes for no obvious reason. Some people with OI have only a few fractures in their lifetimes. Others have hundreds. People who have severe forms of OI have fragile bones that are also deformed. Most people with OI experience physical disability. OI also can cause weak muscles, brittle teeth, a curved spine, and hearing loss. Most forms of OI are caused by abnormal genes that are passed down from one or both parents to their children.

There are currently 11 types of OI. Types I through IV are the most common. They are autosomal dominant forms of the disease. Autosomal dominance is a pattern of inheritance common to some genetic diseases. “Autosomal” means that the abnormal gene is located on one of the numbered, or non-sex, chromosomes. “Dominant” means that a single copy of the abnormal gene is enough to cause the disease; in other words, a person only needs to get the abnormal gene from one parent in order to inherit the disease, even though the matching gene from the other parent is normal. This is in contrast to an autosomal recessive disorder, where two copies of the mutation are needed to cause the disease; in other words, a person must inherit the abnormal gene from both parents in order to inherit the disease. Types VI through XI are autosomal recessive.

Osteogenesis imperfecta is a genetic disorder that causes a person's bones to break easily, often from little or no apparent trauma.

What is Osteogenesis imperfecta?

Osteogenesis imperfecta (OI) is a genetic disorder that causes a person's bones to break easily, often from little or no apparent trauma. OI is also called "brittle bone disease." OI varies in severity from person to person, ranging from a mild type to a severe type that causes death before or shortly after birth. In addition to having fractures, people with OI also have teeth problems (dentinogenesis imperfecta), and hearing loss when they are adults. People who have OI may also have muscle weakness, loose joints (joint laxity) and skeletal malformations.

OI occurs in approximately 1 in 20,000 individuals, including people diagnosed after birth. OI occurs with equal frequency among males and females and among racial and ethnic groups. Life expectancy varies depending on how severe the OI is, ranging from very brief (lethal form, OI type II) to average.

There are four well-known types of OI. These types are distinguished mostly by fracture frequency and severity and by characteristic features. Three additional types of OI (type V, VI and VII) have also been identified.

The vast majority (90 percent) of OI is caused by a single dominant mutation in one of two type I collagen genes: COL1A1 or COL1A2.The COL1A1 and COL1A2 genes provide instructions for making proteins that are used to create a larger molecule called type I collagen. This type of collagen is the most common protein in bone, skin and other tissues that provide structure and strength to the body (connective tissues). OI type VII is caused by recessive mutations in the CRTAP gene.

What are the symptoms of Osteogenesis imperfecta?

Osteogenesis imperfecta (OI) causes bones to be fragile and easily broken and is also responsible for other health problems.

Type I OI is the mildest form of the condition. People who have type I OI have bone fractures during childhood and adolescence often due to minor trauma When these individuals reach adulthood they have fewer fractures.

Type II OI is the most severe form of OI. Infants with type II have bones that appear bent or crumpled and fractured before birth. Their chest is narrow and they have fractured and misshapen ribs and underdeveloped lungs. These infants have short, bowed arms and legs; hips that turn outward; and unusually soft skull bones. Most infants with type II OI are stillborn or die shortly after birth, usually from breathing failure.

Type III OI also has relatively severe signs and symptoms. Infants with OI type III have very soft and fragile bones that may begin to fracture before birth or in early infancy. Some infants have rib fractures that can cause life-threatening problems with breathing. Bone abnormalities tend to get worse over time and often interfere with the ability to walk.

Type IV OI is the most variable form OI. Symptoms of OI type IV can range from mild to severe. About 25 percent of infants with OI type IV are born with bone fractures. Others may not have broken bones until later in childhood or adulthood. Infants with OI type IV have leg bones that are bowed at birth, but bowing usually lessens as they get older.

Some types of OI are also associated with progressive hearing loss, a blue or grey tint to the part of the eye that is usually white (the sclera), teeth problems (dentinogenesis imperfecta), abnormal curvature of the spine (scoliosis) and loose joints. People with this condition may have other bone abnormalities and are often shorter in stature than average.

How is Osteogenesis imperfecta diagnosed?

OI is often inherited from an affected parent. The diagnosis of OI is made on the basis of family history and/or clinical presentation. Frequent fractures, short stature, a blue hue to the white part of the eye (blue sclera), teeth problems (dentinogenesis imperfecta) and hearing loss that progresses after puberty may be present.

X-rays are also used to diagnose OI. X-ray findings include fractures that are at different stages of healing; an unexpected skull bone pattern called Wormian bones; and bones in the spine called "codfish vertebrae."

Laboratory testing for OI may include either biochemical testing or DNA-based sequencing of COL1A1 and COL1A2. Biochemical testing involves studying collagens taken from a small skin biopsy. Changes in type I collagen are an indication of OI.

DNA sequencing of COL1A1 and COL1A2 is used to identify the type I collagen gene mutation responsible for the altered collagen protein. DNA testing requires a blood sample for DNA extraction. Both tests are relatively sensitive, detecting approximately 90 percent and 95 percent, respectively, of individuals with the clinical diagnosis of OI. Normal biochemical and molecular testing in a child with OI warrants additional testing of less common collagen genes (CRTAP and P3H (LEPRE1)) responsible for some of the rare recessive forms of OI.

What is the treatment for Osteogenesis imperfecta?

There is currently no cure for OI. Treatment involves supportive therapy to decrease the number of fractures and disabilities, help with independent living and maintain overall health. OI is best managed by a medical team including the child's own doctor, and genetic, orthopedic and rehabilitation medicine. Supportive therapy is unique to each individual depending on the severity of their condition and their age.

Physical and occupational therapies to help improve their ability to move, to prevent fractures and to increase muscle strength are often useful.

Fractures are treated as they would be in children and adults who do not have OI. An orthopedic treatment called intramedullary rodding (placing rods in the bones) is used to help with positioning of legs that helps with more normal functioning when necessary.

A newer treatment with medication called biophosphonates is being used to help with bone formation and to decrease the need for surgery.

Is Osteogenesis imperfecta inherited?

Most types of OI are 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. 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.

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.

Overview of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic or heritable disease in which bones fracture (break) easily, often with no obvious cause or injury. OI is also known as brittle bone disease, and the symptoms can range from mild with only a few fractures to severe with many medical complications.

What Happens in OI?

For most people, a change or defect in the genes that carry the instructions for making type I collagen causes OI. Type I collagen is a material in bones that helps make them strong. The defect in the genes causes the body to make collagen incorrectly or not make enough, leading to weak bones that break more easily. There is no way to prevent the disease.

Who Gets Osteogenesis Imperfecta?

Though anyone can be born with OI, people with a family history of the disease are at greater risk of inheriting the disease through an abnormal gene that is passed on from one or both parents. Genetic counselors can help you better understand the genetics of OI.

Types of Osteogenesis Imperfecta

There are several types of OI, and different classifications are used based on the severity of the disease or on the nature of the underlying gene defect . Type I is the mildest and most common form of OI. Type II is the most severe form of OI. Other types of OI have symptoms that fall between Type I and Type II. Following is an overview of the types most often diagnosed. The remaining types are rare and still being studied.

Type I

• Bones likely to break from mild to moderate trauma, with most broken bones occurring before puberty.
• No change or only slight changes to stature with aging.
• Loose joints and muscle weakness.
• Blue, purple, or gray tint to sclera (whites of the eyes).
• Triangular face.
• Curved spine with potential for compression of the vertebrae (spine bones) with aging.
• Mild or no bone deformity.
• Possible changes to the strength and color of teeth.
• Possible hearing loss.
• Normal collagen structure, but less than the normal amount.

Type II

• Frequently causes death at birth or shortly after, because of the inability to breathe.
• Numerous broken bones that develop before birth while the baby is still in the womb.
• Severe bone deformities.
• Very small stature.
• Underdeveloped lungs.
• Blue, purple, or gray tint to sclera.
• Improperly formed collagen.

Type III

• Most severe type among those who survive the neonatal period and usually results in the greatest number of physical disabilities.
• Easily broken bones with very little trauma over a lifetime. (Broken bones are often present at birth, and x-rays may reveal healed bone breaks that occurred before birth.)
• Small stature.
• Blue, purple, or gray tint to sclera.
• Loose joints.
• Poor muscle development in arms and legs.
• Barrel-shaped rib cage.
• Triangular face.
• Curved spine and compression or collapse of vertebrae.
• Possible lung problems that worsen with age.
• Often severe bone deformity.
• Possible changes to the strength and color of teeth.
• Possible hearing loss.
• Improperly formed collagen.

Type IV

• Bones break easily, sometimes before birth, with most broken bones occurring before puberty.
• Smaller than average stature.
• White or blue tint to sclera.
• Mild to moderate bone deformity.
• Vertebra compression or collapse.
• Barrel-shaped rib cage.
• Triangular face.
• Possible changes to strength and color of teeth.
• Possible hearing loss.
• Improperly formed collagen.

Type V

• Clinically similar to Type IV OI in appearance and symptoms.
• A dense band seen on x-rays by the cartilage growth plate of the long bones.
• Unusually large calluses, called hypertrophic calluses, at the sites of fractures or surgical procedures. (A callus is an area of new bone that is laid down at the fracture site as part of the healing process.)
• Calcification of the membrane between the radius and ulna (the bones of the forearm), which results in restricted arm movement.
• Possible loose joints.
• White sclera.
• No changes to teeth.
• “Mesh-like” appearance to bone when viewed under the microscope.
• Changes in the minerals in the bone.

Type VI

• Resembles Type IV OI in appearance and symptoms.
• Not always diagnosed at birth, and symptoms progress over time.
• “Fish-scale” appearance to bone when viewed under the microscope.
• Curved spine.
• Diagnosed by bone biopsy or genetic studies.
• Changes in the minerals in the bone.

Type VII

• Resembles Type II and Type III OI in appearance and symptoms.
• White sclera.
• Small stature.
• Short humerus (upper arm bone) and short femur (upper leg bone).
• Possible smaller head size.
• Changes in the process of forming collagen.

Type VIII

• Resembles Type II and Type III OI in appearance and symptoms.
• White sclera.
• Small stature.
• Short humerus (upper arm bone) and short femur (upper leg bone).
• Possible smaller head size.
• Changes in the process of forming collagen.

There are rarer types of the disease, and in general they are moderately severe forms. These types are similar to OI types III or IV. Some of these rare forms do not affect the structure of collagen but instead affect the function of bone-forming cells.

Symptoms of Osteogenesis Imperfecta

All people with OI have weak, brittle bones. Some people with OI may have only a few broken bones over their lifetime. Others may have hundreds of broken bones in their lifetime, including broken bones that occur before birth.

People with OI may have other symptoms, which can range from mild to severe and vary from person to person. These include:

• Malformed or bowing of long bones.
• Small stature.
• Skin that bruises easily.
• Loose joints.
• Weak muscles.
• Whites of the eyes (sclera) that look blue, purple, or gray.
• A face shaped like a triangle.
• A rib cage shaped like a barrel.
• A curved spine.
• Collapse or compression of the vertebrae in the spine.
• Brittle, misshapen, or discolored teeth.
• Hearing loss.
• Breathing problems.
• A deformed hip joint in which the neck of the femur is bent downward, a condition called coxa vara.

Causes of Osteogenesis Imperfecta

A mutation or change in a gene causes OI. Genes carry information that determines which features are passed to you from your parents. We have two copies of most of our genes, one from each parent.

People with OI have a gene that carries incorrect instructions for making collagen, a substance that makes bones strong. The gene causes the body to not make enough collagen or the collagen does not work properly. This leads to weak bones that break easily.

Most people with OI inherit this gene from one parent. In other forms, the child has to inherit a mutation in a gene from both parents. Parents do not have to have OI to pass on the gene that causes it. Sometimes, neither parent passes on the gene. Instead, the gene stops working properly on its own before the child is born.

Dominant OI

Most people with OI have a dominant form. This means they inherit one normal copy and one copy of the gene that causes OI. The abnormal copy of the gene is stronger or “dominant” over the normal copy of the gene. This causes a person to have OI. A person with a dominant mutation has a 50-percent chance (1 in 2) of passing on the disorder to each of his or her children. Some children with the dominant form of OI inherit a gene that causes OI from a parent. While others are born with the dominant form of OI even though there is no family history of the disorder and the mutation occurs in their genome for the first time in the family.

Recessive OI

Some people with OI have a recessive form of the disease. People with recessive OI have parents who do not have OI but who both have an abnormal gene that causes the disease. When both parents carry the recessive gene for OI, there is a 25% chance (1 out of 4) per pregnancy of having a child with the disease. Unaffected or asymptomatic siblings of a person with recessive OI have a two-thirds chance (2 out of 3) of carrying an abnormal gene that causes OI, making them carriers of the disease. If one parent has OI because of a recessive mutation, all of their children will carry an abnormal gene that causes OI but will not necessarily have OI.

Diagnosis of Osteogenesis Imperfecta

Doctors may diagnose OI by:

• Asking about family and medical history.
• Completing a physical exam.
• Ordering x-rays and bone density tests.

In addition, doctors can also diagnose OI and identify the type of OI with a genetic blood test that detects the changed in the inherited gene. These tests can detect OI in most people who have it. Sometimes, additional genetic testing may be necessary. People who have genetic testing should see a specialist or genetic counselor to help them understand the test results.

Treatment of Osteogenesis Imperfecta

There is no cure for OI. The goal of treatment, depending on the type of OI, is to prevent or control symptoms, increase bone mass and muscle strength, and maximize a person’s ability to be independent. These treatments include:

Physical or Occupational Therapy

People with OI may benefit from physical or occupational therapy, which can help the person:

• Build muscle strength; improve joint movement, mobility, and gross motor skills; and prevent broken bones.
• Learn how to avoid injuries.
• Safely perform activities of daily living.
• Recover from broken bones.

Therapists and doctors also may recommend swimming to condition and build strength.

Medicines

Although there are no medicines approved by the U.S. Food and Drug Administration to treat OI, your doctor may recommend a therapy approved for a related condition. Your doctor may prescribe:

• Bone strengthening medicines approved to treat other bone diseases can help slow bone loss and reduce the frequency and seriousness of broken bones.
• Pain medicines to treat pain caused by broken bones and chronic bone pain.

In addition, some medicines are currently being studied to help prevent the complications of or to treat OI in adults and children. Talk to your primary care provider or your child’s pediatrician about the using these medicines or participating in studies.

Bone Care

An orthopaedic specialist can treat broken bones with a cast, splint, or brace. Sometimes people need surgery to repair a broken bone.

In addition, doctors perform surgery to support or correct bones that are curved or bowed, including the spine. Many children with OI have rodding surgery, in which a metal rod is placed into a bone. Rodding surgery is performed to support the bone and prevent the bone from breaking. Some of these rods are “telescoping” and can be adjusted to lengthen as a child with OI grows.

Mobility Aids

Using a mobility aid may help people safely perform daily activities and reduce injuries. These aids include:

• Walkers.
• Canes and crutches.
• Braces or prosthetics.
• Wheelchairs.

Oral and Dental Care

Some people with OI have:

• Teeth that easily chip or break.
• Changes in tooth color and shape.
• Tooth decay.
• Small jaw size.
• Incorrect position of teeth.

Regular dental check-ups and care are important to prevent dental symptoms and improve bite, alignment and appearance of teeth. In addition, some people need to see:

• Oral-maxillofacial surgeon, who specializes in oral and jaw surgery.
• Orthodontist, who treats tooth alignment and jaw position.

Hearing

Doctors recommend hearing testing beginning in childhood, with regular testing throughout the person’s life. It’s important to see an audiologist who specializes in caring for people with OI. Treatment can include:

• Hearing aids, small electronic devices worn outside the ear that make sound louder.
• Cochlear implants, small electronic devices that have two pieces, one outside behind the ear and another under the skin.
• Surgery called stapedectomy, when a surgeon places a prosthetic or artificial device into the middle ear, allowing sound waves to reach the inner ear.

Who Treats Osteogenesis Imperfecta?

People with OI usually require a health care team of several doctors and health care providers. Your health care team may include:

• Primary care physicians, who diagnose and treat adults.
• Pediatricians, who diagnose and treat children.
• Clinical geneticists, who diagnose and treat children and adults with genetic disorders.
• Orthopaedists, who treat and perform surgery for bone and joint diseases, and have experience treating people with OI.
• Occupational therapists, who teach how to safely perform activities of daily living.
• Physical therapists, who teach ways to build muscle strength, recover from broken bones, and prevent broken bones.
• Dental providers such as orthodontists and oral-maxillofacial surgeons.

Living With Osteogenesis Imperfecta

Certain activities can help people with OI stay healthy and prevent broken bones.

• Follow a nutritious diet.
• Exercise as much as possible. Regular physical activity can help strengthen muscles and bones. Swimming and water therapy are common choices for people with OI because exercising in water has little risk for causing broken bones. Talk with your doctor or physical therapist to discuss appropriate and safe exercise.
• Keep a healthy weight. Being overweight increases the risk for many health problems, such as diabetes and heart disease. Extra weight also adds stress to the bones, which is especially unhealthy for people with OI.
• Don’t smoke, and avoid secondhand smoke, because smoking can also weaken bones.
• Do not drink a lot of alcohol or caffeine because they may weaken your bones.
• Seek counseling or talk to a health care professional if you feel depressed or anxious about OI and its symptoms.

Research Progress Related to Osteogenesis Imperfecta

Research is underway to help people with OI, including:

• Continuing to find genes that cause OI.
• Studying medicines to help manage and control symptoms of OI.
• Studying how bones form to find ways to increase bone mass.
• Using bone marrow or stem cells to treat OI.

Scleroderma means hard skin. It is a group of diseases that cause abnormal growth of connective tissue. Connective tissue is the material inside your body that gives your tissues their shape and helps keep them strong. In scleroderma, the tissue gets hard or thick. It can cause swelling or pain in your muscles and joints.

Symptoms of scleroderma include

• Calcium deposits in connective tissues
• Raynaud's phenomenon, a narrowing of blood vessels in the hands or feet
• Swelling of the esophagus, the tube between your throat and stomach
• Thick, tight skin on your fingers
• Red spots on your hands and face

No one knows what causes scleroderma. It is more common in women. It can be mild or severe. Doctors diagnose scleroderma using your medical history, a physical exam, lab tests, and a skin biopsy. There is no cure, but various treatments can control symptoms and complications.

Your soft tissues connect, support, or surround other tissues. Examples include your muscles, tendons, fat, and blood vessels. Soft tissue sarcoma is a cancer of these soft tissues. There are many kinds, based on the type of tissue they started in. They may cause a lump or swelling in the soft tissue. Sometimes they spread and can press on nerves and organs, causing problems such as pain or trouble breathing.

No one knows exactly what causes these cancers. They are not common, but you have a higher risk if you have been exposed to certain chemicals, have had radiation therapy, or have certain genetic diseases.

Doctors diagnose soft tissue sarcomas with a biopsy. Treatments include surgery to remove the tumor, radiation therapy, chemotherapy, or a combination.

Achondrogenesis is a group of severe disorders that affect cartilage and bone development. These conditions are characterized by a small body, short limbs, and other skeletal abnormalities. As a result of serious health problems, infants with achondrogenesis usually die before birth, are stillborn, or die soon after birth from respiratory failure. However, some infants have lived for a short time with intensive medical support.

Researchers have described at least three forms of achondrogenesis, designated as type 1A, type 1B, and type 2. The types are distinguished by their signs and symptoms, inheritance pattern, and genetic cause. However, types 1A and 1B are often hard to tell apart without genetic testing.

Achondrogenesis type 1A, which is also called the Houston-Harris type, is the least well understood of the three forms. Affected infants have extremely short limbs, a narrow chest, short ribs that fracture easily, and a lack of normal bone formation (ossification) in the skull, spine, and pelvis.

Achondrogenesis type 1B, also known as the Parenti-Fraccaro type, is characterized by extremely short limbs, a narrow chest, and a prominent, rounded abdomen. The fingers and toes are short and the feet may turn inward and upward (clubfeet). Affected infants frequently have a soft out-pouching around the belly-button (an umbilical hernia) or near the groin (an inguinal hernia).

Infants with achondrogenesis type 2, which is sometimes called the Langer-Saldino type, have short arms and legs, a narrow chest with short ribs, and underdeveloped lungs. This condition is also associated with a lack of ossification in the spine and pelvis. Distinctive facial features include a prominent forehead, a small chin, and, in some cases, an opening in the roof of the mouth (a cleft palate). The abdomen is enlarged, and affected infants often have a condition called hydrops fetalis, in which excess fluid builds up in the body before birth.

Dupuytren contracture is characterized by a deformity of the hand in which the joints of one or more fingers cannot be fully straightened (extended); their mobility is limited to a range of bent (flexed) positions. The condition is a disorder of connective tissue, which supports the body's muscles, joints, organs, and skin and provides strength and flexibility to structures throughout the body. In particular, Dupuytren contracture results from shortening and thickening of connective tissues in the hand, including fat and bands of fibrous tissue called fascia; the skin is also involved.

In men, Dupuytren contracture most often occurs after age 50. In women, it tends to appear later and be less severe. However, Dupuytren contracture can occur at any time of life, including childhood. The disorder can make it more difficult or impossible for affected individuals to perform manual tasks such as preparing food, writing, or playing musical instruments.

Dupuytren contracture often first occurs in only one hand, affecting the right hand twice as often as the left. About 80 percent of affected individuals eventually develop features of the condition in both hands.

Dupuytren contracture typically first appears as one or more small hard nodules that can be seen and felt under the skin of the palm. In some affected individuals the nodules remain the only sign of the disorder, and occasionally even go away without treatment, but in most cases the condition gradually gets worse. Over months or years, tight bands of tissue called cords develop. These cords gradually draw the affected fingers downward so that they curl toward the palm. As the condition worsens, it becomes difficult or impossible to extend the affected fingers. The fourth (ring) finger is most often involved, followed by the fifth (little), third (middle), and second (index) fingers. Occasionally the thumb is involved. The condition is also known as Dupuytren disease, and "Dupuytren contracture" most accurately refers to later stages when finger mobility is affected; however, the term is also commonly used as a general name for the condition.

About one-quarter of people with Dupuytren contracture experience uncomfortable inflammation or sensations of tenderness, burning, or itching in the affected hand. They may also feel pressure or tension, especially when attempting to straighten affected joints.

People with Dupuytren contracture are at increased risk of developing other disorders in which similar connective tissue abnormalities affect other parts of the body. These include Garrod pads, which are nodules that develop on the knuckles; Ledderhose disease, also called plantar fibromatosis, which affects the feet; scar tissue in the shoulder that causes pain and stiffness (adhesive capsulitis or frozen shoulder); and, in males, Peyronie disease, which causes abnormal curvature of the penis.