connective tissue disorders
More than 200 heritable disorders that affect connective tissues are known. These disorders result from mutations (alterations) in genes that are responsible for building tissues, and which may change the structure and development of skin, bones, joints, the heart, blood vessels, lungs, eyes, and ears. Some mutations also change how these tissues work.
Some other connective tissue problems are not directly linked to mutations in tissue-building genes, although some people may be genetically predisposed to becoming affected.
The disorders discussed below are heritable (genetic) disorders of connective tissue (HDCTs). Many, but not all, of them are rare.
Some common heritable disorders of connective tissue
Some of the more common connective tissue disorders are listed below. Some of these are really groups of disorders and may be known by other names.
The problems present in Ehlers-Danlos syndrome (EDS), a group of more than 10 disorders, include changes in the physical properties of skin, joints, blood vessels, and other tissues such as ligaments and tendons. People with EDS have some degree of joint looseness, fragile small blood vessels, and abnormal scar formation and wound healing. Soft, velvety skin stretches excessively but returns to normal after being pulled. Some forms of EDS can present problems with the spine, including a curved spine, and the eyes. EDS can also lead to weak internal organs, including the uterus, intestines, and large blood vessels. Mutations in several different genes are responsible for varying symptoms in the several types of EDS. In most cases, the genetic defect involves collagen, the major protein-building material of bone.
See main page on Ehlers-Danlos syndrome
The characteristic feature of epidermolysis bullosa (EB) is blistering of the skin. Some forms of the disease may involve the gastrointestinal tract, the pulmonary system, the muscles, or the bladder. Most forms are evident at birth. This disorder can be both disabling and disfiguring, and some forms may lead to early death. Blisters result when skin layers separate after minor trauma. Defects of several proteins within the skin are at fault.
People with Marfan syndrome tend to have excessively long bones and are commonly thin, with long, "spider-like" fingers. Other problems include skeletal malformations; abnormal position of the lens of the eye; and enlargement at the beginning part of the aorta, the major vessel carrying blood away from the heart. If left untreated, an enlarged aorta can lead to hemorrhage and even death. This disorder results from mutations in the gene that determines the structure of fibrillin-1, a protein important to connective tissue.
See main page on Marfan syndrome
People with osteogenesis imperfecta (OI) have bones that fracture easily, low muscle mass, and joint and ligament laxity. There are six major types of OI, ranging in severity from mild to lethal. The appearance of people with OI varies considerably. Individuals may have a blue or gray tint to the sclera (whites of the eyes), thin skin, growth deficiencies, and fragile teeth. They may develop scoliosis, respiratory problems, and hearing loss. Also known as "brittle bone disease," this disorder arises from mutations in the two genes that make type I collagen, a protein important to bones and skin. These mutations cause the body to make either too little or poor-quality type I collagen.
Connective tissue and heritable disorders
Connective tissue is the material between the cells of the body that gives tissues form and strength. This "cellular glue" is also involved in delivering nutrients to the tissue, and in the special functioning of certain tissues. Connective tissue is made up of dozens of proteins, including collagens, proteoglycans, and glycoproteins. The combination of these proteins can vary between tissues.
The genes that encode these proteins can harbor defects or mutations, which can affect the functioning of certain properties of connective tissue in selected tissues. When this occurs, the result can be a heritable disorder – one that can be inherited, or passed from parent to child – of connective tissue.
How people get gene alterations
People with heritable disorders of connective tissue inherit an altered gene either from one or from both parents. We have two copies of most genes: one inherited from each parent. Males have one copy of each gene on the X chromosome, because they have only one X chromosome; and one copy of each gene on the Y chromosome. In contrast, females have two copies of X chromosome genes because they have two X chromosomes.
Some genetic disorders require that only a single copy of a gene be altered. These disorders can be seen in many generations of a family because the altered copy of the gene is passed from parent to child (dominant inheritance). The same disorder can occur in an individual without a family history of the condition if there is a new mutation in the right gene at conception. Some disorders are seen only when the individual has received an altered copy of the gene from each parent (recessive inheritance); in these families, the person with only a single copy is called a carrier and is not actually affected.
If a mutation occurs on an X chromosome, it generally produces a condition in which the pattern of affected individuals in a family is unusual. Often, women are carriers (that is, they have only a single altered copy of the gene), but males show the condition because they do not have a second protective copy of the gene. Such a condition is referred to as X-linked.
Incidence of HDCTs
By one estimate, more than a half million people in the United States are affected by the more than 200 heritable disorders of connective tissue. Generally, these conditions affect people of all ethnic groups and ages, and both sexes are affected. Many of these disorders are rare. Some may not be evident at birth, but only appear after a certain age or after exposure to a particular environmental stress.
Several factors increase the likelihood that a person will inherit an alteration in a gene. A person concerned about his or her risk should talk to a health care provider or a genetic counselor. The following factors may increase the chance of getting or passing on a genetic disease:
People seek genetic counseling to make better decisions about their lives and families. Because genetic counselors understand how genetic disorders are passed on through families, they can help couples estimate the risks of having children with genetic diseases. They can also tell parents about tests to determine if they are carrying certain altered genes, tests for newborns who may have inherited certain altered genes, and tests that can be done in early pregnancy to determine if a fetus either carries an altered copy of a gene or is affected with a disorder. The information derived from all these studies can facilitate family planning.
Each disorder has different symptoms. Some diseases cause bone growth problems. People with bone growth disorders may have brittle bones or bones that are too long or too short. Some disorders cause people to be unusually tall (Marfan syndrome) or short (chondrodysplasias, osteogenesis imperfecta), or to have head and facial structure malformations (Apert syndrome, Pfeiffer syndrome). In some of these disorders, joint looseness or joints that are too tight can cause problems.
The skin can be affected as well. Ehlers-Danlos syndrome results in stretchy or loose skin, while in another connective tissue disorder, cutis laxa, deficient elastic fibers cause the skin to hang in folds. Epidermolysis bullosa results in blistered skin. Pseudoxanthoma elasticum causes skin, eye, and heart problems, and closed-off or blocked blood vessels. Marfan syndrome and some forms of Ehlers-Danlos syndrome lead to weak blood vessels.
It is critical for affected individuals and their family members to work closely with their health care teams. Symptoms of HDCTs are extremely variable, and some disorders can pose severe health risks even when affected individuals have no symptoms.
Diagnosis always rests first on a combination of family history, medical history, and physical examination. Because many of these conditions are uncommon, the family physician may suspect a diagnosis but be uncertain about how to confirm it. At this point, referral to experienced clinicians, often medical geneticists, can be extremely valuable to either confirm or exclude the suspected diagnosis. Laboratory tests are available to confirm the diagnosis for many HDCTs, but not for all. Once a diagnosis is made, laboratory studies may be available to provide some or all of the following:
The term heritable disorders of connective tissue refers to a wide range of disorders, each requiring a specific program for management and treatment. In most instances, regular monitoring is important to assess, for example, the diameter of the aorta in people with Marfan syndrome, the extent of scoliosis (spine curvature) in people with OI and those with some forms of EDS, and whether there is protrusion of the spine into the base of the skull in people with OI. For some conditions, specific metabolic treatment is useful (for example, vitamin B6 in people with homocystinuria, a metabolic disorder resulting from a liver enzyme deficiency). In others, systemic treatment with drugs like beta blockers is appropriate. Maintaining general health is also important for people with all HDCTs.