Heritable Disorders of Connective Tissue
This fact sheet describes a family of more than 200 disorders that affect connective tissues. These disorders result from alterations (mutations) in genes responsible for building tissues. Alterations in these genes may change the structure and development of skin, bones, joints, heart, blood vessels, lungs, eyes, and ears. Some mutations also change how these tissues work.
All of these diseases are directly related to mutations in genes, and thus are called "heritable." 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 in this fact sheet are called heritable (genetic) disorders of connective tissue (HDCTs). Many, but not all, of them are rare. (See the box for a description of some of the more common HDCTs.)
Some Common Heritable Connective Tissue Disorders Physicians and scientists have identified more than 200 heritable connective tissue disorders. Some of the more common ones are listed below. Some of these are really groups of disorders and may be known by other names. Ehlers-Danlos syndrome--The problems present in Ehlers-Danlos syndrome (EDS), a group of approximately 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 curved spine; the eyes; and weak internal organs, including the uterus, intestines, and large blood vessels. Mutations in several different genes are responsible for different symptoms in the several types of EDS. In most cases, the genetic defect involves collagen, the major protein-building material of bone. Epidermolysis bullosa--The characteristic feature of epidermolysis bullosa (EB) is blistering in the skin. Some forms of the disease may involve the gastrointestinal tract, the pulmonary system, muscle, 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. The disease results when skin layers separate after minor trauma. Defects of several proteins within the skin are at fault. Marfan syndrome--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 haemorrhage and even death. This disorder results from mutations in the gene that makes fibrillin-1, a protein important to connective tissue. Osteogenesis imperfecta--People with osteogenesis imperfecta (OI) have bones that fracture easily, low muscle mass, and joint and ligament laxity. There are four major types of OI ranging in severity from mild to lethal. The appearance of people with OI varies considerably. Individuals may also 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. |
What Is Connective Tissue?
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. This can lead to a HDCT.
How Do People Get Gene Alterations?
Either people inherit an altered gene from either or both parents, or--more rarely--an alteration occurs in a copy of the gene during the formation of the egg or sperm that gives rise to the individual. We have two copies of most genes: ones that we 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, women have two X chromosomes and therefore have two copies of X chromosome genes.
Some genetic disorders require that only a single copy of a gene be altered. These disorders can be inherited in many generations of a family because the altered copy of the gene can be 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 in either the egg or sperm that gives rise to that person. 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."
Who Gets HDCTs?
Scientists estimate that as many as 1 million people in the United States may have a heritable disorder of connective tissue. Generally, these conditions affect people of all ethnic groups and ages, and both genders are commonly affected. Many of these disorders are rare. Some may not be evident at birth, but only declare themselves after a certain age or after exposure to a particular environmental stress.
Does Anything Increase the Chances of Having a Genetic Disease?
Several factors increase the likelihood that a person will inherit an alteration in a gene. If you are concerned about your risk, you should talk to your health care provider or a genetic counsellor.
The following factors may increase the chance of getting or passing on a genetic disease:
- Parents who have a genetic disease
- A family history of a genetic disease
- Parents who are closely related or part of a distinct ethnic or geographic community
- Parents who do not show disease symptoms, but "carry" a disease gene in their genetic makeup (this can be discovered through genetic testing).
How Does Genetic Counselling Help?
People seek genetic counselling to help them make better decisions about their lives and families. Because genetic counsellors 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 people 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 foetus either carries an altered copy of a gene or is affected with a disorder. The information derived from all these studies can be valuable aids in family planning.
Your health care team can help you find genetic counselling if you wish to better understand your disease or risk of disease.
What Are the Symptoms of a HDCT?
Each disorder has different symptoms. For instance, some diseases, such as Marfan syndrome, osteogenesis imperfecta, and certain chondrodysplasias (disorders of long-bone development) cause bone growth problems. People with bone growth disorders may have brittle bones or bones that are too long or too short. 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 the disease 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. 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).
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.
How Do Doctors Diagnose HDCTs?
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 either to confirm or to 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:
- Prenatal testing to identify an affected foetus to assist in family planning.
- Newborn screening to spot a condition that may become evident later in life.
- Carrier testing to identify adults who, without symptoms, carry a genetic mutation for a disease.
- Predictive testing to spot people at risk for developing a genetic connective tissue disease later in life. These tests are helpful for diseases that run in the family.
What Treatments Are Available?
Each disorder requires a specific programme for management and treatment. In most instances, regular monitoring is important to assess, for example, diameter of the aorta in people with Marfan syndrome, extent of scoliosis (spine curvature) in people with OI or 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, as is staying in touch with specialists who will be aware of emerging new treatments.
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