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.)
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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 hemorrhage 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 counselor.
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 Counseling Help?
People seek genetic counseling to help them 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 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 fetus 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 counseling
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 fetus 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 program 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.
What Research Is Being Done on
HDCTs?
Scientists are working to better understand these
disorders at several levels: (1) to identify the genes in which the
mutations reside, (2) to identify the mutations that result in the
condition, (3) to understand how these mutations result in the clinical
condition, and (4) to use all available information about the condition
to plan new therapies and to test their use and value, both in animal
models and in affected individuals. Because most of these conditions are
uncommon, and individuals with them are widely scattered, it is often
difficult to gather information about the clinical course of the
disorder and to assemble enough people to plan effective clinical
trials. In addition, genetic changes can sometimes be influenced by
lifestyle and environment.
The National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), a part of the National Institutes of Health
(NIH), is the lead Federal agency for connective tissue research.
Several other NIH institutes are also studying HDCTs. The NIAMS supports
research through grants to scientists around the country, in national
and international clinical trials, and at the NIH campus itself. Here is
some of the research that is being done:
- The NIAMS is conducting an in-depth natural history study of
people who have Marfan syndrome (which leads to abnormally long
bones), nail-patella syndrome (a congenital skeletal disorder),
Stickler syndrome (which causes eye and joint problems), and
Ehlers-Danlos syndrome (which causes skin and blood vessel problems).
All of these disorders have multiple, interrelated symptoms. NIAMS
scientists are studying these people closely and over a long period to
get a more complete picture of the diseases. They hope to improve
their understanding of the genetic origins of the symptoms, of disease
progression, and of mutations in patients and their relatives.
Scientists expect their findings to apply to other HDCTs as well.
- The NIAMS is supporting a study looking for ways to treat diseases
such as osteogenesis imperfecta by using gene therapy. Stem cells,
which have the potential to develop into more specialized cells, would
replace bone cells that have gene defects. This research is being
conducted on specially bred mice.
- Another NIAMS project is examining gene defects that lead to
abnormal elastin, the connective tissue protein that allows arteries,
muscles, and other organs to respond in certain ways to movement. So
far, the investigators have shown how elastin gene mutations cause two
specific diseases: a skin disease (cutis laxa) and a blood vessel
disease (supravalvular aortic stenosis). Scientists hope to learn more
about how mutations affect elastin fiber and tissue growth. They also
hope to find out how gene defects lead to the development of elastin
disease.
- The NIAMS is encouraging the establishment of new research
registries for connective tissue disorders and other conditions. These
registries would support the collection of demographic and medical
data from patients and families to be used in research on disorders.
Epidermolysis bullosa is one of the disorders for which the Institute
has already established a research registry.
Other NIAMS researchers are exploring
- the chemistry and biology of elastin genes
- collagen gene defects (several types) that cause bone
diseases
- collagen IV gene defects in mice and in humans (Alport
syndrome)
- proteoglycans, a group of proteins that maintain tissue
stiffness
- fibroblasts, cells that form the fibrous tissues in the
body
- cartilage, joints, and skin layers.
Ongoing studies of aneurysms--a weak spot in a blood
vessel wall that threatens to burst--are taking place at several NIH
Institutes. Aneurysms can prove deadly to people with Marfan syndrome
and other HDCTs. These studies have been helped by a pioneering project
at the NIAMS that developed a breed of mice prone to aneurysms.
Scientists hope the mutant mice will improve understanding of aneurysms
and ways to prevent them.
At the National Institute of Child Health and Human
Development, scientists are working with young patients who have
osteogenesis imperfecta. They hope to learn more about the genetics of
the disease and the natural history of the many secondary features
involved, as well as rehabilitation techniques. Research is also ongoing
in animal models and human clinical trials into the use of
bisphosphonates--drugs used to treat osteoporosis.
The National Human Genome Research Institute is conducting
a clinical study of mind-body therapy for chronic pain in people with
Ehlers-Danlos syndrome. At the National Eye Institute, research is being
supported on alterations in the gene that causes pseudoxanthoma
elasticum (PXE) and on which variations cause different signs and
symptoms. And scientists at the National Institute of Dental and
Craniofacial Research are carrying out clinical studies on fibrous
dysplasia of bone.
Keeping on Top of Your Condition
Keeping in tune with your disease or condition not only makes treatment less intimidating but also increases its chance of success, and has been shown to lower a patients risk of complications. As well, as an informed patient, you are better able to discuss your condition and treatment options with your physician.
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Where Can People Find More Information
About HDCTs?
People with HDCTs can contact professional and support
groups that can supply more detailed information than is found here.
Most of them also have Internet Web sites. Some major groups are listed
below.
National Institute of Arthritis and Musculoskeletal and
Skin Diseases
National Institutes of Health
1 AMS
Circle
Bethesda, MD 20892-3675
Phone: 301-495-4484 or
877-22-NIAMS (226-4267) (free of charge)
TTY:
301-565-2966
Fax: 301-718-6366
http://www.niams.nih.gov/index.htm
American Academy of Orthopaedic Surgeons
P.O.
Box 2058
Des Plaines, IL 60017
Phone: 800-824-BONE (2663) (free
of charge)
www.aaos.org
Coalition for Heritable Disorders of Connective
Tissue
382 Main Street
Port Washington, NY 11050
Phone:
800-862-7326 (free of charge)
Fax: 516-883-8712
www.chdct.org
Genetic Alliance
4301 Connecticut Avenue, N.W.,
Suite 404
Washington, DC 20008
Phone: 202-966-5557 or
800-336-GENE (4363) (free of charge)
Fax:
202-966-8553
www.geneticalliance.org
National Organization for Rare Disorders, Inc.
P.O. Box 8923
New Fairfield, CT 06812-8923
Phone:
203-746-6518 or 800-999-6673 (free of charge)
Fax:
203-746-6481
www.rarediseases.org
National Society of Genetic Counselors, Inc.
233
Canterbury Drive
Wallingford, PA 19086-6617
Phone: 610-872-7608
E-mail: nsgc@aol.com
www.nsgc.org
Dystrophic Epidermolysis Bullosa Research Association
(D.E.B.R.A.) of America
5 West 36th Street, Suite 404
New
York, NY 10018
Phone: 212-868-1573
Fax: 212-868-9296
E-mail: staff@debra.org
www.debra.org
Ehlers-Danlos National Foundation
6399 Wilshire
Boulevard, Suite 510
Los Angeles, CA 90048
Phone:
323-651-3038
www.ednf.org/frame2.html
National Association for Pseudoxanthoma
Elasticum
8764 Manchester Road
Suite 200
St. Louis, MO
63144
Phone: 314-962-0100
Fax: 314-962-0100
E-mail: pxenape@estreet.com
www.napxe.org
National Marfan Foundation
382 Main
Street
Port Washington, NY 11050
Phone: 516-883-8712 or
800-8-MARFAN (862-7326) (free of charge)
Fax:
516-883-8040
E-mail: staff@marfan.org
www.marfan.org
Osteogenesis Imperfecta Foundation
804 West
Diamond Avenue, Suite 210
Gaithersburg, MD 20878
Phone:
800-981-2663 (free of charge)
Fax: 301-947-0456
E-mail: bonelink@oif.org
www.oif.org
PXE International
4301 Connecticut Avenue NW,
Suite 404
Washington, DC 20008-2304
Phone: 202-362-9599
Fax:
202-966-8553
E-mail: pxe@pxe.org
www.pxe.org
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