Pendred syndrome

Definition

Pendred syndrome is an inherited condition that causes hearing loss typically beginning at birth and usually leads to the development of an enlarged thyroid, called a goiter. The thyroid is a gland responsible for normal body growth and metabolism. People with Pendred syndrome often have altered development of certain bones in the inner ear and/or balance problems as well. Vaughan Pendred first described the presence of hearing loss and goiter in two sisters in 1896, and thus the condition became known as Pendred syndrome. Genetic research has identified a gene on chromosome number seven that is usually altered in people with Pendred syndrome.

Description

Pendred syndrome is sometimes called goiter-sensorineural deafness, due to the common existence of both goiter and a form of hearing loss called sensorineural hearing loss in affected individuals. In order to understand how goiter occurs, it is helpful to first understand how the thyroid gland normally works. The thyroid is located underneath the larynx (voice box), in the front of the neck. The main role of the thyroid is to trap iodine, an essential nutrient found in various foods as well as salt, and to use it to make two important hormones: T3 and T4. These thyroid hormones allow the body to grow normally and to increase the speed of metabolism (breakdown) of nutrients. The thyroid is able to create these hormones because of a series of chemical reactions. A portion of the brain called the hypothalamus is responsible for controlling many body functions. One of its functions is to make a chemical called thyroid releasing hormone (TRH). This hormone travels to another gland, called the anterior pituitary gland, which is located underneath the brain. The TRH stimulates the anterior pituitary gland, which makes a chemical called thyroid stimulating hormone (TSH). This hormone travels to the thyroid, and activates the release of T3 and T4 into the body.

The word goiter is used to describe an enlargement of the thyroid gland. People with goiter may have hypothyroidism (they make too little T3/T4), hyperthyroidism (they make too much T3/T4), or they may have thyroid glands that work normally. Approximately 44–50% of people with Pendred syndrome have hypothyroidism, while the remaining 50–56% have thyroid glands that create a normal amount of thyroid hormones. However, approximately 75% develop goiter at some point in time, although it is rarely present at birth. Thirty to 40% of individuals develop an enlarged thyroid in late childhood or during their early teen-age years. The remaining 60–70% show symptoms during their early adult years. The enlargement of the thyroid gland happens because the mechanisms that control iodine transfer within the cells of the thyroid do not work well. This transfer is necessary to allow the iodine to bind to (and in doing so, help generate) thyroid hormones stored inside the thyroid. Since the iodine is not moved to the correct area of the thyroid, it becomes "pooled," rather than attaching itself to thyroid hormones. This faulty processing of iodine among people with Pendred syndrome can often be confirmed by the use of a perchlorate discharge test. Perchlorate is a chemical that causes the pooled iodine to be pushed out of the thyroid into the bloodstream where it can be measured. Since people with Pendred syndrome usually have more pooled iodine than normal, they will push out or discharge a larger amount of iodine when they are exposed to perchlorate. However, not all affected individuals show abnormal results, so the test is not perfect.

Pendred syndrome causes a specific type of hearing impairment called sensorineural hearing loss (SNHL). The ear can be divided into three main parts: the outer ear, the middle ear, and the inner ear. The parts of the outer ear include the pinna (the visible portion of the ear), the ear canal and the eardrum. The pinna directs sound waves from the environment through the ear canal, toward the eardrum. The eardrum vibrates, and causes tiny bones (called ossicles), which are located in the middle ear, to move. This movement causes pressure changes in fluids surrounding the parts that make up the inner ear. The main structures of the inner ear are the cochlea and the vestibular system. These structures send information regarding hearing and balance to the brain. The cochlea is shaped like a snail shell, and it contains specialized sensory cells (called hair cells) that change the sound waves into electrical messages. These messages are then sent to the brain through a nerve (called the auditory nerve) that allows the brain to "hear" sounds from the environment. The vestibular system is a specialized organ that helps people maintain their balance. The vestibular system contains three structures called semi-circular canals, which send electrical messages to the brain about movement and body position. This allows people to maintain their balance when moving by sensing changes in their direction and speed.

Sensorineural hearing loss occurs when parts of the inner ear (including the cochlea and/or auditory nerve) do not work correctly. The amount (or degree) of hearing loss can be described by measuring the hearing threshold (the sound level that a person can just barely hear) in decibels (dB). The greater a person's dB hearing level, the louder the sound must be to just barely be heard. Hearing loss is often defined as mild, moderate, severe, or profound. For people with mild hearing loss (26–45 dB), understanding conversations in a noisy environment, at a distance, or with a soft-spoken person is difficult. Moderate hearing loss (46–65 dB) causes people to have difficulty understanding conversations, even if the environment is quiet. People with severe hearing loss (66–85 dB) have difficulty hearing conversation unless the speaker is standing nearby or is talking loudly. Profound hearing loss (>85 dB) may prevent people from hearing sounds from their environment or even loud conversation. People with Pendred syndrome generally have severe to profound SNHL that is congenital (i.e. present at birth) in both ears. However, some affected individuals develop SNHL during childhood, after they have learned to speak.

People with SNHL often undergo specialized imaging tests, such as computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, which create detailed images of the tissue and bone structures of the inner ear. Approximately 85% of people affected with Pendred syndrome have physical changes in the inner ear that can be seen with these tests. A common finding is a visible change in the snail-shaped cochlea called a Mondini malformation, in which the cochlea is underdeveloped and has too few coils compared to a normal cochlea. Another visible change sometimes seen in the inner ear is called enlarged vestibular aqueduct. The vestibular aqueduct is a narrow canal that allows fluid to move within the inner ear. Enlarged vestibular aqueduct (EVA) is the most common form of inner ear abnormality that is seen with CT or MRI scans. As the name implies, the vestibular aqueduct (canal) is larger than normal in people with EVA. Although EVA is seen in approximately 10–12% of people who are born with SNHL, some people with EVA can have SNHL that fluctuates (comes and goes) or is progressive (gradually worsening) as well as balance problems. In spite of the fact that Pendred syndrome has typically been diagnosed among people with both SNHL and goiter/thyroid problems, as of 2000, preliminary studies support the finding that some people with EVA and SNHL have a form of Pendred syndrome, even if they do not have goiter or thyroid problems.

Pendred syndrome also causes vestibular dysfunction in approximately 66% of affected individuals, which means they have abnormalities in their vestibular (balance) system. This may cause problems such as dizziness because they cannot sense changes in direction or speed when they are moving.

Genetic profile

Pendred syndrome is inherited in an autosomal recessive manner. "Autosomal" means that males and females are equally likely to be affected. "Recessive" refers to a specific type of inheritance in which both copies of a person's gene pair (i.e. both alleles) need to be changed or altered in order for the condition to develop. In this situation, an affected individual receives an altered copy of the same gene from each parent. If the parents are not affected, they each have one working copy of the gene and one non-working (altered) copy, and are only "carriers" for Pendred syndrome. The chance that two carrier parents will have a child affected with Pendred syndrome is 25% for each pregnancy. They also have a 50% chance to have an unaffected child who is simply a carrier, and a 25% chance to have an unaffected child who is not a carrier, with each pregnancy.

The gene for Pendred syndrome is located on chromosome 7q31 and has been named the PDS gene. The gene tells the body how to make a specific protein called pendrin. The pendrin protein is believed to be responsible for transporting negatively charged elements called iodide and chloride (forms of iodine and chlorine) within the thyroid and likely the inner ear as well. Changes within the PDS gene create an altered form of pendrin protein that does not work properly, and thus causes the symptoms of Pendred syndrome. As of March 2001, genetic researchers identified at least 47 different types of alterations in the PDS gene among different families. However, four of these are more common than the others, and it is estimated that approximately 75% of affected people have these common changes.

Genetic research on the PDS gene has revealed that different types of gene changes can lead to different symptoms. For example, changes that completely inactivate the pendrin protein have been seen among people with Pendred syndrome (i.e. SNHL and goiter), whereas other types of alterations that only decrease the activity of pendrin have been found in people who have an inherited form of deafness called DFNB4. These individuals do have SNHL, but do not develop goiter. The researchers who published this finding in 2000 believed that the small amount of pendrin activity in these individuals likely prevented or delayed the symptoms of goiter. Another study published in 2000 showed that a large portion (greater than 80%) of people with EVA and SNHL were found to have one or more changes in the PDS gene, even though they did not all have thyroid changes such as goiter or abnormal perchlorate discharge test results. Thus, it is believed that changes in the pendrin gene actually cause a number of overlapping conditions. These conditions range from Pendred syndrome (i.e. SNHL and thyroid changes) to SNHL with EVA.

Demographics

Pendred syndrome has been estimated to occur in approximately 7.5 in 100,000 births in Great Britain, and one in 100,000 births in Scandinavia. It has been diagnosed in many different ethnic groups, including Japanese, East Indian, and other Caucasian groups, as well as among people of African descent. Inherited forms of congenital SNHL occur in approximately one of every 2,000 children. Prior to the discovery of the PDS gene, researchers estimated that up to 10% of all children born with SNHL could actually have Pendred syndrome. However, the percentage may be even higher. This is because changes in the PDS gene have been found in people who have SNHL and EVA, even though they do not have thyroid changes that would have helped make a clear diagnosis of Pendred syndrome in the past. Thus, future genetic studies on large groups of individuals with SNHL will help researchers understand how common Pendred syndrome truly is, as well as the range of symptoms that are caused by changes in the PDS gene.

Signs and symptoms

Although the symptoms of Pendred syndrome can vary among different individuals, the findings may include:

• Sensorineural hearing loss that is usually congenital
• Thyroid changes such as goiter, abnormal perchlorate discharge test results, and/or hypothyroidism
• Inner ear changes, such as enlarged vestibular aqueduct (EVA) or Mondini malformation
• Altered vestibular function that leads to balance problems

Diagnosis

The diagnosis of Pendred syndrome is typically based upon the results from a variety of tests that measure hearing, thyroid appearance/function, inner ear structure, and balance. Sometimes the diagnosis is not made until a person with SNHL reaches adolescence or adulthood and develops thyroid problems such as goiter or hypothyroidism. These problems are usually detected by physical examination and blood tests, and thus help diagnose Pendred syndrome. However, children who are born with SNHL often undergo special imaging tests such as CT or MRI scans. These may show inner ear changes that raise the question of possible changes in the PDS gene, even if the children do not have thyroid problems. In each of these situations, genetic testing may provide useful information that can confirm the diagnosis of Pendred syndrome.

Genetic research testing can be done for people with suspected or known Pendred syndrome by studying their DNA . The laboratory can check for the four common changes and some unique changes that have been found in the PDS gene. If this testing identifies an affected person's specific genetic changes, other people in the same family who are not affected can have their DNA examined as well. This can determine whether an unaffected person is a carrier for Pendred syndrome or not. In addition, testing could be done during a pregnancy if both of a baby's parents are carriers and have each had specific changes diagnosed in their DNA.

If genetic testing is done for people with known or suspected Pendred syndrome and the laboratory finds only one changed gene or no changes in the PDS gene, the diagnosis of Pendred syndrome cannot be confirmed. However, this does not rule out the possibility of Pendred syndrome. Sometimes this happens simply because the affected person has a very unique change in the PDS gene that the lab cannot clearly identify. Over time, further genetic research could potentially provide useful information about their specific genetic changes as knowledge about the PDS gene grows.

Treatment and management

There is no cure for Pendred syndrome. However, there are several ways to treat some of the symptoms.

Treatment and management of SNHL

Regular visits with an audiologist (a hearing specialist) and an ENT (a physician specializing in the ear, nose, and throat) are important for people with Pendred syndrome. Hearing tests are necessary to check for changes in hearing ability, especially if people have milder forms of hearing loss and have some ability to hear. Among people with milder forms of hearing loss, hearing aids and speech therapy may be useful. However, people with profound SNHL and their families usually benefit from sign language training, which provides a good method of communication. Some people with severe to profound forms of hearing loss may also consider a procedure called cochlear implantation, in which a small electronic device is surgically placed behind the ear (underneath the skin) and is attached to a wire that stimulates the inner ear. This may allow people to hear useful sounds.

Treatment and management of thyroid problems

Regular examinations by an endocrinologist (a physician specializing in the treatment of hormone problems) who is familiar with Pendred syndrome is important. People who develop goiter and/or hypothyroidism are sometimes treated with a medication called thyroxine, which is basically the hormone called T4. Other people with goiter have most of their thyroid surgically removed. However, this form of treatment is not a cure, and the remaining thyroid tissue can grow and redevelop into goiter again. Among some people, the goiter does not require treatment or it simply disappears on its own.

There are a number of support groups available that provide education, support and advice to help people cope with the symptoms of SNHL and thyroid problems that often occur among individuals with Pendred syndrome.

Prognosis

Pendred syndrome does not cause a shortened life span for affected individuals. Those who develop hypothyroidism and do not seek treatment may experience a variety of health problems including low energy level, weight gain, constipation, and dry skin. However, hypothyroidism and goiter can usually be well managed with medication or surgery. The degree of hearing loss that occurs is typically severe to profound from an early age and usually changes very little over the years. However, among affected people who develop SNHL during childhood (after learning to speak), the degree of hearing loss can worsen over time. Sign language training (and sometimes cochlear implants) allow alternative methods of communication and thus help people reach their full potential. Support groups for people with hearing loss often help individuals with SNHL (whether due to Pendred syndrome or other causes) maintain and/or improve their quality of life as well.

Resources

BOOKS

Gorlin, R. J., H. V. Toriello, and M. M. Cohen. "Goiter and profound congenital sensorineural hearing loss (Pendred syndrome)." In Hereditary Hearing Loss and Its Syndromes. Oxford Monographs on Medical Genetics No. 28. New York and Oxford: Oxford University Press, 1995.

PERIODICALS

Reardon, William, et al. "Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome." Journal of Medical Genetics 36 (August 1999): 595–98.

Reardon, William, et al. "Enlarged vestibular aqueduct: a radiological marker of Pendred syndrome, and mutation of the PDS gene." Quarterly Journal of Medicine 93, no. 2 (2000): 99–104.

Scott, Daryl A., et al. "Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4)." Human Molecular Genetics 9, no. 11 (2000): 1709–15.

Scott, Daryl A., et al. "The Pendred syndrome gene encodes a chloride-iodide transport protein." Nature Genetics 21, no. 4 (April 1999): 440–43.

ORGANIZATIONS

American Society for Deaf Children. PO Box 3355, Gettysburg, PA 17325. (800) 942-ASDC or (717) 334-7922 v/tty. <http://www.deafchildren.org/asdc2k/home/home.shtml>.

American Thyroid Association. Townhouse Office Park, 55 Old Nyack Turnpike, Ste. 611, Nanuet, NY 10954. <http://www.thyroid.org>.

Boys Town National Research Hospital. 555 N. 30th St., Omaha, NE 68131. (402) 498-6749. <http://www.boystown.org/Btnrh/Index.htm>.

National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. (301) 587-1788. [email protected]. <http://www.nad.org>.

National Institute on Deafness and Other Communication Disorders. 31 Center Dr., MSC 2320, Bethesda, MD 20814. <http://www.nidcd.nih.gov>.

Vestibular Disorders Association. PO Box 4467, Portland, OR 97208-4467. (800) 837-8428. <http://www.vestibular.org>.

WEBSITES

Smith, Richard R. J., MD, and Guy Van Camp, PhD. "Pendred Syndrome." GeneClinics. University of Washington, Seattle. <http://www.geneclinics.org/profiles/pendred17>. (May 2001).

Pamela J. Nutting, MS, CGC