Cowden syndrome

Related Terms

BMPR1A gene, breast cancer, Cowden's disease, Cowden's syndrome, CS, hamartoma, MHAM, MMAC1 gene, multiple hamartoma syndrome, PTEN gene, TEP1 gene, thyroid cancer.

Background

Cowden syndrome is a rare genetic disorder characterized by the development of multiple noncancerous growths called hamartomas. These growths tend to develop on the skin and mucous membranes, including the lining of the nose and mouth, as well as in other parts of the body, such as the digestive tract. Other signs and symptoms of Cowden syndrome can include an enlarged head and a rare, noncancerous brain tumor called Lhermitte-Duclos disease.
About 85% of Cowden syndrome cases are caused by mutations or defects in the PTEN gene. The causes of the remaining cases are unknown. PTEN is a tumor suppressor gene that encodes for the PTEN protein, which normally prevents cells from growing and dividing too rapidly or in an uncontrolled way. Uncontrolled cell division can lead to the formation of hamartomas and cancerous tumors. Mutations in the PTEN gene have been identified in about 85% of people with Cowden syndrome.
Cowden syndrome is inherited, or passed down among family members, as an autosomal dominant trait. Individuals inherit two copies of most genes, one from the mother and one from the father. To inherit an autosomal dominant trait, only one copy of the defective PTEN gene needs to be inherited. Some cases of Cowden syndrome occur in individuals with no family history of the disease. This is the result of a spontaneous genetic mutation in the egg, sperm cells, or developing embryo.
Cowden syndrome affects about one in 200,000 people worldwide. There have been reports of about 300 cases in the scientific literature. Males and females are affected in equal numbers. Males are more likely to develop certain complications such as thyroid cancer, while females are more likely to develop breast cancer. This syndrome appears to affect people of all races and ethnicities equally.
Individuals with Cowden syndrome may have nearly normal life spans. Abnormal growths on the skin and mucous membranes typically appear by the late twenties, although the age at onset of clinical manifestations of Cowden syndrome varies, ranging from birth to 46 years. While these growths may be benign, individuals with Cowden syndrome are at an increased risk of developing several types of cancer, including cancers of the breast, thyroid, and uterus. Most common complications arise from cancerous tumors. About 40% of people with Cowden syndrome develop at least one cancerous tumor. When detected early, many of these cancers are treatable. Cowden syndrome is primarily associated with increased frequency of malignant, or cancerous, tumors. Benign, or noncancerous, tumors in patients with Cowden syndrome also can cause significant illness.

Signs and symptoms

General: Cowden syndrome is a rare genetic disorder characterized by the development of multiple noncancerous growths called hamartomas. These growths tend to develop on the skin and mucous membranes, including the lining of the nose and mouth, as well as in other parts of the body, such as the digestive tract. People with Cowden syndrome have an increased risk of developing several types of cancer, including cancers of the breast, thyroid, and uterus. Individuals with Cowden syndrome may have an enlarged head.
Hamartomas: Approximately 90% of people with Cowden syndrome develop these multiple noncancerous tumors. These tumors may develop on the skin and mucosa, such as the lining of the nose and mouth, as well as in the digestive tract, central nervous system, eyes, urinary system, and genitals. Onset of symptoms occurs between birth and 46 years of age. Most individuals with Cowden syndrome develop hamartomas by their twenties.
Hamartomas tend to affect the body in four areas, the face, mucosa, palms of the hands, and soles of the feet, as well as in other areas. Tumors on the face tend to be flesh-colored and flat and tend to develop around the mouth. Mucosal tumors are often small and white and may have a cobblestone appearance. These develop on the gums, roof of the mouth, insides of the lips, and tongue. About 40% of people with Cowden syndrome have tumors on the palms of the hands and soles of the feet. Other tumors may develop on the backs of the hands and tops of the feet and tend to be flesh-colored or slightly colored and smooth in texture. There do not appear to be any symptoms associated with these noncancerous growths.
Thyroid: About 66% of people with Cowden syndrome develop thyroid problems. These may include goiter, a swelling of the thyroid gland; noncancerous tumors; cysts, which are small, fluid-filled sacs; and cancerous tumors. The main symptoms of goiter are swelling in the front part of the neck and protruding eyes. Many benign thyroid growths do not cause signs or symptoms. Symptoms of thyroid cancer may include a fast-growing growth in the neck region, difficulty swallowing or breathing, and enlarged lymph nodes under the jaw or in the neck. Some growths may cause the thyroid to produce too much thyroxine, a hormone secreted by the thyroid gland. The extra thyroxine can cause signs and symptoms, including sudden unexplained weight loss, nervousness, or rapid heart rate.
Other: Other signs and symptoms of Cowden syndrome may include macrocephaly (a large head); a small jaw; eye problems, including myopia (nearsightedness); a high-arched palate; breast cysts; ovarian cysts; intellectual disabilities; and a rare, noncancerous brain tumor known as Lhermitte-Duclos disease, which affects the area of the brain that controls muscle control and coordination. Symptoms of this include headache, movement disorders, tremors, and visual disturbances.

Diagnosis

General: Most people with Cowden syndrome seek medical care because of the development of visible tumors on the skin.
Biopsy: In a biopsy, a small sample of tissue is removed from the body and analyzed in a lab. People suspected of having Cowden syndrome may undergo a skin biopsy to assess the presence of hamartomas and other cancerous or noncancerous tumors. If thyroid problems are suspected, a biopsy may also be done on the thyroid gland to determine whether cancer has developed.
Blood tests: People suspected of having Cowden syndrome should undergo blood tests. Anemia, a blood disorder characterized by a low red blood cell count, can be a sign of cancer, usually from blood loss in the gastrointestinal system. An abnormal white blood cell count may indicate a compromised immune system. Blood tests should also check levels of calcium to test for parathyroid disease. Parathyroid glands are pea-sized glands located near each corner of the thyroid gland in the neck, and they produce a substance called parathyroid hormone (PTH), which controls the levels of calcium and phosphorus in the blood. PTH also helps the body make vitamin D and helps prevent the loss of too much calcium in the urine.
Imaging studies: Imaging studies such as mammograms, which are used to detect breast cancer, and thyroid scans, which can determine the functioning of the thyroid gland and the presence of a cancerous growth, may aid in the diagnosis and monitoring of Cowden syndrome. Mammograms should be performed regularly and started early in individuals with Cowden syndrome. If there are problems with the nervous system, a magnetic resonance imaging (MRI) scan, which uses magnets to create an image of internal organs, may help a clinician to see whether the structure of the heart is abnormal. This test would be done if the patient displays neurological symptoms and to rule out a diagnosis of Lhermitte-Duclos disease, a rare, slow-growing tumor in the area of the brain that controls muscle control and coordination. Symptoms of this include headache, movement disorders, tremors, and visual disturbances. An endoscopy is a technique used to visualize internal organs of the body by inserting a tube with a camera into the esophagus. An endoscopy may be done to examine the upper and lower digestive tract for the presence of tumors.
Physical exam: A thorough physical exam and complete family history should be done. Careful attention should be paid to the distinctive characteristics of Cowden syndrome. In 90-100% of patients, skin lesions will be present on the face, in the mouth, and on the palms of the hands and soles of the feet. Up to 80% of patients will have an enlarged head, and some will have a small jaw and a high-arched palate. Family history should focus on family members with breast and thyroid cancer.
Thyroid function tests: People suspected of having Cowden syndrome should undergo thyroid function tests. Blood tests can be performed to determine levels of thyroid-stimulating hormone (THS), which stimulates the thyroid to secrete thyroxine (T4) and triiodothyronine (T3). These tests may give clues as to whether the patient is suffering from goiter, thyroid inflammation, and cancer.
Genetic testing: If Cowden syndrome is suspected, a DNA test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for the defect in the PTEN gene. If this defect is detected, a positive diagnosis is made. However, if the test is negative, an individual may be tested for a defect in the BMPR1A gene.
Prenatal DNA testing: If there is a family history of Cowden syndrome, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose Cowden syndrome. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.
During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
In CVS a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation in the PTEN gene. Miscarriage occurs in about 0.5-1% of women who undergo this procedure.

Complications

Cancer: People with Cowden syndrome are at increased risk for some cancers, including cancer of the breast, thyroid, and the endometrium, which is the lining of the uterus. About 40% of people with Cowden syndrome develop at least one cancerous tumor. Current statistics indicate that males are more likely to develop thyroid cancer, while females are more likely to develop breast cancer. There have been reports of people with Cowden syndrome developing colon cancer, esophageal cancer, cancer of the small or large intestine, lung cancer, acute myelogenous leukemia, bladder cancer, cervical cancer, non-Hodgkin's lymphoma, kidney cancer, and bone cancer.
Coordination and development: A tumor may develop in the cerebellum of individuals with Cowden syndrome. This condition is called Lhermitte-Duclos disease, which may cause ataxia (problems with balance and coordination). Problems with coordination and development depend on how severely the brain is affected with this condition.
Developmental delay: About 20% of affected individuals have delays in developmental milestones early on, including in gross and fine motor skills and in expressive and receptive language. About 30% have a learning disability. Severe intellectual disability, characterized by an intelligence quotient (IQ) of less than 70, is very rare. The presence of these developmental disabilities may require specialized programs while in school to address them.
Hyperthyroidism: Growths, cancerous or noncancerous, may develop on the thyroid gland. It may be possible for these growths to interfere with the normal functioning of the gland, thereby producing hyperthyroidism, an increased activity of the gland.
Hypothyroidism: Growths, cancerous or noncancerous, may develop on the thyroid gland. It may be possible for these growths to interfere with the normal functioning of the gland, thereby producing hypothyroidism, a decreased activity of the gland. Hypothyroidism may result in unhealthy cholesterol levels, high blood pressure, and impaired heart muscle contraction. A more serious complication is coma.

Treatment

General: There is no cure for Cowden syndrome. Instead, treatment aims to reduce symptoms and prevent complications. People with Cowden syndrome should be seen regularly by a geneticist, dermatologist, neurologist, gastroenterologist, and endocrinologist. Female patients should also visit a gynecologist regularly. Most common complications arise from cancerous tumors that may develop. About 40% of people with Cowden syndrome develop at least one cancerous tumor. When detected early, many of these cancers are treatable.
Chemotherapy: Individuals with Cowden syndrome may develop cancer. Chemotherapy is the use of drugs designed to kill cancer cells by interfering with their ability to grow and reproduce. Many cancer drugs used today do not specifically attack cancer cells. This means that they affect not only cancer cells but also normal cells in the patients who take them, which is why chemotherapy drugs often produce severe side effects, including nausea, vomiting, diarrhea, hair loss, skin problems, and damage to blood and immune cells. Other types of side effects may also occur, depending on the specific drug used.
Education: By law, patients with Cowden syndrome who have intellectual disabilities must have access to education that is tailored to their specific strengths and weaknesses. According to the Individuals with Disabilities Education Act, all children with disabilities must receive free and appropriate education. This law states that staff members of the patient's school must consult with the patient's parents or caregivers to design and write an individualized education plan based on the child's needs. The school faculty must document the child's progress in order to ensure that the child's needs are being met.
Educational programs vary among patients, depending on the child's specific learning disabilities. In general, most experts believe that children with disabilities should be educated alongside their nondisabled peers. The idea is that nondisabled students will help the patient learn appropriate behavioral, social, and language skills. Therefore, some Cowden syndrome patients are educated in mainstream classrooms. Others attend public schools but take special education classes. Still others attend specialized schools that are equipped to teach children with disabilities.
Occupational therapy: Patients with Cowden syndrome may benefit from occupational therapy. During sessions, a therapist helps the child learn the skills needed to perform basic daily tasks, such as eating, dressing, and communicating with others. Some patients work with therapists who specialize in disorders and disabilities. Parents and caregivers can ask their child's pediatrician for recommended therapists.
Radiation therapy: Individuals with Cowden syndrome may develop cancer and receive a course of treatment that uses either radioactivity or X-rays. Radiation therapy is used to destroy cancerous growths and to slow down or stop the spread of abnormal cells.
Screening: People with Cowden syndrome should be regularly screened for cancerous and noncancerous tumors of the skin, breast, thyroid, and other susceptible areas. Screening can be conducted through various imaging techniques, such as mammography or physical examination.
Surgery: People with Cowden syndrome may opt for cosmetic surgical procedures, including a chemical peel, which is a technique used to improve the appearance of the skin. In this treatment, a chemical solution is applied to the skin, which causes the top layers of skin to blister and eventually peel off. The regenerated skin is usually smoother and less wrinkled than the old skin. The new skin also is temporarily more sensitive to the sun. There is a risk of permanently changing the color of the face and of scarring. Laser resurfacing accomplishes a similar result using lasers. Common minor side effects may include crusting, mild swelling, redness, or brown discoloration at the treatment sites. Excisions of skin tumors involve cutting out the tumor from the surface of the skin. In some cases, a preventive mastectomy (removal of breast tissue) is done before breast cancer develops. This procedure should be thoroughly discussed with a qualified healthcare provider and a surgeon.
Thyroid treatment: There are four main types of thyroid disease: hypothyroidism, or too little thyroid hormone; hyperthyroidism, or too much thyroid hormone; benign, or noncancerous, thyroid disease; and thyroid cancer. Individuals with Cowden syndrome may have any of these conditions. If an individual is diagnosed with hypothyroidism (underactive thyroid), he or she takes synthetic hormones to make up for the decreased hormone levels for the rest of his or her life. Some individuals may need to have their thyroid gland surgically removed. These people will also need to take hormones for the rest of their lives, but they are able to live normal, healthy lives.
If an individual is diagnosed with hyperthyroidism (overactive thyroid), several treatment options exist, including radioactive iodine, which is absorbed by the thyroid gland, where it causes the gland to shrink and symptoms to subside, usually within 3-6 months; and antithyroid medications, which gradually reduce symptoms of hyperthyroidism by preventing the thyroid gland from producing excess amounts of hormones. These medications include propylthiouracil (PTU) and methimazole (Tapazole?). Symptoms usually begin to improve in 6-12 weeks, but treatment with antithyroid medications typically continues for at least a year and often longer. For some individuals, symptoms of hyperthyroidism disappear completely, but others may experience a relapse. Beta-blockers, which are commonly used to treat hypertension (high blood pressure), are sometimes prescribed for hyperthyroidism. These drugs will not reduce thyroid levels, but they can reduce a rapid heart rate and help prevent palpitations. Individuals with hyperthyroidism may be prescribed beta-blockers until the thyroid levels return close to normal and heart symptoms disappear. Thyroidectomy, which is removal of the gland, is used when the individual cannot tolerate antithyroid drugs and does not want to have radioactive iodine therapy. These individuals may be at an increased risk for complications when using drugs or radioactive therapy.

Integrative therapies

Currently there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of Cowden syndrome.

Prevention

General: Cowden syndrome may be inherited or is a spontaneous mutation. Therefore, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with a family history of Cowden syndrome.
Genetic testing and counseling: Individuals who have Cowden syndrome may meet with a genetic counselor to discuss the risks of having children with the disease. Genetic counselors can explain the options and the associated risks of various tests, including preimplantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
PGD may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective PTEN gene, and only the embryos that are not affected may be selected for implantation. Because Cowden syndrome can be detected in a fetus, parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

Author information

This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Chen YM, Ott DJ, Wu WC, et al. Cowden's disease: a case report and literature review. Gastrointest Radiol. 1987;12(4):325-9.
Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22(3):183-98.
Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37(11):828-30.
Fackenthal JD, Marsh DJ, Richardson AL, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001;38(3):159-64.
Genetics Home Reference. .
Gustafson S, Zbuk KM, Scacheri C, et al. Cowden syndrome. Semin Oncol. 2007;34(5):428-34.
Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16(1):64-7.
Lindor NM, Greene MH. The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst. 1998;90(14):1039-71.
Mallory SB. Cowden syndrome (multiple hamartoma syndrome). Dermatol Clin. 1995;13(1):27-31.
McGarrity TJ, Wagner Baker MJ, Ruggiero FM, et al. GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol. 2003;98(6):1429-34.
Natural Standard: The Authority on Integrative Medicine. .
Nelen MR, van Staveren WC, Peeters EA, et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997;6(8):1383-7.
Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. 2004;41(5):323-6.
Schaffer JV, Kamino H, Witkiewicz A, et al. Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol. 2006;142(5):625-32.
Waite KA, Eng C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. 2003;12(6):679-84.
Walton BJ, Morain WD, Baughman RD, et al. Cowden's disease: a further indication for prophylactic mastectomy. Surgery. 1986;99(1):82-6.
Woodhouse J, Ferguson MM. Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J Radiol. 2006;79(946):801-3.

Causes

Genetic mutations: About 80% of Cowden syndrome cases are caused by mutations or defects in the PTEN gene, which is also known as MMAC1 or TEP1. The PTEN gene plays a role in cell growth regulation. PTEN is a tumor suppressor gene that encodes the PTEN protein, which normally prevents cells from growing and dividing too rapidly or in an uncontrolled way. Uncontrolled cell division can lead to the formation of hamartomas and cancerous tumors. Mutations in the PTEN gene have been identified in about 85% of people with Cowden syndrome.
When the PTEN protein is not produced properly or is produced in inadequate quantities, cells may grow uncontrollably, leading to cancerous and noncancerous tumors. In rare cases, Cowden syndrome appears to be caused by mutations in the BMPR1A gene, which provides instructions for making the morphogenetic proteins of the bone, a group of growth factors known for their ability to induce bone and cartilage formation. This rare form of Cowden syndrome may result in the development of bone cancer.
Autosomal dominant inheritance: In most cases, Cowden syndrome is inherited as an autosomal dominant trait. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to occur, only one defective copy of the PTEN gene is necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.
Random occurrence: Some cases of Cowden syndrome occur in individuals with no family history of the disease. This is the result of a spontaneous genetic mutation in the egg, sperm cells, or developing embryo. The percentage of cases resulting from these mutations is unknown.

Risk factors

Cowden syndrome may be inherited, or passed down among family members. Therefore, a risk factor is a family history of the condition.
Environmental factors may increase the risk of developing genetically linked diseases.
Cowden syndrome affects about one in 200,000 people worldwide and affects males and females in equal numbers. Certain complications to Cowden syndrome are more to specific to a person's sex. For example, males are more likely to develop thyroid cancer, while females are more likely to develop breast cancer.