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Copyright 2007, 2012
NORD is very grateful to Charis Eng, MD, PhD, Chair and Director, Genomic Medicine Institute, and Director, Center for Personalized Genetic Healthcare, Cleveland Clinic; Professor and Vice Chairman, Department of Genetics, Case Western Reserve University School of Medicine, and Jessica Mester, MS, CGC, Cleveland Clinic Genetic Counselor and PTEN Study Coordinator for assistance in the preparation of this report.
The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations of the PTEN gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for benign tumor-like malformation composed of mature cells and tissue normally found in the affected area that have grown in a disorganized manner.
Individuals with a variety of clinical diagnoses who ultimately have been found to carry a germline PTEN mutation as the underlying cause are said to have PHTS. When the strictest diagnostic criteria are used, patients with a personal and family history of Cowden syndrome (CS) features have up to an 85% chance to have a PTEN mutation. Patients with features of Bannayan-Riley-Ruvalcaba syndrome (BRRS) and with features reminiscent of but not meeting diagnostic criteria for Proteus syndrome (called Proteus-like syndrome) have also been found to have an underlying PHTS diagnosis. Recently a mutation risk calculator has been developed which can estimate the risk for adults to have a PTEN mutation based on their personal history characteristics; this tool is available online at http://www.lerner.ccf.org/gmi/ccscore/.
Once thought to be completely separate conditions, patients with features of CS or BRRS and an underlying PTEN mutation are unified as all having PHTS, with CS being a diagnosis traditionally given to adults and BRRS being first described in the pediatrics literature. This makes sense given that many of the characteristics first associated with CS tend to not appear until adulthood. PHTS is inherited as an autosomal dominant trait, which means it can be passed down in a 50-50 fashion. The symptoms vary greatly from patient to patient, even among individuals in the same family. For more information on Bannayan-Riley-Ruvalcaba syndrome and Proteus syndrome, see NORD's individual reports on these disorders in the Rare Disease Database.
The primary findings in PHTS include increased risk for certain types of cancer, benign tumors and tumor-like malformations (hamartomas), and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.
Cancer in PHTS
Previous data, which focused only on patients with a clinical diagnosis of Cowden syndrome without understanding whether an underlying PTEN mutation was present estimated lifetime breast cancer risk to be 25-50% and risk for non-medullary thyroid cancer to be 10%. Risks for endometrial (uterine) and renal cell (kidney) cancer were thought to be increased, but an exact risk level was undetermined.
Current data focusing on patients known to have PHTS provide the following lifetime risk estimates, with the majority of diagnoses occurring after age 30:
·Breast cancer: 85%
·Thyroid cancer: 35%
·Renal cell cancer: 34%
·Endometrial cancer: 28%
·Colorectal cancer: 9%
Benign tumors in PHTS
Benign skin or oral lesions are very common and most commonly appear in adulthood. The most common types of benign skin lesions seen in PHTS include:
·Lipomas - benign fatty tumors which can appear just under the skin or elsewhere (breast area, GI tract)
·Acral keratosis - rough patches of skin most often seen on the extremities (arms, hands, legs, feet)
·Papillomatous skin papules - wart-like lesions which can appear anywhere, with feet and hands commonly being affected
·Mucosal papillomas - Benign overgrowth of tissue affecting the tongue, gums, or inside the nose
·Trichilemmomas - Benign tumor of the hair follicle
·Fibromas - another kind of overgrowth involving the skin and other connective tissue; may also affect tissue covering organs, such as the ovaries.
Gastrointestinal polyps are very common in adults with PHTS. Among patients who had undergone endoscopy, 93% were found to have polyps. The kinds of polyps found most often were hyperplastic or hamartomatous, which rarely develop into malignancy; however adenomas, which may develop into a cancer, were also identified. Many polyps were very small and did not cause symptoms to make their presence known such as pain or rectal bleeding.
Benign breast, thyroid, and uterine lesions are also common in persons with PHTS. Some women have severe fibrocystic disease or changes which lead to multiple breast biopsies and complications with imaging. Multinodular goiter and Hashimoto’s thyroiditis may develop in children and adults. Uterine fibroids may appear and cause bleeding or discomfort to the extent that hysterectomy is indicated without an underlying cancer diagnosis.
Vascular tumors, including hemangiomas, arteriovenous malformations, and developmental venous anomalies, have also been observed in patients with PHTS. Treatment of some lesions has been complicated by tendency for regrowth.
A minority of adults develop a rare tumor known as a cerebellar dysplastic gangliocytoma (Lhermitte-Duclos syndrome). Symptoms of Lhermitte-Duclos syndrome include increased intracranial pressure, impaired ability to coordinate voluntary movements (ataxia), and seizures. It is rare when a person with adult-onset Lhermitte-Duclos does not have an underlying PTEN mutation, and observing this tumor type is an automatic indicator of need for PTEN testing.
Neurodevelopmental concerns in PHTS
Macrocephaly (large head size) is found in 94% measured patients with PHTS and can be a helpful screening tool to identify patients at increased risk for PTEN mutation. In most patients large head size is caused by overgrowth of brain tissue as opposed to hydrocephalus. The head shape also tends to be longer than wide (dolicocephaly).
Autism and other developmental disorders, such as mental retardation and developmental delays, have been observed in patients with PHTS. In previous case series, up to 12% of children presenting with macrocephaly and an autism spectrum disorder alone were found to have an underlying PTEN mutation.
PHTS is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
PHTS is caused by germline mutations of PTEN, a tumor suppressor gene. PTEN stands for phosphatase, tensin homologue, deleted on chromosome 10. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often lead to cancer. The PTEN gene regulates the production of an enzyme (protein tyrosine phosphatase), which is believed to mediate cell growth arrest and apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies.
The PTEN gene is located on the long arm (q) of chromosome 10 (10q23). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 10q23" refers to band 23 on the long arm of chromosome 10. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Cowden syndrome was estimated to affect 1 in 200,000 individuals; this study was conducted just as PTEN was discovered. However, because the disorder is difficult to recognize, researchers believe it is under-diagnosed, making it difficult to determine its true frequency in the general population. Men and women are affected equally with PHTS; PHTS is not more commonly found in persons of a particular racial or ethnic group.
Symptoms of the following disorders can be similar to those of PHTS. Comparisons may be useful for purposes of formulating a genetic differential diagnosis.
Hereditary breast and ovarian cancer syndrome (HBOC) is similar to PHTS in that patients are at high lifetime risk of developing breast cancer. Ovarian, pancreatic, and prostate cancers as well as melanoma have also been associated. However, patients with HBOC are not at increased risk for the other benign or malignant tumors or neurodevelopmental concerns associated with PHTS. HBOC is inherited in an autosomal dominant manner and is caused by mutation in either the BRCA1 or BRCA2 gene, located at 17q21 (long arm of chromosome 17) and 13q12.3 (long arm of chromosome 13), respectively.
Lynch syndrome, formerly called hereditary nonpolyposis colorectal cancer syndrome, causes increased risks for primarily colon, uterine, ovarian, and stomach cancers. Debate exists regarding whether risk for breast cancer is increased as well. Lynch syndrome is inherited in an autosomal dominant manner. Like in HBOC, patients with Lynch syndrome are not at increased risk for thyroid cancer or the other benign tumors and neurodevelopmental features seen in PHTS. At present five genes are known to cause Lynch syndrome; these genes are part of the mismatch repair complex.
Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are conditions which like PTHS, cause increased risks for polyposis and colorectal cancers. However patients with FAP/MAP tend to develop adenomatous polyps, whereas patients with PHTS are found to mostly have hyperplastic or hamartomatous polyps. Additionally, the extra-colonic features of PHTS are not identified in patients with FAP/MAP with the exception of papillary thyroid cancer, which has been associated with FAP. FAP is inherited in an autosomal dominant manner and MAP in an autosomal recessive manner. FAP and MAP are caused by mutation of the APC gene located at 5q21 (long arm of chromosome 5) and the MUTYH gene located at 1p34 (short arm of chromosome 1).
Familial juvenile polyposis is characterized by small multiple growths (polyps) within the gastrointestinal system. Symptoms may include gastrointestinal bleeding, abdominal pain, diarrhea, rectal prolapse, collapse of a portion of the bowel into itself, and/or gastrointestinal obstruction. Some affected individuals may experience protein loss, malnutrition, and a feeling of general ill health (cachexia). Individuals affected by familial juvenile polyposis may have an increased risk of colon cancer. Other symptoms may include clubbing of the finger and toes, failure to thrive, low levels of circulating red blood cells (anemia). Familial juvenile polyposis is inherited as an autosomal dominant trait. Familial juvenile polyposis may be caused by mutations in the BMPR1A gene located on chromosome 10 (10q22.3) or mutations in the SMAD4 gene also known as the MADH4 or DPC4 gene, located on the long arm of chromosome 18 (18q21.1). A rare subset of juvenile polyposis called juvenile polyposis of infancy can be caused by deletion of a piece of chromosome 10 encompassing both BMPR1A and PTEN.
Peutz-Jeghers syndrome is a rare, inherited gastrointestinal disorder characterized by the development of polyps on the mucous lining of the intestine and dark discolorations on the skin and mucous membranes. Symptoms include nausea, vomiting, and abdominal pain that occurs because of a form of intestinal obstruction (intussusception). Additional symptoms include bleeding from the rectum and dark skin discolorations around the lips, inside the cheeks, and on the arms. Severe rectal bleeding can cause anemia and episodes of recurring, severe abdominal pain. Peutz-Jeghers syndrome is inherited as an autosomal dominant trait and occurs due to mutations of a gene located on chromosome 19. (For more information on this disorder, choose "Peutz-Jeghers" as your search term in the Rare Disease Database.)
Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally). At birth, affected infants have unusually increased body length that is abnormal in proportion to weight, which may also be above average; in addition, newborns typically demonstrate advanced bone growth, abnormally large hands and/or feet, and characteristic facial features. Abnormally rapid growth continues after birth until approximately four or five years of age, at which time growth may slow to a normal rate. An affected individual's final height often is within normal range. Affected infants and children may also demonstrate developmental abnormalities including delays in reaching developmental milestones (e.g., sitting, crawling, walking); delays in the acquisition of skills requiring the coordination of muscular and mental activity (psychomotor retardation); delayed language skills; and mild to severe mental retardation. Characteristic facial abnormalities may include an unusually large head (macrocephaly) that may appear elongated (dolichocephalic) with an abnormally prominent forehead (frontal bossing); widely-spaced eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); a highly-arched roof of the mouth (palate); protrusion of the lower jaw (prognathism); and/or a pointed chin. Most cases of Sotos syndrome occur randomly, for no known reason (sporadically). In rare cases, however, when a positive family history is found, the disorder may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Sotos" as your search term in the Rare Disease Database.)
Neurofibromatosis 1 (NF1) can mimic PHTS in that patients with each condition may develop skin lesions and gastrointestinal ganglioneuromatosis (a type of hamartoma) and have macrocephaly and developmental delays. However, the vast majority of patients with NF1 also have multiple café-au-lait macules (light brown birthmarks), freckling in the armpit and groin region, and lisch nodules, benign freckle-like lesions over the colored part of the eye. Additionally the primary skin lesion which develops is a neurofibroma. NF1 is inherited in an autosomal dominant manner and is caused by mutation of the Neurofibromin gene, located on the long arm of chromosome 17 (17q11.2).
Multiple endocrine neoplasia 2B (MEN 2B) shares overlap with PHTS in that both conditions cause gastrointestinal ganglioneuromatosis, mucosal lesions, and risk for thyroid cancer. However in MEN 2B the kind of thyroid cancer is different (medullary) than in PHTS (most follicular or papillary). Additionally patients with MEN 2B do not have the other systemic manifestations of PHTS, and tend towards having a Marfanoid body structure (tall and thin with long arms and legs). Furthermore, in contrast to the MEN 2B-related ganglioneuromatosis, the PHTS-associated lesions are ganglioneuromatous polyps.
A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation, a detailed patient history and the presence of characteristic findings. Recently, a mutation risk calculator has been developed which can estimate the risk for adults to have a PTEN mutation based on their personal history characteristics; this tool is available online at http://www.lerner.ccf.org/gmi/ccscore/. The diagnosis can only be confirmed when a mutation of the PTEN gene is identified.
Individuals with PTEN mutations should undergo cancer surveillance and screening at the time of diagnosis as follows to enable healthcare providers to detect any tumors at the earliest, most treatable stages. Current suggested screening by age includes:
Pediatric (below age 18)
·Yearly thyroid ultrasound
·Yearly skin check with physical examination
·Consider neurodevelopmental evaluation
·Monthly breast self-examination
·Yearly thyroid ultrasound and dermatologic evaluation
·Women: breast screening (at minimum mammogram) yearly at age 30; MRI may also be incorporated
·Women: annual transvaginal ultrasound or endometrial biopsy beginning at age 30
·Colonoscopy beginning at age 35-40; frequency dependent on degree of polyposis identified
·Biannual renal imaging (CT or MRI preferred) beginning at age 40
For patients with a family history of a particular cancer type at a very early age screening for the patient may be considered 5-10 years prior to the youngest diagnosis in the family. For example, a patient whose mother developed breast cancer at 30 may begin breast surveillance at age 25-30.
Additional treatment for PHTS is symptomatic and supportive. Various techniques may be used to treat the mucocutaneous symptoms of Cowden syndrome including topical agents, the use of extreme cold to destroy affected tissue (cryosurgery), the removal of tissue or growths by through a process called curettage, in which a surgical tool shaped like a spoon (curette) is used to scrape away affect tissue, or destroying affected tissue by exposing it to laser beams (laser ablation). Genetic counseling may be of benefit for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Clinical trial information may also be found at www.clinicaltrials.gov.
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about PTEN hamartoma tumor syndrome:
Charis Eng, MD, PhD, FACP
Sondra J. & Stephen R. Hardis Chair in Cancer Genomic Medicine
Chair and Director, Genomic Medicine Institute
Director, Center for Personalized Genetic Healthcare
American Cancer Society Clinical Research Professor
Cleveland Clinic Lerner Research Institute
9500 Euclid Avenue, Mailstop NE-50 (Rm NE5-314)
Cleveland, OH 44195
Tel +1 216 444 3440
Fax +1 216 636 0655
Jessica Mester, MS, CGC
PTEN Study Coordinator
9500 Euclid Ave. NE50
Cleveland, OH 44195
250 Williams NW St
Atlanta, GA 30303 USA
Phone #: 404-320-3333
800 #: 800-227-2345
Home page: http://www.cancer.org
16057 Tampa Palms Blvd. W.
Tampa, FL 33647
Phone #: 954-827-2200
800 #: 866-288-7475
Home page: http://www.facingourrisk.org
PO Box 8126
Gaithersburg, MD 20898-8126
Phone #: 301-251-4925
800 #: 888-205-2311
Home page: http://rarediseases.info.nih.gov/GARD/
PO Box 241956
Los Angeles, CA 90024
Phone #: 310-264-0826
800 #: N/A
Home page: http://www.madisonsfoundation.org
1275 Mamaroneck Avenue
White Plains, NY 10605
Phone #: 914-997-4488
800 #: 888-663-4637
Home page: http://www.marchofdimes.com
6116 Executive Blvd Suite 300
Bethesda, MD 20892-8322 USA
Phone #: 301-435-3848
800 #: 800-422-6237
Home page: http://www.cancer.gov
Phone #: 256--52-0-8529
800 #: N/A
Home page: http://www.ptenfoundation.org
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Home page: http://www.ptenworld.com
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Green Valley, AZ 85614 USA
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800 #: --
Home page: http://www.rare-cancer.org
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Report last updated: 2012/03/16 00:00:00 GMT+0