Version May 2024
INTRODUCTION — This monograph summarizes the interpretation of germline testing of the phosphatase and tensin homolog (PTEN) gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately [1].
OVERVIEW
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).
●Genotype – Identifies the variants in the gene(s) tested. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory) if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected cancer syndrome).
●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for variants of unknown significance (VUS). (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Molecular genetics'.)
The table provides a glossary of genetic testing terms (table 2).
PTEN gene — The PTEN gene, which is located on chromosome 10q23, is considered to be a tumor suppressor gene. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Molecular genetics'.)
Pathogenic variants in PTEN are the most common cause of PTEN hamartoma tumor syndromes (PHTS) and are inherited in an autosomal dominant fashion. Of note, other genes have been proposed as potential contributors to PHTS and many cases remain idiopathic even after thorough genetic evaluation. Involvement of a genetic counselor or hereditary cancer syndrome expert is important in individuals with PHTS for whom a pathogenic variant in PTEN cannot be identified. They may suggest additional testing (eg, with a gene panel) and provide specialized physical examination that can contribute to a clinical diagnosis. (See 'Locating a genetics expert or hereditary cancer syndrome expert' below.)
Disease associations — Germline pathogenic variants in the PTEN gene have been described in a variety of rare syndromes with different clinical presentations that are collectively known as PHTS. The defining clinical feature of PHTS is the presence of hamartomatous lesions, which are disorganized benign growths of native cells in native tissues. Besides multiple hamartomas in a variety of tissues, patients have macrocephaly, neurodevelopmental impairment (developmental delay/intellectual disability and/or autism), characteristic dermatologic manifestations such as trichilemmomas, oral fibromas, and punctate palmoplantar keratoses, and an increased risk of breast, endometrial, and other cancers.
Cowden syndrome — Patients with Cowden syndrome have characteristic mucocutaneous lesions and an elevated risk of breast, endometrial, thyroid, colorectal, and renal cancers as well as various other manifestations such as macrocephaly and dysplastic gangliocytoma of the cerebellum. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Clinical manifestations'.)
●Mucocutaneous – Skin and oral findings are a distinctive and common manifestation of Cowden syndrome. Common lesions associated with Cowden syndrome are trichilemmomas, acral keratoses, and facial papules/oral papillomas. Although commonly noticed in the second decade of life, the age of onset may vary from 4 to 75 years.
●Breast – Breast cancer is the most common malignancy in Cowden syndrome, although it is one of the more rare causes of hereditary breast cancer. The onset of breast cancer is often early, with diagnosis at a mean of 38 to 46 years of age.
●Thyroid – Thyroid disease is the most frequent extracutaneous manifestation of Cowden syndrome, occurring in over one-half of patients. Benign thyroid abnormalities include multinodular goiter, lymphocytic (Hashimoto) thyroiditis, and adenomas. Individuals with Cowden syndrome have an approximately 70-fold increased incidence of nonmedullary thyroid cancer relative to the general population.
●Genitourinary
•The risk of endometrial cancer and renal cell carcinoma is elevated in individuals with pathogenic variants in PTEN.
•Benign genitourinary abnormalities include uterine fibroids and lipomatosis of the testes.
●Gastrointestinal tract
•Polyps can occur throughout the gastrointestinal tract. Hamartomatous and inflammatory polyps are the most prevalent, but ganglioneuromas, adenomas, leiomyomas, lipomas, and hyperplastic polyps can also be found.
•An increased risk of early-onset colorectal cancer has also been reported.
•Diffuse glycogenic acanthosis of the esophagus has been described in association with Cowden disease. This benign lesion typically appears as multiple, uniformly sized gray-white round elevations, usually in the midportion of the esophagus.
●Neurologic – Neurologic disorders associated with germline PTEN pathogenic variants include:
•Dysplastic gangliocytoma of the cerebellum (adult Lhermitte-Duclos disease) is a histologically benign hamartomatous tumor of the cerebellar cortex.
•Macrocephaly, neurodevelopmental impairment (developmental delay/intellectual disability and/or autism).
Bannayan-Riley-Ruvalcaba syndrome — Bannayan-Riley-Ruvalcaba syndrome (BRRS) is characterized by macrocephaly, penile pigmented macules (lentigines), lipomas, vascular abnormalities, hamartomatous gastrointestinal polyps, and neurodevelopmental impairment (intellectual disability and/or autism). An increased risk of cancer has not been consistently demonstrated in BRRS, although several cases of thyroid cancer have been reported. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Bannayan-Riley-Ruvalcaba syndrome'.)
Other syndromes — Adult Lhermitte-Duclos disease may arise in conjunction with Cowden syndrome or without other signs of PHTS. Other syndromes have also been linked with PTEN pathogenic variants, include Proteus-like (segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus [SOLAMEN]) syndrome and autism spectrum disorder with macrocephaly. (See 'Pathogenic or likely pathogenic variant' below and "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Phenotypic spectrum of PHTS'.)
IMPLICATIONS BY TEST RESULT
Pathogenic or likely pathogenic variant — Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for at-risk family members. (See 'Counseling at-risk relatives' below.)
Counseling may require additional visits or referral to a genetic counselor, clinical geneticist, or oncologist. Acting upon genetic test results is usually not an emergency; the individual can be reassured that management decisions can be deferred until questions have been answered.
We consider all variants in PTEN that are pathogenic or likely pathogenic the same for purposes of counseling and cancer risk reduction, regardless of the initial reason for testing and the family history (algorithm 1).
In addition to genetic counseling and education regarding the syndrome and possible manifestations, recommendations for all patients include (see "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Management'):
●Annual comprehensive physical exam, with particular attention to breast and thyroid, starting at 18 years of age or five years before the youngest age of diagnosis of a component cancer in the family. Consider psychomotor assessment in children at diagnosis and brain magnetic resonance imaging (MRI) if there are symptoms.
●Several other interventions are recommended to reduce the risk of associated cancers. However, the use of these strategies depends on the patient's age, values, and preferences. These interventions include:
•Annual dermatology examinations.
•Annual thyroid ultrasound from age seven years.
•Colonoscopy at least every five years starting at age 35 unless symptomatic or if close relative with colon cancer before age 40; then start 5 to 10 years before the earliest known colorectal cancer in the family. Repeat every five years or more frequently if patient is symptomatic or polyps are noted.
•Renal ultrasound at age 40, then every one to two years.
•Biannual or annual clinical breast exam at age 25 years and annual mammography and breast MRI at age 30 to 35 or 5 to 10 years before the earliest known breast cancer in the family (whichever comes first).
•Endometrial biopsies every one to two years beginning at age 35, or five years younger than the earliest familial endometrial cancer diagnosis, for premenopausal women and annual transvaginal ultrasound examination for postmenopausal women. Random endometrial biopsies every one to two years. Transvaginal ultrasound (TVUS) to screen for endometrial cancer in postmenopausal individuals is insufficiently sensitive or specific to support a positive recommendation; however, it could be considered at the clinician's discretion. TVUS is not recommended for premenopausal individuals.
•Discussion of the option of risk-reducing mastectomy and hysterectomy.
•Screening for brain tumors is controversial. However, given the increased incidence of dysplastic gangliocytoma of the cerebellum and the nonspecific and insidious symptoms, there should be a low threshold to perform neuroimaging in any patient with a persistent headache or in children with abnormal psychomotor assessment.
The type of cancer and age of onset in a family member may also inform screening (eg, screening at an earlier age if a family member has an earlier age of onset). Additional details and the supporting evidence are discussed separately. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)
Negative test — Negative testing means no pathogenic or likely pathogenic variants were identified. However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes (algorithm 1).
●If the familial variant in PTEN is known and the tested individual does not have that variant, they can be reassured that they are not at high risk for PHTS-associated cancers, with the caveats outlined above (see 'How to read the report' above). However, it is important to assess family history and other cancer risk factors to provide an individualized risk.
●If a familial variant in PTEN is not known and the negative genetic testing was conducted on a relative with no features of PHTS, it is possible that other family members could harbor a pathogenic PTEN variant that the tested family members did not inherit. Additional risk factors (genetic or acquired) may be present and additional testing and/or surveillance based on family history and other risk factors may be needed. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of cancer. (See 'Locating a genetics expert or hereditary cancer syndrome expert' below.)
Involvement of a genetic counselor, clinical geneticist, or other expert is appropriate if a PTEN-related syndrome is suspected and genetic testing is negative. (See 'Locating a genetics expert or hereditary cancer syndrome expert' below.)
Variant of uncertain significance — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).
For individuals with a VUS for whom there are reasons to be concerned about a genetic cause, additional genetic testing may be appropriate. The need for additional testing may be discussed with a genetic counselor, the primary oncologist, or other specialists with expertise in managing hereditary colorectal cancer syndromes. In addition, new information may become available, and the testing laboratory or other resource should be consulted periodically for updates in the classification of the VUS (eg, annually). (See 'Locating a genetics expert or hereditary cancer syndrome expert' below.)
CONSIDERATIONS FOR FAMILY MEMBERS
Reproductive counseling — Reproductive counseling is appropriate for individuals with a pathogenic or likely pathogenic variant in PTEN who are considering childbearing.
Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
Counseling at-risk relatives — Individuals who test positive for a pathogenic variant or likely pathogenic variant should inform their at-risk relatives about the importance of genetic counseling and possible testing.
●The risk of having inherited the variant is 50 percent for first-degree relatives (parents, full siblings, and children). Other at-risk relatives who might have a risk of carrying the variant might include half siblings, aunts/uncles, nieces/nephews, grandparents, grandchildren, and cousins.
●Usually the variant segregates on the side of the family with PTEN hamartoma tumor syndromes (PHTS) manifestations, including a history of cancer; however, if possible, it is recommended to test a parent or other relative with cancer to determine the at-risk side of the family.
●Genetic testing for at-risk relatives may be considered in childhood.
●Families facing decisions to test minors should meet with a certified genetic counselor or other health care provider with genetics expertise. If genetic testing is deferred in a child at 50 percent risk, cancer screening is recommended until informative genetic testing is obtained. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and 'Implications by test result' above.)
RESOURCES
UpToDate topics
•PTEN hamartoma tumor syndromes (PHTS) and associated cancers – (See "PTEN hamartoma tumor syndromes, including Cowden syndrome".)
•Hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2 – (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'PTEN (PTEN hamartoma tumor syndrome)'.)
•Autism spectrum disorder – (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis", section on 'Genetic testing'.)
●Genetics:
•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
Locating a genetics expert or hereditary cancer syndrome expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
●National Institutes of Health (NIH) Cancer Genetics Services Directory
●Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA)
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