PTEN Hamartoma Tumor Syndrome

Clinical characteristics.

The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome.

• CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, kidney, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. The lifetime risk of developing breast cancer is 85%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 35%. The lifetime risk for renal cell cancer (predominantly of papillary histology) is 34%. The risk for endometrial cancer may approach 28%.
• BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis.
• PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses.
• Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

Diagnosis/testing.

The diagnosis of PHTS is established in a proband by identification of a heterozygous germline PTEN pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: Treatment for the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts. Topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may alleviate the mucocutaneous manifestations of CS but are rarely utilized; cutaneous lesions should be excised only if malignancy is suspected or symptoms (e.g., pain, deformity, increased scarring) are significant.

Surveillance: To detect tumors at the earliest, most treatable stages:

• Children (age <18 years). Yearly thyroid ultrasound from the time of diagnosis (earliest reported at age 7 years) and skin check with physical examination
• Adults. Yearly thyroid ultrasound and dermatologic evaluation
• Women beginning at age 30 years. Monthly breast self-examination; annual breast screening (at minimum mammogram; MRI may also be incorporated). Starting by age 35 years, consider transvaginal ultrasound or endometrial biopsy.
• Men and women. Colonoscopy beginning at age 35 years with frequency dependent on degree of polyposis identified or family history of early-onset colon cancer (before age 40); biennial (every 2 years) renal imaging (CT or MRI preferred) beginning at age 40 years
• Those with a family history of a particular cancer type at an early age. Consider initiating screening 5 to 10 years prior to the youngest age of diagnosis in the family.

Evaluation of relatives at risk: When a PTEN pathogenic variant has been identified in a proband, molecular genetic testing of asymptomatic at-risk relatives can identify those who have the family-specific pathogenic variant and warrant ongoing surveillance.

Genetic counseling.

PHTS is inherited in an autosomal dominant manner. Because CS is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as ≥2 related affected individuals) cannot be determined. The majority of CS cases are simplex. Perhaps 10%-50% of individuals with CS have an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing PHTS. Once a PTEN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.

Suggestive Findings

The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome.

PTEN hamartoma tumor syndrome (PHTS) should be suspected in individuals with the following clinical features.

Establishing the Diagnosis

The diagnosis of PHTS is established in a proband by identification of a heterozygous germline pathogenic variant in PTEN on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with macrocephaly, developmental delay, and/or early-onset tumors are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

PTEN hamartoma tumor syndrome (PHTS) is characterized by hamartomatous tumors and germline PTEN pathogenic variants. Clinically, PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome.

• CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Renal cell carcinoma and colorectal carcinoma have also been shown to be in the PHTS spectrum.
• BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, vascular malformations, and pigmented macules of the glans penis.
• PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues.
• Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

Clinical Implications of All PHTS Phenotypes

The two most serious clinical manifestations in individuals with germline PTEN pathogenic variants are organ-specific cancers and neurodevelopmental disorders, including autism spectrum disorder (ASD).

PTEN-related lifetime neoplasia risks. Regardless of clinical diagnosis, individuals with a germline PTEN pathogenic variant are thought to have the same cancer risks as individuals with CS [Tan et al 2012].

Neurodevelopmental disorders. Neurodevelopmental phenotypes such as megalencephaly, ASD, and developmental delay have been reported in individuals with PHTS [Goffin et al 2001, Butler et al 2005, Hansen-Kiss et al 2017]. Germline PTEN pathogenic variants have been identified in 10%-20% of individuals with ASD and macrocephaly [Yehia et al 2020]. The extent of macrocephaly observed in PTEN-related ASD is often more severe than in individuals with macrocephalic ASD unrelated to PTEN [Mester et al 2011]. Individuals with PTEN-related ASD show increases in cortical white matter and a distinctive neurocognitive and behavioral phenotype including delayed language development, poor working memory and processing speed, and adaptive and sensory abnormalities [Frazier et al 2015, Busch et al 2019].

Genotype-Phenotype Correlations

For purposes of PTEN genotype-phenotype analyses, a series of 37 unrelated probands with CS were ascertained by the operational diagnostic criteria of the International Cowden Consortium, 1995 version [Nelen et al 1996, Eng 2000]. Association analyses revealed that families with CS and a germline PTEN pathogenic variant are more likely to develop malignant breast disease than are families who do not have a PTEN pathogenic variant [Marsh et al 1998]. In addition, pathogenic missense variants and others 5' to or within the phosphatase core motif appeared to be associated with involvement of five or more organs, a surrogate phenotype for severity of disease [Marsh et al 1998].

More than 90% of families that included individuals with CS and also individuals with BRRS were found to have a germline PTEN pathogenic variant. The mutational spectra of BRRS and CS have been shown to overlap. No difference in mutation frequencies was observed between BRRS occurring in a single individual in a family and BRRS occurring in multiple family members.

An individual presenting as a simplex case (i.e., one with no known family history) of Proteus-like syndrome comprising hemihypertrophy, macrocephaly, lipomas, connective tissue nevi, and multiple arteriovenous malformations was found to have a germline p.Arg335Ter PTEN pathogenic variant and the same somatic pathogenic variant (p.Arg130Ter) in three separate tissues, possibly representing germline mosaicism [Zhou et al 2000]. Both pathogenic variants have been previously described in individuals with clinical features of CS and BRRS.

Two of nine individuals who met the clinical diagnostic criteria of Proteus syndrome and three of six with Proteus-like syndrome were found to have germline PTEN pathogenic variants. Subsequently multiple individuals with germline PTEN pathogenic variants who met the clinical diagnostic criteria of Proteus syndrome have been reported [Yehia & Eng 2018].

Penetrance

More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [Nelen et al 1996, Eng 2000, Yehia et al 2020]. By the fourth decade, 99% of affected individuals develop the mucocutaneous stigmata, primarily trichilemmomas and papillomatous papules, as well as acral and plantar keratoses. (See also Clinical Description, Cowden Syndrome for the age at which specific manifestations are likely to become evident.)

Nomenclature

Cowden syndrome, Cowden disease, and multiple hamartoma syndrome have been used interchangeably.

Bannayan-Riley-Ruvalcaba syndrome, Bannayan-Ruvalcaba-Riley syndrome, Bannayan-Zonana syndrome, and Myhre-Riley-Smith syndrome refer to a similar constellation of signs that comprise what the authors refer to as BRRS. When a PTEN pathogenic variant is found, the gene-related name, PHTS, should be used.

One form of Proteus-like syndrome, with a clinical presentation similar to that first described by Zhou et al [2000] and with a germline PTEN pathogenic variant, was termed SOLAMEN (segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus) syndrome [Caux et al 2007]. This is not useful, especially in the molecular era, as any phenotype associated with a PTEN pathogenic variant should be termed PHTS with all its implications for clinical management [Yehia et al 2020].

Prevalence

Because the diagnosis of CS is difficult to establish, the true prevalence is unknown. The prevalence estimate of 1:200,000 [Nelen et al 1999] is likely low. Because of the variable and often subtle external manifestations of CS and BRRS, many individuals remain undiagnosed [Yehia et al 2020].

Evaluations and Surveillance Guidelines Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with PTEN hamartoma tumor syndrome (PHTS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. The most serious consequences of PHTS relate to the increased risk of cancers including breast, thyroid, endometrial, renal, and to a lesser extent, colon. In this regard, the most important aspect of management of any individual with a PTEN pathogenic variant is increased cancer surveillance to detect any tumors at the earliest, most treatable stages. Current suggested screening and surveillance by age are detailed in Table 4.

Treatment of Manifestations

Prevention of Primary Manifestations

Some women at increased risk for breast cancer consider prophylactic mastectomy, especially if breast tissue is dense or if repeated breast biopsies have been necessary. Prophylactic mastectomy reduces the risk of breast cancer by 90% in women at high risk [Hartmann et al 1999]. Note: The recommendation of prophylactic mastectomy is a generalization for women at increased risk for breast cancer from a variety of causes, not just from PHTS.

No direct evidence supports the routine use of agents such as tamoxifen or raloxifene in individuals with PHTS to reduce the risk of developing breast cancer. Physicians should discuss the limitations of the evidence and the risks and benefits of chemoprophylaxis with each individual. In addition, the clinician must discuss the increased risk for endometrial cancer associated with tamoxifen use in a population already at increased risk for endometrial cancer.

Agents/Circumstances to Avoid

Because of the propensity for rapid tissue regrowth and the propensity to form keloid tissue, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms (e.g., pain, deformity) are significant.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the PTEN pathogenic variant identified in the proband. Family members who have the familial PTEN pathogenic variant (and therefore have PHTS) are in need of initial evaluation and ongoing surveillance.

Molecular testing is appropriate for at-risk individuals younger than age 18 years, given the possible early disease presentation in individuals with BRRS and PTEN-related Proteus syndrome. In individuals with PHTS, the earliest documented breast cancer and thyroid cancer are at age 17 years and at age seven years, respectively.

Family members who have not inherited the PTEN pathogenic variant and their subsequent offspring have cancer risks similar to the general population.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Although mTOR inhibitors show promise for treatment of malignancies in individuals who have a germline PTEN pathogenic variant, use should be limited to clinical trials. A Phase II open-label clinical trial (NCT00971789) utilized the mTOR inhibitor sirolimus in adults with PHTS and showed evidence of improvement of symptoms throughout the duration of the trial [Komiya et al 2019]. Another double-blind drug-placebo cross-over clinical trial with the mTOR inhibitor everolimus is completing accrual of pediatric, adolescent, and young adults with germline PTEN pathogenic variants and autism spectrum disorder (NCT02461446).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are autosomal dominant disorders caused by either an inherited or a de novo PTEN pathogenic variant.

PTEN-related Proteus syndrome and Proteus-like syndrome are also autosomal dominant disorders but are almost always caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Cowden syndrome (CS). Because CS is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as ≥2 related affected individuals) cannot be determined. Based on practical experience, about 50% of individuals diagnosed with CS have an affected relative [Author, unpublished data]. De novo PTEN pathogenic variants occur in 10%-44% of PHTS probands [Mester & Eng 2012].
• Bannayan-Riley-Ruvalcaba syndrome (BRRS). The majority of evidence suggests that PTEN pathogenic variants occur in both simplex and familial occurrences of BRRS [Mester & Eng 2012, Yehia & Eng 2018].
• PTEN-related Proteus syndrome and Proteus-like syndrome. Virtually all individuals have a de novo pathogenic variant.
• If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
    * A parent with somatic and germline mosaicism for a PTEN pathogenic variant may be mildly/minimally affected.
• The family history of many individuals diagnosed with PTEN hamartoma tumor syndrome (PHTS) may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

• If a parent of the proband has the PTEN pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%. The penetrance of PHTS is close to 99% by the 30s in individuals with a PTEN pathogenic variant.
• If the PTEN pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Pritchard et al 2013].
• If the parents have not been tested for the PTEN pathogenic variant but are clinically unaffected and are in their thirties, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PHTS because of the possibility of age-related penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with PHTS has a 50% chance of inheriting the PTEN pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PTEN pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic family members requires prior identification of the germline PTEN pathogenic variant in the family.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ^®, National Cancer Institute).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the PTEN pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

While much functional research has been accomplished, complete function of PTEN is not yet fully understood. PTEN belongs to a subclass of phosphatases called dual-specificity phosphatases that remove phosphate groups from tyrosine as well as serine and threonine. In addition, PTEN is the major phosphatase for phosphoinositide-3,4,5-triphosphate, and thus downregulates the PI3K/AKT pathway [Yehia et al 2019].

The PTEN protein localizes to specific nuclear and cytoplasmic components. The wild type protein is a major lipid phosphatase that downregulates the PI3K/AKT pathway to cause G1 cell cycle arrest and apoptosis. In addition, the protein phosphatase appears to play an important role in inhibition of cell migration and spreading, as well as downregulating several cell cyclins. It appears that nuclear PTEN mediates cell cycle arrest, while cytoplasmic PTEN is required for apoptosis [Yehia & Eng 2018, Yehia et al 2019].

Germline pathogenic variants have been found throughout PTEN and include missense, nonsense, and splice site variants, small deletions, insertions, and large deletions. More than 150 unique pathogenic variants are currently listed in the Human Gene Mutation Database (see Table A). Nearly 40% of pathogenic variants are found in exon 5, which encodes the phosphate core motif [Yehia et al 2019]. Most pathogenic variants are unique, although a number of recurrent pathogenic variants have been reported, particularly those in Table 6.

Mechanism of disease causation. The majority (76%) of germline pathogenic variants in PTEN predict either truncated PTEN protein, lack of protein (haploinsufficiency), or dysfunctional protein. Many missense variants are functionally null and several act as dominant negatives [Papa et al 2014]. When PTEN is absent, decreased, or dysfunctional, phosphorylation of AKT1 is uninhibited, leading to the inability to activate cell cycle arrest and/or to undergo apoptosis. In addition, through lack of protein phosphatase activity, the mitogen-activated protein kinase (MAPK) pathway is dysregulated, leading to abnormal cell survival [Yehia et al 2019].

PTEN-specific laboratory technical considerations. PTEN has a highly homologous pseudogene (PTENP1) on chromosome 9 [Dahia et al 1998]. Special consideration should be taken when designing PTEN-specific primers to ensure specificity and to avoid cross-amplification of this pseudogene [Ngeow & Eng 2016].

Cancer and Benign Tumors

Sporadic cancers (including endometrial cancer, prostate cancer, glioblastoma) occurring as single tumors in the absence of any other findings of PHTS frequently harbor somatic variants in PTEN that are not present in the germline. Somatic PTEN variants and loss of gene expression are frequently found in both endometrioid endometrial adenocarcinoma and precancerous endometrial lesions (intraepithelial neoplasia) [Mutter et al 2000]. In these circumstances predisposition to these tumors is not heritable.

Author Notes

Dr Eng is the chair and coordinator of the International Cowden Syndrome Consortium, founding Chairwoman of the Cleveland Clinic Genomic Medicine Institute, and a primary researcher in the field of PTEN-related disorders. Dr Yehia is an Ambrose Monell Foundation Cancer Genomic Medicine Fellow at the Cleveland Clinic Genomic Medicine Institute. The Cleveland Clinic Genomic Medicine Institute program features the only multidisciplinary Cowden Syndrome center in the US, with ongoing clinical and molecular research protocols in PHTS.

Acknowledgments

We are eternally grateful to the many patients and families who have participated in our research and who continue to educate us in the ever-broadening clinical spectrum of PHTS, without which this review and these management recommendations could not have been written. Our PHTS research has been continuously supported by the American Cancer Society and the Doris Duke Distinguished Clinical Scientist Award, and, recently, by the National Cancer Institute. Dr Charis Eng is the Sondra J and Stephen R Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic.

Author History

Charis Eng, MD, PhD (2001-present)
Heather Hampel, MS; Ohio State University (2001-2006)
Robert Pilarski, MS; Ohio State University (2001-2006)
Jennifer L Stein, MS, CGC; Cleveland Clinic (2006-2009)
Lamis Yehia, PhD (2021-present)
Kevin M Zbuk, MD; Cleveland Clinic (2006-2009)

Revision History

• 11 February 2021 (sw) Comprehensive update posted live
• 2 June 2016 (sw) Comprehensive update posted live
• 23 January 2014 (me) Comprehensive update posted live
• 19 April 2012 (ce) Somatic AKT1 pathogenic variants reported to result in Proteus syndrome [Lindhurst et al 2011]
• 21 July 2011 (me) Comprehensive update posted live
• 5 May 2009 (me) Comprehensive update posted live
• 10 January 2006 (me) Comprehensive update posted live
• 19 May 2004 (ce) Revision: Genetic Counseling
• 17 December 2003 (me) Comprehensive update posted live
• 23 May 2003 (ce) Revision: Differential Diagnosis
• 29 November 2001 (me) Review posted live
• 10 July 2001 (ce) Original submission

Published Guidelines / Consensus Statements

• American Society of Clinical Oncology. Policy statement update: genetic and genomic testing for cancer susceptibility. Available online. 2015. Accessed 2-24-22. [PubMed: 26324357]
• Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. Available online. 2000. Accessed 2-24-22. [PMC free article: PMC1734465] [PubMed: 11073535]

Literature Cited

• Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84:389–95. [PubMed: 10360391]
• Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, Martinez-Agosto JA, Sahin M, Eng C, et al. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl Psychiatry. 2019;9:253. [PMC free article: PMC6783427] [PubMed: 31594918]
• Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42:318–21. [PMC free article: PMC1736032] [PubMed: 15805158]
• Caux F, Plauchu H, Chibon F, Faivre L, Fain O, Vabres P, Bonnet F, Selma ZB, Laroche L, Gérard M, Longy M. Segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLEMAN) syndrome is related to mosaic PTEN nulligosity. Eur J Hum Genet. 2007;15:767–73. [PubMed: 17392703]
• Dahia PLM, FitzGerald MG, Zhang X, Marsh DJ, Zheng Z, Pietsch T, von Deimling A, Haluska FG, Haber DA, Eng C. A highly conserved processed PTEN pseudogene is located on chromosome band 9p21. Oncogene. 1998;16:2403–6. [PubMed: 9620558]
• Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37:828–30. [PMC free article: PMC1734465] [PubMed: 11073535]
• Fackenthal JD, Marsh DJ, Richardson AL, Cummings SA, Eng C, Robinson BG, Olopade OI. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001;38:159–64. [PMC free article: PMC1734834] [PubMed: 11238682]
• Frazier TW, Embacher R, Tilot AK, Koenig K, Mester JL, Eng C. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism spectrum disorder. Mol Psychiatry. 2015;20:1132–8. [PMC free article: PMC4388743] [PubMed: 25288137]
• Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP. PTEN mutation in a family with Cowden syndrome and autism. Am J Med Genet. 2001;105:521–4. [PubMed: 11496368]
• Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet. 1992;44:307–14. [PubMed: 1336932]
• Hansen-Kiss E, Beinkampen S, Adler B, Frazier T, Prior T, Erdman S, Eng C, Herman G. A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children. J Med Genet. 2017;54:471–8. [PubMed: 28526761]
• Harach HR, Soubeyran I, Brown A, Bonneau D, Longy M. Thyroid pathologic findings in patients with Cowden disease. Ann Diagn Pathol. 1999;3:331–40. [PubMed: 10594284]
• Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77–84. [PubMed: 9887158]
• Heald B, Mester J, Rybicki L, Orloff MS, Burke CA, Eng C. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010;139:1927–33. [PMC free article: PMC3652614] [PubMed: 20600018]
• Hildenbrand C, Burgdorf WH, Lautenschlager S. Cowden syndrome-diagnostic skin signs. Dermatology. 2001;202:362–6. [PubMed: 11455162]
• Kim RH, Wang X, Evans AJ, Campbell SC, Nguyen JK, Farncombe KM, Eng C. Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome. NPJ Genom Med. 2020;5:40. [PMC free article: PMC7525494] [PubMed: 33083010]
• Komiya T, Blumenthal GM, DeChowdhury R, Fioravanti S, Ballas MS, Morris J, Hornyak TJ, Wank S, Hewitt SM, Morrow B, Memmott RM, Rajan A, Dennis PA. A pilot study of sirolimus in subjects with Cowden syndrome or other syndromes characterized by germline mutations in PTEN. Oncologist. 2019;24:1510–e1265. [PMC free article: PMC6975943] [PubMed: 31350329]
• Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP. WWP1 gain-of-function inactivation of PTEN in cancer predisposition. N Engl J Med. 2020;382:2103–16. [PMC free article: PMC7839065] [PubMed: 32459922]
• Lindhurst MJ, Sapp JC, Teer JL, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. A mosaic activating mutation in AKT1 associated with Proteus syndrome. N Engl J Med. 2011;365:611–9. [PMC free article: PMC3170413] [PubMed: 21793738]
• Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboué B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, Eng C, LePrat F, Odent S, Toulouse C, Olopade OI, Sobol H, Tishler S, Woods CG, Robinson BG, Weber HC, Parsons R, Peacocke M, Longy M, Eng C. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507–15. [PubMed: 9467011]
• McGarrity TJ, Wagner Baker MJ, Ruggiero FM, Thiboutot DM, Hampel H, Zhou XP, Eng C. 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;98:1429–34. [PubMed: 12818292]
• Mester J, Eng C. Estimate of de novo mutation frequency in probands with PTEN hamartoma tumor syndrome. Genet Med. 2012;14:819–22. [PMC free article: PMC3651836] [PubMed: 22595938]
• Mester JL, Tilot AK, Rybicki LA, Frazier TW, Eng C. Analysis of prevalence and degree of macrocephaly in patients with germline PTEN mutations and of brain weight in Pten knock-in murine model. Eur J Hum Genet. 2011;19:763–8. [PMC free article: PMC3137495] [PubMed: 21343951]
• Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 2012;79:1187.e1–7. [PMC free article: PMC3341468] [PubMed: 22381246]
• Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP, Eng C. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92:924–30. [PubMed: 10841828]
• Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, Woods CG, Fryns JP, Hamel B, Hoefsloot LH, Peeters EA, Padberg GW. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999;7:267–73. [PubMed: 10234502]
• Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet. 1996;13:114–6. [PubMed: 8673088]
• Ngeow J, Eng C. Germline PTEN mutation analysis for PTEN hamartoma tumor syndrome. Methods Mol Biol. 2016;1388:63–73. [PubMed: 27033071]
• Ngeow J, Mester J, Rybicki LA, Ni Y, Milas M, Eng C. Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab. 2011;96:E2063–71. [PMC free article: PMC3232626] [PubMed: 21956414]
• Ngeow J, Stanuch K, Mester JL, Barnholtz-Sloan J, Eng C. Second malignant neoplasms in Cowden syndrome patients with underlying germline PTEN mutations. J Clin Oncol. 2014;32:1818–24. [PMC free article: PMC4039869] [PubMed: 24778394]
• Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008;83:261–8. [PMC free article: PMC2495063] [PubMed: 18678321]
• Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, Eng C. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013;92:76–80. [PMC free article: PMC3542473] [PubMed: 23246288]
• Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM, Lunardi A, Webster K, Ng C, Newton RH, Knoblauch N, Guarnerio J, Ito K, Turka LA, Beck AH, Pinton P, Bronson RT, Wei W, Pandolfi PP. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell. 2014;157:595–610. [PMC free article: PMC4098792] [PubMed: 24766807]
• Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W, Walsh T, Bennett RL. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med. 2013;15:1004–7. [PubMed: 23619277]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Tan MH, Mester J, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400–7. [PMC free article: PMC3261579] [PubMed: 22252256]
• Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA, Milas K, Pederson H, Remzi B, Orloff MS, Eng C. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88:42–56. [PMC free article: PMC3014373] [PubMed: 21194675]
• Yehia L, Eng C. 65 Years of the double helix: One gene, many endocrine and metabolic syndromes: PTEN-opathies and precision medicine. Endocr Relat Cancer. 2018;25:T121–T140. [PubMed: 29792313]
• Yehia L, Eng C. PTEN hamartoma tumour syndrome: what happens when there is no PTEN germline mutation? Hum Mol Genet. 2020;29:R150–R157. [PMC free article: PMC7574959] [PubMed: 32568377]
• Yehia L, Keel E, Eng C. Clinical spectrum of PTEN mutations. Annu Rev Med. 2020;71:103–16. [PubMed: 31433956]
• Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019;129:452–64. [PMC free article: PMC6355220] [PubMed: 30614812]
• Yehia L, Niazi F, Ni Y, Ngeow J, Sankunny M, Liu Z, Wei W, Mester JL, Keri RA, Zhang B, Eng C. Germline heterozygous variants in SEC23B are associated with Cowden syndrome and enriched in apparently sporadic thyroid cancer. Am J Hum Genet. 2015;97:661–76. [PMC free article: PMC4667132] [PubMed: 26522472]
• Zhou XP, Marsh DJ, Hampel H, Mulliken JB, Gimm O, Eng C. Germline and germline mosaic PTEN mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arteriovenous malformations and lipomatosis. Hum Mol Genet. 2000;9:765–8. [PubMed: 10749983]
• Zhou XP, Marsh DJ, Morrison CD, Chaudhury AR, Maxwell M, Reifenberger G, Eng C. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet. 2003a;73:1191–8. [PMC free article: PMC1180498] [PubMed: 14566704]
• Zhou XP, Waite KA, Pilarski R, Hampel H, Fernandez MJ, Bos C, Dasouki M, Feldman GL, Greenberg LA, Ivanovich J, Matloff E, Patterson A, Pierpont ME, Russo D, Nassif NT, Eng C. Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet. 2003b;73:404–11. [PMC free article: PMC1180378] [PubMed: 12844284]