DiagnosisClinical DiagnosisThe PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome. A presumptive diagnosis of PHTS is based on clinical signs; by definition, however, the diagnosis of PHTS is made only when a PTEN mutation is identified (see Molecular Genetic Testing). Cowden syndrome (CS). Consensus diagnostic criteria for CS have been developed [Eng 2000] and are updated each year by the National Comprehensive Cancer Network [NCCN 2006]. See . Clinical criteria have been divided into three categories: pathognomonic, major, and minor.Pathognomonic criteriaAdult Lhermitte-Duclos disease (LDD), defined as the presence of a cerebellar dysplastic gangliocytoma [Zhou et al 2003a]Mucocutaneous lesions (Figures 1, 2): Trichilemmomas (facial) (see Figure 1)Acral keratosesPapillomatous lesions (see Figure 2)Mucosal lesionsFigureFigure 1. Trichilemmoma FigureFigure 2. Papillomatous papules in the periocular region (A) and on the dorsum of the hand (B) Major criteriaBreast cancerEpithelial thyroid cancer (non-medullary), especially follicular thyroid cancerMacrocephaly (occipital frontal circumference ≥97th percentile)Endometrial carcinomaMinor criteriaOther thyroid lesions (e.g., adenoma, multinodular goiter)Intellectual disability (IQ ≤75)Hamartomatous intestinal polypsFibrocystic disease of the breastLipomasFibromasGenitourinary tumors (especially renal cell carcinoma)Genitourinary malformationUterine fibroidsAn operational diagnosis of CS is made if an individual meets any one of the following criteria:Pathognomonic mucocutaneous lesions combined with one of the following:Six or more facial papules, of which three or more must be trichilemmomaCutaneous facial papules and oral mucosal papillomatosisOral mucosal papillomatosis and acral keratosesSix or more palmo-plantar keratosesTwo or more major criteriaOne major and three or more minor criteriaFour or more minor criteriaIn a family in which one individual meets the diagnostic criteria for CS listed above, other relatives are considered to have a diagnosis of CS if they meet any one of the following criteria:The pathognomonic criteriaAny one major criterion with or without minor criteriaTwo minor criteriaHistory of Bannayan-Riley-Ruvalcaba syndromeBannayan-Riley-Ruvalcaba syndrome (BRRS). Diagnostic criteria for BRRS have not been set but are based heavily on the presence of the cardinal features of macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis [Gorlin et al 1992]. Proteus syndrome (PS) is highly variable and appears to affect individuals in a mosaic distribution (i.e., only some organs/tissues are affected). Thus, it is frequently misdiagnosed despite the development of consensus diagnostic criteria [Biesecker et al 1999]. Mandatory general criteria for diagnosis include mosaic distribution of lesions, progressive course, and sporadic occurrence. Additional specific criteria for diagnosis include:Connective tissue nevi (pathognomonic)OR two of the following:Epidermal nevusDisproportionate overgrowth (one or more)Limbs: arms/legs; hands/feet/digitsSkull: hyperostosesExternal auditory meatus: hyperostosisVertebrae: megaspondylodysplasiaViscera: spleen/thymusSpecific tumors before end of second decade (either one)Bilateral ovarian cystadenomasParotid monomorphic adenomaOR three of the following:Dysregulated adipose tissue (either one)LipomasRegional absence of fatVascular malformations (one or more)Capillary malformationVenous malformationLymphatic malformationFacial phenotypeDolichocephalyLong faceMinor downslanting of palpebral fissures and/or minor ptosisLow nasal bridgeWide or anteverted naresOpen mouth at restProteus-like syndrome is undefined but describes individuals with significant clinical features of PS but who do not meet the diagnostic criteria.TestingPathologic review is essential in confirming the appropriate histopathology of the characteristic dermatologic, thyroid, breast, endometrial, and colonic lesions that can be seen with PHTS.Molecular Genetic TestingGene. PTEN is the only gene in which mutations are known to cause PTEN hamartoma tumor syndrome (PHTS). TestingSequence analysis. Virtually all missense mutations in PTEN are believed to be deleterious [Eng 2003; Zbuk & Eng 2007; Eng, unpublished data]. Early studies suggest that up to 85% of individuals who meet the diagnostic criteria for CS [Marsh et al 1998, Zhou et al 2003b] and 65% of individuals with a clinical diagnosis of BRRS [Marsh et al 1999, Zhou et al 2003b] have a detectable PTEN mutation [Zbuk & Eng 2007]. More recently, it was found that approximately 25% of individuals who meet the strict diagnostic criteria for CS have a pathogenic PTEN mutation, including large deletions [Tan et al 2011]. Of note, Tan et al [2011] did not consider all variants of unknown significance; therefore, the estimate of 25% is very conservative.
Note: The discrepancy between the early studies and the more recent study of Tan et al [2011] is likely explained by the early studies analyzing CS that segregated in families and individuals with the most obvious phenotypes. The early series comprised part of the series that mapped and identified the gene. Data suggest that up to 50% of individuals with a Proteus-like syndrome and up to 20% of individuals with Proteus syndrome have PTEN mutations [Zhou et al 2001a, Smith et al 2002, Eng 2003, Loffeld et al 2006, Orloff & Eng 2008].
Note: In the Thiffault et al [2004] study, no PTEN mutations were detected in individuals with Proteus syndrome, potentially signaling the existence of other genes in this syndrome or the relative insensitivity of the mutation detection technique used. See Differential Diagnosis.Deletion/duplication analysis. Southern blotting, real-time PCR, MLPA and other methods of detecting gene copy number variation can each be used to detect large PTEN deletions and rearrangements that are not detectable by PCR-based sequence analysis.It was previously believed that individuals with CS do not harbor large deletions; however, individuals with CS who have such deletions have been reported [Zbuk & Eng 2007, Orloff & Eng 2008, Tan et al 2011].Approximately 10% of individuals with BRRS who do not have a mutation detected in the PTEN coding sequence have large deletions within or encompassing PTEN [Zhou et al 2003b]. Promoter analysis. Direct sequencing of the promoter region detects mutations that alter the function of the gene in approximately 10% of those individuals with CS who do not have an identifiable mutation in the PTEN coding region [Zhou et al 2003b].Table 1. Summary of Molecular Genetic Testing Used in PTEN Hamartoma Tumor SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method and Phenotype ^{1Test AvailabilityCSBRRSPLSPSPTENSequence analysisSequence variants 280%60%50%20%Clinical Deletion/ duplication analysis 3Exonic or whole-gene deletionsSee footnote 411% 5UnknownUnknownPromoter analysisPromoter mutations10% 5, 6See footnote 4UnknownUnknownResearch onlyCS= Cowden syndromeBRRS= Bannayan-Riley-Ruvalcaba syndromePLS= Proteus-like syndromePS= Proteus syndrome1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. 4. Finite but unknown 5. Zhou et al [2003b]6.10% of individuals with CS phenotype who do not have an identifiable sequence variantInterpretation of test results. Failure to detect a mutation does not exclude a clinical diagnosis of CS, BRRS, PS, or Proteus-like syndrome in an individual with significant signs associated with these disorders.For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband requires identification of a PTEN mutation. Based on clinical and demographic features in 3042 probands with Cowden syndrome and Cowden-like syndrome, the PTEN Cleveland Clinic Risk Calculator provides the prior probability of finding a PTEN mutation in children and adults (www.lerner.ccf.org/gmi/ccscore). It is recommended that clinical testing be considered for adults with a PTEN Cleveland Clinic Score of ≥10. Of note, this is the first risk calculator designed specifically to assess children as well.The order of PTEN testing to optimize yield would be:1.Sequencing of PTEN exons 1-9 and flanking intronic regions. If no mutation is identified, perform: 2.Deletion/duplication analysis. If no mutation is identified, consider: 3.Promoter analysis
If no PTEN mutation is identified, consider:4.Other testing, especially in those with Cowden syndrome (CS) and Cowden-like syndrome:KLLN promoter methylation analysis (see Differential Diagnosis, Germline KLLN epimutation) SDHB-D analysis (see Differential Diagnosis, New susceptibility genes in individuals with non-PHTS CS and a CS-like disorder) Predictive testing for at-risk asymptomatic family members (including children) requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersNo phenotypes other than Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome are known to be consistently caused by mutations in PTEN.Phenotypes that can be associated with PTEN germline mutations:Lhermitte-Duclos disease (LDD). Most, if not all, adult-onset Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum, a hamartomatous overgrowth known to be a feature of CS) can be attributed to mutations in PTEN, even in the absence of other clinical signs of CS/BRRS. However, germline PTEN mutations appear to be rare in individuals with childhood-onset LDD [Zhou et al 2003a].Autism/pervasive developmental disorder and macrocephaly. Germline PTEN mutations were identified in individuals with these findings, especially in the presence of other personal or family history consistent with CS/BRRS [Dasouki et al 2001, Goffin et al 2001]. Butler et al [2005] found that approximately 20% of individuals with autism spectrum disorders and macrocephaly have germline PTEN mutations. The 10%-20% prevalence of germline PTEN mutations in autism spectrum disorders with macrocephaly has now been confirmed by several independent groups [Herman et al 2007a, Herman et al 2007b, Orrico et al 2009, Varga et al 2009].}

Natural HistoryThe PTEN hamartoma tumor syndrome (PHTS) is characterized by hamartomatous tumors and germline PTEN mutations. Clinically, PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, 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.Cowden syndrome (CS). More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [Nelen et al 1996, Eng 2000]. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, primarily trichilemmomas and papillomatous papules, as well as acral and plantar keratoses. In addition, individuals with Cowden syndrome usually have macrocephaly and dolicocephaly. Hamartomatous and mixed gastrointestinal polyps, seen frequently in the majority of people with PHTS, do confer an increased risk for colorectal cancers [Heald et al 2010]. Based on anecdotal observations, glycogenic acanthosis in the presence of features of CS appears to be associated with a high likelihood of finding a PTEN mutation [Eng 2003, McGarrity et al 2003].Tumor risk. Individuals with CS have a high risk of breast, thyroid, and endometrial cancers. As with other hereditary cancer syndromes, the risk of multifocal and bilateral (in paired organs such as the breasts) cancer is increased:Breast diseaseWomen with Cowden syndrome have as high as a 67% risk for benign breast disease. Prior to gene identification, estimates of lifetime risk to females of developing breast cancer were 25%-50%, with an average age of diagnosis between 38 and 46 years [Brownstein et al 1978, Starink et al 1986]; however, a recent analysis of prospectively accrued and followed probands and family members with a PTEN mutation reveal an 85% lifetime risk for female breast cancer, with 50% penetrance by age 50 years [Tan et al 2012]. Although breast cancer has been described in males with a PTEN mutation [Fackenthal et al 2001], it was not observed in a recent study of more than 3000 probands [Tan et al 2011].Thyroid diseaseBenign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [Harach et al 1999]. The lifetime risk for epithelial thyroid cancer is approximately 35% [Tan et al 2012]. Median age of onset was 37 years; seven years was the youngest age at diagnosis [Ngeow et al 2011].
Note: (1) Follicular histology is over-represented in adults compared to the general population in which papillary histology is over-represented. (2) No medullary thyroid carcinoma was observed in the mutation-positive cohort.Endometrial diseaseBenign uterine fibroids are common. Lifetime risk for endometrial cancer is estimated at 28%, with the starting age-at-risk in the late 30s-early 40s [Tan et al 2012].Gastrointestinal neoplasiasMore than 90% of individuals with a PTEN mutation who underwent at least one upper or lower endoscopy were found to have polyps [Heald et al 2010]. Histologic findings varied, ranging from ganglioneuromatous polyps, hamartomatous polyps, and juvenile polyps to adenomatous polyps. Lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [Tan et al 2012].Renal cell carcinomaLifetime risk for renal cell carcinoma is estimated at 35%, with the starting age at risk in the 40s [Tan et al 2012]. The predominant histology is papillary renal cell carcinoma [Mester et al 2012].OtherLifetime risk for cutaneous melanoma is estimated at more than 5%.Brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS.
Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS.A rare central nervous system tumor, cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease) is also found in CS and may be pathognomonic.Bannayan-Riley-Ruvalcaba syndrome (BRRS). Common features of BRRS, in addition to those mentioned above, include high birth weight, developmental delay, and mental deficiency (50% of affected individuals), a myopathic process in proximal muscles (60%), joint hyperextensibility, pectus excavatum, and scoliosis (50%) [Gorlin et al 1992, Zbuk & Eng 2007]. Although cancer was initially not believed to be a component of the syndrome, individuals with BRRS and a PTEN mutation are currently thought to have the same cancer risks as individuals with CS [Marsh et al 1999]. Note: It is not clear whether these risks apply to individuals with BRRS who do not have a PTEN mutation. The gastrointestinal hamartomatous polyps in BRRS (seen in 45% of affected individuals) may occasionally be associated with intussusception, but rectal bleeding and oozing of "serum" is more common. These polyps are not believed to increase the risk for colorectal cancer. PHTS hamartomatous polyps are different in histomorphology from the polyps seen in Peutz-Jeghers syndrome.Juvenile polyposis of infancy (JPI). In this rare condition, caused by germline deletion of BMPR1A and PTEN, juvenile polyposis is diagnosed before age six years [Delnatte et al 2006]. Often the gastrointestinal manifestations of bleeding, diarrhea, and protein-losing enteropathy are severe. External stigmata may mimic BRRS. Proteus syndrome (PS) is a complex disorder comprising malformations and hamartomatous overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, and hyperostoses. The manifestations are commonly present at birth and persist or progress postnatally. Tumors or malignancies are not frequently reported in PS. However, certain unusual tumor types, such as cystadenoma of the ovary, various types of testicular tumors, central nervous system tumors, and parotid monomorphic adenomas, are occasionally associated with PS and therefore can be of diagnostic value when present. PS is uncommon; approximately 120 affected individuals have been reported [Cohen 1999]. Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS who do not meet the diagnostic criteria.

Genotype-Phenotype CorrelationsFor 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 mutation are more likely to develop malignant breast disease than are families who do not have a PTEN mutation [Marsh et al 1998]. In addition, missense mutations and mutations 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 with CS-BRRS overlap were found to have a germline PTEN mutation. The mutational spectra of BRRS and CS have been shown to overlap, thus lending formal proof that CS and BRRS are allelic [Marsh et al 1999]. 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.Arg335X PTEN mutation and the same somatic mutation (p.Arg130X) in three separate tissues, possibly representing germline mosaicism [Zhou et al 2000]. Both mutations have been previously described in classic CS and BRRS. Two of nine individuals with Proteus syndrome and three of six with Proteus-like syndrome were found to have germline PTEN mutations [Zhou et al 2001a]. Since then multiple single cases of germline PTEN mutations in Proteus and Proteus-like syndrome have been reported [Smith et al 2002, Loffeld et al 2006].

Differential DiagnosisGermline KLLN epimutation. Bennett et al [2010] determined that approximately 30% of individuals with Cowden syndrome (CS) and Cowden-like syndrome who do not have a PTEN germline mutation have a germline KLLN epimutation, which resulted in down-regulation of expression of KLLN, but not PTEN. Of note, KLLN shares a bidirectional promoter with PTEN. Pilot data suggest that individuals with CS and Cowden-like syndrome with a germline KLLN epimutation have a greater prevalence of breast and renal cell carcinomas than do those with a germline PTEN mutation. Thus, individuals with Cowden-like syndrome (especially those with breast and/or renal carcinomas or a family history of such tumors) should be offered KLLN methylation analysis first because it accounts for 30% of such individuals, whereas PTEN germline mutations account for 5%-10%.New susceptibility genes in individuals with non-PHTS CS and a CS-like disorder. A pilot study found that individuals with CS and a CS-like disorder without germline PTEN mutations (but with increased levels of manganese superoxide dismutase) harbored germline variants in SDHB and SDHD [Ni et al 2008]. That germline variants in SDHB, SDHC, and SDHD occur in approximately 10% of persons with Cowden syndrome (CS) or Cowden-like syndrome who do not have a PTEN mutation has been validated in an independent series of 608 research participants [Ni et al 2012]. These variants were associated with stabilization of HIF1a, destabilization of p53 secondary to decreased NQ01 interaction, and increased reactive oxygen species with consequent apoptosis resistance.The primary differential diagnoses to consider are other hamartoma syndromes, including juvenile polyposis syndrome (JPS) and Peutz-Jeghers syndrome (PJS), both inherited in an autosomal dominant manner.Juvenile polyposis syndrome (JPS) is characterized by predisposition for hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp, not the age of onset of polyps. Juvenile polyps are hamartomas that show a normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria.Most individuals with JPS have some polyps by age 20 years. Some individuals may have only four or five polyps over a lifetime, whereas others in the same family may have more than one hundred. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur.Approximately 20% of individuals with JPS have mutations in MADH4; another approximately 20% have mutations in BMPR1A [Howe et al 1998, Howe et al 2001]:Prior case reports have claimed that germline PTEN mutations can occur in individuals with JPS [Olschwang et al 1998, Huang et al 2000]. However, closer inspection of these probands revealed that one likely had CS, another was too young for CS to be clinically excluded, and for the third it is suspected that thorough examination would have revealed signs of PHTS, since little clinical information was provided. Indeed, in a systematic study of individuals with the diagnosis of JPS examined for germline PTEN mutations, one individual with JPS was found to have a germline PTEN mutation [Kurose et al 1999]. Upon re-examination of this individual, clinical features of CS were identified [Kurose et al 1999].Conversely, a germline BMPR1A mutation was identified in an individual with only colonic polyposis but a family history suggestive of Cowden syndrome. Although this could suggest that BMPR1A may be responsible for a small proportion of CS/BRRS-like cases, the authors felt that on the basis of the mutation status this individual should be classified as having JPS [Zhou et al 2001b].Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. PJS-type hamartomatous polyps are most prevalent in the small intestine, but also occur in the stomach and large bowel in the majority of affected individuals. The Peutz-Jeghers polyp has a diagnostic appearance and is quite different from the hamartomatous polyps seen in CS or JPS. Clinically, Peutz-Jeghers polyps are often symptomatic (intussusception, rectal bleeding), whereas CS polyps are rarely so.The pigmentation of the perioral region is pathognomonic, particularly if it crosses the vermilion border. Hyperpigmented macules on the fingers are also common. Molecular genetic testing of STK11 reveals disease-causing mutations in approximately 70% of individuals who have a positive family history and 20%-70% of individuals who have no family history of PJS.Other, less likely, differential diagnoses to consider for PHTS:Birt-Hogg-Dubé syndrome (BHD) is characterized by cutaneous findings (fibrofolliculomas, trichodiscomas, and acrochordons), pulmonary cysts/history of pneumothorax, and renal tumors (most commonly renal oncocytoma, chromophobe renal cell carcinoma, or a hybrid of oncocytoma and chromophobe histologic cell types). Disease severity can vary significantly. Skin lesions typically appear during the third or fourth decade of life and increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but have a high risk for spontaneous pneumothorax. Approximately 15% of individuals with BHD syndrome have renal tumors; median age of tumor diagnosis is 48 years. FLCN, the gene encoding folliculin, is the only gene known to be associated with BHD. Inheritance is autosomal dominant.Neurofibromatosis type 1 (NF1). The only two features seen in both NF1 and CS/BRRS are café-au-lait macules and fibromatous tumors of the skin. The diagnosis of NF1 is sometimes mistakenly given to individuals with CS/BRRS because of the presence of ganglioneuromas in the gastrointestinal tract.Nevoid basal cell carcinoma (Gorlin) syndrome is characterized by basal cell nevi, basal cell carcinoma, and diverse developmental abnormalities. Affected individuals can also develop other tumors and cancers including fibromas, hamartomatous gastric polyps, and medulloblastomas. However, the dermatologic findings and developmental features in CS and nevoid basal cell carcinoma (Gorlin) syndrome are quite different.AKT1-related Proteus syndrome. Lindhurst et al [2011] reported mosaicism for a somatic activating AKT1 mutation in 26 of 29 individuals with Proteus syndrome. Since PTEN downregulates AKT1 by decreasing phosphorylation, the finding of an activating AKT1 mutation in Proteus syndrome corroborates that Proteus syndrome is a ‘PTEN-pathway-opathy.’Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Bannayan-Riley-Ruvalcaba syndromeCowden syndromeProteus syndrome

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with PTEN hamartoma tumor syndrome (PHTS), the following evaluations are recommended:Complete history, especially family historyPhysical examination with particular attention to:SkinMucous membranesThyroidBreastsIn children: consider neurodevelopmental evaluationUrinalysis with cytospinBaseline thyroid ultrasound examination at age 18 years* For women age 30 years or older at diagnosis*: Breast screening (at minimum mammogram; MRI may also be incorporated)Transvaginal ultrasound or endometrial biopsy For men and women age 35-40 years or older at diagnosis*: colonoscopy For men and women age 40 years or older at diagnosis*: renal imaging (CT or MRI preferred) Medical genetics consultation*Note: For individuals with a family history of a particular cancer type at an early age, screening may be considered five to ten years prior to the youngest diagnosis in the family. Treatment of ManifestationsThe mucocutaneous manifestations of Cowden syndrome are rarely life threatening:If asymptomatic, observation alone is prudent.When symptomatic, topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may provide only temporary relief [Hildenbrand et al 2001]. Surgical excision is sometimes complicated by cheloid formation and recurrence (often rapid) of the lesions [Eng, unpublished data].Treatment for the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts.Prevention of Primary ManifestationsSome 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 of endometrial cancer associated with tamoxifen use in a population already at increased risk for endometrial cancer.SurveillanceThe most serious consequences of PHTS relate to the increased risk of cancers including breast, thyroid, endometrial, and to a lesser extent, renal. In this regard, the most important aspect of management of any individual with a PTEN mutation is increased cancer surveillance to detect any tumors at the earliest, most treatable stages. Current suggested screening by age includes:Cowden SyndromePediatric (age <18 years)Yearly thyroid ultrasound examination*Yearly skin check with physical examinationAdultYearly thyroid ultrasound* and dermatologic evaluationWomen beginning at age 30 years: Monthly breast self-examination* Yearly breast screening (at minimum mammogram); MRI may also be incorporated*Yearly transvaginal ultrasound or endometrial biopsy*For men and women: Colonoscopy beginning at age 35-40 years*; frequency dependent on degree of polyposis identifiedBiennial renal imaging (CT or MRI preferred) beginning at age 40 years** For those with a family history of a particular cancer type at an early age screening may be initiated five to ten years prior to the youngest diagnosis in the family. For example, in a woman whose mother developed breast cancer at age 30 years breast surveillance may begin at age 25-30 years.Note: Although the NCCN Guidelines removed endometrial surveillance after 2007 (without expert PHTS input), it is prudent to ensure the minimal surveillance for endometrial cancer as detailed if family history is positive for endometrial cancer.Bannayan-Riley-Ruvalcaba SyndromeScreening recommendations have not been established for BRRS. Given recent molecular epidemiologic studies, however, individuals with BRRS and a germline PTEN mutation should undergo the same surveillance as individuals with CS.Individuals with BRRS should also be monitored for complications related to gastrointestinal hamartomatous polyposis, which can be more severe than in CS.Proteus Syndrome/Proteus-Like SyndromeAlthough the observation of germline PTEN mutations in Proteus and Proteus-like syndromes is relatively new, clinicians should consider instituting the CS surveillance recommendations for individuals with these disorders who have germline PTEN mutations.Agents/Circumstances to AvoidBecause 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 RiskWhen a PTEN mutation has been identified in a proband, testing of asymptomatic at-risk relatives can identify those who have the family-specific mutation and, therefore, have PHTS. These individuals 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 Proteus syndrome. In individuals with PHTS, the earliest documented breast cancer and thyroid cancer are at age 17 years and before age nine years, respectively.Relatives who have not inherited the PTEN mutation found in an affected relative do not have PHTS or its associated cancer risks.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAlthough mTOR inhibitors show promise for treatment of malignancies in individuals who have a germline PTEN mutation, use should be limited to clinical trials. At this time, one clinical trial is specifically directed at PHTS. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. PTEN Hamartoma Tumor Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPTEN10q23​.31Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTENCatalogue of Somatic Mutations in Cancer (COSMIC)
PTEN homepage - Mendelian genesPTENData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for PTEN Hamartoma Tumor Syndrome (View All in OMIM) View in own window 153480BANNAYAN-RILEY-RUVALCABA SYNDROME; BRRS 158350COWDEN SYNDROME 1; CWS1 176920PROTEUS SYNDROME 601728PHOSPHATASE AND TENSIN HOMOLOG; PTENMolecular Genetic PathogenesisWhile much functional research has been accomplished, complete function of PTEN is not yet fully understood. PTEN belongs to a sub-class 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. In vitro and human immunohistochemical data suggest that PTEN trafficks in and out of the nucleus [Ginn-Pease & Eng 2003, Chung et al 2005, Minaguchi et al 2006]. When PTEN is in the nucleus, it predominantly signals down the protein phosphatase and MAPK pathway to elicit cell cycle arrest [Chung & Eng 2005]. One of the nuclear functions of PTEN is to stabilize the genome [Shen et al 2007]. When in the cytoplasm, its lipid phosphatase predominantly signals down the AKT pathway to elicit apoptosis. Somatic PTEN mutations and loss of gene expression are frequently found in both endometrioid endometrial adenocarcinoma and precancerous endometrial lesions (intraepithelial neoplasia), confirming the critical role that PTEN must play in endometrial tissues [Mutter et al 2000].Normal allelic variants. PTEN comprises nine exons and likely spans a genomic distance of more than 120 kb. The 1209-bp coding sequence is predicted to encode a 403-amino acid protein.Pathologic allelic variants. Germline mutations have been found throughout PTEN (with the exception of exon 9) and include missense and nonsense mutations, splice site mutations, small deletions, insertions, and several large deletions. More than 150 unique mutations are currently listed in the Human Gene Mutation Database (see Table A). Nearly 40% of mutations are found in exon 5, which encodes the phosphate core motif [Eng 2003]. Most mutations are unique, although a number of recurrent mutations (particularly p.Arg130X, p.Arg233X, and p.Arg335X) have been reported (see Table 2) [Bonneau & Longy 2000, Zbuk & Eng 2007, Orloff & Eng 2008]. Table 2. Selected PTEN Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequencesc.388C>Tp.Arg130XNM_000314​.4
NP_000305​.3c.697C>Tp.Arg233Xc.1003C>Tp.Arg335XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Approximately 10% of individuals with CS who do not have a mutation detected in the PTEN coding sequence have heterozygous germline mutations in the PTEN promoter [Zhou et al 2003b]. In contrast, 10% of individuals with BRRS who do not have an identifiable PTEN mutation on sequence analysis have large deletions within or encompassing PTEN [Zhou et al 2003b].Normal gene product. PTEN encodes an almost ubiquitously expressed dual specificity phosphatase. 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 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 [Eng 2003]. It appears that nuclear PTEN mediates cell cycle arrest, while cytoplasmic PTEN is required for apoptosis [Chung & Eng 2005].Abnormal gene product. The majority (76%) of germline mutations in PTEN result in either truncated protein, lack of protein (haploinsufficiency), or dysfunctional protein. Many missense mutations are functionally null and several act as dominant negatives. 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 [Eng 2003].