Clinical Diagnosis

The 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 criteria

• Adult 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 keratoses
  • Papillomatous lesions (see Figure 2)
  • Mucosal lesions

Figure

Figure 1. Trichilemmoma

Figure

Figure 2. Papillomatous papules in the periocular region (A) and on the dorsum of the hand (B)

Major criteria

• Breast cancer
• Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer
• Macrocephaly (occipital frontal circumference ≥97th percentile)
• Endometrial carcinoma

Minor criteria

• Other thyroid lesions (e.g., adenoma, multinodular goiter)
• Intellectual disability (IQ ≤75)
• Hamartomatous intestinal polyps
• Fibrocystic disease of the breast
• Lipomas
• Fibromas
• Genitourinary tumors (especially renal cell carcinoma)
• Genitourinary malformation
• Uterine fibroids

An 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 trichilemmoma
  • Cutaneous facial papules and oral mucosal papillomatosis
  • Oral mucosal papillomatosis and acral keratoses
  • Six or more palmo-plantar keratoses
• Two or more major criteria
• One major and three or more minor criteria
• Four or more minor criteria

In 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 criteria
• Any one major criterion with or without minor criteria
• Two minor criteria
• History of Bannayan-Riley-Ruvalcaba syndrome

Bannayan-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 nevus
• Disproportionate overgrowth (one or more)
  • Limbs: arms/legs; hands/feet/digits
  • Skull: hyperostoses
  • External auditory meatus: hyperostosis
  • Vertebrae: megaspondylodysplasia
  • Viscera: spleen/thymus
• Specific tumors before end of second decade (either one)
  • Bilateral ovarian cystadenomas
  • Parotid monomorphic adenoma

OR three of the following:

• Dysregulated adipose tissue (either one)
  • Lipomas
  • Regional absence of fat
• Vascular malformations (one or more)
  • Capillary malformation
  • Venous malformation
  • Lymphatic malformation
• Facial phenotype
  • Dolichocephaly
  • Long face
  • Minor downslanting of palpebral fissures and/or minor ptosis
  • Low nasal bridge
  • Wide or anteverted nares
  • Open mouth at rest

Proteus-like syndrome is undefined but describes individuals with significant clinical features of PS but who do not meet the diagnostic criteria.

Testing

Pathologic 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 Testing

Gene. PTEN is the only gene in which mutations are known to cause PTEN hamartoma tumor syndrome (PHTS).

Clinical testing

• Sequence 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].

Research testing

• 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 Syndrome

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method and Phenotype 1				Test Availability
			CS	BRRS	PLS	PS
PTEN	Sequence analysis	Sequence variants 2	80%	60%	50%	20%	Clinical
	Deletion/ duplication analysis 3	Exonic or whole-gene deletions	See footnote 4	11% 5	Unknown	Unknown
	Promoter analysis	Promoter mutations	10% 5, 6	See footnote 4	Unknown	Unknown	Research only

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

CS= Cowden syndrome

BRRS= Bannayan-Riley-Ruvalcaba syndrome

PLS= Proteus-like syndrome

PS= Proteus syndrome

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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. See array GH.

4. Finite but unknown

5. Zhou et al [2003b]

6.10% of individuals with CS phenotype who do not have an identifiable sequence variant

Interpretation 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 and/or Pathologic allelic variants).

Testing Strategy

To 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 (research)

Note: Clinical confirmation of mutations identified in a research laboratory may be available. See .

If no PTEN mutation is identified, consider:

4.

Other research 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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No 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 History

The 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 disease
  • Women 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 disease
  • Benign 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 disease
  • Benign 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 neoplasias
  • More 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 carcinoma
  • Lifetime 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].
• Other
  • Lifetime 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 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 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].

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, Zbuk & Eng 2007]. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, primarily trichilemmomas and papillomatous papules, as well as acral and plantar keratoses. (See also Natural History for age at which specific manifestations are likely to become evident.)

Anticipation

Anticipation is not observed.

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 mutation 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 mutation, 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 mutation should be termed PHTS with all its implications for clinical management [Zbuk & Eng 2007, Orloff & Eng 2008].

Prevalence

Because the diagnosis of CS is difficult to establish, the true prevalence is unknown. The prevalence has been estimated at one in 200,000 [Nelen et al 1999]; this is likely an underestimate. Because of the variable and often subtle external manifestations of CS/BRRS, many individuals remain undiagnosed [Haibach et al 1992; Schrager et al 1998; Zbuk & Eng 2007; Eng, unpublished].

Evaluations Following Initial Diagnosis

To 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 history
• Physical examination with particular attention to:
  • Skin
  • Mucous membranes
  • Thyroid
  • Breasts
• In children: consider neurodevelopmental evaluation
• Urinalysis with cytospin
• Baseline 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 Manifestations

The 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 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 of endometrial cancer associated with tamoxifen use in a population already at increased risk for endometrial cancer.

Surveillance

The 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:

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

When 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 Investigation

Although 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

PTEN hamartoma tumor syndrome (PHTS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband. Because Cowden syndrome (CS) is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as two or more related affected individuals) cannot be determined:

• From the literature and the experience of both major CS centers in the US, the majority of individuals with CS have no obvious family history. As a broad estimate, perhaps 10%-50% of individuals with CS have an affected parent [Marsh et al 1999].
• The majority of evidence suggests that PTEN mutations occur in both simplex and familial occurrences of Bannayan-Riley-Ruvalcaba syndrome (BRRS) [Eng 2003, Zbuk & Eng 2007].
• If a PTEN mutation is identified in the proband, the parents should be offered molecular genetic testing to determine if one of them has previously unidentified PHTS. If no mutation is identified in the proband, both parents should undergo thorough clinical examination to help determine if either parent has signs of PHTS.

Note: Although some individuals diagnosed with PHTS have an affected parent, the family history 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 disease in the affected parent.

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 PHTS, the risk to sibs is 50%.
• If it has been shown that neither parent has the PTEN mutation found in the proband, the risk to sibs is probably negligible, as germline mosaicism has not been reported in PHTS.
• If a mutation cannot be identified in the proband, PHTS can be excluded on clinical grounds. Normal clinical examinations in parents in their thirties done looking specifically for signs of CS/BRRS would make the risk to sibs of the proband minimal, since an estimated 99% of affected individuals have signs by that age.

Offspring of a proband. Each child of an affected individual has a 50% chance of inheriting the mutation and developing PHTS.

Other family members of a proband

• The risk to other family members depends on the genetic status of the proband's parents.
• If a parent is affected, his or her family members are 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.

Testing of at-risk relatives. When a mutation has been identified in a proband, testing of asymptomatic at-risk relatives can identify those who also have the mutation and 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.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

While 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].

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].

Published Guidelines/Consensus Statements

1. American Society of Clinical Oncology. Policy Statement Update: Genetic Testing for Cancer Susceptibility. Available online. 2003. Accessed 4-16-12.
2. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 37:828-30. Available online. 2000. Accessed 4-16-11. [PMC free article: PMC1734465] [PubMed: 11073535]
3. National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Clinical Practice Guidelines in Oncology. Version 1.2006 (pdf). Available online (registration required). 2006.

Literature Cited

1. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM, Viljoen DL, Cohen MM. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet. 1999;84:389–95. [PubMed: 10360391]
2. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA. 2010;304:2724–31. [PMC free article: PMC3655326] [PubMed: 21177507]
3. Bonneau D, Longy M. Mutations of the human PTEN gene. Hum Mutat. 2000;16:109–22. [PubMed: 10923032]
4. Brownstein MH, Wolf M, Bikowski JB. Cowden's disease: a cutaneous marker of breast cancer. Cancer. 1978;41:2393–8. [PubMed: 657103]
5. 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]
6. 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]
7. Chung JH, Eng C. Nuclear-cytoplasmic partitioning of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) differentially regulates the cell cycle and apoptosis. Cancer Res. 2005;65:8096–100. [PubMed: 16166282]
8. Chung JH, Ginn-Pease ME, Eng C. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has nuclear localization signal-like sequences for nuclear import mediated by major vault protein. Cancer Res. 2005;65:4108–16. [PubMed: 15899801]
9. Cohen MM Jr. Overgrowth syndromes: an update. Adv Pediatr. 1999;46:441–91. [PubMed: 10645472]
10. Dasouki MJ, Ishmael H, Eng C. Macrocephaly, macrosomia and autistic behavior due to a de novo PTEN germline mutation. Am J Hum Genet Suppl. 2001;69:S280.
11. Delnatte C, Sanlaville D, Mougenot JF, Vermeesch JR, Houdayer C, Blois MC, Genevieve D, Goulet O, Fryns JP, Jaubert F, Vekemans M, Lyonnet S, Romana S, Eng C, Stoppa-Lyonnet D. Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. Am J Hum Genet. 2006;78:1066–74. [PMC free article: PMC1474102] [PubMed: 16685657]
12. 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]
13. Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22:183–98. [PubMed: 12938083]
14. 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]
15. Ginn-Pease ME, Eng C. Increased nuclear phosphatase and tensin homologue deleted on chromosome 10 is associated with G0G1 in MCF-7 cells. Cancer Res. 2003;63:282–6. [PubMed: 12543774]
16. 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]
17. Gorlin RJ, Cohen MM, Condon LM, Burke BA. Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet. 1992;44:307–14. [PubMed: 1336932]
18. Haibach H, Burns TW, Carlson HE, Burman KD, Deftos LJ. Multiple hamartoma syndrome (Cowden's disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am J Clin Pathol. 1992;97:705–12. [PubMed: 1575215]
19. 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]
20. 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]
21. 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]
22. Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A. Increasing knowledge of germline PTEN mutations: two additional patients with autism and macrocephaly. Am J Med Genet A. 2007a;143:589–93. [PubMed: 17286265]
23. Herman GE, Henninger N, Ratliff-Schaub K, Pastore M, Fitzgerald S, McBride KL. Genetic testing in autism: how much is enough? Genet Med. 2007b;9:268–74. [PubMed: 17505203]
24. Hildenbrand C, Burgdorf WH, Lautenschlager S. Cowden syndrome-diagnostic skin signs. Dermatology. 2001;202:362–6. [PubMed: 11455162]
25. Howe JR, Bair JL, Sayed MG, Anderson ME, Mitros FA, Petersen GM, Velculescu VE, Traverso G, Vogelstein B. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet. 2001;28:184–7. [PubMed: 11381269]
26. Howe JR, Roth S, Ringold JC, Summers RW, Järvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086–8. [PubMed: 9582123]
27. Huang SC, Chen CR, Lavine JE, Taylor SF, Newbury RO, Pham TT, Ricciardiello L, Carethers JM. Genetic heterogeneity in familial juvenile polyposis. Cancer Res. 2000;60:6882–5. [PubMed: 11156385]
28. Kurose K, Araki T, Matsunaka T, Takada Y, Emi M. Variant manifestation of Cowden disease in Japan: hamartomatous polyposis of the digestive tract with mutation of the PTEN gene. Am J Hum Genet. 1999;64:308–10. [PMC free article: PMC1377733] [PubMed: 9915974]
29. 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]
30. Loffeld A, McLellan NJ, Cole T, Payne SJ, Fricker D, Moss C. Epidermal naevus in Proteus syndrome showing loss of heterozygosity for an inherited PTEN mutation. Br J Dermatol. 2006;154:1194–8. [PubMed: 16704655]
31. 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. et al. 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]
32. Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed SF, Bodurtha J, Crowe C, Curtis MA, Dasouki M, Dunn T, Feit H, Geraghty MT, Graham JM, Hodgson SV, Hunter A, Korf BR, Manchester D, Miesfeldt S, Murday VA, Nathanson KL, Parisi M, Pober B, Romano C, Eng C. et al. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan- Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet. 1999;8:1461–72. [PubMed: 10400993]
33. 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]
34. Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 2012 [PMC free article: PMC3341468] [PubMed: 22381246]
35. Minaguchi T, Waite KA, Eng C. Nuclear localization of PTEN is regulated by Ca(2+) through a tyrosil phosphorylation-independent conformational modification in major vault protein. Cancer Res. 2006;66:11677–82. [PubMed: 17178862]
36. 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]
37. NCCN. Genetic/Familial High-Risk Assessment: Breast and Ovarian. Clinical Practice Guidelines in Oncology. Version 1.2006 (pdf). Available at www​.nccn.org (registration required). 2006.
38. 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]
39. 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]
40. 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]
41. 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 Endo Metab. 2011;96:E2063–71. [PMC free article: PMC3232626] [PubMed: 21956414]
42. Olschwang S, Serova-Sinilnikova OM, Lenoir GM, Thomas G. PTEN germ-line mutations in juvenile polyposis coli. Nat Genet. 1998;18:12–4. [PubMed: 9425889]
43. Orloff MS, Eng C. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene. 2008;27:5387–97. [PubMed: 18794875]
44. Orrico A, Galli L, Buoni S, Orsi A, Vonella G, Sorrentino V. Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Clin Genet. 2009;75:195–8. [PubMed: 18759867]
45. Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum Pathol. 1998;29:47–53. [PubMed: 9445133]
46. Shen WH, Balajee AS, Wang J, Wu H, Eng C, Pandolfi PP, Yin Y. Essential role of PTEN in the maintenance of chromosome integrity. Cell. 2007;128:157–70. [PubMed: 17218262]
47. Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ. Germline mutation of the tumour suppressor PTEN in Proteus syndrome. J Med Genet. 2002;39:937–40. [PMC free article: PMC1757209] [PubMed: 12471211]
48. Starink TM, van der Veen JP, Arwert F, de Waal LP, de Lange GG, Gille JJ, Eriksson AW. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986;29:222–33. [PubMed: 3698331]
49. 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]
50. 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]
51. Thiffault I, Schwartz CE, Der Kaloustian V, Foulkes WD. Mutation analysis of the tumor suppressor PTEN and the glypican 3 (GPC3) gene in patients diagnosed with Proteus syndrome. Am J Med Genet A. 2004;130A:123–7. [PubMed: 15372512]
52. Varga EA, Pastore M, Prior T, Herman GE, McBride KL. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay and macrocephaly. Genet Med. 2009;11:111–7. [PubMed: 19265751]
53. Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007;7:35–45. [PubMed: 17167516]
54. Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet. 2001a;358:210–1. [PubMed: 11476841]
55. 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]
56. 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]
57. 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]
58. Zhou XP, Woodford-Richens K, Lehtonen R, Kurose K, Aldred M, Hampel H, Launonen V, Virta S, Pilarski R, Salovaara R, Bodmer WF, Conrad BA, Dunlop M, Hodgson SV, Iwama T, Järvinen H, Kellokumpu I, Kim JC, Leggett B, Markie D, Mecklin JP, Neale K, Phillips R, Piris J, Rozen P, Houlston RS, Aaltonen LA, Tomlinson IP, Eng C. Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes. Am J Hum Genet. 2001b;69:704–11. [PMC free article: PMC1226057] [PubMed: 11536076]

Suggested Reading

1. Eng C. Mendelian genetics of rare--and not so rare--cancers. Ann N Y Acad Sci. 2010;1214:70–82. [PubMed: 20946573]
2. Eng C, Parsons R. Cowden syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 45. Available at www​.ommbid.com. Accessed 4-16-12.
3. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009;11:687–94. [PubMed: 19668082]
4. Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, Khoo SK, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior TW, Frebourg T, Teh BT, Marchuk DA, Aaltonen LA, Eng C. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA. 2005;294:2465–73. [PubMed: 16287957]
5. Epstein CJ, Erickson RP, Wynshaw-Boris A, eds, Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis, Oxford University Press, Oxford, UK, 2008.
6. Page DT, Kuti OJ, Prestia C, Sur M. Haploinsufficiency for Pten and serotonin transporter cooperatively influences brain size and social behavior. Proc Natl Acad Sci U S A. 2009;106:1989–94. [PMC free article: PMC2644151] [PubMed: 19208814]
7. Trepanier A, Ahrens M, McKinnon W, Peters J, Stopfer J, Grumet SC, Manley S, Culver JO, Acton R, Larsen-Haidle J, Correia LA, Bennett R, Pettersen B, Ferlita TD, Costalas JW, Hunt K, Donlon S, Skrzynia C, Farrell C, Callif-Daley F, Vockley CW. National Society of Genetic Counselors; Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. J Genet Couns. 2004;13:83–114. [PubMed: 15604628]

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. The Cleveland Clinic Genomic Medicine Institute program features the only 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. CE 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)
Kevin M Zbuk, MD; Cleveland Clinic (2006-2009)

Revision History

• 19 April 2012 (ce) Somatic AKT1 mutations 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 to live Web site
• 19 May 2004 (ce) Revision: Genetic Counseling posted to live Web site
• 17 December 2003 (me) Comprehensive update posted to live Web site
• 23 May 2003 (ce) Revision: Differential Diagnosis
• 29 November 2001 (me) Review posted to live Web site
• 10 July 2001 (ce) Original submission