PTEN Hamartoma Tumor Syndrome (PHTS)

[Includes: Cowden Syndrome, Bannayan-Ruvalcaba-Riley Syndrome (Bannayan-Riley-Ruvalcaba Syndrome, Bannayan-Zonana Syndrome, Riley-Smith Syndrome, Ruvalcaba-Myhre-Smith Syndrome), Proteus Syndrome]

Clinical Diagnosis

A presumptive diagnosis of PTEN hamartoma tumor syndrome (PHTS) is based on clinical signs; by definition, however, the diagnosis of PHTS is made only when a PTEN mutation is identified.

Cowden syndrome. Consensus diagnostic criteria for Cowden syndrome have been developed [Eng 2000] and are updated each year by the National Comprehensive Cancer Network [2006] (NCCN). Clinical criteria have been divided into three categories:

Pathognomonic criteria

• Adult Lhermitte-Duclos disease (LDD), defined as the presence of a cerebellar dysplastic gangliocytoma [Zhou et al 2003a]

• 

  

  Figure 1. Trichilemmoma

  

  Figure 1. Trichilemmoma

  

  

  Figure 2. Papillomatous papules in the periocular (more...)

  

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

  Mucocutaneous lesions (Figures 1, 2):

  • Trichilemmomas (facial) (see Figure 1)

  • Acral keratoses

  • Papillomatous lesions (see Figure 2)

  • Mucosal lesions

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)

• Mental retardation (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 Cowden syndrome 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 Cowden syndrome 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-Ruvalcaba-Riley 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). 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. 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

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Gene. PTEN is the only gene known to be associated with PTEN hamartoma tumor syndrome (PHTS).

Clinical testing

• Sequence analysis

  • Virtually all missense mutations in PTEN are believed to be deleterious [Eng 2003; Eng, unpublished data]

  • Approximately 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 gene mutation [Zbuk & Eng 2007].

  • 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.

• 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.
  
  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]. 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; Eng, unpublished data].

Research testing

• Promoter analysis. Direct sequencing of the promoter region detects mutations that alter the function of the gene in approximately 10% of individuals with CS who do not have an identifiable mutation in the PTEN coding region [Zhou et al 2003b].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in PTEN Hamartoma Tumor Syndrome

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

CS= Cowden syndrome

BRRS= Bannayan-Riley-Ruvalcaba syndrome

PLS= Proteus-like syndrome

PS= Proteus syndrome

1. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array CGH may be used.

2. Zhou et al [2003b]

3.10% of individuals with CS phenotype who do not have an identifiable sequence variant

4. Finite but unknown

Interpretation of test results. Failure to detect a mutation does not exclude a clinical diagnosis of CS, BRRS, or Proteus/Proteus-like syndromes in an individual with significant signs associated with these disorders.

For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband requires PTEN molecular genetic testing. The order of testing to optimize yield would be:

• 1

  Sequencing of exons 1-9 and flanking intronic regions

• 2

  Promoter analysis (research)

• 3

  Deletion/rearrangement analysis

• 4

  SDHB-D analysis (research) (see Differential Diagnosis)

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) 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 the PTEN gene.

Phenotypes that can be associated with PTEN germline mutations are:

• 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), 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. 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 gastrointestinal polyps can be seen in CS but are usually minute and cause few symptoms. 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.

  • The lifetime risk to females of developing breast cancer is 25%-50%, with an average age of diagnosis between 38 and 46 years [Brownstein et al 1978, Starink et al 1986]. Breast cancer has been described in PTEN mutation-positive males [Fackenthal et al 2001].

• 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 thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is around 10% [Zbuk & Eng 2007]. It is not clear if the age of diagnosis of thyroid cancer is earlier than in the general population.

• Endometrial disease

  • Benign uterine fibroids are common.

  • Risk for endometrial cancer, although not well defined, may approach 5%-10%.

• Other

  • Skin cancers, renal cell carcinomas, and 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.

  • Although hamartomatous polyps may occur in the gastrointestinal tract, it is felt that the risk for colorectal cancer is not increased; unlike BRRS polyps, the polyps in CS are rarely symptomatic.

Bannayan-Ruvalcaba-Riley 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 PTEN gene mutations are currently thought to have the same cancer risks as individuals with CS [Marsh et al 1999]. It is not clear whether these risks apply to individuals with BRRS without PTEN gene mutations.

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). Proteus syndrome 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; only approximately 120 affected individuals have been reported [Cohen 1999].

Proteus-like syndrome. 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 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 germline PTEN mutations 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].

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. More than 90% of families with CS-BRRS overlap were found to have germline PTEN mutations. In addition, the presence of PTEN mutations in BRRS was found to be associated with the development of lipomas and tumors of the breast [Marsh et al 1999]. Therefore, individuals with BRRS and PTEN mutations may have increased cancer risks (despite the fact that this syndrome was previously not believed to be associated with malignancy).

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.

Anticipation

Anticipation is not observed.

Nomenclature

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

Bannayan-Riley-Ruvalcaba 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 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 in 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

• Urinalysis with cytospin

• Baseline thyroid ultrasound examination at age 18 years or five years younger than the earliest age at thyroid cancer 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.

There is no direct evidence to support 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.

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.

Testing 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 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.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 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 US Cowden syndrome centers, the majority of individuals with CS have no obvious family history. As a broad estimate, perhaps 10%-50% of individuals with Cowden syndrome have an affected parent [Marsh et al 1999].

• The majority of evidence suggests that PTEN mutations occur in both simplex and familial occurrences of 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 for information on testing 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 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:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

• 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.

• Decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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 of being affected.

DNA banking. 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 particularly when the sensitivity of currently available testing is less than 100%. 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 15-18 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 .

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 illicit 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. The gene 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.

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 Akt 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].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

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

• 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