• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

PTEN Hamartoma Tumor Syndrome (PHTS)

Includes: Bannayan-Riley-Ruvalcaba Syndrome, Cowden Syndrome, PTEN-Related Proteus Syndrome, Proteus-Like Syndrome
, MD, PhD
Genomic Medicine Institute
Cleveland Clinic
Department of Genetics & Genome Sciences
Case Western Reserve University School of Medicine
Cleveland, Ohio

Initial Posting: ; Last Update: January 23, 2014.

Summary

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

Diagnosis/testing. The diagnosis of PHTS is made only when a PTEN pathogenic variant is identified. When accrued from tertiary referral centers, up to 85% of individuals who meet the diagnostic criteria for CS and 65% of individuals with a clinical diagnosis of BRRS have a detectable PTEN pathogenic variant. However, in prospective accrual series, from both academic and community clinical settings, approximately 25% of individuals who meet the clinical diagnostic criteria for CS have a germline PTEN pathogenic variant. Preliminary data also suggest that up to 50% of individuals with a Proteus-like syndrome and up to 20% of individuals who meet the clinical diagnostic criteria of Proteus syndrome have an identifiable PTEN pathogenic variant.

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

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

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

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

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

Diagnosis

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 pathogenic variant is identified (see Molecular Genetic Testing).

Cowden syndrome (CS). Based on more than 3000 prospectively accrued individuals with CS/CSL from the community, a scoring system, which can be found online, has been developed which takes into account phenotype and age at diagnosis. The scoring system allows input of clinical information on an individual suspected of having CS/CSL and subsequently generates the prior probability of finding a PTEN pathogenic variant.

  • In adults, a clinical threshold score of 10 or more leads to a recommendation for referral to a genetics professional to consider PHTS.
  • In children, macrocephaly and at least one of the following leads to the consideration of PHTS:
    • Autism or developmental delay
    • Dermatologic features, including lipomas, trichilemmomas, oral papillomas, or penile freckling
    • Vascular features, such as arteriovenous malformations or hemangiomas
    • Gastrointestinal polyps

Additionally, consensus diagnostic criteria for CS have been developed [Eng 2000] and are updated each year by the National Comprehensive Cancer Network [NCCN 2006] (see Published Guidelines/Consensus Statements for full text; registration required). However, the CS scoring system discussed has been shown to be more accurate than the NCCN diagnostic criteria [Tan et al 2011].

The consensus clinical diagnostic criteria from the NCCN 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 1

Figure

Figure 1. Trichilemmoma

Figure 2

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 palmoplantar 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], which can be found in the GeneReview on Proteus 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

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

Clinical testing

  • Sequence analysis of coding and flanking intronic regions. Virtually all missense pathogenic variants in PTEN are believed to be deleterious [Eng 2003; Zbuk & Eng 2007; Tan et al 2011; 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 pathogenic variant [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 pathogenic variant, 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.

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

Gene 1Test MethodProportion of Probands by Phenotype with a Pathogenic Variant Detectable by This Method
CSBRRSPLSPS
PTENSequence analysis of coding region 225%-80%60%50% 320%
Deletion/ duplication analysis 4See footnote 511% 6UnknownUnknown
Sequence analysis of promoter region 210% 7See footnote 5UnknownUnknown

CS = Cowden syndrome

BRRS = Bannayan-Riley-Ruvalcaba syndrome

PLS = Proteus-like syndrome

PS = PTEN-related Proteus syndrome

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Data suggest that up to 50% of individuals with a Proteus-like syndrome and 20% of individuals who meet the clinical diagnostic criteria of Proteus syndrome have PTEN mutations [Zhou et al 2001a, Smith et al 2002, Eng 2003, Loffeld et al 2006, Orloff & Eng 2008].

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Finite but unknown; individuals with CS who have large deletions have been reported [Zbuk & Eng 2007, Orloff & Eng 2008, Tan et al 2011].

6. 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].

7.10% of individuals with CS phenotype do not have an identifiable PTEN sequence variant in the coding/flanking intronic regions [Zhou et al 2003b].

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

Testing Strategy

To confirm/establish the diagnosis in a proband requires identification of a PTEN pathogenic variant.

The PTEN Cleveland Clinic Risk Calculator provides the prior probability of finding a PTEN pathogenic variant in children and adults (see Clinical Diagnosis).

The appropriate order of PTEN testing to optimize yield:

1.

Sequence all PTEN coding exons 1-9 and flanking intronic regions. If no pathogenic variant is identified, perform:

2.

Deletion/duplication analysis. If no pathogenic variant is identified, consider:

3.

Sequence analysis of the promoter region for variants that decrease gene expression

If no PTEN pathogenic variant is identified, consider:

4.

Other testing, especially in those with Cowden syndrome (CS) and Cowden-like syndrome:

Predictive testing for at-risk asymptomatic family members (including children) requires prior identification of the disease-causing variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing variant in the family.

Clinical Description

Natural History

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

  • CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Renal cell carcinoma and colorectal carcinoma have recently been shown to be in the PHTS spectrum.
  • 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 pathogenic variant [Eng 2003, McGarrity et al 2003].

Tumor risk. Individuals with CS are at high risk for 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 are at 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 pathogenic variant 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 pathogenic variant [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 pathogenic variant-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 to early 40s [Tan et al 2012].
  • Gastrointestinal neoplasias
    • More than 90% of individuals with a PTEN pathogenic variant 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 pathogenic variant 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 pathogenic variant.

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.

PTEN-related Proteus syndrome (PS) is characterized by progressive, segmental or patchy overgrowth of diverse tissues of all germ layers, most commonly affecting the skeleton, skin, and adipose and central nervous systems. In most individuals Proteus syndrome has minimal or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism.

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 pathogenic variant are more likely to develop malignant breast disease than are families who do not have a PTEN pathogenic variant [Marsh et al 1998]. In addition, pathogenic missense variants and others 5' to or within the phosphatase core motif appeared to be associated with involvement of five or more organs, a surrogate phenotype for severity of disease [Marsh et al 1998].

More than 90% of families with CS-BRRS overlap were found to have a germline PTEN pathogenic variant. 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.Arg335Ter PTEN pathogenic variant and the same somatic mutation (p.Arg130Ter) 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 who met the clinical diagnostic criteria of 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 individuals who met the clinical diagnostic criteria of 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 pathogenic variant is found, the gene-related name, PHTS, should be used.

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

Differential Diagnosis

Germline 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 pathogenic variant have a germline KLLN methylation epimutation, which resulted in down-regulation of expression of KLLN, but not of 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 pathogenic variant. 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 pathogenic variants 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 Cowden syndrome (CS) and a CS-like (CSL) disorder without germline PTEN pathogenic variants (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 CS or CSL who do not have a PTEN pathogenic variant 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. Approximately 10% of individuals with CS/CSL disorder without germline PTEN or SDHX pathogenic variants have been found to harbor germline PIK3CA or AKT1 pathogenic variants [Orloff et al 2013].

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 pathogenic variants in MADH4; another approximately 20% have pathogenic variants in BMPR1A [Howe et al 1998, Howe et al 2001]:

  • Prior case reports have claimed that germline PTEN pathogenic variants 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 pathogenic variants, one individual with JPS was found to have a germline PTEN pathogenic variant [Kurose et al 1999]. Upon re-examination of this individual, clinical features of CS were identified [Kurose et al 1999].
  • Conversely, a germline BMPR1A pathogenic variant was identified in an individual with only colonic polyposis but a family history suggestive of Cowden syndrome. While this finding could suggest that mutation of BMPR1A is responsible for a small proportion of CS/BRRS-like cases, the authors felt that on the basis of the pathogenic variant status this individual should be classified as having JPS [Zhou et al 2001b].

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by the association of gastrointestinal polyposis, mucocutaneous pigmentation, and cancer predisposition. PJS-type hamartomatous polyps are most common in the small intestine (in order of prevalence: in the jejunum, ileum, and duodenum), but can also occur in the stomach, large bowel, and extraintestinal sites including the renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, and ureters. 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 variants in approximately 80%-94% of affected individuals.

Other, less likely, differential diagnoses to consider for PHTS:

  • Birt-Hogg-Dubé syndrome (BHD) is characterized by cutaneous findings (fibrofolliculomas, trichodiscomas/angiofibromas, perifollicular fibromas, and acrochordons), pulmonary cysts/history of pneumothorax, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear during the third or fourth decade of life and usually increase in size and number with age. Lung cysts are mostly bilateral and multifocal; most individuals are asymptomatic but are at high risk for spontaneous pneumothorax. Individuals with BHDS have an increased risk of renal tumors that are typically bilateral and multifocal and usually slow growing; 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 the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs) usually from the third decade onward. 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 pathogenic variant in 26 of 29 individuals with Proteus syndrome. Since PTEN down-regulates AKT1 by decreasing phosphorylation, the finding of an activating AKT1 pathogenic variant 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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*
  • 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 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.
  • Cutaneous lesions should be excised only if malignancy is suspected or symptoms (e.g., pain, deformity, increased scarring) are significant.
    • 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 pathogenic variant is increased cancer surveillance to detect any tumors at the earliest, most treatable stages. Current suggested screening by age follows:

Cowden Syndrome

Pediatric (age <18 years)

  • Yearly thyroid ultrasound examination*
  • Yearly skin check with physical examination

Adult

  • Yearly thyroid ultrasound* and dermatologic evaluation
  • Women 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 years*; frequency dependent on degree of polyposis identified
    • Biennial 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 Syndrome

Screening recommendations have not been established for BRRS. Given recent molecular epidemiologic studies, however, individuals with BRRS and a germline PTEN pathogenic variant 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 Syndrome

Although the observation of germline PTEN pathogenic variants in a minority of individuals who meet the clinical diagnostic criteria for Proteus syndrome and Proteus-like syndrome is relatively new, clinicians should consider instituting the CS surveillance recommendations for individuals with these disorders who have germline PTEN pathogenic variants.

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 pathogenic variant has been identified in a proband, testing of asymptomatic at-risk relatives can identify those who have the family-specific pathogenic variant 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 pathogenic variant 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 pathogenic variant, use should be limited to clinical trials. A clinical trial specifically directed at PHTS recently concluded; results have not been published at the time of this GeneReview update.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 ≥2 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, however, perhaps 55%-90% of individuals with CS have an affected parent [Marsh et al 1999, Mester et al 2012].
  • The majority of evidence suggests that PTEN pathogenic variants occur in both simplex and familial occurrences of Bannayan-Riley-Ruvalcaba syndrome (BRRS) [Eng 2003, Zbuk & Eng 2007].
  • If a PTEN pathogenic variant 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 pathogenic variant 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 pathogenic variant found in the proband, the risk to sibs is probably negligible, as germline mosaicism has rarely been reported in PHTS [Pritchard et al 2013].
  • If a pathogenic variant 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 pathogenic variant 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 pathogenic variant has been identified in a proband, testing of asymptomatic at-risk relatives can identify those who also have the pathogenic variant 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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the disease-causing variant 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, pathogenic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing variant has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

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 an option for some families in which the disease-causing variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org
  • National Alliance of Breast Cancer Organizations
    An advocacy group that serves as an umbrella for 370 breast cancer groups nationwide. Provides information, a newsletter, and treatment information. Also provides grants for programs on early detection and education.
    9 East 37th Street
    10th Floor
    New York NY 10016
    Phone: 888-806-2226; 212-889-0606
    Fax: 212-689-1213
    Email: nbcamquestions@yahoo.com
  • National Breast Cancer Coalition (NBCC)
    An advocacy group seeking public policy change to benefit breast cancer patients and survivors
    1101 17th Street Northwest
    Suite 1300
    Washington DC 20036
    Phone: 800-622-2838 (toll-free); 202-296-7477
    Fax: 202-265-6854
    Email: info@stopbreastcancer.org
  • National Coalition for Cancer Survivorship (NCCS)
    A consumer organization that advocates on behalf of all people with cancer
    1010 Wayne Avenue
    Suite 770
    Silver Spring MD 20910
    Phone: 888-650-9127 (toll-free); 301-650-9127
    Fax: 301-565-9670
    Email: info@canceradvocacy.org
  • Susan G. Komen Breast Cancer Foundation
    Information, referrals to treatment centers. Answers questions from recently diagnosed women and provides emotional support. Funds research programs for women who do not have adequate medical service and support.
    5005 LBJ Freeway
    Suite 250
    Dallas TX 75244
    Phone: 877-465-6636 (Toll-free Helpline)
    Fax: 972-855-1605
    Email: helpline@komen.org

Molecular Genetics

Information 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 Databases

Data 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)

153480BANNAYAN-RILEY-RUVALCABA SYNDROME; BRRS
158350COWDEN SYNDROME 1; CWS1
601728PHOSPHATASE AND TENSIN HOMOLOG; PTEN

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 down-regulates the PI3K/AKT pathway.

In vitro and human immunohistochemical data suggest that PTEN traffics 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 variants 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].

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Germline pathogenic variants have been found throughout PTEN (with the exception of exon 9) and include missense, nonsense, splice site, small deletion, insertion, and large deletion alterations. More than 150 unique pathogenic variants are currently listed in the Human Gene Mutation Database (see Table A). Nearly 40% of pathogenic variants are found in exon 5, which encodes the phosphate core motif [Eng 2003]. Most pathogenic variants are unique, although a number of recurrent pathogenic variants have been reported, particularly those in Table 2.

Table 2. Selected PTEN Recurrent Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.388C>T 1p.Arg130TerNM_000314​.4
NP_000305​.3
c.697C>T 1p.Arg233Ter
c.1003C>T 1p.Arg335Ter

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Recurrent pathogenic variants [Bonneau & Longy 2000, Zbuk & Eng 2007, Orloff & Eng 2008]

Approximately 10% of individuals with CS who do not have a pathogenic variant detected in the PTEN coding sequence have heterozygous germline pathogenic variants in the PTEN promoter [Zhou et al 2003b]. In contrast, 10% of individuals with BRRS who do not have an identifiable PTEN pathogenic variant 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 down-regulates the PI3K/Akt pathway to cause G1 cell cycle arrest and apoptosis. In addition, the protein phosphatase appears to play an important role in inhibition of cell migration and spreading, as well as down-regulating 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 pathogenic variants in PTEN predict either truncated protein, lack of protein (haploinsufficiency), or dysfunctional protein. Many missense variants are functionally null and several act as dominant negatives [Weng et al 2001a, Weng et al 2001b]. 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].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy Statement Update: Genetic Testing for Cancer Susceptibility. Available online. 2003. Accessed 1-9-14.
  2. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 37:828-30. Available online. 2000. Accessed 1-9-14. [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. 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]
  2. 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]
  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. 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.
  10. 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]
  11. 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]
  12. Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22:183–98. [PubMed: 12938083]
  13. 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]
  14. 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]
  15. 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]
  16. Gorlin RJ, Cohen MM, Condon LM, Burke BA. Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet. 1992;44:307–14. [PubMed: 1336932]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. Hildenbrand C, Burgdorf WH, Lautenschlager S. Cowden syndrome-diagnostic skin signs. Dermatology. 2001;202:362–6. [PubMed: 11455162]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboué B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, Eng C, LePrat F, Odent S, Toulouse C, Olopade OI, Sobol H, Tishler S, Woods CG, Robinson BG, Weber HC, Parsons R, Peacocke M, Longy M, Eng C. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7:507–15. [PubMed: 9467011]
  31. 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, Tolmie JL, Trembath R, Winter RM, Zackai EH, Zori RT, Weng LP, Dahia PLM, Eng C. 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]
  32. 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]
  33. Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 2012;79:1187.e1-7. [PMC free article: PMC3341468] [PubMed: 22381246]
  34. 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]
  35. 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]
  36. 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.
  37. 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]
  38. 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]
  39. Ngeow J, Mester J, Rybicki LA, Ni Y, Milas M, Eng C. Incidence and clinical characteristics of thyroid cancer in prospective series of individuals with Cowden and Cowden-like syndrome characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab. 2011;96:E2063–71. [PMC free article: PMC3232626] [PubMed: 21956414]
  40. Ni Y, He X, Chen J, Moline J, Mester J, Orloff MS, Ringel MD, Eng C. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. 2012;21:300–10. [PMC free article: PMC3276278] [PubMed: 21979946]
  41. 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]
  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. Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, Eng C. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013;92:76–80. [PMC free article: PMC3542473] [PubMed: 23246288]
  45. 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]
  46. Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W, Walsh T, Bennett RL. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med. 2013;15:1004–7. [PubMed: 23619277]
  47. 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]
  48. 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]
  49. 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]
  50. 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]
  51. 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]
  52. 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]
  53. 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]
  54. Weng LP, Brown JL, Eng C. PTEN coordinates G1 arrest by down regulating cyclin D1 via its protein phosphatase activity and up regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet. 2001a;10:599–604. [PubMed: 11230179]
  55. Weng LP, Brown JL, Eng C. PTEN induces apoptosis and cell cycle arrest through phosphoinositol-3-kinase/Akt-dependent and independent pathways. Hum Mol Genet. 2001b;10:237–42. [PubMed: 11159942]
  56. Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer. 2007;7:35–45. [PubMed: 17167516]
  57. 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]
  58. 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]
  59. 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]
  60. 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]
  61. 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 Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 45. Available online. Accessed 4-16-12.
  3. Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis. Oxford, UK: Oxford University Press; 2008.
  4. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009;11:687–94. [PubMed: 19668082]
  5. 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]
  6. 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]
  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]

Chapter Notes

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

  • 23 January 2014 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1488PMID: 20301661
PubReader format: click here to try

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...