Pten Hamartoma Tumor Syndrome

Clinical characteristics.

The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and 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 may approach 28%.
• BRRS is a congenital disorder characterized by macrocephaly, intestinal hamartomatous polyposis, lipomas, and pigmented macules of the glans penis.
• PS is a complex, highly variable disorder involving congenital malformations and hamartomatous overgrowth of multiple tissues, as well as connective tissue nevi, epidermal nevi, and hyperostoses.
• Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.

Diagnosis/testing.

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

Management.

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

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

• Children (age <18 years). Yearly thyroid ultrasound from the time of diagnosis 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. Once a PTEN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk is possible.

Suggestive Findings

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

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

Cowden Syndrome (CS)

Based on more than 3,000 prospectively accrued individuals with CS or a Cowden-like syndrome (CSL) from the community, a scoring system (which can be found online) that takes into account phenotype and age at diagnosis has been developed. 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 leads to a recommendation for referral to a genetics professional to consider PHTS.
• In children, macrocephaly and ≥1 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 2015]. However, the CS scoring system discussed in this section has been shown to be more accurate than the NCCN diagnostic criteria [Tan et al 2011].

The NCCN consensus clinical diagnostic criteria have been divided into three categories: pathognomonic, major, and minor.

Pathognomonic criteria

• Adult Lhermitte-Duclos disease (LDD), defined as the presence of a cerebellar dysplastic gangliocytoma [Zhou et al 2003a]
• Mucocutaneous lesions:
  • Trichilemmomas (facial) (see Figure 1)
  • Acral keratoses
  • Papillomatous lesions (see Figure 2)
  • Mucosal lesions

Figure 1.

Trichilemmoma

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

Establishing the Diagnosis

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

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of PTEN is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. If a pathogenic variant is not identified with deletion/duplication analysis, perform sequence analysis of the PTEN promoter region for variants that decrease gene expression.
  Note: In individuals with Cowden syndrome (CS) and Cowden-like syndrome also consider KLLN promoter methylation analysis (see Differential Diagnosis, Germline KLLN Epimutation), SDHB-D analysis (see Differential Diagnosis, New Susceptibility Genes in Individuals with Non-PHTS CS and a CS-Like Disorder) including PIK3CA, AKT1 [Orloff et al 2013], and SEC23B [Yehia et al 2015].
• A multigene panel that includes PTEN and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing or genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes PTEN) fails to confirm a diagnosis in an individual with features of PHTS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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.

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 pathogenic variant (p.Arg130Ter) in three separate tissues, possibly representing germline mosaicism [Zhou et al 2000]. Both pathogenic variants 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 pathogenic variants [Zhou et al 2001]. Since then multiple single cases of germline PTEN pathogenic variants 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 Clinical Description for age at which specific manifestations are likely to become evident.)

Nomenclature

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

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

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

Germline KLLN Epimutation

Bennett et al [2010] determined that approximately 30% of individuals with Cowden syndrome (CS) (OMIM 615107) and Cowden-like syndrome who do not have a PTEN germline pathogenic variant have a germline KLLN methylation epimutation, which resulted in downregulation 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 (OMIM 612359) and SDHD (OMIM 615106) [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 (see PIK3CA-Related Segmental Overgrowth) or AKT1 pathogenic variants [Orloff et al 2013]. Another 3%-6% of CS and CS-like individuals without pathogenic variants in the above known genes have germline heterozygous SEC23B pathogenic variants, which are particularly associated with thyroid carcinoma [Yehia et al 2015].

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 medical history and family history
• Physical examination with particular attention to skin, mucous membranes, thyroid, breasts
• In children: consideration of neurodevelopmental evaluation
• Urinalysis with cytospin
• Baseline thyroid ultrasound examination* (on identification of a PTEN pathogenic variant)
• For women age ≥30 years at diagnosis*:
  • Breast screening (at minimum mammogram; MRI may also be incorporated)
  • Transvaginal ultrasound or endometrial biopsy
• For men and women age ≥35 years at diagnosis*: colonoscopy
• For men and women age ≥40 years at diagnosis*: renal imaging (CT or MRI preferred)
• Consultation with a clinical geneticist and/or genetic counselor

* 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