Cowden Disease – Causes, Symptoms, Diagnosis, Treatment

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.

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.

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.
• A multigene panel – that includes PTEN and other genes of interest 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. More detailed information for clinicians ordering genetic tests can be found.
• 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. More detailed information for clinicians ordering genomic testing can be found.

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 the involvement of five or more organs, a surrogate phenotype for the 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].

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 the neurodevelopmental evaluation
• Urinalysis with cytospin
• Baseline thyroid ultrasound examination* (on the 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 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 cloud formation and recurrence (often rapid) of the lesions.

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:

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.

Therapies Under Investigation

Although mTOR inhibitors show promise for the 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.

An mTOR inhibitor trial will open shortly for pediatric, adolescent, and young adult patients with germline PTEN pathogenic variants and an autism spectrum disorder.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

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

The risk to Family Members

Parents of a proband

• Cowden syndrome (CS). 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. As a broad estimate, 55%-90% of individuals with CS have an affected parent [Marsh et al 1999, Mester et al 2012]. However, a family history estimate based on practical experience is likely nearer to 50%.
• Bannayan-Riley-Ruvalcaba syndrome (BRRS). The majority of evidence suggests that PTEN pathogenic variants occur in both simplex and familial occurrences of BRRS [Eng 2003, Zbuk & Eng 2007].
• PTEN-related Proteus syndrome and Proteus-like syndrome. Virtually all individuals are simplex cases.
• 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.
• The family history of many individuals diagnosed with PHTS 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 the PTEN pathogenic variant, the risk to the sibs of inheriting the variant 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 the genetic status of the parents is unknown but they have no clinical signs of CS/BRRS and are in their thirties, it is unlikely either parent is heterozygous for a PTEN pathogenic variant and the risk to sibs is therefore minimal (penetrance of PHTS is close to 99% by the thirties in individuals with a PTEN pathogenic variant).

Offspring of a proband. Each child of an individual with PHTS has a 50% chance of inheriting the PTEN pathogenic variant and developing PHTS.

Other family members. The risk to other family members depends on the status of the proband’s parents: if a parent has the PTEN pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

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, and of thyroid cancer in PHTS.

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

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through a cancer risk assessment with or without molecular genetic testing

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PTEN pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for PHTS are possible.

References