Cowden Disease – Causes, Symptoms, Diagnosis, Treatment

Cowden disease, also known as Cowden syndrome or multiple hamartoma syndrome, is a genodermatosis originally described in 1963 by Lloyd and Dennis. It is an uncommon condition that is inherited in an autosomal dominant fashion and is part of a spectrum of other disorders that have mutations in the phosphatase and tensin homolog gene (PTEN). Cowden syndrome represents the most common phenotypical presentation of this spectrum and classically is characterized by multiple hamartomas that can occur in any organ. Characteristically, patients with Cowden syndrome develop mucocutaneous lesions and macrocephaly. The majority of patients affected with the disease go on to develop a malignant neoplasm of the thyroid, endometrium, or breast. An interprofessional approach to treatment is necessary, with cancer screening tests paramount.  Medications currently being studied show encouraging results.

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.

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 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 [] and are updated each year by the National Comprehensive Cancer Network []. However, the CS scoring system discussed in this section has been shown to be more accurate than the NCCN diagnostic criteria [].

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 []
  • Mucocutaneous lesions:
    • Trichilemmomas (facial)
    • Acral keratoses
    • Papillomatous lesions
    • Mucosal lesions

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

Proteus Syndrome

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 [].

Proteus-Like Syndrome

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

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 Characteristics

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.

Cowden Syndrome (CS)

More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s []. 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 [].

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 [].

Tumor risk. Individuals with CS are at high risk for breast, thyroid, and endometrial cancers. As with other hereditary cancer syndromes, the risk for 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.
    • An analysis of prospectively accrued and followed probands and family members with a PTEN pathogenic variant revealed an 85% lifetime risk for female breast cancer, with 50% penetrance by age 50 years [].
    • Although breast cancer has been described in males with a PTEN pathogenic variant [], it was not observed in a study of more than 3,000 probands [].
  • 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 [].
    • The lifetime risk for epithelial thyroid cancer is approximately 35% []. Median age of onset was 37 years; seven years was the youngest age at diagnosis [].
      Note: (1) Follicular histology is overrepresented in adults compared to the general population in which papillary histology is overrepresented. (2) No medullary thyroid carcinoma was observed in the cohort with molecularly confirmed CS.
  • Endometrial disease
    • Benign uterine fibroids are common.
    • The lifetime risk for endometrial cancer is estimated at 28%, with the starting age at risk in the late 30s to early 40s [].
  • 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 []. Histologic findings varied, ranging from ganglioneuromatous polyps, hamartomatous polyps, and juvenile polyps to adenomatous polyps.
    • The lifetime risk for colorectal cancer is estimated at 9%, with the starting age at risk in the late 30s [].
  • Renal cell carcinoma. The lifetime risk for renal cell carcinoma is estimated at 35%, with the starting age at risk in the 40s []. The predominant histology is papillary renal cell carcinoma [].
  • Other
    • The 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 intellectual disability (50% of affected individuals), a myopathic process in proximal muscles (60%), joint hyperextensibility, pectus excavatum, and scoliosis (50%) [].

Individuals with BRRS and a PTEN pathogenic variant are thought to have the same cancer risks as individuals with CS. 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 of colorectal cancer. PHTS hamartomatous polyps are different in histomorphology from the polyps seen in Peutz-Jeghers syndrome.

PTEN-Related Proteus Syndrome (PS)

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

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 []. 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 []. 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 [].

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 []. 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 []. 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 []. 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 [].


More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s []. 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.)


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  and with a germline PTEN pathogenic variant, was termed SOLAMEN (segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus) syndrome []. 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 [].

Germline KLLN Epimutation

 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) []. That germline variants in SDHBSDHC, 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 []. 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 []. 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 [].


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 []. 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 []. 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.


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** (on identification of a PTEN pathogenic variant)
  • Yearly skin check with physical examination


  • 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 the 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.

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 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.

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.

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 []. 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 [].
  • 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 [].
  • 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.


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