Disease characteristics. The PTEN hamartoma tumor syndrome (PHTS) includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules and present by the late 20s. The lifetime risk of developing breast cancer is 25%-50%, 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 around 10%, and the risk for endometrial cancer may approach 5%-10%. 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 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 mutation is identified. Approximately 80% of individuals who meet the diagnostic criteria for CS and 60% of individuals with a clinical diagnosis of BRRS have a detectable PTEN gene mutation. Preliminary data also suggest that up to 50% of individuals with a Proteus-like syndrome and up to 20% of individuals with Proteus syndrome have PTEN mutations. Full sequencing of the PTEN gene is available on a clinical basis.
Management. Because the most serious consequences of PHTS relate to the increased risk of breast, thryoid, endometrial, and renal cancers, the most important aspect of management of an individual with a PTEN mutation is increased cancer surveillance. Surveillance in general for individuals with PTEN mutations (with CS, BRRS, PS, or Proteus-like syndromes) includes annual physical examination from age 18 years, annual urinalysis, and baseline colonoscopy at age 50 years. Specific surveillance for breast cancer in individuals with CS includes monthly self-examination beginning at age 18 years (for females and males), annual clinical breast examinations beginning at age 25 years, and annual mammography and breast MRI beginning at age 30-35 years; surveillance for thyroid cancer includes baseline thyroid ultrasound examination at age 18 years and annual thyroid ultrasound examinations; surveillance for endometrial cancer includes annual suction biopsies beginning at age 35-40 years for premenopausal women and annual transvaginal ultrasound examination for postmenopausal women. 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) are significant. Molecular testing of asymptomatic at-risk relatives can identify those who have a family-specific PTEN mutation and ensure appropriate 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 two or more related affected individuals) cannot be determined. The majority of CS cases are simplex. Perhaps 10%-50% of individuals with CS have an affected parent. If a parent of the proband has PHTS, the risk to sibs is 50%. Each child of an affected individual has a 50% chance of inheriting the mutation and developing PHTS. Prenatal testing is available.
A presumptive diagnosis of PHTS is based on clinical signs; by definition, however, the diagnosis of PHTS is made only when a PTEN mutation is identified.
Cowden syndrome. Consensus diagnostic criteria for Cowden syndrome have been developed [Eng 2000] and updated each year by the National Comprehensive Cancer Network (NCCN). Clinical criteria have been divided into three categories:
Pathognomonic criteria
Adult Lhermitte-Duclos disease (LDD), defined as the presence of a cerebellar dysplastic gangliocytoma [Zhou et al 2003a]
Mucocutaneous lesions:
Trichilemmomas (facial)
Acral keratoses
Papillomatous lesions
Mucosal lesions
Major criteria
Breast cancer
Thyroid cancer (non-medullary), especially follicular thyroid epithelial cancer
Macrocephaly (occipital frontal circumference ≥97th percentile)
Endometrial carcinoma
Minor criteria
Other thyroid lesions (e.g., adenoma, multinodular goiter)
Mental retardation (IQ ≤75)
Hamartomatous intestinal polyps
Fibrocystic disease of the breast
Lipomas
Fibromas
Genitourinary tumors (especially renal cell carcinoma)
Genitourinary malformation
Uterine fibroids
An operational diagnosis of Cowden syndrome is made if an individual meets any one of the following criteria:
Pathognomonic mucocutaneous lesions alone if there are:
Six or more facial papules, of which three or more must be trichilemmoma, or
Cutaneous facial papules and oral mucosal papillomatosis, or
Oral mucosal papillomatosis and acral keratoses, or
Six or more palmo-plantar keratoses
One of the following:
Two or more major criteria
One major and at least three minor criteria
At least four minor criteria
In a family in which one individual meets the diagnostic criteria for Cowden syndrome listed above, other relatives are considered to have a diagnosis of CS if they meet any of the following criteria:
The pathognomonic criteria OR
Any one major criterion with or without minor criteria OR
Two minor criteria OR
History of Bannayan-Riley-Ruvalcaba syndrome
Bannayan-Ruvalcaba-Riley syndrome. 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, Jones 1997].
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 [Biesecker et al 1999]. Mandatory general criteria for diagnosis include mosaic distribution of lesions, progressive course, and sporadic occurrence.
Additional specific criteria for diagnosis include:
Connective tissue nevi (pathognomonic)
OR two of the following:
Epidermal nevus
Disproportionate overgrowth (one or more)
Limbs (arms/legs, hands/feet/digits)
Skull (hyperostoses)
External auditory meatus (hyperostosis)
Vertebrae (megaspondylodysplasia)
Viscera (spleen/thymus)
Specific tumors before end of second decade (either one)
Bilateral ovarian cystadenomas
Parotid monomorphic adenoma
OR three of the following:
Dysregulated adipose tissue (either one)
Lipomas
Regional absence of fat
Vascular malformations (one or more)
Capillary malformation
Venous malformation
Lymphatic malformation
Facial phenotype
Dolichocephaly
Long face
Minor downslanting of palpebral fissures and/or minor ptosis
Low nasal bridge
Wide or anteverted nares
Open mouth at rest
Proteus-like syndrome. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS but who do not meet the diagnostic criteria.
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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. PTEN is the only gene known to be associated with PTEN hamartoma tumor syndrome (PHTS).
Clinical uses
Confirmation of the diagnosis. Failure to detect a mutation does not exclude a clinical diagnosis of CS, BRRS, or Proteus/Proteus-like syndromes in an individual with significant signs associated with these disorders.
Predictive testing
Prenatal diagnosis
Clinical testing
Sequence analysis. Virtually all missense mutations in PTEN are believed to be deleterious [Eng, unpublished data]:
Approximately 85% of individuals who meet the diagnostic criteria for CS [Marsh et al 1998, Zhou et al 2003b] and 65% of individuals with a clinical diagnosis of BRRS [Marsh et al 1999, Zhou et al 2003b] have a detectable PTEN
gene mutation.
Note: To date, no individuals with CS have had large deletions.
Data suggest that up to 50% of individuals with a Proteus-like syndrome and up to 20% of individuals with Proteus syndrome have PTEN mutations [Zhou et al 2001a, Eng 2003].
Note: (1) These observations were confirmed by Smith et al (2002), who found a germline PTEN mutation in a child with Proteus syndrome who met published diagnostic criteria. (2) In the Thiffault et al (2004) study, no PTEN mutations were detected in individuals with Proteus syndrome, potentially signaling the existence of other genes in this syndrome or the relative insensitivity of the mutation detection technique used.
Research testing
Deletion analysis. Southern blotting, monochromosomal hybrid analysis, real-time PCR, and semiquantitative multiplex PCR can each be used to detect PTEN
deletions on a research basis only.
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].
Promoter analysis. Direct sequencing of the promoter region detects mutations that alter the function of the gene in approximately 10% of individuals with CS who do not have an identifiable mutation in the PTEN coding region [Zhou et al 2003b].
Table 1 summarizes molecular genetic testing for this disorder.
1. Zhou et al 2003b
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
No phenotypes other than Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome are known to be consistently caused by mutations in the PTEN gene.
Phenotypes that can be associated with PTEN germline mutations:
Lhermitte-Duclos disease (LDD). Most, if not all, adult-onset Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum, a hamartomatous overgrowth known to be a feature of CS) can be attributed to mutations in PTEN, even in the absence of other clinical signs of CS/BRRS. However, germline PTEN mutations appear to be rare in individuals with childhood-onset LDD [Zhou et al 2003a].
Autism/pervasive developmental disorder and macrocephaly. Germline PTEN mutations were identified in individuals with these findings, epecially in the presence of other personal or family history consistent with CS/BRRS [Dasouki et al 2001, Goffin et al 2001]. Recently, Butler et al (2005) found that approximately 20% of individuals with autism spectrum disorders and macrocephaly have germline PTEN mutations.
The PTEN hamartoma tumor syndrome (PHTS) is characterized by hamartomatous tumors and germline PTEN mutations. Clinically, PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. CS is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. BRRS is a congenital disorder characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. PS is a complex, highly variable disorder involving congenital malformations and overgrowth of multiple tissues. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria for PS.
Cowden syndrome. Over 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s [Nelen et al 1996, Eng 2000]. By the third decade, 99% of affected individuals develop the mucocutaneous stigmata, primarily trichilemmomas and papillomatous papules, as well as acral and plantar keratoses. In addition, individuals with Cowden syndrome usually have macrocephaly and dolicocephaly. Hamartomatous gastrointestinal polyps can be seen in CS but are usually minute and cause few symptoms. Based on anecdotal observations, glycogenic acanthosis in the presence of features of CS appears to be associated with a high likelihood of finding a PTEN mutation [Eng 2003, McGarrity et al 2003]:
Tumor risk. Individuals with CS have a high risk of breast, thyroid, and endometrial cancers. As with other hereditary cancer syndromes, the risk of multifocal and bilateral (in paired organs such as the breasts) cancer is increased.
Breast disease. Women with Cowden syndrome have as high as a 67% risk for benign breast disease. The lifetime risk to females of developing breast cancer is 25%-50%, with an average age of diagnosis between 38 and 46 years [Brownstein et al 1978, Starink et al 1986]. Breast cancer has been described in PTEN mutation-positive males [Fackenthal et al 2001].
Thyroid disease. Benign multinodular goiter of the thyroid as well as adenomatous nodules and follicular adenomas are common, occurring in up to 75% of individuals with CS [Harach et al 1999]. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is around 10% [Eng 1997]. It is not clear if the age of diagnosis of thyroid cancer is earlier than in the general population.
Endometrial disease. Benign uterine fibroids are common. Risk for endometrial cancer, although not well defined, may approach 5%-10%.
Other
Skin cancers, renal cell carcinomas, and brain tumors as well as vascular malformations affecting any organ are occasionally seen in individuals with CS.
Note: Because meningioma is so common in the general population, it is not yet clear if meningioma is a true manifestation of CS.
A rare central nervous system tumor, cerebellar dyplastic gangliocytoma (Lhermitte-Duclos disease) is also found in CS and may be pathognomonic.
Although hamartomatous polyps may occur in the gastrointestinal tract, it is felt that the risk for colorectal cancer is not increased; unlike BRRS polyps, the polyps in CS are rarely symptomatic.
Bannayan-Ruvalcaba-Riley syndrome (BRRS). Common features of BRRS, in addition to those mentioned above, include high birth weight, developmental delay, and mental deficiency (50% of affected individuals), a myopathic process in proximal muscles (60%), joint hyperextensibility, pectus excavatum, and scoliosis (50%) [Gorlin et al 1992, Jones 1997]. Although cancer was initially not believed to be a component of the syndrome, individuals with BRRS and PTEN gene mutations are currently thought to have the same cancer risks as individuals with CS [Marsh et al 1999]. It is not clear whether these risks apply to individuals with BRRS without PTEN gene mutations. The gastrointestinal hamartomatous polyps in BRRS (seen in 45% of affected individuals) may occasionally be associated with intussusception, but rectal bleeding and oozing of "serum" is more common. These polyps are not believed to increase the risk for colorectal cancer. PHTS hamartomatous polyps are different in histomorphology from the polyps seen in Peutz-Jeghers syndrome.
Proteus syndrome (PS). Proteus syndrome is a complex disorder comprising malformations and hamartomatous overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, and hyperostoses. The manifestations are commonly present at birth and persist or progress over postnatal life. Tumors or malignancies are not frequently reported in PS. However, certain unusual tumor types, such as cystadenoma of the ovary, various types of testicular tumors, central nervous system tumors, and parotid monomorphic adenomas, are occasionally associated with PS and therefore can be of diagnostic value when present. PS is uncommon; only approximately 120 affected individuals have been reported [Cohen 1999].
Proteus-like syndrome. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of PS who do not meet the diagnostic criteria.
For purposes of genotype-phenotype analyses, a series of 37 unrelated probands with CS were ascertained by the operational diagnostic criteria of the International Cowden Consortium, 1995 version [Nelen et al 1996, Eng 2000]. Association analyses revealed that families with CS and germline PTEN mutations are more likely to develop malignant breast disease when compared to families that do not have a PTEN mutation [Marsh et al 1998]. In addition, missense mutations and mutations 5' to or within the phosphatase core motif appeared to be associated with involvement of five or more organs, a surrogate phenotype for severity of disease [Marsh et al 1998].
The mutational spectra of BRRS and CS have been shown to overlap, thus lending formal proof that CS and BRRS are allelic [Marsh et al 1999]. No difference in mutation frequencies was observed between BRRS occurring in a single individual in a family and BRRS occurring in multiple family members. Over 90% of families with CS-BRRS overlap were found to have germline PTEN mutations. In addition, the presence of PTEN mutations in BRRS was found to be associated with the development of lipomas and tumors of the breast [Marsh et al 1999]. Therefore, individuals with BRRS and PTEN mutations may have increased cancer risks (despite the fact that this syndrome was previously not believed to be associated with malignancy).
An individual representing 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 R335X PTEN mutation and the same somatic mutation (R130X) in three separate tissues, possibly representing germline mosaicism [Zhou et al 2000]. Both these mutations have been previously described in classic CS and BRRS. Two of nine individuals (22%) with Proteus syndrome and three of six (50%) individuals with Proteus-like syndrome were found to have germline PTEN mutations [Zhou et al 2001a].
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.
Anticipation is not observed.
Cowden syndrome, Cowden disease, and multiple hamartoma syndrome have been used interchangeably.
Bannayan-Riley-Ruvalcaba syndrome, Bannayan-Zonana syndrome, and Myhre-Riley-Smith syndrome refer to a similar constellation of signs that comprise what the authors refer to as BRRS. When a PTEN mutation is found, the gene-related name, PHTS, should be used.
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 1997, Nelen et al 1999]; this is likely an underestimate. Because of the variable and often subtle external manifestations of CS/BRRS, many individuals remain undiagnosed [Haibach et al 1992; Schrager et al 1998; Eng, unpublished].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 their lifetimes, 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 mutations in the MADH4 gene; approximately 20% of individuals with JPS have mutations in the BMPR1A gene [Howe et al 1998, Howe et al 2001]:
Prior case reports have claimed that germline PTEN mutations can occur in 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 to clinically exclude CS, 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 mutations, one individual with JPS was found to have a germline PTEN mutation [Kurose et al 1999]. Upon re-examination of this individual, clinical features of CS were identified [Kurose et al 1999].
Conversely, a germline BMPR1A mutation was identified in an individual with only colonic polyposis but a family history suggestive of Cowden syndrome. Although this might suggest that BMPR1A may be responsible for a small proportion of CS/BRRS-like cases, the authors felt that on the basis of the mutation status this individual should be classified as having JPS [Zhou et al 2001b].
Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. PJS-type hamartomatous polyps are most prevalent in the small intestine, but also occur in the stomach and large bowel in the majority of affected individuals. 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 peri-oral region is pathognomonic, particularly if it crosses the vermilion border [Eng & Blackstone 1988, Rustgi 1994]. Hyperpigmented macules on the fingers are also common.
Molecular genetic testing of STK11/LKB1 reveals disease-causing mutations in approximately 70% of individuals who have a positive family history and 20%-70% of individuals who have no family history of PJS.
Other less likely differential diagnoses to consider for PHTS include the following:
Birt-Hogg-Dube (BHD) syndrome. This syndrome is characterized by the triad of fibrofolliculomas, trichodiscomas, and acrochordons, along with an increased risk for renal cell carcinoma. Affected individuals may have skin papules, trichilemmomas, and lipomas, which are seen in CS/BRRS. Germline mutations in the BHD gene encoding folliculin are associated with BHD, which is thus genetically distinct from PHTS.
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. This syndrome is characterized by basal cell nevi, basal cell carcinoma, and diverse developmental abnormalities. Affected individuals can also develop other tumors and cancers, such as 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.
The mucocutaneous manifestations of Cowden syndrome are rarely life threatening:
If asymptomatic, observation alone is prudent.
When symptomatic, topical agents (e.g., 5-fluorouracil), curettage, cryosurgery, or laser ablation may provide only temporary relief [Hildenbrand et al 2001]. Surgical excision is sometimes complicated by cheloid formation and recurrence (often rapid) of the lesions [Eng, unpublished data].
Treatment for the benign and malignant manifestations of PHTS is the same as for their sporadic counterparts.
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% women at high risk [Hartmann et al 1999]. Note: the recommendation of prophylactic mastectomy is a generalization for women at increased risk of breast cancer from a variety of causes, not just from PTHS.
There is no direct evidence to support the routine use of agents such as tamoxifen or raloxifene in individuals with PHTS to reduce the risk of developing breast cancer. Physicians should discuss the limitations of the evidence and the risks and benefits of chemoprophylaxis with each individual. In addition, the clinician must discuss the increased risk of endometrial cancer associated with tamoxifen use in a population already at increased risk for endometrial cancer.
The most serious consequences of PHTS relate to the increased risk of cancers including breast, thyroid, endometrial, and to a lesser extent, renal. In this regard, the most important aspect of management of any individual with a PTEN mutation is increased cancer surveillance.
General
Annual comprehensive physical examination starting at age 18 years (or five years before the youngest component cancer diagnosis in the family), with attention paid to skin changes and the neck region
Consider annual dermatologic examination
Annual urinalysis. Consider annual cytololgy and renal ultrasound examination if the family history is positive for renal cell carcinoma
Baseline colonoscopy at age 50 years (unless symptoms arise earlier). If only hamartomas are found, the American Cancer Society guidelines for colon cancer screening (i.e., annual fecal occult blood testing and sigmoidoscopy every five years or colonoscopy every ten years) should be followed.
Breast cancer
Women [Eng 2000, National Comprehensive Cancer Network 2006]
Monthly breast self-examination beginning at age 18 years
Annual clinical breast examinations beginning at age 25 years or 5-10 years earlier than earliest known breast cancer diagnosis in the family (whichever is earliest)
Annual mammography and breast MRI beginning at age 30-35 years or 5-10 years before the earliest known breast cancer diagnosis in the family (whichever is earliest)
Men. Monthly breast self-examination
Thyroid cancer
Baseline thyroid ultrasound examination at age 18 years
Consider annual thyroid ultrasound examination thereafter
Endometrial cancer
Premenopausal women. Annual blind repel (suction) biopsies beginning at age 35-40 years (or five years before the youngest endometrial cancer diagnosis in the family)
Postmenopausal women. Annual transvaginal ultrasound examination with biopsy of suspicious areas
Screening recommendations have not been established for BRRS. Given recent molecular epidemiologic studies, however, individuals with BRRS and a germline PTEN mutation 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.
Although the observation of germline PTEN mutations in Proteus and Proteus-like syndromes is relatively new, clinicians should consider instituting the CS surveillance recommendations for individuals with these disorders who have germline PTEN mutations.
Because of the propensity for rapid tissue regrowth and the propensity to form cheloid tissue, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms (e.g., pain, deformity) are significant.
When a PTEN mutation has been identified in a proband, testing of asymptomatic at-risk relatives can identify those who have the family-specific mutation and, therefore, have PHTS. These individuals are in need of ongoing surveillance, as discussed above.
Molecular testing is appropriate for at-risk children, given the possible early disease presentation in individuals with BRRS and Proteus syndrome.
Relatives who have not inherited the PTEN mutation found in an affected relative do not have PHTS or its associated cancer risks.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Although mTOR inhibitors show promise for treatment of malignancies in individuals who have a germline PTEN mutation, use should be limited to clinical trials. At this time no clinical trials are specifically directed at individuals with PHTS.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
PHTS is inherited in an autosomal dominant manner.
Parents of a proband
Because Cowden syndrome is likely underdiagnosed, the actual proportion of simplex cases (defined as individuals with no obvious family history) and familial cases (defined as two or more related affected individuals) cannot be determined.
From the literature and the experience of both major US Cowden syndrome centers, the majority of individuals with CS have no obvious family history. As a broad estimate, perhaps 10%-50% of individuals with Cowden syndrome have an affected parent [Marsh et al 1999].
The majority of evidence suggests that PTEN mutations occur in both simplex and familial occurrences of BRRS [Eng 2003].
If a PTEN mutation is identified in the proband, the parents should be offered molecular genetic testing to determine if one of them has previously unidentified PHTS. If no mutation is identified in the proband, both parents should undergo thorough clinical examination to help determine if either parent has signs of PHTS.
Note: Although some individuals diagnosed with PHTS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.
Sibs of a proband
The risk to the sibs of the proband depends on the genetic status of the parents.
If a parent of the proband has PHTS, the risk to sibs is 50%.
If it has been shown that neither parent has the PTEN mutation found in the proband, the risk to sibs is probably negligible, since germline mosaicism has not been reported in PHTS.
If a mutation cannot be identified in the proband, PHTS can be excluded on clinical grounds. Normal clinical examinations in parents in their thirties, done looking specifically for signs of CS/BRRS, would make the risk to sibs of the proband minimal, since an estimated 99% of affected individuals would have signs by that age.
Offspring of a proband. Each child of an affected individual has a 50% chance of inheriting the mutation and developing PHTS.
Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at-risk.
Testing of at-risk relatives. When a mutation has been identified in a proband, testing of asymptomatic at-risk relatives can identify those who also have the mutation and have PHTS. These individuals are in need of ongoing surveillance, as discussed above. Molecular testing is appropriate for at-risk individuals younger than age 18 years, given the possible early disease presentation in individuals with BRRS and Proteus syndrome.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations, including alternate paternity or 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.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD). Although successful PGD for PHTS has not been reported in the medical literature, PGD may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
PTEN | 10q23.3 | Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
153480 | BANNAYAN-RILEY-RUVALCABA SYNDROME; BRRS |
158350 | COWDEN DISEASE; CD |
176920 | PROTEUS SYNDROME |
601728 | PHOSPHATASE AND TENSIN HOMOLOG; PTEN |
Gene Symbol | Entrez Gene | HGMD |
---|---|---|
PTEN | 5728 (MIM No. 601728) | PTEN |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
The complete function of PTEN is not yet fully understood. PTEN belongs to a sub-class of phosphatases called dual-specificity phosphatases that remove phosphate groups from tyrosine as well as serine and threonine. In addition, PTEN is the major phosphatase for phosphoinositide-3,4,5-triphosphate, and thus downregulates the PI3K/Akt pathway.
Somatic PTEN mutations and loss of gene expression are frequently found in both endometrioid endometrial adenocarcinoma and precancerous endometrial lesions (intraepithelial neoplasia), confirming the critical role that PTEN must play in endometrial tissues [Mutter et al 2000].
Normal allelic variants: The gene comprises nine exons and likely spans a genomic distance of more than 120 kb. The 1209-bp coding sequence is predicted to encode a 403-amino acid protein.
Pathologic allelic variants: Germline mutations have been found throughout PTEN (with the exception of exon 9) and include missense and nonsense mutations, splice site mutations, small deletions, insertions, and several large deletions. More than 150 unique mutations are currently listed in the Human Gene Mutation Database (see Genomic Databases table). Nearly 40% of mutations are found in exon 5, which encodes the phosphate core motif [Eng 2003]. Most mutations are unique, although a number of recurrent mutations have been reported, particularly R130X, R233X, and R335X [Bonneau & Longy 2000]. Approximately 10% of individuals with CS who do not have a mutation detected in the PTEN coding sequence have heterozygous germline mutations in the PTEN promoter [Zhou et al 2003b]. In contrast, 10% of individuals with BRRS who do not have an identifiable PTEN mutation on sequence analysis have large deletions within or encompassing PTEN [Zhou et al 2003b].
Normal gene product: PTEN encodes an almost ubiquitously expressed dual specificity phosphatase. The PTEN protein localizes to specific nuclear and cytoplasmic components. The wild-type protein is a major lipid phosphatase that downregulates the PI3K/Akt pathway to cause G1 arrest and apoptosis. In addition, the protein phosphatase appears to play an important role in inhibition of cell migration and spreading, as well as downregulating several cell cyclins [Eng 2003]. It appears that nuclear PTEN mediates cell cycle arrest, while cytoplasmic PTEN is required for apoptosis [Chung & Eng 2005].
Abnormal gene product: The majority (76%) of germline mutations in PTEN result in either truncated protein, lack of protein (haploinsufficiency), or dysfunctional protein. Many missense mutations are functionally null and several act as dominant negatives. When PTEN is absent, decreased, or dysfunctional, phosphorylation of Akt is uninhibited, leading to the inability to activate cell cycle arrest and/or to undergo apoptosis. In addition, through lack of protein phosphatase activity, the mitogen-activated protein kinase (MAPK) pathway is dysregulated, leading to abnormal cell survival [Eng 2003].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
Cowdens Syndrome & Bannayan-Riley-Ruvalcaba Syndrome Foundation
1394 Wedgewood Drive
Salne MI 48176
Phone: 734-944-8313
Email: Rosalita@comcast.net
Cowden Syndrome
Genetics of Breast and Ovarian Cancer (PDQ)
A service of the National Cancer Institute
Cowden syndrome
National Library of Medicine Genetics Home Reference
Cowden syndrome
American Cancer Society
Provides contact information for regional support.
1599 Clifton Road NE
Atlanta GA 30322
Phone: 800-227-2345
www.cancer.org
CancerCare
275 Seventh Avenue Floor 22
New York NY 10001
Phone: 800-813-HOPE (800-813-4673); 212-712-8400
Fax: 212-712-8495
Email: info@cancercare.org
www.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
www.nbcam.org
The National Breast Cancer Coalition/Fund
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
www.stopbreastcancer.org
The National Coalition for Cancer Survivorship
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
www.canceradvocacy.org
The 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); 972-855-1600
Fax: 972-855-1605
Email: helpline@komen.org
http://cms.komen.org/komen/index.htm
Y-Me National Breast Cancer Organization
Hotline staffed by counselors and volunteers who have had breast cancer. Information, referrals, support.
212 West Van Buren Street Suite 1000
Chicago IL 60607
Phone: 800-221-2141; 312-986-8338
Fax: 312-294-8597
www.y-me.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Dr. Eng is the director of the International Cowden Syndrome Consortium and a primary researcher in the field of PTEN-related disorders. Dr. Zbuk is a clinical cancer genetics fellow and Ms Stein is a genetic counselor in Cleveland Clinic's Genomic Medicine Institute, which is directed by Dr. Eng. 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.
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 (2006-present)
Kevin M Zbuk, MD (2006-present)
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