PTEN hamartoma tumor syndromes, including Cowden syndrome

INTRODUCTION — Germline pathogenic variants in the phosphatase and tensin homolog (PTEN) gene have been described in a variety of rare syndromes with different clinical presentations that are collectively known as PTEN hamartoma tumor syndromes (PHTS). The defining clinical feature of PHTS is the presence of hamartomatous tumors, which are disorganized growths of native cells in native tissues. PHTS is inherited in an autosomal dominant fashion.

PHENOTYPIC SPECTRUM OF PHTS — The phenotypic spectrum of PHTS includes the following entities:

●Cowden syndrome (also known as Cowden disease or multiple hamartoma syndrome) is the best-described phenotype within PHTS. Besides multiple hamartomas in a variety of tissues, patients have characteristic dermatologic manifestations such as trichilemmomas, oral fibromas, and punctate palmoplantar keratoses, and an increased risk of breast, endometrial, thyroid, kidney, and colorectal cancers.

●Bannayan-Riley-Ruvalcaba syndrome is another rare subset of PHTS. In addition to hamartomas, these patients have multiple subcutaneous lipomas, macrocephaly, and penile lentigines (picture 1). High penetrance of cancer, as reported in Cowden syndrome, has not been as clearly documented, but is presumed to be present.

Genotype analyses have concluded that a similar spectrum of pathogenic variants in the PTEN gene is found in the Bannayan-Riley-Ruvalcaba syndrome as in other PHTS, leading to the conclusion that they are related allelic disorders [1-3]. Both conditions are now considered phenotypically distinct, age-related presentations of a similar genetic abnormality [4,5].

●Adult Lhermitte-Duclos disease is characterized by hamartomatous outgrowths of the cerebellum (cerebellar dysplastic gangliocytoma) and has also been associated with PTEN pathogenic variants [6,7]. This syndrome may arise in conjunction with Cowden syndrome or without other signs of PHTS.

●Two other conditions have been associated with PTEN pathogenic variants and, although they lack hamartomas, some argue that they should be incorporated into the definition of PHTS:

•A Proteus-like syndrome with a distinct type of epidermal nevus (also referred to as segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus [SOLAMEN)] syndrome or type 2 segmental Cowden syndrome) that likely relates to the early loss of heterozygosity at the PTEN allele in the affected tissues in patients with an underlying germline PTEN pathogenic variant [8-10]. (See 'Proteus-like syndrome' below and "Capillary malformations (port wine stains) and associated syndromes", section on 'Proteus syndrome'.)

•Autism spectrum disorders with macrocephaly [11]. (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Anatomic megalencephaly'.)

This topic review will review the major clinical syndromes that are associated with PTEN pathogenic variants and are considered part of the spectrum of PHTS.

COWDEN SYNDROME — Cowden syndrome was first reported in 1963; an autosomal dominant pattern of inheritance was first suggested in 1972 and later confirmed [12-14]. It is estimated that the rate of de novo pathogenic variants is likely 10 to 30 percent [15].

Although data are limited, the estimated prevalence of Cowden syndrome is 1 in 200,000 to 250,000 [16].

Molecular genetics — The PTEN gene is a negative regulator of the phosphoinositide-3-kinase (PI3K)-AKT and the mechanistic (previously called mammalian) target of rapamycin (mTOR) signaling pathways, which are critical for cell proliferation, cell cycle progression, and apoptosis [17]. Loss of function of this gene contributes to oncogenesis, and somatic mutations are frequently identified in various malignancies. As a result, the PTEN gene, which is located on chromosome 10q23 [18], is considered to be a tumor suppressor gene [19-21].

Germline pathogenic variants in PTEN are found in many patients with Cowden syndrome [22]. Although it was initially reported that up to 83 percent of individuals meeting clinical criteria for Cowden syndrome had a detectable PTEN pathogenic variant [3], this was an overestimate attributable to the highly selected nature of earlier Cowden syndrome cohorts. More recent estimates are that germline PTEN pathogenic variants are found in approximately 20 to 34 percent of individuals who meet clinical criteria for Cowden syndrome or who meet criteria for genetic testing [23,24]. Most mutations are unique to a given family. (See 'Diagnostic criteria' below.)

Genetic testing for Cowden syndrome is discussed below. (See 'Testing for pathogenic variants' below.)

Allelic heterogeneity has been observed in Cowden syndrome, with subsets of patients who have Cowden syndrome lacking detectable nonsynonymous point mutations at the PTEN locus, but harboring either deletions or large structural rearrangements in the PTEN gene. The effect of mutations or deletions in the PTEN promoter region, however, is less clear. (See 'Testing for pathogenic variants' below.)

There is also limited but inconclusive evidence of locus heterogeneity, with alterations reported at other loci:

●In some patients with features of Cowden syndrome who lack PTEN pathogenic variants, hypermethylation of the promoter of the KILLIN gene (KLLN), leading to reduced expression of KLLN, has been described [25]. Patients with KLLN gene promoter hypermethylation were said to have a higher risk of breast and renal cancer than those with PTEN pathogenic variant-positive disease [25]. The clinical utility of this finding is unknown. The KLLN gene, which is located on chromosome 10q23 and functions as a p53-regulated inhibitor of DNA synthesis, shares the same transcription site as the PTEN gene [26].

●Other Cowden-like patients have been reported with pathogenic variants in the succinate dehydrogenase (SDH) gene, subunits B and D [25,27-29]. However, others have disputed this association, pointing out that the majority of the SDH variants identified appear to be polymorphisms rather than pathogenic variants [30].

●Germline PIK3CA and v-akt murine thymoma viral oncogene homolog 1 (AKT1) variants have also been reported in a small number of phenotypic Cowden-like patients without PTEN, SDH, or KLLN mutations in one report [31].

●Variants in the S cerevisiae, B homolog (SEC23B) gene have been associated with Cowden syndrome in a single family [32].

●A heterozygous germline epidermal growth factor receptor (EGFR) pathogenic variant was found by exome sequencing in a 41-year old with Lhermitte-Duclos syndrome [33].

●Some patients who have the Cowden syndrome phenotype but who lack germline PTEN mutations have germline gain of function variants in the WW domain-containing protein 1 (WWP1) gene, which encodes an E3 ubiquitin ligase that negatively regulates the function of PTEN [34]. A study of patients with multiple colon polyps who also had some features of Cowden syndrome (but did not meet clinical diagnostic criteria and did not have detectable PTEN germline pathogenic variants) found germline gain of function variants in the WWP1 gene in a small number of patients (4 percent, 5 out of 126 subjects) [35]. The clinical significance of this is unknown at this point.

Clinical manifestations — Historically, the published data on clinical manifestations have come mainly from small case series or compilations of published cases, most of which predated the development of consensus criteria for diagnosis and genetic testing for Cowden syndrome. More recently, data have been published on several larger cohorts of patients identified through genetic testing programs, but these suffer from significant ascertainment bias [23,36-38]. As a result, the true frequencies of the clinical features of Cowden syndrome are not known [39]. (See 'Diagnostic criteria' below.)

The range of clinical manifestations of Cowden syndrome includes hamartomatous tumors in multiple organ systems, both mucocutaneous and extracutaneous, and an increased risk for malignancy (including second malignant neoplasms [40]).

Mucocutaneous — Skin and oral findings are a distinctive and common manifestation of Cowden syndrome; they are often the initial finding that leads to the diagnosis. Although commonly noticed in the second decade of life, the age of onset may vary from 4 to 75 years [13,41]. The prevalence of mucocutaneous abnormalities in patients with Cowden syndrome was thought to be close to 100 percent based upon early case series, but this may be an overestimate based upon prevalence data driven by genetic testing [13,23,42,43].

The common lesions are trichilemmomas, acral keratoses, and facial papules/oral papillomas:

●Trichilemmomas (picture 2) are hamartomatous tumors of the outer root sheath of the hair follicle or other skin appendages that occur on the face and neck of patients with Cowden syndrome. Trichilemmoma is a clinically significant sign of Cowden syndrome when seen in multiplicity (three or more). They present as wart-like, skin-colored papules with slightly rough surfaces; histologically, the lesions contain large glycogen-rich cells [44]. Clinically, trichilemmomas are indistinguishable from trichoepitheliomas and other benign follicular tumors affecting the pilosebaceous unit, including fibrofolliculomas and trichodiscomas (which are characteristic lesions of Birt-Hogg-Dube syndrome) [45]. At least one lesion should be biopsied given the difficulty with clinical diagnosis [46]. (See "Birt-Hogg-Dubé syndrome".)

A trichilemmoma is rarely a sporadic feature. One study found a complete loss of PTEN expression by immunohistochemistry in five of six (83 percent) trichilemmomas from patients with Cowden syndrome compared with only 1 of 33 (3 percent) sporadic trichilemmomas [47]. (See "Cutaneous manifestations of internal malignancy", section on 'Heritable conditions associated with skin disorders and malignancy'.)

●Acral keratoses present as 1 to 4 mm keratotic verrucous papules that are located on the dorsal hands, wrists, or feet. Patients can also develop translucent punctate keratoses on the palms or soles [13,41,48].

●Facial papules are the most frequent lesions and are found in up to 86 percent of cases [49]. They have a predilection for periorificial regions, sometimes extending into the nostrils. Oral papules and papillomas (coalesced papules) on the lips, buccal mucous membranes or palate are pink or white smooth lesions of 1 to 4 mm in diameter. When they coalesce, they can form a distinctive cobblestone appearance (picture 3) [44,48].

●Multiple other histologies have been reported occasionally (eg, clear cell acanthomas [50]), so consideration of PHTS is warranted in the context of multiple different types of cutaneous lesions in a family or individual.

The differential diagnosis of the mucocutaneous findings includes tuberous sclerosis, Gardner syndrome, epidermodysplasia verruciformis, Brooke-Spiegler syndrome [51], neurofibromatosis type I, and multiple fibrofolliculomas (Birt-Hogg-Dubé syndrome) [48]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis" and "Hereditary kidney cancer syndromes" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Epidermodysplasia verruciformis".)

There have been case reports to suggest that melanoma may be associated with Cowden syndrome [52,53]. More recently, one study of PTEN pathogenic variant carriers projected an 8.5-fold greater risk when compared with the average population and a 6 percent lifetime risk [36], and another noted an elevated standardized incidence ratio (SIR) for melanoma in women (SIR 28.3, 95% CI 7.6-35.4) and men (SIR 39.4, 95% CI 10.6-100.9) with PHTS [37]. However, an international study of PTEN pathogenic variant carriers did not find an increased frequency of melanoma [54]. Additional studies are necessary to clarify this risk before melanoma can be considered a clinical feature of PHTS [46]. (See 'Diagnostic criteria' below.)

Breast — Breast cancer is the most common malignancy in Cowden syndrome, although overall, germline pathogenic variants in PTEN are rare causes of a genetic predisposition to breast cancer [55]. For example, no PTEN pathogenic variants were reported among 1781 individuals (1750 women) referred for commercial breast cancer susceptibility gene (BRCA) testing because of a diagnosis of breast cancer [56]. (See "Overview of hereditary breast and ovarian cancer syndromes associated with genes other than BRCA1/2".)

The lifetime risk of breast cancer for affected female patients is frequently reported at between 25 and 50 percent [36,38,39,57], although more recent reports project a cumulative risk as high as 81 to 85 percent [36,37,54,58]. These, however, suffer from ascertainment biases. The onset of breast cancer is often early, with a diagnosis at a mean of 38 to 46 years of age [39,57]. Although there are several rare reports of breast cancer in male patients with Cowden syndrome, the association is unproven [59,60]. (See "Breast cancer in men".)

Based on limited information, the malignant breast tumors in women are usually ductal in origin and are often surrounded by densely collagenized hamartomatous lesions, suggesting that the tumor arose from areas of hamartomatous change within the breast [57]. There may be a tendency towards more aggressive disease in patients with Cowden syndrome:

●An increased incidence of both multifocality and bilateral involvement has been observed for both benign and malignant breast disorders.

●In a report of 46 patients who presented to the Mayo Clinic over a 30-year period and who met only clinical diagnostic criteria for PHTS, five of the six breast cancers in this cohort were triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) [61]. However, among 1824 women with triple-negative breast cancer not selected for any family history criteria, only one person was found to have a pathogenic PTEN variant [62]. Among women with pathogenic PTEN variants who developed breast cancer, only 3 of 19 were triple negative, suggesting the clinical criteria include women with other etiologies [63-65]. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer".)

Approximately 50 percent of women with Cowden syndrome have benign breast conditions such as ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, fibrocystic change, and densely fibrotic hyalinized nodules [13,49,57]. However, the reported frequencies of these conditions are nearly identical to those reported in the general population, and a systematic review concluded that there was insufficient evidence to include benign breast disease as a diagnostic criterion [46]. (See 'Diagnostic criteria' below and "Overview of benign breast diseases", section on 'Miscellaneous benign lesions of the breast'.)

Thyroid — The most frequently reported extracutaneous manifestation of Cowden syndrome is thyroid disease, occurring in over one-half of patients [66]. Benign thyroid abnormalities such as multinodular goiter, lymphocytic (Hashimoto) thyroiditis, and adenomas are very common and reported in up to 68 percent of patients [13,66-68]. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'History and physical examination'.)

According to one estimate, individuals with Cowden syndrome have an approximately 70-fold increased incidence of non-medullary thyroid cancer relative to the general population [69]. The reported risk of thyroid cancer in affected individuals ranges from 3 to 38 percent in large case series [36-39,43,54,61,67,69]. The median age at diagnosis was 35 in one case series, which is younger than the general population based on Surveillance, Epidemiology, and End Results data [70]. (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Family history'.)

Notably, there are multiple reports of thyroid cancer diagnosed in children as young as age seven [52,69,71,72]. Children presenting with non-medullary thyroid cancer should be tested for PTEN pathogenic variants. (See 'Testing for pathogenic variants' below and "Thyroid nodules and cancer in children", section on 'Genetic predisposition'.)

In most series, papillary neoplasms predominate. However, follicular thyroid cancer may be over-represented compared with the general population [46,69].

Genitourinary — Several genitourinary lesions, including endometrial cancer and renal cell cancer (RCC), may arise in patients with Cowden syndrome:

●Benign

•Benign uterine abnormalities such as uterine fibroids are common findings in female patients. A systematic review concluded that it was not clear that these rates represented an increase over that expected in the general population and that there was insufficient evidence to include uterine fibroids as a diagnostic criterion [46]. (See 'Diagnostic criteria' below and "Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential", section on 'Cowden syndrome'.)

•Men with Cowden syndrome may have multiple bilateral hyperechoic testicular lesions on ultrasound; they represent lipomatosis of the testes [73-75].

●Malignant

•The risk of endometrial cancer is elevated in female patients, with a reported cumulative lifetime risk of 13 to 28 percent [23,36,38,43,54]. There are rare reports of endometrial cancer occurring in adolescents as young as age 14 [76]. (See "Endometrial carcinoma: Epidemiology, risk factors, and prevention", section on 'Other potential heritable factors' and "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening", section on 'Patients with Cowden syndrome'.)

•RCC is also increased in individuals with PTEN pathogenic variants. In large case series of patients with PTEN mutations, RCC was reported in 2 to 5 percent [23,24,37]. Some project a 13 to 34 percent cumulative lifetime risk of RCC, but this may reflect an overestimate due to ascertainment bias [36-38,61]. There is also a suggestion that papillary histology may be more common than expected [77]. (See "Hereditary kidney cancer syndromes".)

Gastrointestinal — There are several gastrointestinal (GI) manifestations of Cowden syndrome.

Esophageal glycogen acanthosis — Glycogenic acanthosis of the esophagus typically appears as multiple, uniformly sized gray-white round elevations in an otherwise normal-appearing mucosa, usually in the midportion of the esophagus (picture 4) [78]. The exact frequency of esophageal glycogen acanthosis is unclear, but in one report, diffuse dozens or scores of lesions were observed in 8 of 10 patients with Cowden syndrome who underwent evaluation [79]. Although usually clinically irrelevant, when present in conjunction with hamartomatous GI tract polyps, further work-up for Cowden syndrome should occur. (See "Benign lesions of the esophagus", section on 'Glycogen acanthosis'.)

Gastric and duodenal polyps — Polyps have been reported throughout the GI tract among PTEN pathogenic variant carriers, with 66 to 100 percent of affected individuals reported to have gastric or duodenal polyps [43,79,80]. Polyp histologies include hamartomas, hyperplastic polyps, ganglioneuromas, adenomas, and inflammatory polyps. Interestingly, there is a report of significant regression of gastric polyps in a Cowden syndrome patient after eradication of Helicobacter pylori [81]. There are rare case reports of gastric cancer [82,83] and duodenal carcinoma [84], but these have not been found to be common in larger case series.

Colon polyps — The prevalence of colon polyps among PTEN pathogenic variant carriers is as high as 93 percent of those undergoing colonoscopy [43,80,85]. The histologic spectrum is diverse. Hamartomatous and inflammatory polyps are the most prevalent, but ganglioneuromas, adenomas, leiomyomas, lipomas, and hyperplastic polyps can also be found. Many patients have multiple synchronous histologic types of polyps [43,85,86]. (See "Juvenile polyposis syndrome" and "Overview of colon polyps", section on 'Hamartomatous polyps' and "Overview of colon polyps", section on 'Inflammatory polyps'.)

Colorectal cancer — Only more recently has an increased risk of early onset colorectal cancer been reported in patients with Cowden syndrome:

●A Japanese series found a 9 percent prevalence of colon cancer, a remarkable finding in view of the low rates of colorectal cancer in this population [80].

●In a series of PTEN pathogenic variant carriers, 13 percent of patients undergoing screening colonoscopy were found to have colorectal adenocarcinomas; all were under the age of 50 (average age 44.4, range 35 to 49) [43]. In a report from the same group of 368 PTEN pathogenic variant-positive patients, the risk of colorectal cancer was estimated at 10-fold higher than the general population, with an estimated lifetime risk of 9 percent [36].

●A multinational series of 156 patients with germline PTEN pathogenic variants found an 18 percent risk of colorectal cancer by the age of 60 [87].

It remains unclear whether colonic malignancy arises from adenomatous polyps or whether it can also arise from hamartomatous polyps. Because of these associations, guidelines suggest that PTEN pathogenic variant carriers undergo routine endoscopic surveillance. (See 'Management' below.)

Neurologic

Tumors and vascular malformations — A wide range of brain tumors has been purportedly linked to PTEN pathogenic variants [88]. Dysplastic gangliocytoma of the cerebellum, or adult Lhermitte-Duclos disease, refers to a hamartomatous tumor of the cerebellar cortex that can occur in the setting of a PTEN pathogenic variant and Cowden syndrome in adults [6,7]. This histologically benign entity is reported to develop in 6 to 32 percent of Cowden syndrome patients, with the lower estimate derived from a case series that did not include specific imaging of the head, and the upper estimates projected from cohorts with likely ascertainment biases [38,43,89]. Symptoms arise secondary to mass effect in the posterior fossa and commonly include headache, nausea and vomiting, ataxia, and papilledema [90].

Dysplastic gangliocytoma of the cerebellum can be familial or sporadic. It remains unclear whether all familial cases, even without features of Cowden syndrome, are caused by germline PTEN pathogenic variants, and whether somatic PTEN pathogenic variants occur in sporadic cases; this should be further clarified as genetic testing becomes more readily available [91].

Many consider that dysplastic gangliocytoma of the cerebellum is a defining feature of Cowden syndrome [6,39,92]. However, a systematic review concluded that although adult onset Lhermitte Duclos disease had a stronger association with PHTS than pediatric cases, there was insufficient evidence to consider it a pathognomonic criterion [46]. (See 'Diagnostic criteria' below.)

The Pilarski-revised clinical diagnostic criteria for PHTS include dysplastic gangliocytoma of the cerebellum as a major criterion (table 1) [46]. If diagnosed outside of a known PHTS kindred, affected patients should be thoroughly investigated for other manifestations of Cowden syndrome and considered for PTEN germline testing [93]. (See 'Pilarski et al diagnostic criteria' below.)

In addition to dysplastic gangliocytoma of the cerebellum, one study found intracranial vascular malformations such as venous and cavernous angiomas in 30 percent of asymptomatic patients who underwent screening magnetic resonance imaging (MRI) [89], and there is a case report of multiple intracranial arteriovenous fistulas in a person with Cowden syndrome [94]. However, this has not been commonly reported [46].

Meningiomas have also been reported in patients with Cowden syndrome [39,89]; however, the data are insufficient to conclude whether they are associated with Cowden syndrome or not [46]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma", section on 'Other schwannomatoses'.)

Macrocephaly — Macrocephaly, defined as an occipital-frontal head circumference greater than the 97^th percentile (greater than two standard deviations above the mean for a given age, sex, and gestation), has historically been reported in 21 to 38 percent of patients with Cowden syndrome [13,49]. At the time, however, it was not routinely assessed, and more recent studies note macrocephaly in 152 of 181 (94.4 percent) patients with confirmed PTEN pathogenic variants, with a mean occipital-frontal circumference 60 cm in adult females and 62.8 cm in adult males (3.5 standard deviations over the general population) [95]. Children with an increased brain size (anatomic megalencephaly) and clinical manifestations consistent with PHTS should be referred for PTEN testing. (See 'Diagnostic criteria' below and "Macrocephaly in infants and children: Etiology and evaluation", section on 'Anatomic megalencephaly' and "Macrocephaly in infants and children: Etiology and evaluation", section on 'Other tests'.)

Intellectual disability, developmental delay, and autism — Intellectual disability or developmental delay has been reported in 12 to 20 percent of Cowden syndrome patients [49,96]. Autism (typically with macrocephaly) has also been reported in conjunction with Cowden syndrome [97,98]. (See 'Autism spectrum disorders and macrocephaly' below.)

Immune dysregulation — Immune dysregulation (including defects in T and B cell homeostasis, autoimmunity, intestinal lymphoid hyperplasia, thymus hyperplasia, and thymoma as well as T-cell lymphoma) has been described in mice with heterozygous PTEN deletions, and murine models confirm a functional role for PTEN/PI3K signaling pathways in a broad variety of cell types including B cell subsets [99,100]. Data suggest that PTEN deficiency in humans is associated with immune dysregulation that can be manifest as autoimmunity/tissue inflammation and lymphoid hyperplasia [101,102], but the clinical implications for these observations in humans carrying germline PTEN mutations are unclear.

Diagnostic criteria

International Cowden Consortium diagnostic criteria — The first modern diagnostic criteria for Cowden syndrome/PHTS were crafted by an international group of experts labeled the International Cowden Consortium in 1996 and updated in 2000 [103,104].

The specificity of the early Consortium criteria is lower than initially estimated, with only approximately 20 to 34 percent of individuals meeting these clinical criteria having germline PTEN pathogenic variant [23,24]. This has led to efforts to develop more robust criteria for PTEN genetic testing.

Pilarski et al diagnostic criteria — Alternative clinical diagnostic criteria have been proposed by a multi-center United States group and based upon an updated systematic review of the literature (table 1) [46]. These diagnostic criteria have now been adopted by the National Comprehensive Cancer Network (NCCN) [105]. One of the main differences from the International Cowden Consortium guidelines is that they demoted the dermatologic manifestations from pathognomonic findings to major criteria, and included GI hamartomas and penile pigmentation as major criteria. Several features were also added as minor criteria, including autism spectrum disorders, colon cancer, glycogenic acanthosis of the esophagus, and testicular lipomatosis. They found insufficient evidence to support the inclusion of benign breast disease, uterine fibroids, or genitourinary malformations as minor diagnostic criteria.

There are major and minor criteria, and an operational diagnosis in an individual with no prior family history of PHTS/Cowden syndrome requires either three or more major criteria (one of which must be macrocephaly, Lhermitte-Duclos disease, or GI hamartomas) or two major plus three minor criteria.

The following criteria permit an operational diagnosis of Cowden syndrome/PHTS in a family in which one individual meets the revised clinical diagnostic criteria or has a PTEN pathogenic variant:

●Any two major criteria with or without minor criteria; or

●One major and two minor criteria; or

●Three minor criteria

To assess the revised criteria, 48 individual patients with known PTEN pathogenic variants and sufficient clinical information were analyzed, and 44 (91.6 percent) met the new diagnostic criteria.

We recommend using the Pilarski et al diagnostic criteria at this point, although further confirmation of the high positive and negative predictive values for PTEN pathogenic variants is needed. These criteria are based upon updated evidence and are less reliant on expert opinion than the International Cowden Consortium diagnostic criteria. In addition, it has a simplified schema using only major and minor criterion that we find easier to navigate.

Testing criteria — Testing criteria for Cowden syndrome/PHTS are available from the NCCN (as part of their genetic risk assessment for breast, ovarian, and pancreatic cancer, but not colorectal cancer) [105] that have been adapted to include updated clinical criteria (table 2) [24] (see 'Pilarski et al diagnostic criteria' above).

The most recent update of the NCCN testing criteria (v2.2021) include consideration of germline testing for pathogenic or likely pathogenic PTEN variants identified on somatic tumor profiling. Somatic PTEN variants are common, so germline testing should only be considered in patients with Cowden syndrome/PHTS features in the personal or family history. For patients meeting any NCCN Cowden syndrome/PHTS testing criteria, it is recommended that the patient undergo pre- and post-test genetic counseling alongside germline PTEN testing. If a familial PTEN pathogenic variant has not been previously established, consideration should be given to initially testing the family member with the highest likelihood of having a PTEN pathogenic variant based upon the clinical presentation. (See "Genetic testing".)

The NCCN criteria are not refined for pediatric populations, and they do not provide quantitative estimates as to the probability of testing positive for a PTEN pathogenic variant [105]. A clinical scoring system has been developed to help select adult and pediatric patients for PTEN pathogenic variant testing that may have improved sensitivity and specificity compared with the NCCN criteria [24]. The adult prediction model involves demographic data such as sex and age, personal history of cancer, as well as weighted scores for dermatologic, neurologic, breast, gynecologic, GI, endocrine, and genitourinary manifestations. The pediatric criteria are derived from the presence of macrocephaly and either autism or developmental delay, dermatologic findings, vascular abnormalities, or GI polyps. A clinical calculator is available online (CCF score for PTEN test). Although use of this calculator has been shown to be a cost-effective method for determining if a patient should undergo germline PTEN testing, it needs independent validation prior to widespread adoption [106].

Testing for pathogenic variants — PTEN germline testing, including sequence analysis of the entire coding region and deletion/duplication analysis, is available from multiple clinical laboratories [92]. The majority of PTEN pathogenic variants are detected by sequencing, but all types of pathogenic variants have been reported including missense and nonsense point mutations, splice site mutations, insertions, and deletions [3,27,28]. Variants have also been reported in the PTEN promoter, and a test for variants in this region of the gene has become clinically available. At present, however, these promoter variants are classified as variants of uncertain significance by most commercial labs based on lack of supportive data for pathogenicity. Several reports from clinical testing laboratories have also questioned the clinical relevance of these variants [107,108]. Current clinical testing is predominantly done as part of a next generation sequencing panel.

Although the clinical utility and applicability of potential results are still unclear, clinical testing is also available for other genes that have been reported to be associated with a Cowden-like presentation, including AKT1, KLLN, PIK3CA, SDH subunit B, and SDH subunit D. The clinician may look up specific test availability in clinically approved molecular genetics diagnostic laboratories at Genetic Testing Registry (GTR).

Management — Cowden syndrome/PHTS has effects on multiple organ systems and a multidisciplinary treatment team is needed, which includes dedicated genetic counseling. (See "Genetic testing".)

The following management recommendations apply to patients with documented PTEN pathogenic variants as well as for those who fit the clinical diagnostic criteria for Cowden syndrome but lack a detected pathogenic variant. It should be noted that these recommendations are based on expert opinion due to the syndromes being too rare to have empiric evidence on which to base recommendations.

Cancer surveillance — Given the high risk of malignancy, cancer surveillance is the major focus of medical management. We agree with updated guidelines from the NCCN (v1.2022) that outline a cancer surveillance program for both males and females with Cowden syndrome [105]. In addition to genetic counseling and education regarding the syndrome and possible manifestations, recommendations for all patients include:

●Annual comprehensive physical exam, with particular attention to breast and thyroid, starting at 18 years of age or five years before the youngest age of diagnosis of a component cancer in the family.

●Annual thyroid ultrasound starting at age seven; this may also be considered for children at 50 percent risk of inheriting a known familial mutation whose parents wish to delay genetic testing until age 18.

●Colonoscopy at age 35 years unless symptomatic or if close relative with colon cancer before age 40; then start 5 to 10 years before the earliest known colorectal cancer in the family. Repeat every five years or more frequently if patient is symptomatic or polyps are noted.

●Consider renal ultrasound at age 40 and repeat every one to two years.

●Annual dermatologic exam is recommended.

●Consider psychomotor assessment in children at diagnosis and brain MRI if there are symptoms.

Recommendations specifically for females include:

●Breast awareness starting at age 18 years.

●Clinical breast exam every 6 to 12 months starting at age 25 years or individualized based on earliest known onset of breast cancer in the family.

●Annual mammography and breast MRI screening starting at age 30 to 35 years or 5 to 10 years before the earliest known breast cancer in the family.

●Education regarding endometrial cancer and prompt response to symptoms consistent with endometrial cancer.

●Consider random endometrial biopsies every one to two years. Transvaginal ultrasound (TVUS) to screen for endometrial cancer in postmenopausal individuals is insufficiently sensitive or specific to support a positive recommendation; however, it could be considered at the clinician's discretion. TVUS is not recommended for premenopausal individuals.

●Discuss options of risk-reducing mastectomy and hysterectomy (at completion of childbearing) and provide counseling regarding all aspects of these procedures.

In addition to these recommendations, several other screening tests not specifically endorsed by the NCCN [105] might be considered:

●Some experts recommend considering prophylactic total thyroidectomy in patients that are unable to undergo routine thyroid surveillance or in those found to have thyroid nodules [70].

●Screening for dysplastic gangliocytoma of the cerebellum has been recommended by some, but there is no evidence of improved outcomes with early detection [109]. However, given the increased incidence of dysplastic gangliocytoma of the cerebellum and the nonspecific and insidious symptoms, there should be a low threshold to perform neuroimaging in any patient with Cowden syndrome who develops a persistent headache [110]. MRI is the preferred imaging modality, but biopsy may be needed for definitive diagnosis [111].

A European group has proposed cancer surveillance guidelines for individuals with PHTS that are fairly similar to our above recommendations, with some small differences [112].

Treatment — Treatment of the benign and malignant manifestations of Cowden syndrome/PHTS is performed as per usual practice for sporadic occurrence.

Although a benign entity, resection of a symptomatic or progressive dysplastic gangliocytoma of the cerebellum is usually undertaken, as hydrocephalus with potentially fatal herniation can result from local growth.

We advise further individualizing colorectal cancer surveillance recommendations based on personal and familial history of the patient. GI polyps should be endoscopically resected given the varied histology, including frequent adenomatous polyps, and the risk for dysplastic change and colorectal cancer. Endoscopic techniques to improve visual differentiation of polyp histology, such as narrow band imaging, should be considered to allow for preferential removal of large polyps (≥1 cm) or those that appear to be adenomatous [86]. (See "Endoscopic removal of large colon polyps" and "Overview of colon polyps", section on 'Hamartomatous polyps'.)

Future treatment options may involve targeting the genetic pathways affected by loss of PTEN gene function. Sirolimus (also known as rapamycin), commonly used for immunosuppression following solid organ transplantation, suppresses cell proliferation by inhibiting the mechanistic (previously called mammalian) target of rapamycin (mTOR). In a mouse model of experimental Cowden syndrome, administration of sirolimus led to regression of mucocutaneous lesions and, if administered prior to their development, decreased the occurrence of mucocutaneous lesions [113]. There are also reports of using sirolimus in severely affected pediatric patients with PTEN pathogenic variants [114-118].

A short pilot trial investigating the use of sirolimus and its effect on disease progression for patients with Cowden syndrome and other PHTS with documented PTEN pathogenic variants has been completed. This showed some evidence of improvement in cerebellar function and dermatologic findings. They reported that therapy was well tolerated, although side effects such as laboratory abnormalities were common. Although these results are intriguing, it is clear that further data are needed regarding the potential benefits and risks of this therapy prior to widespread usage [119].

OTHER LESS COMMON PHENOTYPES

Bannayan-Riley-Ruvalcaba syndrome — Bannayan-Riley-Ruvalcaba syndrome (BRRS; previously referred to as Ruvalcaba-Myhre syndrome, Ruvalcaba-Myhre-Smith syndrome, Riley-Smith syndrome, Bannayan syndrome, or Bannayan-Zonana syndrome [120]) is a rare autosomal dominant disorder that is caused by germline PTEN pathogenic variants [121]. PTEN mutations are present in 55 to 60 percent of patients with a clinical diagnosis [1,23]. Clinical manifestations arise early in childhood, one aspect that can be different from Cowden syndrome. Evaluation is often started in the first few years of life, with a reported median age of diagnosis as young as five years [122]. Given that identical PTEN pathogenic variants have been described in families with BRRS or Cowden syndrome only [123], and the partial clinical overlap, Cowden syndrome and BRRS are considered variable phenotypic presentations of the same syndrome.

Clinical manifestations — Clinical diagnostic criteria have not been established for BRRS. As with other phenotypes of PHTS, published data on clinical manifestations come mainly from small case series or compilations of published cases. As a result, the true frequencies of the clinical features are not clearly known [39]. (See 'Diagnostic criteria' above.)

Widely noted clinical findings include [71,96,124]:

●Macrocephaly (at least two standard deviations above the mean)

●Penile lentigines (a very characteristic marker of the disease [125]) (picture 1)

●GI tract hamartomatous polyps

●Lipomas

●Vascular anomalies including arteriovenous shunts and fistulae [126]

●Intramuscular lesions with a mixture of adipose tissue, fibrous tissue, and abnormal vessels (labeled a PTEN hamartoma of soft tissue [127])

●Hashimoto thyroiditis and other thyroid disorders including thyroid cancer

●Mild-to-severe developmental delay or intellectual disability

●Proximal muscle myopathy

●High palate

●Joint hypermobility

●Eye abnormalities such as downslanting palpebral fissures, strabismus, and amblyopia

An increased risk of internal malignancy has not been consistently documented with BRRS, although several childhood onset non-medullary thyroid cancers have been reported [4,68,71,72], as well as renal cell cancer and granulosa cell tumor of the ovary [128]. Multiple other clinical findings, such as facial dysmorphology and ophthalmologic abnormalities, have been reported but are less consistently described [129].

The differential diagnosis includes CLOVE syndrome (congenital lipomatous overgrowth, vascular malformations, and epidermal nevi) [130,131].

Management — The clinical scoring system noted above for Cowden syndrome/PHTS is also used to select patients with suspected BRRS for germline PTEN testing [23,46]. (See 'Diagnostic criteria' above and 'Testing criteria' above.)

BRRS has effects in multiple organ systems, and a multidisciplinary treatment team is needed, including dedicated genetic counseling. (See "Genetic testing".)

Treatments for symptomatic manifestations should follow standard practices.

There are no consensus guidelines for cancer surveillance in patients with BRRS. We recommend following the complete Cowden syndrome/PHTS cancer surveillance recommendations if a PTEN pathogenic variant is present, given the significant link between this genetic abnormality and cancer risk, and suggest also following these guidelines if clinical manifestations are consistent with the syndrome but a PTEN pathogenic variant is not documented. (See 'Cancer surveillance' above.)

Proteus-like syndrome — There have been previous reports of PTEN pathogenic variants in some patients with phenotypic similarities to the Proteus syndrome. (See "Capillary malformations (port wine stains) and associated syndromes", section on 'Proteus syndrome'.)

This has been termed Proteus-like syndrome by some [8,132-135], but differences have now been established and it is not felt that germline PTEN pathogenic variants are a cause of typical Proteus syndrome [135,136]. Somatic activating mutations in the v-akt murine thymoma viral oncogene homolog 1 (AKT1) oncogene have been delineated as the genetic cause of Proteus syndrome [137]; all cases are sporadic.

Proteus-like manifestations in patients with PTEN germline pathogenic variants have been demonstrated to be caused by a second, mosaic PTEN pathogenic variant that occurred during very early embryogenesis in the affected tissues such that lesions may follow lines of Blaschko at times [9,10]. This has led to the recommendation that patients with phenotypic features suggestive of Proteus syndrome but with PTEN pathogenic variants be labeled as having segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus (SOLAMEN) syndrome [10]. However, if the epidermal nevus is the only finding, then the term linear Cowden nevus, linear PTEN nevus, or type 2 segmental Cowden disease may be more accurately descriptive.

Autism spectrum disorders and macrocephaly — Autism spectrum disorders (ASD) or developmental delay (DD) with macrocephaly and without other signs of a PHTS are associated with germline PTEN pathogenic variants in 1 to 8 percent of patients [138-140]. Initial work has suggested that this phenotype may relate to differences in functional outcomes of PTEN pathogenic variants [141]. One prospective series that specifically excluded patients with PHTS found mutations in 3 of 18 (17 percent) patients with ASD and extreme macrocephaly [11]. In addition, a novel homozygous PTEN pathogenic variant was reported in siblings with severe macrocephaly and mild intellectual disability but no other PHTS features [142]. A study of 481 patients with germline PTEN pathogenic variants found an increased rate of copy number variants (CNVs) throughout the genome in those patients with ASD/DD (10 percent) compared with patients without ASD/DD (2.6 percent) and patients with cancer (1.7 percent), suggesting that CNVs may modify the phenotype of germline PTEN pathogenic variants [143]. The clinical significance of this finding is unknown, however. At present, American College of Medical Genetics and Genomics guidelines recommend genetic testing for PTEN pathogenic variants in individuals with ASD and a head circumference above the 98^th percentile [144]. (See "Autism spectrum disorder: Evaluation and diagnosis".)

Although the reports cited above describe patients with PTEN pathogenic variants who do not meet criteria for a clinical diagnosis of PHTS, they do not describe the clinical outcomes of these patients or comment on the development of PHTS when these subjects reach adulthood. Autism and macrocephaly arise early in life and may be childhood manifestations of PHTS rather than a discrete phenotype. Long-term follow-up of these patients will be needed to determine their risk for development of other manifestations and especially malignancies. Until this is clarified, if a PTEN pathogenic variant is detected, it is reasonable to follow the National Comprehensive Cancer Network (NCCN) screening recommendations for Cowden syndrome/PHTS. (See 'Testing criteria' above and 'Diagnostic criteria' above and "Macrocephaly in infants and children: Etiology and evaluation", section on 'Anatomic megalencephaly'.)

SUMMARY AND RECOMMENDATIONS

●Genetics and phenotypic spectrum of PTEN hamartoma tumor syndrome

•Germline pathogenic variants in the phosphatase and tensin homolog (PTEN) gene are described in a variety of rare syndromes with different clinical presentations that are collectively known as PTEN hamartoma tumor syndromes (PHTS).

•The defining clinical feature of PHTS is the presence of hamartomatous tumors, which are disorganized growths of native cells in native tissues. PHTS are inherited in an autosomal dominant fashion, and have an increased risk of both benign and malignant tumors. (See 'Phenotypic spectrum of PHTS' above.)

●Cowden syndrome

•Definition, diagnosis, and treatment

-Cowden syndrome is the best-described phenotype; it is characterized by mucocutaneous lesions and an elevated risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as various benign manifestations such as macrocephaly and dysplastic gangliocytoma of the cerebellum. (See 'Clinical manifestations' above.)

-Updated clinical diagnostic criteria for Cowden syndrome/PHTS are available (table 1), as are proposed criteria for genetic testing for PTEN pathogenic variants (table 2). (See 'Diagnostic criteria' above.)

-Treatment of the benign and malignant manifestations of Cowden syndrome is performed as per usual practice for sporadic occurrence. (See 'Treatment' above.)

•Cancer screening – A major focus of management of individuals with Cowden syndrome is on cancer surveillance (see 'Cancer surveillance' above):

-We recommend annual comprehensive physical exam, annual thyroid ultrasound from age seven, colonoscopy at least every five years starting at age 35, and annual renal ultrasound starting at age 40.

-Women should undergo biannual or annual clinical breast exam at age 25 and annual mammography and breast magnetic resonance imaging at age 30. In addition, endometrial cancer surveillance with blind biopsies beginning at age 35, or five years younger than the earliest familial endometrial cancer diagnosis, for premenopausal women and annual transvaginal ultrasound examination for postmenopausal women can be considered.

-We do not recommend screening for brain tumors. However, given the increased incidence of dysplastic gangliocytoma of the cerebellum and the nonspecific and insidious symptoms, there should be a high index of suspicion in patients who meet criteria for Cowden syndrome, and a low threshold to perform neuroimaging in any patient with Cowden syndrome who develops a persistent headache.

●Bannayan-Riley-Ruvalcaba syndrome (BRRS)

•BRRS is characterized by macrocephaly, penile lentigines, lipomas, vascular abnormalities, hamartomatous gastrointestinal polyps, and developmental delay. In contrast to Cowden syndrome, clinical diagnostic criteria have not been established for BRRS. (See 'Bannayan-Riley-Ruvalcaba syndrome' above.)

•Given the effects in multiple organ systems, a multidisciplinary treatment team is needed, including dedicated genetic counseling. We recommend following the cancer surveillance protocol for Cowden syndrome in patients who have a documented PTEN pathogenic variant or a clinical diagnosis of BRRS. (See 'Management' above.)

●Other syndromes

•Several other syndromes are linked with PTEN pathogenic variants, including Proteus-like (segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus [SOLAMEN]) syndrome and autism spectrum disorder with macrocephaly.

•It is unclear if these conditions have a similarly elevated risk of malignancy, but if a PTEN pathogenic variant is found, it is reasonable to use the recommended cancer surveillance for Cowden syndrome/PHTS. (See 'Proteus-like syndrome' above and 'Autism spectrum disorders and macrocephaly' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Mrinal Patnaik, MD, Noralane M Lindor, MD, and Brandie Leach, MS, CGC, who contributed to an earlier version of this topic review.