PTEN Hamartoma Tumor Syndromes, Including Cowden Syndrome - UpToDate

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PTEN hamartoma tumor syndromes, including Cowden

syndrome
Author: Peter P Stanich, MD
Section Editors: J Thomas Lamont, MD, Benjamin A Raby, MD, MPH, Robert G Voigt, MD, FAAP
Deputy Editor: Sadhna R Vora, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2023. | This topic last updated: Jan 04, 2023.
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,
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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
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 95 percent of those undergoing colonoscopy [43,80,85,86]. 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
[43,85,87]. (See "Juvenile polyposis syndrome" and "Overview of colon polyps", section on
'Hamartomatous polyps' and "Overview of colon polyps", section on 'Inflammatory polyps'.)
Colorectal cancer — An increased risk of early onset colorectal cancer has 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 [88].
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
Neuroimaging features — The main neuroimaging features associated with Cowden

syndrome are Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum),
increased white matter volume, enlarged corpus callosum and cerebellum,
ventriculomegaly, dilated perivascular spaces, and cavernous malformations [89].
● Tumors and vascular malformations — A wide range of brain tumors has been
purportedly linked to PTEN pathogenic variants [90]. 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 [38,43,91]. Symptoms arise
secondary to mass effect in the posterior fossa and commonly include headache,
nausea and vomiting, ataxia, and papilledema [92].
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 [93].
Many consider that dysplastic gangliocytoma of the cerebellum is a defining feature of

Cowden syndrome [6,39,94]. 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 [95]. (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)
[91], and there is a case report of multiple intracranial arteriovenous fistulas in a
person with Cowden syndrome [96]. However, this has not been commonly reported
[46].
Meningiomas have also been reported in patients with Cowden syndrome [39,91];
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 97th 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) [97]. 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
[49,98]. Autism (typically with macrocephaly) has also been reported in conjunction with
Cowden syndrome [99,100]. (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 [101,102]. Data suggest that PTEN
deficiency in humans is associated with immune dysregulation that can be manifest as
autoimmunity/tissue inflammation and lymphoid hyperplasia [103,104], 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 [105,106].
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) [107]. 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) [107] 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
[107]. 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 [108].
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 [94]. 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 [109,110]. 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 [107]. 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 [107] 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 [111].
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 [112]. MRI is the preferred imaging modality, but biopsy may be
needed for definitive diagnosis [113].
A European group has proposed cancer surveillance guidelines for individuals with PHTS
that are fairly similar to our above recommendations, with some small differences [114].
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 [87]. (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 [115]. There are also reports of using
sirolimus in severely affected pediatric patients with PTEN pathogenic variants [116-120].
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. [121]. There was some evidence of improvement in cerebellar function
and dermatologic findings. Although therapy was well tolerated overall, laboratory
abnormalities were common adverse effects. A more recent randomized controlled trial of
everolimus for neurocognitive symptoms failed to show significant benefit in primary
cognitive or behavioral outcomes [122]. It is clear that further data are needing regarding
this potential therapy prior to widespread usage.
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 [123]) is a rare
autosomal dominant disorder that is caused by germline PTEN pathogenic variants [124].
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 [125]. Given that identical PTEN pathogenic
variants have been described in families with BRRS or Cowden syndrome only [126], 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 [71,98,127]:
● Macrocephaly (at least two standard deviations above the mean)

● Penile lentigines (a very characteristic marker of the disease [128]) ( picture 1)
● GI tract hamartomatous polyps
● Lipomas
● Vascular anomalies including arteriovenous shunts and fistulae [129]
● Intramuscular lesions with a mixture of adipose tissue, fibrous tissue, and abnormal
vessels (labeled a PTEN hamartoma of soft tissue [130])
● 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 [131]. Multiple
other clinical findings, such as facial dysmorphology and ophthalmologic abnormalities,

have been reported but are less consistently described [132].
The differential diagnosis includes CLOVE syndrome (congenital lipomatous overgrowth,

vascular malformations, and epidermal nevi) [133,134].
Neuroimaging features — The main neuroimaging findings of BRRS include

macrocephaly, dilated perivascular spaces, and excess spinal fat in soft tissues, epidural
space, and bone marrow [89].
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 [8,135-138], but differences have now
been established and it is not felt that germline PTEN pathogenic variants are a cause of
typical Proteus syndrome [138,139]. 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 [140]; 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 [141-143].
Initial work has suggested that this phenotype may relate to differences in functional
outcomes of PTEN pathogenic variants [144]. 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 [145]. 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 [146]. 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 98th percentile [147]. (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.
Use of UpToDate is subject to the Terms of Use.
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Topic 16543 Version 45.0
GRAPHICS
Penile lentigines (pigmented macules) of the penis
Reproduced from: Hendriks YM, Verhallen JT, van der Smagt JJ, et al. Bannayan–
Riley–Ruvalcaba syndrome: further delineation of the phenotype and management
of PTEN mutation-positive cases. Familial Cancer 2003; 2:79, with kind permission
from Springer Science + Business Media B.V. Copyright © 2003.
Graphic 62253 Version 4.0
Trichilemmomas and verrucous papules, as well as

oral papillomas on the mucosa are characteristic of
Cowden syndrome
Trichilemmomas (multiple skin-colored warty papules) on the face,

as well as the mucosa of the lower lip.
Reproduced with permission from: Color Atlas and Synopsis of Clinical Dermatology,
3 rd edition, Fitzpatrick, et al (Eds), McGraw-Hill, New York 1997. Copyright © 1997
The McGraw-Hill Companies, Inc.
Oral papillomas on the lips and tongue of a Cowden syndrome

patient
From: Stanich PP, Francis DL, Sweetser S. The spectrum of findings in Cowden syndrome. Clin
Gastroenterol Hepatol 2011; 9:e2. Illustrations used with the permission of Elsevier Inc. All rights
reserved.
Upper endoscopy of esophageal diffuse glycogenic acanthosis
Upper endoscopy showing diffuse glycogenic acanthosis in the entire esophagus.
Reproduced from: Modi RM, Arnold CA, Stanich PP. Diffuse Esophageal Glycogenic Acanthosis and Colon Polyposis in a Patient Wi
Cowden Syndrome. Clin Gastroenterol Hepatol 2017; 15:e131. Illustration used with the permission of Elsevier Inc. All rights reser
Revised PTEN hamartoma tumor syndrome clinical diagnostic criteria
Major criteria
Breast cancer
Endometrial cancer (epithelial)
Thyroid cancer (follicular)
Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps;

≥3)
Lhermitte-Duclos disease (adult)
Macrocephaly (≥97 percentile: 58 cm for females, 60 cm for males)
Macular pigmentation of the glans penis
Multiple mucocutaneous lesions (any of the following):
Multiple trichilemmomas (≥3, at least one biopsy proven)
Acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)
Mucocutaneous neuromas (≥3)
Oral papillomas (particularly on tongue and gingiva), multiple (≥3)
OR biopsy proven OR dermatologist diagnosed
Minor criteria
Autism spectrum disorder
Colon cancer
Esophageal glycogenic acanthosis (≥3)
Lipomas (≥3)
Mental retardation (ie, IQ ≤75)
Renal cell carcinoma
Testicular lipomatosis
Thyroid cancer (papillary or follicular variant of papillary)
Thyroid structural lesions (eg, adenoma, multinodular goiter)
Vascular anomalies (including multiple intracranial developmental venous anomalies)
Operational diagnosis in an individual (either of the following)
1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos
disease, or gastrointestinal hamartomas; or
2. Two major and three minor criteria.
Operational diagnosis in a family where one individual meets revised PTEN

hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN mutation:
1. Any two major criteria with or without minor criteria; or
2. One major and two minor criteria; or
3. Three minor criteria.
Reproduced from: Pilarski R, Burt R, Kohlman W, et al. Cowden Syndrome and the PTEN Hamartoma Tumor Syndrome:
Systematic Review and Revised Diagnostic Criteria. J Natl Cancer Inst 2013; 105(21):1607-1616. By permission of Oxford
University Press on behalf of the National Cancer Institute. Copyright © 2013.
Cowden syndrome/PTEN hamartoma tumor syndrome (PHTS) testing

criteria from the National Comprehensive Cancer Network (NCCN)
Individual from a family with a known PTEN mutation
Individual meeting clinical diagnostic criteria [1] for Cowden syndrome/PHTS
Bannayan-Riley-Ruvalcaba syndrome
OR
Adult Lhermitte-Duclos disease
OR
Autism spectrum disorder AND macrocephaly
OR
Two or more biopsy-proven trichilemmomas
OR
Two or more major criteria (one macrocephaly) [1]
OR
Three major criteria without macrocephaly [1]
OR
One major and three or more minor criteria [1]
OR
Four or more minor criteria [1]
At-risk individual:
With a relative who has a clinical diagnosis of Cowden syndrome, PHTS, or Bannayan-Riley-
Ruvalcaba syndrome for whom testing has not been performed
AND
Who has any one major criterion or two minor criteria [1]
PTEN: phosphatase and tensin homolog.
Reference:
1. Pilarski R, Burt R, Kohlman W, et al. Cowden syndrome and the PTEN hamartoma tumor syndrome: Systematic
review and revised diagnostic criteria. J Natl Cancer Inst 2013; 105:1607.
Contributor Disclosures
Peter P Stanich, MD Grant/Research/Clinical Trial Support: PTEN Research foundation; Pfizer [PTEN
hamartoma tumor syndrome with colon polyposis]. All of the relevant financial relationships listed
have been mitigated. J Thomas Lamont, MD No relevant financial relationship(s) with ineligible
companies to disclose. Benjamin A Raby, MD, MPH No relevant financial relationship(s) with ineligible
companies to disclose. Robert G Voigt, MD, FAAP No relevant financial relationship(s) with ineligible
companies to disclose. Sadhna R Vora, MD No relevant financial relationship(s) with ineligible
companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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PTEN hamartoma tumor syndromes, including Cowden

PHENOTYPIC SPECTRUM OF PHTS

The phenotypic spectrum of PHTS includes the following entities:

● Cowden syndrome (also known as Cowden disease or multiple hamartoma syndrome)

● Bannayan-Riley-Ruvalcaba syndrome is another rare subset of PHTS. In addition to

Genotype analyses have concluded that a similar spectrum of pathogenic variants in

● Adult Lhermitte-Duclos disease is characterized by hamartomatous outgrowths of the

• A Proteus-like syndrome with a distinct type of epidermal nevus (also referred to as

• Autism spectrum disorders with macrocephaly [11]. (See "Macrocephaly in infants

Molecular genetics — The PTEN gene is a negative regulator of the phosphoinositide-3-

which is located on chromosome 10q23 [18], is considered to be a tumor suppressor gene

● A heterozygous germline epidermal growth factor receptor (EGFR) pathogenic variant

Clinical manifestations — Historically, the published data on clinical manifestations have

The range of clinical manifestations of Cowden syndrome includes hamartomatous tumors

Mucocutaneous — Skin and oral findings are a distinctive and common manifestation of

● Trichilemmomas ( picture 2) are hamartomatous tumors of the outer root sheath of

glycogen-rich cells [44]. Clinically, trichilemmomas are indistinguishable from

● Acral keratoses present as 1 to 4 mm keratotic verrucous papules that are located on

The differential diagnosis of the mucocutaneous findings includes tuberous sclerosis,

Breast — Breast cancer is the most common malignancy in Cowden syndrome, although

● An increased incidence of both multifocality and bilateral involvement has been

Thyroid — The most frequently reported extracutaneous manifestation of Cowden

Genitourinary — Several genitourinary lesions, including endometrial cancer and renal cell

• Benign uterine abnormalities such as uterine fibroids are common findings in

• The risk of endometrial cancer is elevated in female patients, with a reported

of endometrial cancer occurring in adolescents as young as age 14 [76]. (See

Esophageal glycogen acanthosis — Glycogenic acanthosis of the esophagus typically

Colon polyps — The prevalence of colon polyps among PTEN pathogenic variant

● A Japanese series found a 9 percent prevalence of colon cancer, a remarkable finding in

● In a series of PTEN pathogenic variant carriers, 13 percent of patients undergoing

Neuroimaging features — The main neuroimaging features associated with Cowden

Dysplastic gangliocytoma of the cerebellum can be familial or sporadic. It remains

Many consider that dysplastic gangliocytoma of the cerebellum is a defining feature of

The Pilarski-revised clinical diagnostic criteria for PHTS include dysplastic

In addition to dysplastic gangliocytoma of the cerebellum, one study found intracranial

● Macrocephaly – Macrocephaly, defined as an occipital-frontal head circumference

Intellectual disability, developmental delay, and autism — Intellectual disability or

Immune dysregulation — Immune dysregulation (including defects in T and B cell

International Cowden Consortium diagnostic criteria — The first modern diagnostic

Pilarski et al diagnostic criteria — Alternative clinical diagnostic criteria have been

The following criteria permit an operational diagnosis of Cowden syndrome/PHTS in a family

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

Testing for pathogenic variants — PTEN germline testing, including sequence analysis of

Management — Cowden syndrome/PHTS has effects on multiple organ systems and a

The following management recommendations apply to patients with documented PTEN

● Annual dermatologic exam is recommended.

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

● Annual mammography and breast MRI screening starting at age 30 to 35 years or 5 to

● Education regarding endometrial cancer and prompt response to symptoms consistent

● Discuss options of risk-reducing mastectomy and hysterectomy (at completion of

In addition to these recommendations, several other screening tests not specifically

● Some experts recommend considering prophylactic total thyroidectomy in patients that

● Screening for dysplastic gangliocytoma of the cerebellum has been recommended by

Treatment — Treatment of the benign and malignant manifestations of Cowden

Although a benign entity, resection of a symptomatic or progressive dysplastic

We advise further individualizing colorectal cancer surveillance recommendations based on

OTHER LESS COMMON PHENOTYPES

Bannayan-Riley-Ruvalcaba syndrome — Bannayan-Riley-Ruvalcaba syndrome (BRRS;

Widely noted clinical findings include [71,98,127]: