Professional Documents
Culture Documents
PTEN Hamartoma Tumor Syndromes, Including Cowden Syndrome - UpToDate
PTEN Hamartoma Tumor Syndromes, Including Cowden Syndrome - UpToDate
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 1/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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].
● 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:
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].
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 2/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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].
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 3/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
● Variants in the S cerevisiae, B homolog (SEC23B) gene have been associated with
Cowden syndrome in a single family [32].
● 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.
The common lesions are trichilemmomas, acral keratoses, and facial papules/oral
papillomas:
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 4/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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'.)
● 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.
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.)
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 5/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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:
● 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'.)
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 6/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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].
● Benign
• Men with Cowden syndrome may have multiple bilateral hyperechoic testicular
lesions on ultrasound; they represent lipomatosis of the testes [73-75].
● Malignant
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 7/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
• 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
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.
Colorectal cancer — An increased risk of early onset colorectal cancer has been
reported in patients with Cowden syndrome:
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 8/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
● 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
● 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].
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 9/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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'.)
Diagnostic criteria
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.
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 11/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 12/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
should undergo germline PTEN testing, it needs independent validation prior to widespread
adoption [108].
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).
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 13/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
● 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.
● Consider psychomotor assessment in children at diagnosis and brain MRI if there are
symptoms.
● 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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 14/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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].
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
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 15/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
cognitive or behavioral outcomes [122]. It is clear that further data are needing regarding
this potential therapy prior to widespread usage.
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.)
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
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 16/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
BRRS has effects in multiple organ systems, and a multidisciplinary treatment team is
needed, including dedicated genetic counseling. (See "Genetic testing".)
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.)
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
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 17/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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.
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'.)
• 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).
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 18/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
● Cowden syndrome
- 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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 19/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
● 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.
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.
REFERENCES
1. Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation spectrum and genotype-phenotype
correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with
Cowden syndrome. Hum Mol Genet 1999; 8:1461.
2. Lachlan KL, Lucassen AM, Bunyan D, Temple IK. Cowden syndrome and Bannayan Riley
Ruvalcaba syndrome represent one condition with variable expression and age-related
penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 2007;
44:579.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 20/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
3. Marsh DJ, Coulon V, Lunetta KL, et al. Mutation spectrum and genotype-phenotype
analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma
syndromes with germline PTEN mutation. Hum Mol Genet 1998; 7:507.
4. Zori RT, Marsh DJ, Graham GE, et al. Germline PTEN mutation in a family with Cowden
syndrome and Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 1998; 80:399.
6. Zhou XP, Marsh DJ, Morrison CD, et al. Germline inactivation of PTEN and dysregulation
of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in
adults. Am J Hum Genet 2003; 73:1191.
7. Abel TW, Baker SJ, Fraser MM, et al. Lhermitte-Duclos disease: a report of 31 cases with
immunohistochemical analysis of the PTEN/AKT/mTOR pathway. J Neuropathol Exp
Neurol 2005; 64:341.
8. Zhou X, Hampel H, Thiele H, et al. Association of germline mutation in the PTEN tumour
suppressor gene and Proteus and Proteus-like syndromes. Lancet 2001; 358:210.
9. Happle R. Linear Cowden nevus: a new distinct epidermal nevus. Eur J Dermatol 2007;
17:133.
10. Caux F, Plauchu H, Chibon F, et al. Segmental overgrowth, lipomatosis, arteriovenous
malformation and epidermal nevus (SOLAMEN) syndrome is related to mosaic PTEN
nullizygosity. Eur J Hum Genet 2007; 15:767.
11. Butler MG, Dasouki MJ, Zhou XP, et al. Subset of individuals with autism spectrum
disorders and extreme macrocephaly associated with germline PTEN tumour
suppressor gene mutations. J Med Genet 2005; 42:318.
12. LLOYD KM 2nd, DENNIS M. Cowden's disease. A possible new symptom complex with
multiple system involvement. Ann Intern Med 1963; 58:136.
13. Starink TM, van der Veen JP, Arwert F, et al. The Cowden syndrome: a clinical and genetic
study in 21 patients. Clin Genet 1986; 29:222.
14. Weary PE, Gorlin RJ, Gentry WC Jr, et al. Multiple hamartoma syndrome (Cowden's
disease). Arch Dermatol 1972; 106:682.
15. Mester J, Eng C. Estimate of de novo mutation frequency in probands with PTEN
hamartoma tumor syndrome. Genet Med 2012; 14:819.
16. Nelen MR, Kremer H, Konings IB, et al. Novel PTEN mutations in patients with Cowden
disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet 1999;
7:267.
17. Stambolic V, Suzuki A, de la Pompa JL, et al. Negative regulation of PKB/Akt-dependent
cell survival by the tumor suppressor PTEN. Cell 1998; 95:29.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 21/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
18. Nelen MR, Padberg GW, Peeters EA, et al. Localization of the gene for Cowden disease
to chromosome 10q22-23. Nat Genet 1996; 13:114.
19. Keniry M, Parsons R. The role of PTEN signaling perturbations in cancer and in targeted
therapy. Oncogene 2008; 27:5477.
20. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor
pathway. J Clin Oncol 2004; 22:2954.
21. Krymskaya VP, Goncharova EA. PI3K/mTORC1 activation in hamartoma syndromes:
therapeutic prospects. Cell Cycle 2009; 8:403.
22. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an
inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16:64.
23. Pilarski R, Stephens JA, Noss R, et al. Predicting PTEN mutations: an evaluation of
Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med
Genet 2011; 48:505.
24. Tan MH, Mester J, Peterson C, et al. A clinical scoring system for selection of patients for
PTEN mutation testing is proposed on the basis of a prospective study of 3042
probands. Am J Hum Genet 2011; 88:42.
25. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and
Cowden-like syndrome. JAMA 2010; 304:2724.
26. Cho YJ, Liang P. Killin is a p53-regulated nuclear inhibitor of DNA synthesis. Proc Natl
Acad Sci U S A 2008; 105:5396.
27. Chibon F, Primois C, Bressieux JM, et al. Contribution of PTEN large rearrangements in
Cowden disease: a multiplex amplifiable probe hybridisation (MAPH) screening
approach. J Med Genet 2008; 45:657.
28. Zhou XP, Waite KA, Pilarski R, et al. Germline PTEN promoter mutations and deletions in
Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and
dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 2003;
73:404.
29. Ni Y, Zbuk KM, Sadler T, et al. Germline mutations and variants in the succinate
dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet 2008;
83:261.
30. Bayley JP. Succinate dehydrogenase gene variants and their role in Cowden syndrome.
Am J Hum Genet 2011; 88:674.
31. Orloff MS, He X, Peterson C, et al. Germline PIK3CA and AKT1 mutations in Cowden and
Cowden-like syndromes. Am J Hum Genet 2013; 92:76.
32. Yehia L, Niazi F, Ni Y, et al. Germline Heterozygous Variants in SEC23B Are Associated
with Cowden Syndrome and Enriched in Apparently Sporadic Thyroid Cancer. Am J Hum
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 22/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
33. Colby S, Yehia L, Niazi F, et al. Exome sequencing reveals germline gain-of-function EGFR
mutation in an adult with Lhermitte-Duclos disease. Cold Spring Harb Mol Case Stud
2016; 2:a001230.
34. Lee YR, Chen M, Lee JD, et al. Reactivation of PTEN tumor suppressor for cancer
treatment through inhibition of a MYC-WWP1 inhibitory pathway. Science 2019; 364.
35. Lee YR, Yehia L, Kishikawa T, et al. WWP1 Gain-of-Function Inactivation of PTEN in
Cancer Predisposition. N Engl J Med 2020; 382:2103.
36. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline
PTEN mutations. Clin Cancer Res 2012; 18:400.
37. Bubien V, Bonnet F, Brouste V, et al. High cumulative risks of cancer in patients with
PTEN hamartoma tumour syndrome. J Med Genet 2013; 50:255.
38. Riegert-Johnson DL, Gleeson FC, Roberts M, et al. Cancer and Lhermitte-Duclos disease
are common in Cowden syndrome patients. Hered Cancer Clin Pract 2010; 8:6.
39. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns
2009; 18:13.
40. Ngeow J, Stanuch K, Mester JL, et al. Second malignant neoplasms in patients with
Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol 2014;
32:1818.
42. Salem OS, Steck WD. Cowden's disease (multiple hamartoma and neoplasia syndrome).
A case report and review of the English literature. J Am Acad Dermatol 1983; 8:686.
43. Heald B, Mester J, Rybicki L, et al. Frequent gastrointestinal polyps and colorectal
adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology
2010; 139:1927.
44. Brownstein MH, Mehregan AH, Bikowski JB, et al. The dermatopathology of Cowden's
syndrome. Br J Dermatol 1979; 100:667.
45. Tellechea O, Cardoso JC, Reis JP, et al. Benign follicular tumors. An Bras Dermatol 2015;
90:780.
46. 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.
47. Al-Zaid T, Ditelberg JS, Prieto VG, et al. Trichilemmomas show loss of PTEN in Cowden
syndrome but only rarely in sporadic tumors. J Cutan Pathol 2012; 39:493.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 23/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
48. Masmoudi A, Chermi ZM, Marrekchi S, et al. Cowden syndrome. J Dermatol Case Rep
2011; 5:8.
49. Hanssen AM, Werquin H, Suys E, Fryns JP. Cowden syndrome: report of a large family
with macrocephaly and increased severity of signs in subsequent generations. Clin
Genet 1993; 44:281.
50. Potenziani S, Applebaum D, Krishnan B, et al. Multiple clear cell acanthomas and a
sebaceous lymphadenoma presenting in a patient with Cowden syndrome - a case
report. J Cutan Pathol 2017; 44:79.
51. Ponti G, Nasti S, Losi L, et al. Brooke-Spiegler syndrome: report of two cases not
associated with a mutation in the CYLD and PTCH tumor-suppressor genes. J Cutan
Pathol 2012; 39:366.
52. Longy M, Lacombe D. Cowden disease. Report of a family and review. Ann Genet 1996;
39:35.
53. Reifenberger J, Rauch L, Beckmann MW, et al. Cowden's disease: clinical and molecular
genetic findings in a patient with a novel PTEN germline mutation. Br J Dermatol 2003;
148:1040.
54. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. Cancer risk and genotype-phenotype
correlations in PTEN hamartoma tumor syndrome. Fam Cancer 2014; 13:57.
55. FitzGerald MG, Marsh DJ, Wahrer D, et al. Germline mutations in PTEN are an infrequent
cause of genetic predisposition to breast cancer. Oncogene 1998; 17:727.
56. Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer
referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene
panel. Cancer 2015; 121:25.
57. Schrager CA, Schneider D, Gruener AC, et al. Clinical and pathological features of breast
disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of
breast cancer. Hum Pathol 1998; 29:47.
58. Hendricks LAJ, Hoogerbrugge N, Schuurs-Hoeijmakers JHM, Vos JR. A review on age-
related cancer risks in PTEN hamartoma tumor syndrome. Clin Genet 2021; 99:219.
59. Fackenthal JD, Marsh DJ, Richardson AL, et al. Male breast cancer in Cowden syndrome
patients with germline PTEN mutations. J Med Genet 2001; 38:159.
60. Gustafson S, Zbuk KM, Scacheri C, Eng C. Cowden syndrome. Semin Oncol 2007; 34:428.
61. Patnaik MM, Raza SS, Khambatta S, et al. Oncophenotypic review and clinical correlates
of phosphatase and tensin homolog on chromosome 10 hamartoma tumor syndrome. J
Clin Oncol 2010; 28:e767.
62. Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility
genes among a large triple-negative breast cancer cohort unselected for family history
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 24/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
64. Peiró G, Adrover E, Guijarro J, et al. Synchronous bilateral breast carcinoma in a patient
with cowden syndrome: a case report with morphologic, immunohistochemical and
genetic analysis. Breast J 2010; 16:77.
65. Sabaté JM, Gómez A, Torrubia S, et al. Evaluation of breast involvement in relation to
Cowden syndrome: a radiological and clinicopathological study of patients with PTEN
germ-line mutations. Eur Radiol 2006; 16:702.
66. Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with Cowden syndrome: A
meta-analysis. Head Neck 2013; 35:1189.
67. Harach HR, Soubeyran I, Brown A, et al. Thyroid pathologic findings in patients with
Cowden disease. Ann Diagn Pathol 1999; 3:331.
68. Laury AR, Bongiovanni M, Tille JC, et al. Thyroid pathology in PTEN-hamartoma tumor
syndrome: characteristic findings of a distinct entity. Thyroid 2011; 21:135.
69. Ngeow J, Mester J, Rybicki LA, et al. Incidence and clinical characteristics of thyroid
cancer in prospective series of individuals with Cowden and Cowden-like syndrome
characterized by germline PTEN, SDH, or KLLN alterations. J Clin Endocrinol Metab 2011;
96:E2063.
70. Milas M, Mester J, Metzger R, et al. Should patients with Cowden syndrome undergo
prophylactic thyroidectomy? Surgery 2012; 152:1201.
71. Tan WH, Baris HN, Burrows PE, et al. The spectrum of vascular anomalies in patients
with PTEN mutations: implications for diagnosis and management. J Med Genet 2007;
44:594.
72. Smith JR, Marqusee E, Webb S, et al. Thyroid nodules and cancer in children with PTEN
hamartoma tumor syndrome. J Clin Endocrinol Metab 2011; 96:34.
73. Woodhouse J, Ferguson MM. Multiple hyperechoic testicular lesions are a common
finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J
Radiol 2006; 79:801.
74. Woodhouse JB, Delahunt B, English SF, et al. Testicular lipomatosis in Cowden's
syndrome. Mod Pathol 2005; 18:1151.
75. Alnajjar HM, Sahai A, Keane A, Gordon S. Testicular pain as a presentation of Cowden
syndrome. Ann R Coll Surg Engl 2011; 93:e51.
76. Baker WD, Soisson AP, Dodson MK. Endometrial cancer in a 14-year-old girl with
Cowden syndrome: a case report. J Obstet Gynaecol Res 2013; 39:876.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 25/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
77. Mester JL, Zhou M, Prescott N, Eng C. Papillary renal cell carcinoma is associated with
PTEN hamartoma tumor syndrome. Urology 2012; 79:1187.e1.
78. Modi RM, Arnold CA, Stanich PP. Diffuse Esophageal Glycogenic Acanthosis and Colon
Polyposis in a Patient With Cowden Syndrome. Clin Gastroenterol Hepatol 2017;
15:e131.
79. Levi Z, Baris HN, Kedar I, et al. Upper and Lower Gastrointestinal Findings in PTEN
Mutation-Positive Cowden Syndrome Patients Participating in an Active Surveillance
Program. Clin Transl Gastroenterol 2011; 2:e5.
80. Kato M, Mizuki A, Hayashi T, et al. Cowden's disease diagnosed through mucocutaneous
lesions and gastrointestinal polyposis with recurrent hematochezia, unrevealed by initial
diagnosis. Intern Med 2000; 39:559.
81. Isomoto H, Furusu H, Ohnita K, et al. Effect of Helicobacter pylori eradication on gastric
hyperplastic polyposis in Cowden's disease. World J Gastroenterol 2005; 11:1567.
82. Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric carcinoma as
manifestations of Cowden's disease. Surgery 1995; 118:115.
83. Al-Thihli K, Palma L, Marcus V, et al. A case of Cowden's syndrome presenting with
gastric carcinomas and gastrointestinal polyposis. Nat Clin Pract Gastroenterol Hepatol
2009; 6:184.
84. de Leon MP, Di Gregorio C, Giunti L, et al. Duodenal carcinoma in a 37-year-old man with
Cowden/Bannayan syndrome. Dig Liver Dis 2013; 45:75.
85. Stanich PP, Owens VL, Sweetser S, et al. Colonic polyposis and neoplasia in Cowden
syndrome. Mayo Clin Proc 2011; 86:489.
86. Khare A, Burke CA, Heald B, et al. Endoscopic Findings in Patients With PTEN
Hamartoma Tumor Syndrome Undergoing Surveillance. J Clin Gastroenterol 2022;
56:e183.
87. Levi Z, Baris HN, Kedar I, et al. Upper and Lower Gastrointestinal Findings in PTEN
Mutation-Positive Cowden Syndrome Patients Participating in an Active Surveillance
Program. Clin Transl Gastroenterol 2011; 2:e5.
88. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. Is colorectal surveillance indicated in
patients with PTEN mutations? Colorectal Dis 2012; 14:e562.
89. Zamary AR, Mamlouk MD. Neuroimaging features of genetic syndromes associated with
CNS overgrowth. Pediatr Radiol 2022; 52:2452.
90. Dhamija R, Hoxworth JM. Imaging of PTEN-related abnormalities in the central nervous
system. Clin Imaging 2020; 60:180.
91. Lok C, Viseux V, Avril MF, et al. Brain magnetic resonance imaging in patients with
Cowden syndrome. Medicine (Baltimore) 2005; 84:129.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 26/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
92. Nowak DA, Trost HA. Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma): a
malformation, hamartoma or neoplasm? Acta Neurol Scand 2002; 105:137.
93. Vinchon M, Blond S, Lejeune JP, et al. Association of Lhermitte-Duclos and Cowden
disease: report of a new case and review of the literature. J Neurol Neurosurg Psychiatry
1994; 57:699.
94. Yehia L, Eng C. PTEN Hamartoma Tumor Syndrome. 2001 Nov 29 [Updated 2021 Feb 11].
In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle
(WA): University of Washington, Seattle; 1993-2021. Available online at: https://www.ncb
i.nlm.nih.gov/books/NBK1488/ (Accessed on May 06, 2021).
95. Robinson S, Cohen AR. Cowden disease and Lhermitte-Duclos disease: characterization
of a new phakomatosis. Neurosurgery 2000; 46:371.
96. Prats-Sánchez LA, Hervás-García JV, Becerra JL, et al. Multiple Intracranial Arteriovenous
Fistulas in Cowden Syndrome. J Stroke Cerebrovasc Dis 2016; 25:e93.
97. Mester JL, Tilot AK, Rybicki LA, et al. Analysis of prevalence and degree of macrocephaly
in patients with germline PTEN mutations and of brain weight in Pten knock-in murine
model. Eur J Hum Genet 2011; 19:763.
98. Parisi MA, Dinulos MB, Leppig KA, et al. The spectrum and evolution of phenotypic
findings in PTEN mutation positive cases of Bannayan-Riley-Ruvalcaba syndrome. J Med
Genet 2001; 38:52.
99. Goffin A, Hoefsloot LH, Bosgoed E, et al. PTEN mutation in a family with Cowden
syndrome and autism. Am J Med Genet 2001; 105:521.
100. Conti S, Condò M, Posar A, et al. Phosphatase and tensin homolog (PTEN) gene
mutations and autism: literature review and a case report of a patient with Cowden
syndrome, autistic disorder, and epilepsy. J Child Neurol 2012; 27:392.
101. Di Cristofano A, Kotsi P, Peng YF, et al. Impaired Fas response and autoimmunity in
Pten+/- mice. Science 1999; 285:2122.
102. Baracho GV, Miletic AV, Omori SA, et al. Emergence of the PI3-kinase pathway as a
central modulator of normal and aberrant B cell differentiation. Curr Opin Immunol
2011; 23:178.
103. Eissing M, Ripken L, Schreibelt G, et al. PTEN Hamartoma Tumor Syndrome and Immune
Dysregulation. Transl Oncol 2019; 12:361.
104. Taylor H, Laurence ADJ, Uhlig HH. The Role of PTEN in Innate and Adaptive Immunity.
Cold Spring Harb Perspect Med 2019; 9.
105. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med
Genet 2000; 37:828.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 27/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
106. Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding
mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet
2004; 41:323.
107. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in o
ncology. Available at: https://www.nccn.org/professionals/physician_gls (Accessed on M
ay 18, 2022).
108. Ngeow J, Liu C, Zhou K, et al. Detecting Germline PTEN Mutations Among At-Risk
Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis. J Clin Oncol
2015; 33:2537.
109. Black MH, Li S, Pesaran T, et al. PTEN Promoter Variants Are Not Associated With
Common Cancers: Implications for Multigene Panel Testing. JCO Precis Oncol 2017; 1:1.
110. Mester JL, Hruska KS. With Regard to PTEN Promoter Testing for Hereditary Cancer Risk
Assessment. JCO Precis Oncol 2018; 2:1.
111. Robinson S, Cohen AR. Cowden disease and Lhermitte-Duclos disease: an update. Case
report and review of the literature. Neurosurg Focus 2006; 20:E6.
112. Fistarol SK, Anliker MD, Itin PH. Cowden disease or multiple hamartoma syndrome--
cutaneous clue to internal malignancy. Eur J Dermatol 2002; 12:411.
113. Huang S, Zhang G, Zhang J. Similar MR imaging characteristics but different
pathological changes: a misdiagnosis for Lhermitte-Duclos disease and review of the
literature. Int J Clin Exp Pathol 2015; 8:7583.
114. Tischkowitz M, Colas C, Pouwels S, et al. Cancer Surveillance Guideline for individuals
with PTEN hamartoma tumour syndrome. Eur J Hum Genet 2020; 28:1387.
115. Squarize CH, Castilho RM, Gutkind JS. Chemoprevention and treatment of experimental
Cowden's disease by mTOR inhibition with rapamycin. Cancer Res 2008; 68:7066.
116. Marsh DJ, Trahair TN, Martin JL, et al. Rapamycin treatment for a child with germline
PTEN mutation. Nat Clin Pract Oncol 2008; 5:357.
117. Zak M, Ledbetter M, Maertens P. Infantile Lhermitte-Duclos Disease Treated Successfully
With Rapamycin. J Child Neurol 2017; 32:322.
118. Iacobas I, Burrows PE, Adams DM, et al. Oral rapamycin in the treatment of patients
with hamartoma syndromes and PTEN mutation. Pediatr Blood Cancer 2011; 57:321.
119. Schmid GL, Kässner F, Uhlig HH, et al. Sirolimus treatment of severe PTEN hamartoma
tumor syndrome: case report and in vitro studies. Pediatr Res 2014; 75:527.
120. Pimpalwar S, Yoo R, Chau A, et al. Temporal Evolution and Management of Fast Flow
Vascular Anomalies in PTEN Hamartoma Tumor Syndrome. Int J Angiol 2018; 27:158.
121. Komiya T, Blumenthal GM, DeChowdhury R, et al. A Pilot Study of Sirolimus in Subjects
with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 28/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
128. 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. Fam Cancer 2003; 2:79.
131. Smpokou P, Fox VL, Tan WH. PTEN hamartoma tumour syndrome: early tumour
development in children. Arch Dis Child 2015; 100:34.
132. Erkek E, Hizel S, Sanlý C, et al. Clinical and histopathological findings in Bannayan-Riley-
Ruvalcaba syndrome. J Am Acad Dermatol 2005; 53:639.
133. Alomari AI. Characterization of a distinct syndrome that associates complex truncal
overgrowth, vascular, and acral anomalies: a descriptive study of 18 cases of CLOVES
syndrome. Clin Dysmorphol 2009; 18:1.
134. Sapp JC, Turner JT, van de Kamp JM, et al. Newly delineated syndrome of congenital
lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome)
in seven patients. Am J Med Genet A 2007; 143A:2944.
135. Zhou XP, Marsh DJ, Hampel H, et al. Germline and germline mosaic PTEN mutations
associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry,
arteriovenous malformations and lipomatosis. Hum Mol Genet 2000; 9:765.
136. Smith JM, Kirk EP, Theodosopoulos G, et al. Germline mutation of the tumour
suppressor PTEN in Proteus syndrome. J Med Genet 2002; 39:937.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 29/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
137. Loffeld A, McLellan NJ, Cole T, et al. Epidermal naevus in Proteus syndrome showing loss
of heterozygosity for an inherited PTEN mutation. Br J Dermatol 2006; 154:1194.
138. Cohen MM Jr, Turner JT, Biesecker LG. Proteus syndrome: misdiagnosis with PTEN
mutations. Am J Med Genet A 2003; 122A:323.
139. Biesecker LG, Rosenberg MJ, Vacha S, et al. PTEN mutations and proteus syndrome.
Lancet 2001; 358:2079.
140. Lindhurst MJ, Sapp JC, Teer JK, et al. A mosaic activating mutation in AKT1 associated
with the Proteus syndrome. N Engl J Med 2011; 365:611.
141. McBride KL, Varga EA, Pastore MT, et al. Confirmation study of PTEN mutations among
individuals with autism or developmental delays/mental retardation and macrocephaly.
Autism Res 2010; 3:137.
142. Orrico A, Galli L, Buoni S, et al. Novel PTEN mutations in neurodevelopmental disorders
and macrocephaly. Clin Genet 2009; 75:195.
143. Buxbaum JD, Cai G, Chaste P, et al. Mutation screening of the PTEN gene in patients with
autism spectrum disorders and macrocephaly. Am J Med Genet B Neuropsychiatr Genet
2007; 144B:484.
144. Spinelli L, Black FM, Berg JN, et al. Functionally distinct groups of inherited PTEN
mutations in autism and tumour syndromes. J Med Genet 2015; 52:128.
145. Schwerd T, Khaled AV, Schürmann M, et al. A recessive form of extreme macrocephaly
and mild intellectual disability complements the spectrum of PTEN hamartoma tumour
syndrome. Eur J Hum Genet 2016; 24:889.
146. Yehia L, Seyfi M, Niestroj LM, et al. Copy Number Variation and Clinical Outcomes in
Patients With Germline PTEN Mutations. JAMA Netw Open 2020; 3:e1920415.
147. Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical
genetics evaluation in identifying the etiology of autism spectrum disorders: 2013
guideline revisions. Genet Med 2013; 15:399.
Topic 16543 Version 45.0
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 30/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
GRAPHICS
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 31/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 32/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 33/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 34/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
Major criteria
Breast cancer
Acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)
Minor criteria
Autism spectrum disorder
Colon cancer
Lipomas (≥3)
Testicular lipomatosis
1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos
disease, or gastrointestinal hamartomas; or
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 35/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 36/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
Bannayan-Riley-Ruvalcaba syndrome
OR
OR
OR
OR
OR
OR
OR
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]
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 37/38
23/02/23, 13:13 PTEN hamartoma tumor syndromes, including Cowden syndrome - UpToDate
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.
https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome/print 38/38