Open Access

Germline PTEN mutations are rare and highly penetrant

  • Cecilie F Rustad1,
  • Merete Bjørnslett2,
  • Ketil R Heimdal1,
  • Lovise Mæhle1,
  • Jaran Apold3 and
  • Pål Møller1Email author
Hereditary Cancer in Clinical Practice20064:177

https://doi.org/10.1186/1897-4287-4-4-177

Received: 31 October 2006

Accepted: 5 December 2006

Published: 15 December 2006

Abstract

Cowden syndrome (multiple hamartoma syndrome, MIM 158350) is an early onset syndrome characterized by multiple hamartomas in the skin, mucous membranes, breast, thyroid and endometrium. Patients with Cowden syndrome have increased risk of breast cancer, thyroid cancer and endometrial cancer. In 1997 germline mutations in PTEN were demonstrated to cause Cowden syndrome. We report the results of diagnostic and predictive testing in all families with Cowden syndrome or suspected Cowden syndrome registered at the Norwegian cancer family clinics. PTEN mutations were found in all six families meeting the clinical criteria for Cowden syndrome, in none of the two families assumed to have Cowden syndrome but not fulfilling the criteria, and in none of the eight families selected in our computerized medical files to have a combination of breast and thyroid cancers. Age-related penetrances for the various neoplasms are given. All families but one were small and de novo mutations were found.

Keywords

breast cancer Cowden syndrome PTEN thyroid cancer

Introduction

In 1963 Lloyd and Dennis described a patient named Rachel Cowden who died of bilateral breast cancer in her thirties [1]. Cowden syndrome is now recognized as an autosomal dominant syndrome characterized by multiple hamartomas originating from all three germ-cell layers. Mucocutaneous lesions including trichilemmomas are seen in 90-100% of patients [2]. There is increased risk of early breast cancer from 14 years of age, and lifetime risk is estimated to 25-50% [35]. Goitre and thyroid adenomas are frequently seen and the estimated prevalence of thyroid cancer is 3-7% [3, 6, 7]. We have previously reported endometrial cancer in one Norwegian family with Cowden syndrome [8].

In 1995 the International Cowden Syndrome Consortium was formed and a set of clinical diagnostic criteria were suggested; see Table 1 [2, 9, 10]. In 1997 the susceptibility gene for Cowden syndrome was identified on chromosome 10q23.3 and was found to be PTEN [11, 12]. Germline mutations are found throughout the PTEN gene, the majority in exons 5, 7 and 8 [2, 13]. The frequency of germline PTEN mutations, including mutations in the promoter region, in Cowden syndrome have been reported to approach 85-90% [14]. Genotype/phenotype correlations have been suggested, but have not been confirmed [1517].
Table 1

International Cowden Syndrome Consortium operational criteria (version 2000) as given by Charis Eng [2]

Pathognomonic criteria

   Trichilemmomas, facial

   Acral keratoses

   Papillomatous papules

   Mucosal lesions

Major criteria

   Breast carcinoma

   Thyroid carcinoma (non-medullary), especially follicular thyroid carcinoma

   Macrocephaly (megalencephaly) (say > 97 percentile)

   Lhermitte-Duclos disease

   Endometrial carcinoma

Minor criteria

   Other thyroid lesions (e.g. adenoma or multinodular goitre)

   Mental retardation

   Gastrointestinal hamartomas

   Fibrocystic disease of the breast

   Lipomas

   Fibromas

   Gastrointestinal tumours (e.g. renal cell carcinoma, uterine fibroids) or malformation

Operational diagnosis in an individual

   1. Mucocutaneous lesions alone if

a. there are six or more facial papules, of which three or more must be trichilemmoma, or

b. cutaneous facial papules and oral mucosal papillomatosis, or

c. oral mucosal papillomatosis and acral keratoses, or

d. palmo-plantar keratoses, 6 or more

   2. Two major criteria but one must include macrocephaly or LDD

   3. One major and three minor criteria

   4. Four minor criteria

Operational diagnosis in a family where one individual is diagnostic for Cowden syndrome

   1. The pathognomonic criterion/criteria

   2. Any major criterion with or without minor criteria

   3. Two minor criteria

Nelen has estimated the incidence to be between 1 per 200,000 and 1 per 250,000 in the Dutch population [16].

As for all inherited cancer syndromes, the penetrance of the underlying genetic defects and the full clinical spectrum of their expressions have been difficult to assess without access to genetic testing.

Fifty to sixty percent of patients with Bannayan-Riley-Ruvalcaba syndrome (BRRS, MIM 153480) have been shown to have germline mutations in the PTEN gene [14, 18]. An association between germline PTEN mutations and Proteus syndrome (MIM 176920) has been disputed [1922].

Our aim was to validate strategies to identify families with PTEN mutations and to estimate prevalences and penetrances of PTEN mutations.

Materials and methods

The computerized medical files at the Section for Inherited Cancer, Rikshospitalet-Radiumhospitalet Medical Centre, include more than 40,000 patients belonging to more than 3,000 families. These files were analyzed and all families with a diagnosis of Cowden syndrome, all families suspected to have Cowden syndrome, and all families with a combination of breast and thyroid cancers were identified. All of the five other Norwegian genetic centres contributed their families with Cowden stigmata. The four families previously reported to harbour PTEN mutations were included.

We had no families with suspected Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome or Proteus-like syndrome. Our two patients with Lhermitte-Duclos disease were also classified as having Cowden syndrome and included above.

All families were extended and offered genetic testing according to our genetic health care standards [23]. Because all activity was provided as health service, all information was kept in the medical files and no research registry was created. All activities were according to Norwegian legislation. All diagnoses were confirmed in the medical files after written informed consent from each patient if alive or from their relatives if dead. All family members were offered genetic counselling. All genetic testing was subjected to written informed consent.

We sequenced all nine exons, their flanking areas and 1500 basepairs upstream of ATG (the promoter region) in the PTEN gene in all patients examined.

Kaplan-Meier survival estimates were calculated using the computer program Systat 10©. The data were stored in Oracle©, pedigrees were displayed in Cyrillic© and the application to run the database as an electronic patient file system was programmed in dB+©.

Results

We identified six families (family A, B, C, D, E and F) which fulfilled the International Cowden Syndrome Consortium Criteria; for details see Table 2. Four of them had been identified prior to the present study (B, C, D, F) [8]. Two families (G and H) had been clinically assumed to have Cowden syndrome earlier on, but did not fulfil the diagnostic criteria. Eight families had a combination of breast cancer and thyroid cancer.
Table 2

Clinical signs in all demonstrated and assumed mutation carriers in the six Cowden syndrome families with PTEN mutation. Families ordered by genetic position of mutations

   

Phenotype (Age in years at diagnosis)

Mutation(s)!

Family

Patient (sex, year of birth)

Breast

Thyroid

Endometrium

CNS

Gastrointestinal tract ‡

Skin lesions Histology

Others

c.50delAA Frameshift

A

Pid* 1 (F, 1970)

Bilateral mastectomy (34)

Goitre (23)

 

Lhermitte-Duclos disease (24) Macrocephaly

Hyperplastic colon polyps without dysplasia (26, 8)

 

Cavernous haemangioma (18)

  

Pid 3 (F, 1999)

   

Macrocephaly Born with hydrocephalus

  

Born with neural tube defect

  

Pid 4 (F) Dead, not tested

Cancer (46)

      

c.68T>A Nonsense

B

Pid 1 (F, 1958)

Cancer (24)

Follicular cancer (13)

Simple hyperplasia (43)

Macrocephaly

Hyperplastis colon polyps (42, 3)

+ (35) skin with trichilemmomal hyperplasia

Liver haemangioma (35)

  

Pid 4 (F) Dead, not tested

Bilateral cancer (45)

Goitre (35)

   

Gastric leiomyoma (45)

 

c.328C>T Nonsense

C

Pid 1 (F, 1958)

Cancer (35) Prophylactic contra lateral mastectomy

 

Atypical hyperplasia (36)

Macrocephaly

 

+(29) Multiple Trichillemmomas periorally

Cavernous haemangioma (17) Lipoma (36)

c.565A>T Nonsense

D

Pid 1 (F, 1950)

Bilateral cancer (30) (31)

Adenoma (31)

Uterine polyp (52)

Macrocephaly

Multiple non classifiable gastric, duodenal, colon and rectal fibrous polyps (30)

+ (44)

Hypersementosis in teeth (32) Osteoma (32) Haemangioma (38) Neurofibroma (45)

  

Pid 2 (F, 1972)

Adenoma (29)

Goitre (30)

 

Macrocephaly

Colon polyps with erosions and teleangiestatic granulation tissue (22, 30)

+ (22) Papules on right ankle and squamous cell hyperplasia And Hyperkeratosis

Ethmoidectomy with removal of polyp from maxillary sinus (22) Dysplasia in nevus (22) Von Willebrands disease (30)

  

Pid 3 (F, 1974)

Bilateral adenoma (21)

Goitre and follicular adenoma (22)

 

Macrocephaly

   
  

Pid 18 (F, 2003)

   

Macrocephaly

   

c.1008C>G Nonsense

E

Pid 1 (F, 1946)

Cancer (45)

Goitre (21) and papillary cancer (45)

 

Lhermitte-Duclos disease (51) Macrocephaly

 

+ (52) Squamous cell hyperplasia on hands

Lipoma (5) Parathyroid adenoma (45) Haemangioma (54)

  

Pid 12 (M, 1975)

 

Goitre (14) Goitre and thyroiditis (31) Thyroidectomy (31)

 

Macrocephaly

   

c.1028T>A, c.1039T>C Missense, missense†

F

Pid 1 (F, 1962)

Atypical hyperplasia and adenoma (33) Bilateral mastectomy (44)

Goitre (33)

Cancer (31)

Macrocephaly

Multiple hyperplastic duodenal and colon polyps (30)

  
  

Pid 2 (F, 1948)

Adenoma (30)

Goitre (31) Follicular adenoma (40)

Cancer (47)

Macrocephaly

Hyperplastic gastric, small intestine, colon and rectal polyps (37)

+ (36) Fibroepithelial polyps in the axilla

 
  

Pid 3 (F, 1967)

Adenoma (33)

Follicular cancer (11

Polyps (29)

Macrocephaly

Not examined

 

Haemangioma (9 months) Cephalic haematoma (1) Chronic cheilitis (5) Ectopic breast tissue (16)

  

Pid 4 (F) Dead, not tested

Bilateral cancer (56)

Adenoma (49)

Nodular cystic hyperplasia (50)

   

Malignant schwannoma in peripheral nerves (33)

  

Pid 5 (F, 1965)

Bilateral adenoma (38)

Goitre(38)

Polyp (39)

Macrocephaly

Hyperplastic colon and rectal polyps (39)

+ (38) Dermatofibroma and fibroepithelial polyp

Neavi with cell changes (39)

  

Pid 7 (M, 1950)

 

Goitre (31)

Pineal gland tumour (42)

Macrocephaly

Multiple colon polyps seeming like ganglioneuroma and Peutz Jeghers polyps (42) Colectomized (42) Gastric, duodenal and small intestine polyps (53) Inflammatory polyp and multiple polyps perianally (53)

 

Epilepsy (42)

  

Pid 8 (F, 1952)

Bilateral cancer (43, 53)

Goitre (28)

Polyp and simple hyperplasia (50)

Macrocephaly

Hyperplastic colon polyp and juvenile hamartomata type colon polyp (49, 2)

Removed epidermal cyst (52)

Liver haemangioma (51) Kidney cancer (52)

  

Pid 9 (F, 1955)

Small cysts bilaterally (50)

Goitre (25)

Myoma (39) Uterus removed (45) Polyp isthmus uteri (48)

Macrocephaly

Hyperplastic colon and rectal polyps with focal fibrosis (48, 7)

+ (48)

Lipoma (36)

  

Pid 32 (F, 1973)

   

Macrocephaly

  

Polydactylia foot (5)

  

Pid 42 (M, 1989)

   

Macrocephaly

  

Haemangioma (11)

! reference sequence NM_000314.1; * pid - patient identification number within the family; † all affected carried both mutations; ‡ age at first detected polyp and total number of polyps up until last date of data collection are given.

If the exact number is not given in the medical charts, polyps are interpreted as meaning a few.

Mutations in the coding sequence of PTEN were identified in all living affected members of the six families fulfilling the International Cowden Syndrome Consortium Criteria. All together 56 persons were subjected to genetic testing, out of whom 19 were identified as mutation carriers. None of the 37 healthy relatives in these families had mutations. In the two families clinically assumed to have Cowden syndrome, but not fulfilling the clinical criteria, no PTEN mutation was identified; for details see Table 3. In the eight families selected by a combination of breast and thyroid cancer no PTEN mutation was identified. Different cancer types were seen in these families; for details see Table 3.
Table 3

Number of patients with benign neoplasms and different cancer types, and the age range

 

PTEN mutation positive families fulfilling the Cowden syndrome criteria (6 families, only demonstrated mutation carriers included)

Assumed Cowden syndrome families but not fulfilling the criteria, no PTEN mutation detected (2 families)

Breast- and thyroid-cancer kindreds, no PTEN mutation detected (8 families)

 

Number of patients

Median/Mean age (range) years

Number of patients

Median/Mean age (range) years

Number of patients

Median/Mean age (range) years

Benign neoplasms

Goitre and/or adenoma

12

29/27.25 (14-38)

  

1**

34

Polyps of GI tract

10

38/36.5 (22-49)

    

Haemangioma

8

26.5/28.1 (0.75-54)

    

Mucocutaneous lesions

9

36/36.6 (22-52)

1

59

  

Endometrial polyps/simple hyperplasia

7

43/42.4 (29-52)

    

Benign tumours of the breast

7

33/33.4 (21-50)

  

1**

25

Lipoma

3

36/27.3 (10-36)

    

Cancers

Breast

5*

35/35.4 (24-45)

4

42.5/46.5 (25-76)

12

50.5/52 (40-65)

Thyroid

3

13/23 (11-45)

5

50/49.2 (24-84)

11

45/46.4 (22-83)

Brain

3†

42/39 (24-51)

    

Endometrial

2

39/39 (31-47)

  

1

67

Kidney

1

52

1

27

  

Testicular

  

1

62

  

Mediastinal

  

1

54

  

Ovarian

    

2

51.5/51.5 (49-54)

Colon

    

2

57/57 (49-65)

Prostate

    

1

58

Histiocytoma

    

1

45

Malignant melanoma

    

2

57.5/57.7 (56-59)

Cervical

    

1

34

Adrenal

    

1

56

* two patients had bilateral disease, scored for age at first cancer; † two patients had a gangliocytoma (Lhermitte-Duclos disease), one had a tumour of the pineal gland; ** same patient.

Of the tested families, five families had a frameshift or nonsense mutation and one family had two missense mutations located in exon 9 located on the same chromosome. The detected mutations were located in exon 1 (c.50delAA and c.68T>A), exon 5 (c.328C>T), exon 6 (c.565A>T), exon 8 (c.1008C>G) and exon 9 (c.1028T>A and c.1039T>C) (reference sequence: NM_000314.1). No mutations were found in regulatory regions.

Except for one family (F), the mutation carrying families were small. One family had a demonstrated de novo mutation (D) and two families most likely had de novo mutations (C and E). We did not observe skipped generations.

The mothers of three of our probands had had breast cancer at age 45 (bilateral breast cancer), 46 and 56 (bilateral breast cancer) years old. Since they all were deceased and our attempts to perform mutation analysis from paraffin embedded tissue from these patients were unsuccessful, they were considered to be mutation carriers by state.

All mutation carriers were examined and all had clinical signs. The youngest mutation carrier was born with a demonstrated clinical sign (macrocephaly, D-18). Most patients had more than one clinical sign; for details see Table 2. Twelve (63.2%) patients had goitre and/or adenoma of the thyroid gland, ten (52.6%) patients had polyps of the gastrointestinal tract, seven (36.8%) patients had benign tumours of the breast, seven (36.8%) patients had endometrial polyps and/or hyperplasia; for details see Table 3. Fig. 1 shows age-related distribution of first clinical sign, as estimated by the Kaplan-Meier algorithm.
Figure 1

Age at onset of first clinical sign estimated by Kaplan-Meier algorithm for demonstrated mutation carriers. See Table 2 for details of clinical signs

One patient (A-1) had multiple small colonic polyps interpreted as not having any dysplasia at age 33. Two years later she still had multiple small polyps less than 5 millimetres in diameter, now histologically described as lymphoid infiltrations and interpreted as an inflammatory condition. Mutation analysis of the APC gene showed APC 7542 G>A, G2502S and APC 1496 C>T, Y486Y, interpreted as normal variation. MYH testing was normal.

Macrocephaly is defined as a head circumference above the 97th percentile [2]. We used centile charts for Norwegian boys and girls aged 0-17 and for all patients above 17 years of age we used the centile for age 17. All our patients that were alive were clinically assessed to have macrocephaly. Macrocephaly was confirmed by exact measurement in 15 patients and judged to be clinically present in the remaining four.

Cancer appeared from age 11. The oldest mutation carrier without diagnosed neoplasia was 49 years old. She had, however, been hysterectomized at age 45. Five (26.3%) patients had breast cancer, age range from 24 to 45 years. Three (15.8%) patients had thyroid cancer, age range 11-45 years. Three (15.8%) patients had tumours of the brain (two had a gangliocytoma at age 24 and 51 and one had a tumour of the pineal gland at age 42). Two (10.5%) patients had endometrial cancer at 31 and 47 years of age. One (5.3%) patient had kidney cancer at 52 years of age. For details, see Table 3. Results of Kaplan-Meier analysis for age of onset of cancer are given in Fig. 2.
Figure 2

Age at onset of first cancer estimated by Kaplan-Meier algorithm for demonstrated mutation carriers.

Discussion

Cowden syndrome is rarely found in families attending our cancer genetics clinic. In the national survey presented here, PTEN mutations were found in all families fully meeting the Cowden syndrome criteria, but in no Cowden syndrome-like families not meeting the criteria. Penetrance of PTEN mutations was high and expressions were Cowden syndrome stigmata in early infancy or childhood and cancer in adolescence or early adulthood [24, 25]. In addition, the families were small with demonstrated de novo mutations, indicating low fitness before modern treatment and low population burden of mutation carriers.

Ten years ago we reported the well defined Cowden syndrome families we knew at the time at Rikshospitalet-Radiumhospitalet Medical Centre [8]. The national survey presented here revealed just two additional families, both fulfilling the clinical criteria for Cowden syndrome. Obviously, the numbers are too small to arrive at conclusions with respect to clinical manifestations in the mutation carriers. On the other hand, we had a large sample of cancer families initially not ascertained through Cowden criteria - the families may be representative for families selected this way. On the other hand, we did not search for Cowden syndrome without cancer. We described that in familial cancer all mutation carrying families had additional Cowden syndrome stigmata. We have not examined whether or not Cowden syndrome-like families without cancer may have PTEN mutations. We have previously reported on frequent cancer syndromes in Norway; we have a large number of cancer kindreds in our computerized database, and we found no additional families when searching for Cowden syndrome associated cancers. We consider the low prevalence and the expressions found representative for Cowden families with cancer.

All families (100%, 95% CI 37-100%) which fulfilled the Cowden syndrome criteria carried PTEN mutations, which is in keeping with the previously reported estimate of 85-90% [14]. Our observed number of mutation carriers gives an observed prevalence of 1 per 242,063, which is within Nelen's estimate of between 1 per 200,000 and 1 per 250,000 [16]. We found only six families with mutations, which were considered too few for meaningful considerations with respect to where in the gene the mutations were located.

Twelve (63.2%) patients had benign thyroid manifestations, which is a little less than three quarters reported by Merg [7]. The youngest age of onset for thyroid cancer was 11 years, which indicates that PTEN mutation carriers contract thyroid cancer both more frequently and at a younger age than the general population. Seven (36.8%) patients had benign breast lesions, compared to earlier reports of 50-60% [3, 6]. Five out of 19 (26.3%) had breast cancer at 24-45 years, which is within 20-30% and age range as previously reported [4]. Two (10.5%) patients had endometrial cancer compared to earlier reports of 6% [3, 7]. Ten (52.6%) patients had gastrointestinal polyps, which is close to earlier reports [7]. None of our mutation carriers had colon cancer. According to Lynch and de la Chapelle a firm association between Cowden syndrome and colorectal cancer has yet to be identified, and according to Eng colorectal cancers are not components of Cowden syndrome [26, 27]. One (5.3%) of our mutation carriers had renal cell carcinoma, supporting the notion that renal cell carcinoma should be added to the operational criteria for Cowden syndrome [28]. Thus, our findings add empirical support to established conclusions which have been questioned because of low numbers reported.

Nine of 19 (47%) mutation carriers were members of one kindred. We consider this a finding corresponding with low and variable fitness in mutation carriers. If so, the uneven distribution of mutation carriers in families was a finding and possibly not a statistical problem reflecting random variation in low numbers.

In sum, our results were that Cowden syndrome families had PTEN mutations, while Cowden-like families and breast and thyroid cancer kindreds did not. The number of Cowden syndrome-like families was not more than what might be expected by chance alone. All examined mutation carriers had clinical signs, and cancer started to occur before the age of 16.

In Cowden syndrome families, genetic testing to identify individuals at risk of contracting cancer cannot wait until the kindreds are old enough to give informed consent. We find it reasonable to offer genetic testing in infancy/early childhood. Mutation carriers may be offered thyroid screening from childhood, and breast cancer screening may be considered from adolescence (with MRI, to avoid radiation exposure by mammography in puberty). Our material is not large enough to conclude on which age to start breast cancer screening, but the youngest patient with breast cancer described internationally was 14 years old [3]. We feel that we should try to do our best when it comes to screening, and therefore we recommend that one may consider breast cancer screening from adolescence.

Non-mutation carriers and members of Cowden syndrome-like families may not be at risk for cancer in early age, and may need no special health care in infancy or adolescence. Thorough clinical genetic work-up of families and access to genetic testing will discriminate between those who need health service from childhood, and those who do not.

Authors’ Affiliations

(1)
Section for Inherited Cancer, Department of Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Centre
(2)
Section for Molecular Genetics, Department of Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Centre
(3)
Centre for Medical Genetics and Molecular Medicine, Institute of Clinical Medicine, University of Bergen

References

  1. Lloyd KM, Dennis M: Cowdens's disease. A possible new symptom complex with multiple system involvement. Ann Intern Med 1963, 58: 136–142.View ArticlePubMedGoogle Scholar
  2. Eng C: Cowden syndrome and related disorders. In Familial Breast and Ovarian Cancer. Genetics, Screening and Management. Edited by: Morrison PJ, Hodgson SV, Haites NE. Cambridge, UK; 2002:22–42. full_textGoogle Scholar
  3. Starink TM, Veen JP, Arwert F, de Waal LP, de Lange GG, Gille JJ, Eriksson AW: The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986, 29: 222–233.View ArticlePubMedGoogle Scholar
  4. Longy M, Lacombe D: Cowden disease. Report of a family and review. Ann Genet 1996, 39: 35–42.PubMedGoogle Scholar
  5. Eng C: Cowden syndrome. J Genet Couns 1997, 6: 181–191. 10.1023/A:1025664119494View ArticlePubMedGoogle Scholar
  6. Hanssen AM, Fryns JP: Cowden syndrome. J Med Genet 1995, 32: 117–119. 10.1136/jmg.32.2.117PubMed CentralView ArticlePubMedGoogle Scholar
  7. Merg A, Howe JR: Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet C Semin Med Genet 2004, 129: 44–55. 10.1002/ajmg.c.30020View ArticleGoogle Scholar
  8. Lynch ED, Ostermeyer EA, Lee MK, Arena JF, Ji H, Dann J, Swisshelm K, Suchard D, MacLeod PM, Kvinnsland S, Gjertsen BT, Heimdal K, Lubs H, Moller P, King MC: Inherited mutations in PTEN that are associated with breast cancer, cowden disease, and juvenile polyposis. Am J Hum Genet 1997, 61: 1254–1260. 10.1086/301639PubMed CentralView ArticlePubMedGoogle Scholar
  9. Nelen MR, Padberg GW, Peeters EA, Lin AY, Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C: Localization of the gene for Cowden disease to chrmosome 10q22–23. Nat Genet 1996, 13: 114–116. 10.1038/ng0596-114View ArticlePubMedGoogle Scholar
  10. Eng C: Genetics of Cowden syndrome: through the looking glass of oncology. Int J Oncol 1998, 12: 701–710.PubMedGoogle Scholar
  11. Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG, Mariman EC, Padberg GW, Kremer H: Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 1997, 6: 1383–1387. 10.1093/hmg/6.8.1383View ArticlePubMedGoogle Scholar
  12. Liaw D, Marsh DJ, Li J, Dahia PLM, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997, 16: 64–67. 10.1038/ng0597-64View ArticlePubMedGoogle Scholar
  13. Harada N, Sugimura T, Yoshimura R, Motomura S, Shirahama S, Naramoto J, Chijiiwa Y, Nakamura K, Ito K, Nawata H: Novel germline mutation of the PTEN gene in a Japanese family with Cowden disease. J Gastroenterol 2003, 38: 87–91. 10.1007/s005350300012View ArticlePubMedGoogle Scholar
  14. 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: 323–326. 10.1136/jmg.2004.018036PubMed CentralView ArticlePubMedGoogle Scholar
  15. Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboue B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, Eng C, 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: 507–515. 10.1093/hmg/7.3.507View ArticlePubMedGoogle Scholar
  16. Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, Woods CG, Fryns JP, Hamel B, Hoefsloot LH, Peeters EA, Padberg GW: Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet 1999, 7: 267–273. 10.1038/sj.ejhg.5200289View ArticlePubMedGoogle Scholar
  17. Sawada T, Okada T, Miwa K, Satoh H, Asano A, Mabuchi H: Two novel mutations of PTEN gene in Japanese patients with Cowden syndrome. Am J Med Genet A 2004, 128: 12–14. 10.1002/ajmg.a.20309View ArticleGoogle Scholar
  18. Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed SF, Bodurtha J, Crowe C, Curtis MA, Dasouki M, Dunn T, Feit H, Geraghty MT, Graham JM Jr, Hodgson SV, Hunter A, Korf BR, Manchester D, Miesfeldt S, Murday VA, Nathanson KL, Parisi M, Pober B, Romano C, Eng C, 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: 1461–1472. 10.1093/hmg/8.8.1461View ArticlePubMedGoogle Scholar
  19. Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C: Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 2001, 358: 210–11. 10.1016/S0140-6736(01)05412-5View ArticlePubMedGoogle Scholar
  20. Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ: Germline mutation of the tumour suppressor PTEN in Proteus syndrome. J Med Genet 2002, 39: 937–940. 10.1136/jmg.39.12.937PubMed CentralView ArticlePubMedGoogle Scholar
  21. Biesecker LG, Rosenberg MJ, Vacha S, Turner JT, Cohen MM: PTEN mutations and proteus syndrome. Lancet 2001, 358: 2079–2080. 10.1016/S0140-6736(01)07109-4View ArticlePubMedGoogle Scholar
  22. Cohen MM Jr, Turner JT, Biesecker LG: Proteus syndrome: misdiagnosis with PTEN mutations. Am J Med Genet 2003, 122: 323–324. 10.1002/ajmg.a.20474View ArticleGoogle Scholar
  23. Moller P, Evans G, Haites N, Vasen H, Reis MM, Anderson E, Apold J, Hodgson S, Eccles D, Olsson H, Stoppa-Lyonnet D, Chang-Claude J, Morrison PJ, Bevilacqua G, Heimdal K, Mæhle L, Lalloo F, Gregory H, Preece P, Borg A, Nevin NC, Caligo M, Steel CM: Guidelines for follow-up of woman at high risk for inherited breast cancer: consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer. Dis Markers 1999, 15: 207–211.PubMed CentralView ArticlePubMedGoogle Scholar
  24. Marsh DJ, Dahia PL, Caron S, Kum JB, Frayling IM, Tomlinson IP, Hughes KS, Eeles RA, Hodgson SV, Murday VA, Houlston R, Eng C: Germline PTEN mutations in Cowden syndrome-like families. J Med Genet 1998, 35: 881–885. 10.1136/jmg.35.11.881PubMed CentralView ArticlePubMedGoogle Scholar
  25. FitzGerald MG, Marsh DJ, Wahrer D, Bell D, Caron S, Shannon KE, Ishioka C, Isselbacher KJ, Garber JE, Eng C, Haber DA: Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene 1998, 17: 727–731. 10.1038/sj.onc.1201984View ArticlePubMedGoogle Scholar
  26. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 2003, 348: 919–932. 10.1056/NEJMra012242View ArticlePubMedGoogle Scholar
  27. Eng C: Constipation, polyps, or cancer? Let PTEN predict your future. Am J Med Genet A 2003, 122: 315–322. 10.1002/ajmg.a.20477View ArticleGoogle Scholar
  28. Eng C: Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000, 37: 828–830. 10.1136/jmg.37.11.828PubMed CentralView ArticlePubMedGoogle Scholar

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