- Open Access
PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review
Diagnostic Pathology volume 18, Article number: 43 (2023)
PTEN hamartoma tumour syndrome (PHTS) is a rare hereditary disorder caused by germline pathogenic mutations in the PTEN gene. This study presents a case of PHTS referred for genetic evaluation due to multiple polyps in the rectosigmoid area, and provides a literature review of PHTS case reports published between March 2010 and March 2022.
A 39-year-old Iranian female with a family history of gastric cancer in a first-degree relative presented with minimal bright red blood per rectum and resistant dyspepsia. Colonoscopy revealed the presence of over 20 polyps in the rectosigmoid area, while the rest of the colon appeared normal. Further upper endoscopy showed multiple small polyps in the stomach and duodenum, leading to a referral for genetic evaluation of hereditary colorectal polyposis. Whole-exome sequencing led to a PHTS diagnosis, even though the patient displayed no clinical or skin symptoms of the condition. Further screenings identified early-stage breast cancer and benign thyroid nodules through mammography and thyroid ultrasound.
Method and results of literature review
A search of PubMed using the search terms “Hamartoma syndrome, Multiple” [Mesh] AND “case report” OR “case series” yielded 43 case reports, predominantly in women with a median age of 39 years. The literature suggests that patients with PHTS often have a family history of breast, thyroid and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Gastrointestinal polyps are one of the most common signs reported in the literature, and the presence of acral keratosis, trichilemmomas and mucocutaneous papillomas are pathognomonic characteristics of PHTS.
When a patient presents with more than 20 rectosigmoid polyps, PHTS should be considered. In such cases, it is recommended to conduct further investigations to identify other potential manifestations and the phenotype of PHTS. Women with PHTS should undergo annual mammography and magnetic resonance testing for breast cancer screening from the age of 30, in addition to annual transvaginal ultrasounds and blind suction endometrial biopsies.
PTEN hamartoma tumour syndrome (PHTS), commonly defined as multiple hamartoma syndrome, is a rare autosomal genodermatosis with a heterogeneous phenotype that is clinically characterized by numerous hamartomas of ectodermic, mesodermic or endodermic origin with an elevated lifetime risk of developing endometrial, breast, thyroidal, colorectal or renal carcinomas . PHTS is commonly (80% of all cases) associated with pathogenic variants affecting the phosphatase and tensin homologue (PTEN) gene [2, 3]. Other disorders caused by dysfunction of this gene are Bannayan-Riley-Ruvalcaba syndrome (BRRS) and Cowden syndrome (CS) . BRRS tends to affect children, while CS are most commonly seen in adults. PHTS is primarily caused by pathogenic gene mutations (variants) in the PTEN tumour suppressor gene .
The estimated incidence of PHTS is around one in 200,000 people [1, 6], but this is likely to be an underestimation due to its phenotypic diversity and difficulty in recognition. Consequently, PHTS poses a dilemma for clinicians, who must conduct multiple medical evaluations of affected patients before the diagnosis is reached . Early detection is crucial, as the best potential prognosis for patients with PHTS rests on accurate clinical observation plus ongoing surveillance of affected individuals . The diagnosis is primarily clinical with genetic follow-up, and the National Comprehensive Cancer Network (NCCN®) annually reviews and develops the diagnostic criteria created by Eng et al. [8,9,10,11].
Clinical guidelines for diagnosis and surveillance are needed for PHTS due to its diversity and infrequency. Reporting cases with different characteristics can help improve national and international approaches to early diagnosis of affected patients and their family members, who are at increased risk of developing several cancers in their lifetime. Previous case reports have highlighted clinical or skin symptoms associated with PHTS, such as papillomatous skin lesions, macrocephaly, gingival hypertrophy and blood vessel problems [12,13,14,15,16,17,18,19]. CS-related hamartoma polyps in various parts of the body have been reported [6, 17], including a 16-year-old Iranian female with pathognomonic cutaneous features of CS, who was evaluated for the PTEN gene through testing by the polymerase chain reaction (PCR) . However, there are no reports from Iran of breast cancer associated with PHTS.
The Iranian Hereditary Colorectal Cancer Registry (IHCCR) is a programme specifically designed to identify individuals at high risk of hereditary colorectal cancer or polyposis in Iran [20,21,22,23]. IHCCR confirms these cases through whole-exome sequencing (WES), a comprehensive genetic test that sequences all of the protein-coding gene regions . A 39-year-old female with multiple rectosigmoid polyps, who underwent WES to confirm hereditary colorectal polyposis, was unexpectedly diagnosed with PHTS despite absence of any clinical symptoms of the condition. Here, we summarize the disease manifestations, treatment and management of this case. Furthermore, we conducted a literature review of case reports on PHTS, with the secondary objective to compare the clinical signs found with those reported in other relevant cases.
A 39-year-old Iranian woman presented with minimal bright red blood per rectum at Emam Reza Hospital in Mashhad, the referral university hospital in north-eastern Iran. The patient was married, unemployed, had nine siblings and denied any history of alcohol, tobacco or medication. The patient presented with multiple skin tags on her neck, which were determined to be non-PHTS-related. An intraoral examination revealed no significant findings. However, early-stage breast cancer had been detected during mammography screening.
Notably, the patient had a significant family history of cancer. At the age of 52, her father was diagnosed with cancer of the stomach, which subsequently metastasized to the liver and ultimately led to his death, and a cousin had been diagnosed with breast cancer. There was no reported history of radiation exposure or goitre in her family. The patient’s family tree (Fig. 1) represents all close relatives, both affected and unaffected by disease.
Upper endoscopy and colonoscopy were recommended due to resistant dyspepsia, rectal bleeding, family history of stomach cancer and mild anaemia. Oesophago-gastro-duodenoscopy (EGD) revealed 20–50 small sessile polyps in the stomach and duodenum. Microscopic examination of a biopsy from the gastric mucosa showed non-dysplastic, polypoid tissue. Notably, colonoscopy revealed over 50 diminutive sessile polyps in the rectosigmoid area, while other parts of the colon were normal. Subsequent histological examination confirmed these polyps as hyperplastic, hamartomatous polyps.
Since the guidelines issued by the American College of Medical Genetics and Genomics (ACMG)  recommend genetic testing for patients with more than 20 colon polyps, the patient was enrolled in the IHCCR programme for genetic consultation. Its charge is to identify individuals at high risk of hereditary colorectal cancer or polyposis in Iran confirming their findings by WES.
Whole exome sequencing
DNA was extracted from whole blood using standard procedures. Human whole exome enrichment was performed using ‘Agilent SureSelect V6 Target Enrichment Kit’ (www.agilent.com) according to the manufacturer’s protocol. Briefly, genomic DNA was captured using biotinylated RNA probes, which target all exonic regions and 10 flanking base-pairs (bp). After amplification and sequencing using the Illumina HiSeq4000 platform (Illumina, Inc.), the data were analysed using standard bioinformatics tools. Variant calling was performed using the genome analysis toolkit (GATK) software (https://gatk.broading.org)  that detects variations, such as single point mutations and small Indels (within 20 bp). The DNA sequence was mapped and analyzed in comparison with the published human genome build (UCSC hg19 reference sequence). Variants with a minor allele frequency (MAF) ≥ 0.1% (heterozygous variants) or ≥ 1% (homozygous variants) were excluded using 1000 Genomes (Asian), Iranom and the Genome Aggregation Database (gnomAD) . Sorting intolerant from tolerant (SIFT) , Polymorphism Phenotyping, version 2 (PolyPhen2) combined with HumVar, a dataset that provides pre-computed predictions of the functional impact of human non-synonymous (change of amino acids) variants  and combined annotation-dependent depletion (CADD) with Phred score ≥ 20  were used for prediction of missense variants. The raw data used in the genetic evaluation of this case are provided as a supplementary file .
The WES analysis of the patient’s DNA revealed a heterozygous pathogenic variant on the PTEN gene, specifically a pathogenic non-sense variant (c.697C > T, p.Arg233Ter) with a CADD score of 37 and a Deep Neural Network (DANN)  score of 0.997 (Table 1). The PTEN gene is associated with autosomal dominant PHTS , but in this case, the patient did not exhibit any skin or clinical symptoms of the condition. According to guidelines of the National Comprehensive Cancer Network (NCCN) and the European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS), PHTS-suspected cases should undergo gene panel testing [9, 33].
The International Cowden Syndrome Consortium (ICSC) [9, 10] recommends surveillance for additional manifestations of PHTS and potentially related malignancies, as outlined in Table 2. Patients suspected of having PHTS are at increased risk of cancers of the breast, thyroid, colon and rectum necessitating further investigation . Furthermore, the American Gastroenterology Association recommends annual comprehensive physical examination, thyroid ultrasound screening beginning at the time of diagnosis, endometrial suction biopsy starting at the age 30–35 and colonoscopy screening beginning at 35 years of age or 5–10 years before the initial documented case of colon cancer in the family .
The patient in question presented with a solid mass measuring 22 × 17 mm in the lower outer quadrant of the right breast, which was detected by mammography. Ultrasonography confirmed the presence of dense, oval nodules with well-defined margins measuring approximately 20 × 15 mm located at the 6 o’clock position of the right breast, 5 cm from the nipple. Based on the Breast Imaging Reporting and Data System (BIRADS), these nodules were categorized as BIRADS IV, indicating a suspicious abnormality that necessitates further workup to ascertain whether or not likelihood of malignancy.
In addition, thyroid ultrasonography revealed multiple, well-defined, isoechoic and hyperechoic nodules in both thyroid lobes. Further evaluation through fine-needle aspiration (FNA) biopsy showed a follicular lesion with undetermined significance classified as BETHESDA III. This category denotes that the specimen obtained is non-diagnostically relevant but does not exclude the possibility of malignancy, with and clinical correlation, repeat FNA and/or surgical excision recommended.
The patient underwent further evaluation as recommended but a biopsy of the endometrium revealed no abnormalities. Biochemical assessments of renal, liver and thyroid function were within the normal range, and the patient did not exhibit macrocephaly, which is a common PHTS feature.
Histology and immunohistochemistry
Multiple foci of intraductal hyperplasia with mild to moderate nuclear grade and an area of invasive pattern suspicious for cribriform carcinoma were observed in the breast core needle biopsy (Fig. 2). Immunohistochemistry (IHC) staining according to the 2013 ASCO/CAP HER2 guidelines  was performed and revealed positivity for p63 and actin, indicating a solid nest of ductal carcinoma in situ (DCIS). The tumour cells also tested positive for estrogen and progesterone receptors in 90% of the cells. The HER2 status of the tumour was initially equivocal (2 +), with weak membranous staining in 30% of tumoural cells. To clarify the result, fluorescence in situ hybridization (FISH) testing was performed and it revealed a negative HER2/neu gene status in the tumoural cells. As a result, the final HER2 status of the tumour was negative. A Ki-67 index was found in 5% of the tumour cells, indicating a low proliferation rate. Following partial mastectomy, a 2.2 cm invasive cribriform carcinoma with a Bloom-Richardson grade  of 1(2 + 1 + 1) was observed. Notably, there was no evidence of vascular or perineural invasion and the surgical margins were free of tumour involvement.
A literature review was conducted using the PubMed database to identify cases of PHTS reported between March 2010 and March 2022. The search strategy used the terms “Hamartoma Syndrome, Multiple” [Mesh] AND “case report” OR “case series”. A comprehensive reference list search of related literature was performed, with the review limited to articles in the English language, excluding letters to the editor and review articles.
We identified 43 cases of PHTS, the characteristics of whom are summarised in Table 3. The median age of the cases was 39 years (IQR: 31–52; min–max: 14–75) and we noted that the disease predominantly affected women. Of the 43 cases, 23 had a family history of PHTS with complications, such as breast, thyroidal and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Pathognomonic characteristics of PHTS, including acral keratosis, trichilemmomas, and mucocutaneous papillomas were reported in about 70% of the cases. Figure 3 depicts the clinical criteria used to diagnose PHTS patients and their medical history, as reported in the literature review. Gastrointestinal polyps were frequently reported as clinical manifestations. Figure 4 visualizes the mutated sites of the PTEN pathogenic variants indicating that pathogenic variants in exon 5 were frequent.
In this report, we described the features of PHTS in an Iranian female patient. Our initial examination revealed the presence of 50–100 rectosigmoid polyps, which prompted us to apply WES to confirm hereditary colorectal polyposis. Intriguingly, despite the patient’s lack of skin or clinical symptoms of the condition, the WES results revealed a heterozygous c.697C > T (p.Arg233Ter) pathogenic variant of the PTEN gene that is linked with autosomal dominant PHTS. However, the patient’s family history was found to be significant. Previous studies indicate that PHTS have a family history in one-third of patients [70, 71]. The father and a cousin of our patient had cancer, while our literature review revealed a family history of cancer for 42% of patients with PHTS. Therefore, it is important to screen family members and obtain a thorough family history to identify additional cases of PHTS as early as possible.
Acral keratosis, trichilemmomas, and mucocutaneous papillomata are pathognomonic features of PHTS . Literature reports reveal that cutaneous lesions manifest as trichilemmomas and acral keratosis, with pits on the palms, lips and soles in around 70% of PHTS patients. However, our case lacked these lesions.
PHTS is associated with a high prevalence of breast, thyroid, and endometrial neoplasias, which are the primary complications of the disease [34, 73]. The lifetime risk of developing breast cancer in women with PHTS ranges from 54.3 to 75.8% . Hence, women with PHTS are recommended to self-examine their breasts and undergo regular mammography . In the present case, mammography facilitated the early detection of breast cancer. Preventative measures such as bilateral mastectomy are advised for PHTS patients with extensive fibrocystic breast disease or breast cancer .
Compared to previously reported rates [2, 9, 34, 73, 75,76,77], recent literature suggests that PHTS patients may have an even higher risk of developing breast cancer (up to 80%) and endometrial cancer (up to 28%). In addition, these patients may develop a significant number of benign thyroid lesions (up to 60%) and thyroid cancer (over 10%) [34, 78]. Genetic and molecular studies of PHTS have revealed the presence of pathogenic variants in the PTEN/MMAC1 gene, located on chromosome 10 at position q 22–23, which is implicated in breast and thyroid cancer [73, 79,80,81,82]. While the clinical and laboratory diagnostic criteria serve as the foundation for diagnosis , molecular genetic testing can be used to identify these pathogenic variants [55, 83]. However, recent prospective studies suggest that the prevalence of germline pathogenic variants in PTEN can be estimated at only 25% of patients with this condition, which is lower than previously thought [2, 84]. We applied both approaches and obtained positive results for our patient, who was diagnosed with breast cancer, multiple thyroid nodules, and more than the 50–100 range of rectosigmoid polyps in addition to a significant family cancer history.
Patients with PHTS may also develop tumours in various parts of the body, including the gastrointestinal or genitourinary tract, or the brain [85, 86]. Gastrointestinal polyposis is a common symptom that affects any part of the digestive system [20, 87, 88]. It is essential to recommend earlier endoscopic screening due to the high frequency of colon polyps in PHTS, estimated to be between 65.6 and 93% . However, the risks and benefits of early intervention should be carefully weighed against the financial expenses and health risks associated with increased endoscopic surveillance .
Innella et al.  reported two cases of PHTS referred for genetic testing due to endoscopic findings of multiple colorectal polyps, which was similar to our case. While our literature review showed gastrointestinal polyps to be common in PHTS patients, mucocutaneous lesions are the most common diagnostic criteria. Therefore, all the various manifestations of PHTS among these patients should be carefully considered. Colorectal screening, starting at age 35–40 years [85, 89], is recommended for those with PTEN pathogenic variants.
Table 3 demonstrates that both the upper and lower gastrointestinal tracts are frequently involved in PHTS patients, including our case which revealed numerous small rectosigmoid, gastric and duodenal polyps. These findings suggest that colon polyposis is an under-reported characteristic in PHTS guidelines. Furthermore, evidence supports the elevated risk of colorectal cancer in PHTS patients [34, 76, 85, 89, 90]. However, the association between PHTS and gastrointestinal malignancies is still a controversial subject [40, 78, 91,92,93,94,95].
The dysplastic, cerebral ganglion cell tumour LDD is a significant pathological diagnostic criterion for PHTS [40, 74, 96]. To rule out its potential presence, it is recommended that patients presenting with headaches undergo MRI of the brain, as has been stated in multiple sources [61, 65, 67]. While ovarian tumours are a rare occurrence in PHTS, this possibility should not be overlooked as an ovarian dysgerminoma has been documented in a patient with PHTS .
To the best of our knowledge, this is the first reported case of PHTS detected through WES during a hereditary polyposis evaluation of rectosigmoid polyps in an Iranian patient. Although our review was not a systematic one, we found 43 case reports on PHTS. It is therefore probable that this affliction than though so far. Indeed, our search was limited to PubMed and we may well have missed additional cases reported in other databases. Although a language bias may exist with regard to our review, the English tongue is widely perceived as the universal language of science, and studies in medical sciences have not shown any systematic bias resulting from this restriction [97, 98].
The detection of rectosigmoid polyps should prompt practitioners to consider genetic evaluation for hereditary colorectal polyposis and to also consider the possibility of PHTS and thus look for other associated manifestations of this syndrome. Importantly, the finding of pathogenic variants in the PTEN gene led to early screening for breast cancer with a positive outcome. The presence of > 50 polyps in the rectosigmoid, coupled with the absence of typical familial adenomatous polyposis or other forms of colon polyposis, warrants further studies to identify the PHTS phenotype. Early cancer detection through regular surveillance is critical for the management of PHTS and has been shown to improve overall survival. Thus, all PHTS patients should receive annual thyroid ultrasound scans and dermatologic evaluations, while women should receive annual mammograms and breast MRIs from age 30, along with annual transvaginal ultrasound investigations and blind suction endometrial biopsies.
Availability of data and materials
This paper contains all the necessary information for others to reproduce our findings, including the raw data used in the genetic evaluation (WES), which have been made available as a supplementary file . These data can be used for research purposes with appropriate citation of this paper.
Lim A, Ngeow J. The skin in Cowden syndrome. Front Med (Lausanne). 2021;8:658842. https://doi.org/10.3389/fmed.2021.658842. Epub 2021/06/29. PubMed PMID: 34179044; PubMed Central PMCID: PMCPMC8222536.
Gosein MA, Narinesingh D, Nixon CA-AC, Goli SR, Maharaj P, Sinanan A. Multi-organ benign and malignant tumors: recognizing Cowden syndrome: a case report and review of the literature. BMC Res Notes. 2016;9(1):1–7.
Scheper MA, Nikitakis NG, Sarlani E, Sauk JJ, Meiller TF. Cowden syndrome: report of a case with immunohistochemical analysis and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(5):625–31.
Macken WL, Tischkowitz M, Lachlan KL. PTEN Hamartoma tumor syndrome in childhood: a review of the clinical literature. Am J Med Genet C Semin Med Genet. 2019;181(4):591–610. https://doi.org/10.1002/ajmg.c.31743. Epub 2019/10/15. PubMed PMID: 31609537.
Sbordone S, Savastano A, Savastano MC, Romano V, Bifani M, Savastano S. Corneal confocal microscopy anomalies associated with Cowden syndrome: a case report. Case Rep Ophthalmol. 2013;4(2):76–80.
Hammami S, Berriche O, Ali HB, Hellara O, Ansar F, Mahjoub S. Managing the risk of cancer in Cowden syndrome: a case report. J Med Case Reports. 2012;6(1):1–4.
Gammon A, Jasperson K, Champine M. Genetic basis of Cowden syndrome and its implications for clinical practice and risk management. Appl Clin Genet. 2016;9:83.
Eng C. Cowden syndrome. J Genet Couns. 1997;6(2):181–92. https://doi.org/10.1023/a:1025664119494. Epub 1997/06/01. PubMed PMID: 26142096.
Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105(21):1607–16.
Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet. 2000;37(11):828–30. https://doi.org/10.1136/jmg.37.11.828. Epub 2000/11/10. PubMed PMID: 11073535; PubMed Central PMCID: PMCPMC1734465.
Pilarski R. PTEN Hamartoma tumor syndrome: a clinical overview. Cancers (Basel). 2019;11(6):844. https://doi.org/10.3390/cancers11060844. Epub 2019/06/21. PubMed PMID: 31216739; PubMed Central PMCID: PMCPMC6627214.
Villeneuve H, Tremblay S, Galiatsatos P, Hamel N, Guertin L, Morency R, et al. Acinic cell carcinoma of the retromolar trigone region: expanding the tumor phenotype in Cowden syndrome? Fam Cancer. 2011;10(4):691–4. https://doi.org/10.1007/s10689-011-9472-8. Epub 2011/08/09. PubMed PMID: 21822720.
Webber LP, Martins MD, Carrard VC, Trevizani Martins MA, Munerato MC. Cowden syndrome—a case report emphasizing the role of the dental surgeon in diagnosis. Spec Care Dentist. 2015;35(1):51–4.
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(4):876–8.
Matsubayashi H, Higashigawa S, Kiyozumi Y, Horiuchi Y, Hirashima Y, Kado N, et al. Metachronous ovarian endometrioid carcinomas in a patient with a PTEN variant: case report of incidentally detected Cowden syndrome. BMC Cancer. 2019;19(1):1014. https://doi.org/10.1186/s12885-019-6272-2. Epub 2019/10/31. PubMed PMID: 31664961; PubMed Central PMCID: PMCPMC6819610.
Inukai K, Takashima N, Fujihata S, Miyai H, Yamamoto M, Kobayashi K, et al. Arteriovenous malformation in the sigmoid colon of a patient with Cowden disease treated with laparoscopy: a case report. BMC Surg. 2018;18(1):21. https://doi.org/10.1186/s12893-018-0355-x. Epub 2018/04/11. PubMed PMID: 29636101; PubMed Central PMCID: PMCPMC5894182.
Taylor A, Delon I, Allinson K, Trotman J, Liu H, Abbs S, et al. Malignant peripheral nerve sheath tumor in cowden syndrome: a first report. J Neuropathol Exp Neurol. 2015;74(4):288–92. https://doi.org/10.1097/nen.0000000000000178. Epub 2015/03/11. PubMed PMID: 25756585.
Glavina A. Gingival papillomatosis as the oral sign of Cowden’s syndrome. A case report. Acta Dermatovenerol Croat. 2019;27(4):260.
Nassiri I, Faghihi M, Tavassoli M. Mutations in the PTEN/MMAC1 gene associated with Cowden disease and juvenile polyposis syndrome. Int J Cancer Manag. 2008;1(4):141–7.
Khorram MR, Goshayeshi L, Maghool F, Bergquist R, Ghaffarzadegan K, Eslami S, et al. Prevalence of mismatch repair-deficient colorectal adenoma/polyp in early-onset, advanced cases: a cross-sectional study based on Iranian hereditary colorectal cancer registry. J Gastrointest Cancer. 2021;52(1):263–8. https://doi.org/10.1007/s12029-020-00395-y. Epub 2020/03/21. PubMed PMID: 32193764.
Hoseini B, Rahmatinejad Z, Goshayeshi L, Bergquist R, Golabpour A, Ghaffarzadegan K, et al. Colorectal Cancer in North-Eastern Iran: a retrospective, comparative study of early-onset and late-onset cases based on data from the Iranian hereditary colorectal cancer registry. BMC Cancer. 2022;22(1):48. https://doi.org/10.1186/s12885-021-09132-5. Epub 2022/01/10. PubMed PMID: 34998373; PubMed Central PMCID: PMCPMC8742430.
Goshayeshi L, Khooiee A, Ghaffarzadegan K, Rahmani Khorram M, Bishehsari F, Hoseini B, et al. Screening for lynch syndrome in cases with colorectal carcinoma from Mashhad. Arch Iran Med. 2017;20(6):332–7 Epub 2017/06/26 PubMed PMID: 28646840.
Goshayeshi L, Ghaffarzadegan K, Khooei A, Esmaeilzadeh A, Rahmani Khorram M, Mosannen Mozaffari H, et al. Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran. BMJ Open. 2018;8(8):e023102. https://doi.org/10.1136/bmjopen-2018-023102. Epub 2018/09/01. PubMed PMID: 30166308; PubMed Central PMCID: PMCPMC6119423.
Dos Santos W, de Andrade ES, Garcia FAO, Campacci N, Sábato CDS, Melendez ME, et al. Whole-exome sequencing identifies pathogenic germline variants in patients with lynch-like syndrome. Cancers (Basel). 2022;14(17):4233. https://doi.org/10.3390/cancers14174233. Epub 2022/09/10. PubMed PMID: 36077770; PubMed Central PMCID: PMCPMC9454535.
Dosunmu GT, Gurganus C, Krishnan V, Motino DAM, Ozair S, Grimm L, et al. Germline testing of patients with personal history of colorectal polyposis by cancer genetics counseling services. J Clin Oncol. 2021;39(3_suppl):47. https://doi.org/10.1200/JCO.2021.39.3_suppl.47.
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297–303. https://doi.org/10.1101/gr.107524.110. Epub 2010/07/21. PubMed PMID: 20644199; PubMed Central PMCID: PMCPMC2928508.
Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812–4. https://doi.org/10.1093/nar/gkg509. Epub 2003/06/26. PubMed PMID: 12824425; PubMed Central PMCID: PMCPMC168916.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9. https://doi.org/10.1038/nmeth0410-248.
Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47(D1):D886–94. https://doi.org/10.1093/nar/gky1016. Epub 2018/10/30. PubMed PMID: 30371827; PubMed Central PMCID: PMCPMC6323892.
Hoseini B. Raw data used in the genetic evaluation of an Iranian female with PTEN hamartoma tumor syndrome. V1 ed: Harvard Dataverse; 2023. https://doi.org/10.7910/DVN/B0ZV1Z.
Quang D, Chen Y, Xie X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics. 2015;31(5):761–3. https://doi.org/10.1093/bioinformatics/btu703. Epub 2014/10/24. PubMed PMID: 25338716; PubMed Central PMCID: PMCPMC4341060.
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(5):323–6. https://doi.org/10.1136/jmg.2004.018036. Epub 2004/05/04. PubMed PMID: 15121767; PubMed Central PMCID: PMCPMC1735782.
Tischkowitz M, Colas C, Pouwels S, Hoogerbrugge N. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. Eur J Hum Genet. 2020;28(10):1387–93. https://doi.org/10.1038/s41431-020-0651-7. Epub 2020/06/14. PubMed PMID: 32533092; PubMed Central PMCID: PMCPMC7608293 is their sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA) or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains.
Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, Brunet J, Lleuger-Pujol R, Høberg-Vetti H, et al. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. J Natl Cancer Inst. 2022. https://doi.org/10.1093/jnci/djac188. Epub 2022/09/30. PubMed PMID: 36171661.
Bharucha PP, Chiu KE, François FM, Scott JL, Khorjekar GR, Tirada NP. Genetic testing and screening recommendations for patients with hereditary breast cancer. Radiographics. 2020;40(4):913–36. https://doi.org/10.1148/rg.2020190181. Epub 2020/05/30. PubMed PMID: 32469631.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013. https://doi.org/10.1200/jco.2013.50.9984. Epub 2013/10/09. PubMed PMID: 24101045.
Bloom-Richardson Grading System NHS Data Model and Dictionary: NHS. Available from: https://www.datadictionary.nhs.uk/nhs_business_definitions/bloom-richardson_grading_system.html#:~:text=The%20Bloom%2DRichardson%20Grading%20System%20is%20a%20system%20for%20CANCER,and%20invasive%20the%20cancer%20is. Cited 2023 2023–03–19.
Trufant JW, Greene L, Cook DL, McKinnon W, Greenblatt M, Bosenberg MW. Colonic ganglioneuromatous polyposis and metastatic adenocarcinoma in the setting of Cowden syndrome: a case report and literature review. Hum Pathol. 2012;43(4):601–4.
Potenziani S, Applebaum D, Krishnan B, Gutiérrez C, Diwan AH. Multiple clear cell acanthomas and a sebaceous lymphadenoma presenting in a patient with Cowden syndrome–a case report. J Cutan Pathol. 2017;44(1):79–82.
Vasovčák P, Šenkeříková M, Hatlová J, Křepelová A. Multiple primary malignancies and subtle mucocutaneous lesions associated with a novel PTEN gene mutation in a patient with Cowden syndrome: case report. BMC Med Genet. 2011;12(1):1–4.
Morisaki T, Kashiwagi S, Kouhashi R, Yabumoto A, Asano Y, Takashima T, et al. Cowden syndrome diagnosed by bilateral breast cancer with Lhermitte-Duclos disease: a case report. Case Rep Oncol. 2020;13(1):419–23.
Miguelote S, Silva R, Fougo J, Barbosa L, Araújo TJ. Cowden syndrome is a risk factor for multiple neoplasm: a case report. World J Surg Oncol. 2020;18(1):1–6.
Molvi M, Sharma YK, Dash K. Cowden syndrome: case report, update and proposed diagnostic and surveillance routines. Indian J Dermatol. 2015;60(3):255.
Tariq S, Katz J. Cowden syndrome: oral presentations of a paraneoplastic syndrome. Case report and review of the literature. Quintessence Int. 2017;48(5):413–8. https://doi.org/10.3290/j.qi.a38061. Epub 2017/04/12. PubMed PMID: 28396890.
Sadahiro H, Ishihara H, Goto H, Oka F, Shirao S, Yoneda H, et al. Postoperative dural arteriovenous fistula in a patient with Cowden disease: a case report. J Stroke Cerebrovasc Dis. 2014;23(3):572–5. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.04.021. Epub 2013/05/18. PubMed PMID: 23680687.
Perić M, Toma S, Lasserre JF, Brecx M. Cowden syndrome associated with severe periodontal disease: a short literature review and a case report. Oral Health Prev Dent. 2018;16(3):225–32. https://doi.org/10.3290/j.ohpd.a40673. Epub 2018/06/28. PubMed PMID: 29946579.
Kuno I, Tate K, Yoshida H, Takahashi K, Kato T. Endometrial endometrioid carcinoma with ovarian metastasis showing morula-like features in a patient with cowden syndrome: a case report. Int J Gynecol Pathol. 2020;39(1):36–42. https://doi.org/10.1097/pgp.0000000000000576. Epub 2019/01/25. PubMed PMID: 30676432.
Martínez-Doménech A, García-Legaz Martínez M, Magdaleno-Tapial J, Pérez-Pastor G, Rodríguez-López R, Pérez-Ferriols A. Novel PTEN mutation in Cowden syndrome: case report with late diagnosis and non-malignant course. Dermatol Online J. 2019;25(5). Epub 2019/06/22. PubMed PMID: 31220904.
Olofson A, Marotti J, Tafe LJ, Linos K. Intranodal meningothelial proliferation in a patient with Cowden syndrome: a case report. Hum Pathol. 2017;66:183–7. https://doi.org/10.1016/j.humpath.2017.03.002. Epub 2019/06/22. PubMed PMID: 28315423.
Matsumoto K, Nosaka K, Shiomi T, Matsuoka Y, Umekita Y. Tumor-to-tumor metastases in Cowden’s disease: an autopsy case report and review of the literature. Diagn Pathol. 2015;10:172. https://doi.org/10.1186/s13000-015-0408-8. Epub 2015/09/18. PubMed PMID: 26376867; PubMed Central PMCID: PMCPMC4574149.
Neychev V, Sadowski SM, Zhu J, Allgaeuer M, Kilian K, Meltzer P, et al. Neuroendocrine tumor of the pancreas as a manifestation of Cowden syndrome: a case report. J Clin Endocrinol Metab. 2016;101(2):353–8. https://doi.org/10.1210/jc.2015-3684. Epub 2015/12/19. PubMed PMID: 26678657; PubMed Central PMCID: PMCPMC5393589.
Khandpur U, Huntoon K, Smith-Cohn M, Shaw A, Elder JB. Bilateral recurrent dysplastic cerebellar gangliocytoma (Lhermitte-duclos disease) in cowden syndrome: a case report and literature review. World Neurosurg. 2019;127:319–25. https://doi.org/10.1016/j.wneu.2019.03.131. Epub 2019/03/25. PubMed PMID: 30905649.
Hedayat AA, Pettus JR, Marotti JD, Tafe LJ, Holubar SD, Lisovsky M. Proliferative lesion of anogenital mammary-like glands in the setting of Cowden syndrome: case report and review of the literature. J Cutan Pathol. 2016;43(8):707–10. https://doi.org/10.1111/cup.12721. Epub 2016/04/20. PubMed PMID: 27090873.
Fernandez M, Savard C, Farrell M, Christopher J, Shi W. Successful stereotactic radiotherapy of meningiomas in a patient with Cowden syndrome: a case report. 2020.
Conti S, Condò M, Posar A, Mari F, Resta N, Renieri 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(3):392–7. https://doi.org/10.1177/0883073811420296. Epub 2011/10/01. PubMed PMID: 21960672.
Barreras P, Gailloud P, Pardo CA. A longitudinally extensive myelopathy associated with multiple spinal arteriovenous fistulas in a patient with Cowden syndrome: a case report. Spine J. 2018;18(1):e1–5. https://doi.org/10.1016/j.spinee.2016.01.005. Epub 2016/01/23. PubMed PMID: 26795104.
Jang HN, Kim SH, Cho YM, Park DJ. Bariatric surgery for Cowden syndrome with PTEN mutation: a case report. Obes Surg. 2021;31(5):2316–8. https://doi.org/10.1007/s11695-021-05231-1. Epub 2021/01/23. PubMed PMID: 33481191.
Celentano A, Adamo D, Leuci S, Mignogna MD. Oral manifestations of phosphatase and tensin homolog hamartoma tumor syndrome: a report of three cases. J Am Dent Assoc. 2014;145(9):950–4.
Mukamal LV, Ferreira AF, de Moura astro Jacques C, Amorim CA, Pineiro‐Maceira J, Ramos‐e‐Silva M. Cowden syndrome: review and report of a case of late diagnosis. Int J Dermatol. 2012;51(12):1494.
Adachi T, Takigawa H, Nomura T, Watanabe Y, Kowa H. Cowden syndrome with a novel PTEN mutation presenting with partial epilepsy related to focal cortical dysplasia. Intern Med. 2018;57(1):97–9.
Gama I, Almeida L. Lhermitte-Duclos disease associated to Cowden syndrome: de novo diagnosis and management of these extremely rare syndromes in a patient. Case Rep. 2017;2017:bcr2016217974.
Lopez C, Abuel-Haija M, Pena L, Coppola D. Novel Germline PTEN mutation associated with Cowden syndrome and osteosarcoma. Cancer Genomics Proteomics. 2018;15(2):115–20.
Lopes S, Vide J, Moreira E, Azevedo F. Cowden syndrome: clinical case and a brief review. Dermatol Online J. 2017;23(8).
Harada A, Umeno J, Esaki M. Gastrointestinal: Multiple venous malformations and polyps of the small intestine in Cowden syndrome. J Gastroenterol Hepatol (Australia). 2018;33(11):1819.
Joo G, Doumanian J. Radiographic findings of dysplastic cerebellar gangliocytoma (Lhermitte-Duclos Disease) in a woman with Cowden syndrome: a case study and literature review. J Radiol Case Rep. 2020;14(3):1.
Hagelstrom RT, Ford J, Reiser GM, Nelson M, Pickering DL, Althof PA, et al. Breast cancer and Non-Hodgkin lymphoma in a young male with Cowden syndrome. Pediatr Blood Cancer. 2016;63(3):544–6.
Goh CP, Wu B, Feng TT, Chou N. Cowden syndrome and Lhermitte-Duclos disease—a case report and review of the literature. SN Compr Clin Med. 2021;3:2373–7.
Ha M, Chung JW, Hahm KB, Kim YJ, Lee W, An J, et al. A case of Cowden syndrome diagnosed from multiple gastric polyposis. World J Gastroenterol. 2012;18(8):861–4. https://doi.org/10.3748/wjg.v18.i8.861. Epub 2012/03/01. PubMed PMID: 22371648; PubMed Central PMCID: PMCPMC3286151.
Innella G, Miccoli S, Colussi D, Pradella LM, Amato LB, Zuntini R, et al. Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: report of two cases and literature review. Pathol Res Pract. 2021;218:153339. https://doi.org/10.1016/j.prp.2020.153339. Epub 2021/01/23. PubMed PMID: 33482532.
Tsubosa Y, Fukutomi T, Tsuda H, Kanai Y, Akashi-Tanaka S, Nanasawa T, et al. Breast cancer in Cowden’s disease: a case report with review of the literature. Jpn J Clin Oncol. 1998;28(1):42–6. https://doi.org/10.1093/jjco/28.1.42. Epub 1998/03/10. PubMed PMID: 9491141.
Weary PE, Gorlin RJ, Gentry WC Jr, Comer JE, Greer KE. Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol. 1972;106(5):682–90 Epub 1972/11/01 PubMed PMID: 4635800.
Reddy KVK, Anusha A, Maloth KN, Sunitha K, Thakur M. Mucocutaneous manifestations of Cowden’s syndrome. Indian Dermatol Online J. 2016;7(6):512.
Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with Cowden syndrome: a meta-analysis. Head Neck. 2013;35(8):1189–94. https://doi.org/10.1002/hed.22971. Epub 2012/03/21. PubMed PMID: 22431287.
Leão JC, Batista V, Guimarães PB, Belo J, Porter SR. Cowden’s syndrome affecting the mouth, gastrointestinal, and central nervous system: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;99(5):569–72. https://doi.org/10.1016/j.tripleo.2004.08.032. Epub 2005/04/15. PubMed PMID: 15829879.
Tan M-H, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400–7.
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(2):219–25. https://doi.org/10.1111/cge.13875. Epub 2020/11/04. PubMed PMID: 33140411; PubMed Central PMCID: PMCPMC7839546.
Heaney RM, Farrell M, Stokes M, Gorey T, Murray D. Cowden syndrome: serendipitous diagnosis in patients with significant breast disease. Case series and literature review. Breast J. 2017;23(1):90–4. https://doi.org/10.1111/tbj.12691. Epub 2016/11/26. PubMed PMID: 27886412.
Starink TM, van der Veen JP, Arwert F, de Waal LP, de Lange GG, Gille JJ, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986;29(3):222–33. https://doi.org/10.1111/j.1399-0004.1986.tb00816.x. Epub 1986/03/01. PubMed PMID: 3698331.
Sloot YJE, Rabold K, Netea MG, Smit JWA, Hoogerbrugge N, Netea-Maier RT. Effect of PTEN inactivating germline mutations on innate immune cell function and thyroid cancer-induced macrophages in patients with PTEN hamartoma tumor syndrome. Oncogene. 2019;38(19):3743–55. https://doi.org/10.1038/s41388-019-0685-x. Epub 2019/01/24. PubMed PMID: 30670777.
Eissing M, Ripken L, Schreibelt G, Westdorp H, Ligtenberg M, Netea-Maier R, et al. PTEN hamartoma tumor syndrome and immune dysregulation. Transl Oncol. 2019;12(2):361–7. https://doi.org/10.1016/j.tranon.2018.11.003. Epub 2018/12/07. PubMed PMID: 30504085; PubMed Central PMCID: PMCPMC6277246.
Hendricks LAJ, Hoogerbrugge N, Venselaar H, Aretz S, Spier I, Legius E, et al. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort. Eur J Med Genet. 2022;65(12):104632. https://doi.org/10.1016/j.ejmg.2022.104632. Epub 2022/10/22. PubMed PMID: 36270489.
Nieuwenhuis MH, Kets CM, Murphy-Ryan M, Yntema HG, Evans DG, Colas C, et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer. 2014;13(1):57–63. https://doi.org/10.1007/s10689-013-9674-3. Epub 2013/08/13. PubMed PMID: 23934601.
Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns. 2009;18(1):13–27.
Tan M-H, Mester J, Peterson C, Yang Y, Chen J-L, Rybicki LA, 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(1):42–56.
Nieuwenhuis MH, Kets CM, Murphy-Ryan M, Colas C, Möller P, Hes FJ, et al. Is colorectal surveillance indicated in patients with PTEN mutations? Colorectal Dis. 2012;14(9):e562–6. https://doi.org/10.1111/j.1463-1318.2012.03121.x. Epub 2012/06/08. PubMed PMID: 22672595.
D’Ermo G, Genuardi M. Gastrointestinal manifestations in PTEN hamartoma tumor syndrome. Best Pract Res Clin Gastroenterol. 2022;58–59:101792. https://doi.org/10.1016/j.bpg.2022.101792.
Esmaeilzadeh A, Goshayeshi L, Bergquist R, Jarahi L, Khooei A, Fazeli A, et al. Characteristics of gastric precancerous conditions and Helicobacter pylori infection among dyspeptic patients in north-eastern Iran: is endoscopic biopsy and histopathological assessment necessary? BMC Cancer. 2021;21(1):1143. https://doi.org/10.1186/s12885-021-08626-6. Epub 2021/10/28. PubMed PMID: 34702194; PubMed Central PMCID: PMCPMC8546943.
Zhao M, Lin X, Fang Y, Zhuang A, Tong H, Lu W, et al. Case report: duodenal carcinoma in a 40-year-old Asian man with Cowden syndrome. Front Surg. 2022;9:935048. https://doi.org/10.3389/fsurg.2022.935048. Epub 2022/07/30. PubMed PMID: 35903259; PubMed Central PMCID: PMCPMC9320325.
Stanich PP, Pilarski R, Rock J, Frankel WL, El-Dika S, Meyer MM. Colonic manifestations of PTEN hamartoma tumor syndrome: case series and systematic review. World J Gastroenterol. 2014;20(7):1833–8. https://doi.org/10.3748/wjg.v20.i7.1833. Epub 2014/03/04. PubMed PMID: 24587660; PubMed Central PMCID: PMCPMC3930981.
Stanich PP, Owens VL, Sweetser S, Khambatta S, Smyrk TC, Richardson RL, et al. Colonic polyposis and neoplasia in Cowden syndrome. Mayo Clin Proc. 2011;86(6):489–92. Epub 2011/06/02. https://doi.org/10.4065/mcp.2010.0816. PubMed PMID: 21628613; PubMed Central PMCID: PMCPMC3104908.
Chilovi F, Zancanella L, Perino F, Wallnoefer W, Vigl EE, Colombetti V, et al. Cowden’s disease with gastrointestinal polyposis. Gastrointest Endosc. 1990;36(3):323–4. https://doi.org/10.1016/s0016-5107(90)71048-6. Epub 1990/05/01. PubMed PMID: 2365229.
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(5):686–96. https://doi.org/10.1016/s0190-9622(83)70081-2. Epub 1983/05/01. PubMed PMID: 6863628.
Gorensek M, Matko I, Skralovnik A, Rode M, Satler J, Jutersek A. Disseminated hereditary gastrointestinal polyposis with orocutaneous hamartomatosis (Cowden’s disease). Endoscopy. 1984;16(2):59–63. https://doi.org/10.1055/s-2007-1018534. Epub 1984/03/01. PubMed PMID: 6714176.
Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden’s disease. Surgery. 1995;118(1):115–7. https://doi.org/10.1016/s0039-6060(05)80018-2. Epub 1995/07/01. PubMed PMID: 7604372.
Taylor AJ, Dodds WJ, Stewart ET. Alimentary tract lesions in Cowden’s disease. Br J Radiol. 1989;62(742):890–2. https://doi.org/10.1259/0007-1285-62-742-890. Epub 1995/07/01. PubMed PMID: 2684322.
Jiang T, Wang J, Du J, Luo S, Liu R, Xie J, et al. Lhermitte-Duclos Disease (Dysplastic Gangliocytoma of the Cerebellum) and Cowden syndrome: clinical experience from a single institution with long-term follow-up. World Neurosurg. 2017;104:398–406. https://doi.org/10.1016/j.wneu.2017.04.147. Epub 2017/05/10. PubMed PMID: 28479525.
Morrison A, Polisena J, Husereau D, Moulton K, Clark M, Fiander M, et al. The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies. Int J Technol Assess Health Care. 2012;28(2):138–44. https://doi.org/10.1017/s0266462312000086. Epub 2012/05/09. PubMed PMID: 22559755.
Bakhshayesh S, Hoseini B, Bergquist R, Nabovati E, Gholoobi A, Mohammad-Ebrahimi S, et al. Cost-utility analysis of home-based cardiac rehabilitation as compared to usual post-discharge care: systematic review and meta-analysis of randomized controlled trials. Expert Rev Cardiovasc Ther. 2020:1–16. https://doi.org/10.1080/14779072.2020.1819239. Epub 2020/09/08. PubMed PMID: 32893713.
We would like to thank the patient presented in this study for her permission to publish this case report.
This study was supported by National Institute for Medical Research Development (NIMAD) (grant number of 978991) and Mashhad University of Medical Sciences (grant number of 978991).
Ethics approval and consent to participate
The study was approved by Ethics committee of Mashhad University of Medical Sciences (ethics code: IR.MUMS.REC.1396.164) that means this case only could report in this study and has not been reported by anyone else, and any new reporting on this case need to get new approval of this Committee. For experiments involving human participants (including the use of tissue samples), the patient signed an informed consent before the study.
Consent for publication
The written informed consent was obtained from patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Rahmatinejad, Z., Goshayeshi, L., Bergquist, R. et al. PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review. Diagn Pathol 18, 43 (2023). https://doi.org/10.1186/s13000-023-01331-x
- Cowden syndrome
- PTEN hamartoma
- Early diagnosis
- Colorectal polyposis
- Case reports
- Case series