PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review.

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. Fig. 1 Family tree of the patient, with squares representing men and circles women. Arrow indicates the patient Family tree of the patient, with squares representing men and circles women. Arrow indicates the patient 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) [ 25 ] 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. 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 ) [ 26 ] 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) [ 27 ]. Sorting intolerant from tolerant (SIFT) [ 27 ], 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 [ 28 ] and combined annotation-dependent depletion (CADD) with Phred score ≥ 20 [ 29 ] were used for prediction of missense variants. The raw data used in the genetic evaluation of this case are provided as a supplementary file [ 30 ]. 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) [ 31 ] score of 0.997 (Table 1 ). The PTEN gene is associated with autosomal dominant PHTS [ 32 ], 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 ]. Table 1 Details on the methods and results of whole exome sequencing in the study ID Germline candidate gene HGVS.c HGVS.p Coding Impact gnomAD SIFT PolyPhen2 DANN CADD ClinVar database ACMG classification P9 PTEN c.C697T p.R233X rs121909219 Non- sense - - - 0.997 37 Pathogenic Pathogenic The table follows the nomenclature recommended by the Human Genome Variation Society (HKVC) where HGVS.c refers to the coding variant and HGVS.p to the protein level variant gnomAD genome aggregation database (provision of allele frequency), SIFT Sorting intolerant from tolerant, PolyPhen2 Polymorphism Phenotyping, version 2, CADD Combined annotation dependent depletion (provision of Phred score, version 1.6), DANN Deep neural network (provision of a functional prediction score), ClinVar Archive of interpretations of clinically relevant variants, ACMG American College of medical Genetics and genomics Details on the methods and results of whole exome sequencing in the study p.R233X rs121909219 The table follows the nomenclature recommended by the Human Genome Variation Society (HKVC) where HGVS.c refers to the coding variant and HGVS.p to the protein level variant gnomAD genome aggregation database (provision of allele frequency), SIFT Sorting intolerant from tolerant, PolyPhen2 Polymorphism Phenotyping, version 2, CADD Combined annotation dependent depletion (provision of Phred score, version 1.6), DANN Deep neural network (provision of a functional prediction score), ClinVar Archive of interpretations of clinically relevant variants, ACMG American College of medical Genetics and genomics 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 [ 34 ]. 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 [ 35 ]. Table 2 Diagnostic criteria proposed by the International Cowden Syndrome Consortium [ 9 , 10 ] Pathognomonic lesions highly specific for the Cowden syndrome (CS) include: • Six or more facial papules (with at least 3 trichilemmomas) • Facial cutaneous papules with papillomatosis of the oral mucosa • Papillomatosis of the oral mucosa with acral keratosis • Six or more palmoplantar patches of keratosis Diagnosis of CS requires at least one of these pathognomonic lesions Major criteria less specific for CS but are associated with a higher risk of cancer include: • Breast carcinoma • Thyroid carcinoma • Macrocephaly (greater than 97%) • Lhermitte-Duclos disease (LDD) • Endometrial carcinoma Diagnosis of CS requires at least two major criteria, with one of them being macrocephaly or LDD Minor criteria even less specific for CS but still commonly seen in affected individuals include: • Thyroid lesions (other than carcinoma) • Learning difficulties or delayed development • Gastrointestinal hamartomas • Lipomas • Fibromas • Fibrocystic disease of the breast • Genitourinary malformations or carcinoma Diagnosis of CS requires at least four minor criteria Additionally , one major criterion and three minor criteria may also indicate a diagnosis of CS Diagnostic criteria proposed by the International Cowden Syndrome Consortium [ 9 , 10 ] Pathognomonic lesions highly specific for the Cowden syndrome (CS) include: • Six or more facial papules (with at least 3 trichilemmomas) • Facial cutaneous papules with papillomatosis of the oral mucosa • Papillomatosis of the oral mucosa with acral keratosis • Six or more palmoplantar patches of keratosis Diagnosis of CS requires at least one of these pathognomonic lesions Major criteria less specific for CS but are associated with a higher risk of cancer include: • Breast carcinoma • Thyroid carcinoma • Macrocephaly (greater than 97%) • Lhermitte-Duclos disease (LDD) • Endometrial carcinoma Diagnosis of CS requires at least two major criteria, with one of them being macrocephaly or LDD Minor criteria even less specific for CS but still commonly seen in affected individuals include: • Thyroid lesions (other than carcinoma) • Learning difficulties or delayed development • Gastrointestinal hamartomas • Lipomas • Fibromas • Fibrocystic disease of the breast • Genitourinary malformations or carcinoma Diagnosis of CS requires at least four minor criteria Additionally , one major criterion and three minor criteria may also indicate a diagnosis of CS 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. 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 [ 36 ] 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 [ 37 ] 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. Fig. 2 Haematoxylin and eosin staining of breast tissue from the patient (magnification: 100 x); the slides show invasive neoplastic proliferation of atypical epithelial cells with cribriform pattern and desmoplastic stroma consistent with the characteristic features of breast cancer in patients with the PTEN hamartoma tumour syndrome Haematoxylin and eosin staining of breast tissue from the patient (magnification: 100 x); the slides show invasive neoplastic proliferation of atypical epithelial cells with cribriform pattern and desmoplastic stroma consistent with the characteristic features of breast cancer in patients with the PTEN hamartoma tumour syndrome 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. Table 3 Results of the literature review Country (Year) [Ref] Age Sex Chief complaints a Major criteria b Minor criteria c History and other clinical manifestations d Diagnostic measures e USA (2012) [ 38 ] 42 M Rectal bleeding Mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Colon cancer Lipomas Family history: Negative Colonoscopy, genetic test, histology Surgical history: Colectomy Medical observations: Colonic ganglioneuromatous polyps, mucocutaneous features Laboratory results & detailed information f : Colonoscopy & microscopic examination: ganglioneuromatous polyposis , specimen contained an adenomatous polyp in addition to multiple, finger-like polyps and mesenteric lipomas; Genetic test: pathologic non-sense mutation at the PTEN locus Spain (2016) [ 2 ] 57 F Dysphagia & recurrent endometrial carcinoma Breast carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Thyroid lesions Family history: NA Brain and chest CT, MRI of spine, genetic test Surgical history: Thyroidectomy, hysterectomy Medical observations: Uterine leiomyomas, rectal bleeding secondary, anal polyp, sphenoid wing meningioma, meningiomas, thin-walled lung cyst, thoracolumbar scoliosis Laboratory results & detailed information CT: left sphenoid wing meningioma with extra-conal extension and resultant left optic nerve impingement and proptosis; right breast lesions MRI: thoracolumbar scoliosis with spondylosis and multilevel disc disease; Genetic test: pathogenic variants in the PTEN gene: (c.697C > T) (pArg233*) Tunisia (2012) [ 6 ] 30 F Altered bowel habits Macrocephaly, thyroid carcinoma, mucocutaneous lesions, acral keratosis FDB, thyroid lesion, gastrointestinal hamartomas Family history: Negative Endoscopy, colonoscopy, breast US Surgical observations: Surgical excision of breast nodules & thyroidectomy Medical observations: Congenital mental retardation. breast nodules, multiple gastrointestinal polyps, high-arched palate, adenoid facies, kyphoscoliosis and pectus excavatum, iron deficiency anemia Laboratory result & detailed information Breast US: bilateral nodules compatible with fibrocystic disease; Endoscopy: esophageal, duodenal, and gastric sessile polyps; Colonoscopy : multiple lesions in the sigmoid and rectum USA (2013) [ 14 ] 14 F Menorrhagia refractory to intravenous estrogen Endometrial carcinoma, Macrocephaly, mucocutaneous lesions, oral papules, trichilemmoma Lipomas, fibroma Family history : Hashimoto’s thyroiditis in two sisters, thyroid cancer in her father, goiter & fibrocystic breast disease in her mother Endometrial curettage & pathological examination, PET/MRI of ovaries, colonoscopy, genetic test Surgical history: Hysterectomy and laparoscopic excision of ovary at age 19 years Medical observations: Macrocephaly, endometriosis adenocarcinoma, colon polyps, gum fibroids, benign squamous cyst of right ovary Laboratory result & detailed information Endometrial curettage & Pathological examination: focal grade 1 endometriosis adenocarcinoma; PET/MRI: concerning for significant myometrium invasion, showed no involvement of the ovaries at age 14; Colonoscopy: multiple polyposis lesions in transverse and sigmoid colon; Genetic test: Arg335X (1003C > T) mutation in the PTEN gene Brazil (2015) [ 13 ] 36 F Gingival growth Macrocephaly, thyroid carcinoma, mucocutaneous lesions, oral papules NA Family history : NA Histopathologic evaluation Surgical history: Thyroidectomy, removing papules from hand & stomach Medical observations: Thyroid carcinoma, macrocephaly, Hashimoto thyroiditis & gastritis, arthrosis & fibromyalgia, depression, breast nodules, Heck’s disease, ductal ectasia Laboratory result & detailed information histopathologic evaluation: epithelial hyperplasia as a histological finding of biopsy from the gingival nodule Croatia (2019) [ 18 ] 39 F White spot on gingiva, face, & hand Thyroid carcinoma (follicular), mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma FDB, Lipoma, Fibroma, Vascular anomalies Family history : Endometrial polyp in mother & thyroid cancer in sister Gynecological US, cardiological examination Surgical history: Surgery of thyroid, cavernous ovary lymphangioma and leiomyomas of uterus Medical observations: Fibrocystic changes breast papillomatosis, liver hemangioma, lipoma, multiple fibromas, genitourinary tumours, endometrium polyp, myomas, thyroid abnormalities, pericardial effusion Laboratory result & detailed information Gynecological US: polyp in the endometrium and multiple myomas of the myometrium; Cardiological examination: pericardial effusion USA (2017) [ 39 ] 63 M Lesions on calf,abdomen, clavicle & elbow Thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Thyroid lesion Family history: Unremarkable CT-scan of neck, IHC Surgical history: Thyroidectomy, cholecystectomy Medical observations: Thyroid cancer, hypertension, obstructive sleep apnea, nodular lesions in right parotid gland, SLA, CCA Laboratory result & detailed information CT: Nodular lesions in the right parotid gland; IHC: Sebaceous lymph adenoma, Clear Cell Acanthoma, Czech (2011) [ 40 ] 55 F Epileptic paroxysms Macrocephaly, thyroid carcinoma, mucocutaneous lesions Intellectual disability, Thyroid lesion, GI hamartomas Family history: colon cancer in mother Endoscopy, brain CT, IHC, genetic test Surgical history: thyroidectomy, hysterectomy, adnexectomy and abdominoperineal surgery Medical observations: Gastric cancer, Myomatosis, Adenopapilocarcinoma of ovary, epileptic paroxysm, decline in cognitive functions & memory, polyps in stomach, duodenum & colon Laboratory result & detailed information Endoscopy : hundreds of polyps in the stomach, duodenum and colon; CT : frontal lesion; IHC : invasive follicular carcinoma benign meningioma; Genetic test : heterozygous deletion mutation at (c.438delT), exon 5 Japan (2020) [ 41 ] 47 F Tumour in her right breast Breast carcinoma, thyroid carcinoma, LDD Thyroid lesions Family history: Breast cancer in her mother and sister Breast US, pathological examination, chest CT, chest & brain MRI Surgical history: Mastectomy, thyroidectomy Medical observations: Thyroid carcinoma, breast carcinoma, LDD Laboratory result & detailed information Breast US: irregular marginated hypoechoic mass measuring 15.1 × 15 × 9.4 mm in the 12 o’clock region of the right breast; Pathological examination: ductal carcinoma in situ (DCIS) in the right mammary gland and invasive ductal carcinoma in the left mammary gland; Chest MRI: Primary tumour of the right mammary gland to be a mass 15 mm and early phase linear enhancement for the left side =  > stage 0 (cTisN0M0) right breast cancer and stage IIA (cT2N0M0) for the left side; Brain MRI: alternative isointense and hyper intense bands in the left cerebellar hemisphere; Chest CT : no lymph node metastases or distant metastases Portugal (2020) [ 42 ] 28 F NA Macrocephaly, thyroid carcinoma, breast carcinoma, Mucocutaneous lesions: acral keratosis Intellectual disability Family history: thyroid carcinoma in her mother and aunt Breast CT & IHC, thyroid & breast US, genetic test Surgical history: mastectomy, thyroidectomy Medical observations: Hydrocephaly, severe microcytic & hypochromic anemia, macrocephaly, thyroid & breast cancer Laboratory result & detailed information Breast CT and IHC: breast lump, high metastatic breast sarcoma; Thyroid US: 5.6-cm hypoechogenic nodule and anecogenic areas fine-needle biopsy and was diagnosed with follicular lesion of undetermined significance (FLUS) (Bethesda category III); Genetic test: a change in heterozygote, pathogenic variant c.405dupA (p. (Cys136Metfs * 44) in the PTEN gene India (2015) [ 43 ] 41 F Lesion on neck, axillae, forehead Macrocephaly, mucocutaneous lesions, oral papules, acral keratosis Thyroid lesions Family history: NA Ultrasound abdomen & pelvis, chest X-ray & ECG, brain MRI, GI endoscopy, colonoscopy, mammography Surgical history: Thyroidectomy Medical observations: Syndactyly and polydactyly, cobblestone tongue with coalesced papules Laboratory result & detailed information Imaging studies (ultrasound abdomen and pelvis, chest x-ray, ECG, MRI brain and echocardiography) and upper GI endoscopy, colonoscopy and mammography were normal USA (2017) [ 44 ] 64 F Painful gum & red painful palate Breast carcinoma, mucocutaneous lesions, oral papules, acral keratosis NA Family history: NA Extra & intra oral examination, IHC Surgical history: NA Medical observations: Malignancy of GI tract, anemia, asthma, breast cancer Laboratory result & detailed information Intraoral examination: papules, pebbles on the case of the tongue and maxillary; IHC: Superficial keratinized squamous epithelium overlying a mass of dense fibrous connective tissue composed of interlacing bundles of collagen fibers interspersed by fibroblasts and blood vessels Japan (2014) [ 45 ] 37 M Eyeball movement and gait disturbance Mucocutaneous lesions, oral papules, acral keratosis Intellectual disability, Vascular anomalies Family history: CS in his mother with breast, thyroid & uterus cancers Brain CT & MRI, DSA, IHC, genetic test Surgical history: Intracranial surgery Medical observations: H emiparesis, left facial & right abducens nerve palsy, right Horner syndrome Laboratory result & detailed information Brain CT & MRI: hematoma diameter 27 mm & circular area of heterogeneous intensity in the pons; DSA: no abnormal vessels & no tumour staining; IHC: dura mater contained abnormal vessels & ectatic cortical veins presented in the arachnoid space; Genetic test: PTEN mutation Italy (2018) [ 46 ] 43 M Lesion localized on the gingiva Breast carcinoma, thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma NA Family history: Mother & sister suffered from CS and died from breast cancer IHC, panoramic radiography Surgical history: Mastectomy , thyroidectomy Medical observations: Breast & Thyroid carcinoma, periodontal disease Laboratory result & detailed information IHC: hyper plastic epidermoid covering and parakeratosis on the surface; Since the diagnosis of the disease had already been made, there was no information about the diagnostic methods Japan (2020) [ 47 ] 31 F Abnormal genital bleeding Breast carcinoma, Macrocephaly, Endometriosis carcinoma NA Family history: CS in mother Pelvic US, abdominopelvic CT, IHC, genetic test Surgical history: D&C, hysterectomy, salpingo-oophorectomy Medical observations: Obesity, mass in the left ovary, APAM of endometrium and ovarian metastasis Laboratory result & Detailed information: Pelvic US: thickening of the endometrium and a cystic mass in the left ovary; Abdominopelvic CT: endometrial thickening and a 5-cm cystic mass in the left adnexal region; IHC: grade 1 endometriosis carcinoma component presenting cribriform glands; Genetic test: Pathogenic variants of PTEN (c.C1003T, p.R335X) in both the patient and her mother Spain (2019) [ 48 ] 52 F Multiple warts of hands & feet Endometrial carcinoma, Mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Thyroid lesions, Fibroma Family history: Negative GI endoscopy, genetic test Surgical history: hysterectomy, thyroidectomy Medical observations: Bilateral cholesteatoma, trigeminal schwannoma, uterine fibroids, finger fibroma, tracheal fibrotic nodules, trichilemmoma, oral fibroma Laboratory result & Detailed information: GI endoscopy: glycogenic acanthosis and ten colorectal inflammatory and hyperplastic polyps; Genetic test: a heterozygous mutation = a four-nucleotide deletion (c.510_513del) resulting in a premature stop codon (p.Ser170Argfs*12) Lebanon (2017) [ 49 ] 55 F Left axillary sentinel node Breast carcinoma, Macrocephaly, Endometrial, carcinoma Lipomas, Fibroma Family history: Breast cancer in one of siblings Axilla &Brain MRI, IHC, genetic test Surgical history: Partial mastectomy Medical observations: Papillary sclerosing lesion, DCIS, gangliocytoma, neurofibroma meningioma, extracranial meningothelial proliferation Laboratory result & Detailed information: Axilla MRI: not demonstrate any suspicious lymph nodes; IHC : high grade ductal carcinoma in situ; Brian MRI: no lesions suggestive of meningioma; Genetic test: PTEN c.209 + 5G > A alteration confirming the clinical impression of CS Japan (2019) [ 15 ] 39 F Lower abdominal pain & melena Macrocephaly, Endometriosis carcinoma Thyroid lesions, Lipoma, Fibroma, GI hamartomas Family history: Breast cancer in mother and cutaneous papilloma in father Colonoscopy, IHC, GI endoscopy, MRI of pelvic, CT, FDG-PET Surgical history: Pelvic & para-aortic lymphadenectomy, hysterectomy, salpingo-oophorectomy, omentectomy Medical observations: Macrocephaly , breast fibroma, ovarian tumour, endometriosis cancer, colorectal polyposis lesions Laboratory result & Detailed information: Colonoscopy: colorectal polyposis lesions; IHC: hamartoma polyps and ectopic endometrial implants; GI endoscopy: multiple esophageal papillomas and glycogenic acanthosis; MRI: gluteal subcutaneous lipoma CT: heterogeneously enhanced mass, 9 cm; FDG-PET: abnormal uptake by the ovarian tumour (SUVmax: 8.33) Japan (2015) [ 50 ] 75 M Hoarseness & dysphagia Mucocutaneous lesions, oral papules Thyroid lesions, Vascular anomalies Family history: NA MRI, histology & IHC, GI endoscopic, genetic test Surgical history: NA Medical observations: Lung adenocarcinoma, cerebellar tumour, GI polyposis, pneumonia Laboratory result & Detailed information: MRI: cerebellar dysplastic gangliocytoma; IHC : lung adenocarcinoma (T4N2M1b, Stage IV); GI endoscopic: Gastrointestinal polyposis; Genetic test: PTEN gene mutation, a point mutation ( TGT to CGT ) at exon 5 in codon 136 was detected in his serum USA (2016) [ 51 ] 51 M Jaundice & abdominal pain Macrocephaly, thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Lipomas, Thyroid lesions Family history: Macrocephaly Chest, abdomen & pelvis CT& PET-CT, pathological evaluation, IHC, Endoscopic sonography, genetic test Surgical history: Thyroidectomy Medical observations: Macrocephaly, thyroid carcinoma, mucocutaneous, multiple intestinal polyps Laboratory result & Detailed information: CT: large (9 × 8 × 4 cm) ill-defined mass of the head and neck of the pancreas, invading the celiac axis; encasing the celiac artery, superior mesenteric, and splenic arteries and veins; and compressing the portal vein confluence; PET-CT: large central lesion in the abdomen; IHC& pathological evaluation: cytoplasmic staining of tumour cells, grade 1 NET with a Ki-67 < 2% and involved margins; Endoscopic sonography: stage uT4N1Mx determined Genetic test: nonsense mutation c.697C3T (p.R233*) causing a premature stop codon in exon 7 Japan (2018) [ 16 ] 46 M Fresh blood in his stool & shortness of breath Mucocutaneous lesions, oral papules, acral keratoses GI hamartomas, Thyroid lesions, Fibroma, Vascular anomalies Family history: Breast cancer in his mother Neck US, GI endoscopy, pathophysiological examination, CT angiography Surgical history: Gastrectomy Medical observations: Duodenal ulcer, anemia, adenomatous goiter, vascular anomalies Laboratory result & Detailed information: US: adenomatous goiter in the thyroid gland; GI endoscopy: numerous polyposis lesions; CT angiography: vascular malformation in the wall of the sigmoid colon; Pathological examination: vascular malformations expanded from the submucosal layer to the mesocolon USA (2019) [ 52 ] 50 M Vomiting, vertigo and balance difficulties LDD, Macrocephaly Thyroid lesions Family history: CS Brain MRI, IHC Surgical history: Thyroidectomy, right cerebellar LDD resection, Parathyroidectomy Medical observations: multinodular goiter; gangliocytoma, abducens cranial nerve palsy; altered mental status, Parathyroid adenoma Laboratory result & Detailed information: MRI: cerebellar tumour and progression of the left cerebellar gangliocytoma IHC: expansion of the cerebellar folia, with near complete replacement of the small neurons of the internal granular layers by larger, ganglionic neurons USA (2016) [ 53 ] 26 F Painful perianal lesion Macrocephaly, Mucocutaneous lesions, trichilemmoma Thyroid lesion, Lipoma, Colon cancer Family history: NA Histopathologic examination, IHC, breast US Surgical history: hemicolectomy, Subtotal colectomy, Breast lumpectomy Medical observations: Ganglioneuromas, focal intramucosal adenocarcinoma of the colon, proliferative glandular lesion, breast lesions Laboratory result & Detailed information: Histopathological examination: a circumscribed, lobulated, proliferative glandular lesion with areas of expanded fibromyxoid stroma and epithelial hyperplasia with apocrine and columnar cell changes, arranged in a papillary, micropapillary and cribriform architecture; IHC: loss of PTEN expression in the epithelial component of the lesion. USA (2020) [ 54 ] 35 F Forgetfulness and fatigue LDD NA Family history: NA Cerebral MRI, IHC Surgical history: Craniotomy for resection of meningioma, stereotactic radiosurgery Medical observations: Meningiomas, dysplastic gangliocytoma Laboratory result & Detailed information: MRI: lesion in the cerebellum suggesting dysplastic gangliocytoma; IHC: EMA and vimentin, consistent with World Health Organization (WHO) grade I meningioma margin. The patient had already been diagnosed with the CS Italy (2012) [ 55 ] 14 M Epileptic seizures Macrocephaly, Mucocutaneous lesions, oral papules, acral keratosis Autism, Intellectual disability Family history: Macrocephaly, dysthyroidism, GI cancers, autism, and behavioral and psychiatric disorders Cerebral MRI, ECG, IHC, genetic test, laboratory test Surgical history: Nephrectomy Medical observations: Autism, macrocephaly Laboratory result & Detailed information MRI: right periventricular hyperintensity probably due to a remote hypoxic-ischemic insult; ECG: focal spike-wave complexes over the left temporal regions. IHC: focal prominent epidermal hyperplasia that at its periphery is demarcated by elongated rete ridges; Genetic test: an exon 2 deletion was detected; Laboratory test: moderate increase of thyrotrophin-stimulating hormone and free triiodothyronine and uncertain values for anti-endomysial antibodies with positivity for human leukocyte antigen (HLA) haplotypes (HLADQ2 and HLA-DQ8) associated with celiac disease USA (2018) [ 56 ] 57 F Progressive weakness &urinary incontinence Breast carcinoma, Macrocephaly RCC, Lipomas, Vascular anomalies Family history: Positive of cancers MRI, spinal angiography, genetic test Surgical history: Nephrectomy Medical observations: DCIS, multiple malignancies, squamous cell carcinoma of scalp, diabetes, multiple benign colon polyps, longitudinally extensive myelopathy, epidural lesions with bony erosion, thoracolumbar spinal cord lesion Laboratory result & Detailed information MRI: longitudinally extensive myelopathy; Spinal angiography: 2 SEAVFs; Genetic test: A deleterious mutation (209 + 4_209 + 7delAGTA) was found in intron 3 of the PTEN Korea (2021) [ 57 ] 23 F NA Endometrial carcinoma, Mucocutaneous lesions Thyroid lesion, Vascular anomalies Family history: NA Colonoscopy, endoscopy, genetic test Surgical history: Bariatric salpingectomy, Surgery for congenital vascular malformation of the leg, surgery for atypical ductal hyperplasia in the left breast & intraductal papilloma in the right breast, thyroid lobectomy & right central neck dissection pelvic lymph node dissection, left thyroidectomy, total hysterectomy, laparoscopic sleeve gastrectomy Medical observations: Obesity & diabetes; before and after surgery, changes in HOMA-IR and HOMA-B; Cystic lesion in thyroid gland, multiple colon polyps, small bowel polyps, metastatic papillary thyroid cancer to the lung Laboratory result & Detailed information Colonoscopy: multiple colon polyps (biopsy: lymphoidpolyps) were detected; Capsule endoscopy : scattered small bowel polyps; Genetic test: variant in which cytosine, the 289th base of the PTEN gene, was changed to thymine (c.289C > T). Consequently, glutamine, the 97th amino acid, was replaced with a stop codon (p.Gln97*) Italy (2014) [ 58 ] 26 M asymptomatic keratotic lesions of the maxillary & mandibular gingiva Mucocutaneous lesions, oral papules, acral keratosis Fibroma Family history: NA Laboratory tests, IHC, GI endoscopy, genetic test Surgical history: NA Medical observations: celiac disease, papillomatous lesions of the penis, hands & plantar skin, gastric polyposis lesions Laboratory result & Detailed information Hematology and chemistry: hematologic tests, including BS, Na, K, Ca, AST, ALP, LDH, Cr, HCT, RBC, HB, MCV, Plt, WBC, HIV, hepatitis B, C; All Laboratory test values were normal; IHC: proliferation of multiple benign fibromas with overlying hyperkeratosis; GI endoscopy: gastric polyposis lesions; Genetic test: germline mutation in exon 8 Brazil (2012) [ 59 ] 24 F asymptomatic lesions in the oral cavity Macrocephaly, Mucocutaneous lesions, oral papules Thyroid lesion Family history: ovarian & breast cancer in her mother Histopathologic evaluation, endoscopy, Skull x-ray Surgical history: thyroidectomy Medical observations: chronic urticaria with symptomatic dermographism, delayed motor and psychiatric development, hypotonia, macrocephaly, pectus excavatum, scoliosis, dolichocephaly and adenoid facies; polyposis in the GI tract, nodularhyperplasia of the thyroid Laboratory result & Detailed information Hematology and chemistry ; including Ca, ALP and AST and urinalysis were normal; Histopathologic analysis: nodular hyperplasia of the thyroid; Endoscopy: polyposis in the GI tract Japan (2018) [ 60 ] 36 M Facial seizure during sleep Macrocephaly, Mucocutaneous lesions, oral papules NA Family history : hepatocellular carcinoma in his father Brain MRI, CT-scan GI endoscopy, genetic test, PCR Surgical history: NA Medical observations: Macrocephaly , facial seizure Laboratory result & Detailed information Blood tests: for autoantibodies, amino acids, lactate, pyruvate, pituitary hormone, tumour markers, and infectious agents showed no abnormalities; Brain MRI: focal cortical dysplasia; CT: hypometabolism of cortical dysplasia; GI endoscopy: multiple polyps Genetic test: heterozygous deletion in exon 5 (c.486delC) Portugal (2016) [ 61 ] 36 F Headache & visual blurring bilaterally Thyroid cancer, mucocutaneous lesions, acral keratosis, LDD NA Family history : breast carcinoma in her mother & sister CT, MRI, OCT, genetic test Surgical history: thyroidectomy Medical observations: FDB Laboratory result & Detailed information CT: unilateral cerebellar mass in the right hemisphere; MRI: right cerebellar mass with secondary hypertrophy of the cerebellar folia with a striated or tigroid pattern characteristic of LDD; OCT : thickening of peripapillary retinal nerve fiber layer; FA: leakage from the optic discs and confirmed papilledema; Genetic test: PTEN mutation c.493G > T USA (2018) [ 62 ] 32 F Osteosarcoma and its screening process NA FDB Family history: Bladder cancer in her maternal grandfather, ovarian cancer in her maternal grandmother; brain, breast, colon, thyroid cancer in her mother; a soft-tissue mass in her brother Genetic test, colonoscopy, endoscopy Surgical history: Surgery for osteosarcoma of femur, prophylactic bilateral mastectomy Medical observations: Osteosarcoma of her left femur, right benign breast mass Laboratory result & Detailed information Genetic test: non-synonymous c.17_18delAA frameshift mutation in exon 1 of PTEN and a c.116G > T (p.R39L) missense mutation of serine/threonine kinase 11(STK11) of unknown significance; Colonoscopy & Pathological examination : 75–100 polyp and ganglioneuromas in splenic flexure, descending and sigmoid colon Portugal (2017) [ 63 ] 53 M Fibromas on the trunk and hyperkeratotic lesions on the hands Mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma, thyroid carcinoma, penile melanosis, macrocephaly Fibroma, Lipomas, GI hamartomas Family history: Negative Genetic test, laboratory tests Surgical history: Thyroidectomy Medical observations: Malignant thyroid disease, intestinal polyposis, papillomatosis of the oral cavity Laboratory result & Detailed information Genetic test: PTEN mutation; Laboratory test & renal ultrasound : no significant changes Japan (2018) [ 64 ] 65 F Lesions on skin Thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratoses FDB, Vascular anomalies Family history: NA Mammography, genetic test, Ileocolonoscopy Surgical history: Medical observations: Malignant thyroid disease, Intestinal polyps, oral cavity papillomatosis Laboratory result & Detailed information Mammography : carcinoma of the left breast; Genetic test: a heterozygous c.1003C > T (p.R335X) mutation of the phosphatase and tensing homolog ( PTEN ) gene; Ileocolonoscopy: hemispherical or drumstick-shaped multiple polyps in the terminal ileum USA (2020) [ 65 ] 56 F Diplopia Headaches LDD RCC Family history: NA MRI Surgical history: NA Medical observations: Hashimoto’s thyroiditis, RCC Laboratory result & Detailed information MRI: non-enhancing cerebellar lesion, the patient was previously diagnosed with CD and we can exclude it USA (2015) [ 66 ] 31 M Lump in his right breast Macrocephaly, Breast carcinoma Thyroid lesion Family history: Hodgkin lymphoma in great grandparent, leukemia in his aunt, breast cancer and penis cancer in great grandparents Chest CT, thyroid US, abdominal CT, genetic test Surgical history: Bilateral mastectomies Medical observations: lymphadenopathy Laboratory result & Detailed information Chest CT: mediastinal mass; Genetic test: heterozygous missense variant (c.103A > G; p.Met35Val) was observed in the PTEN gene; Thyroid US: multiple nodules; Colonoscopy: sessile polyps Singapore (2021) [ 67 ] 48 F Headache and dizziness Breast carcinoma, LDD GI hamartoma Family history: Brain CT, MRI, IHC Surgical history: resection of the tumor of brain Medical observations: hemangioma, breast cancer, hamartomatous polyps Laboratory result & Detailed information Brain CT : large hypodense lesion at the right cerebellum with resulting hydrocephalus; MRI: tiger-striped pattern of cerebellar folia in the right cerebellum; IHC: ganglion cells were positive for synaptophysin and neurofilament Korea (2012) [ 68 ] 29 F Dyspepsia Mucocutaneous lesions, oral papules, acral keratosis, trichilemmomas, thyroid carcinoma GI hamartoma Thyroid lesion Family history: EGD, colonoscopy, genetic test Surgical history: left lobectomy Medical observations: Laboratory result & Detailed information EGD: gastric, duodenal polyps and esophageal acanthosis; colonoscopy: hamartomatous polyps in the rectum and oral mucosal papillomatosis Genetic test: heterozygous transition of C to A at nucleotide 633 in exon 6 ( NM_000314.4 c.633C > A), which is a nonsense mutation, making a stop codon (p.Cys211*) Iran (2010) [ 19 ] 16 F Subtle signs of CS Mucocutaneous lesions, acral keratosis, trichilemmomas FDB Family history: NA PCR-SSCP, HMA, genetic test Surgical history: Mastectomy Medical observations: FDB Laboratory result & Detailed information PCR-SSCP: all identified mutations were present in exon 5; HMA: heteroduplex bands with mobility shifts in lanes 2,5&6 are mutant samples Genetic test : nucleic acid alteration = c.341 T > G UK (2015) [ 17 ] 48 M Dysphagia Right hearing loss and facial weakness LDD Thyroid lesion Family history: LDD in his nephew IHC, MRI, CT-scan Surgical history: brain& neck resection mass Medical observations: nasal polyps, high-grade neoplasm involving the facial nerve, deafness Laboratory result & Detailed information IHC: for neurofilament protein showed residual nerve fibers infiltrated by the tumour; MRI and CT: brain and neck showed a mass (4.2*2.9 cm) at the cerebellopontine angle; Genetic test: Nucleic acid alteration = c.1003C > T, amino acid alteration = p.(Arg335Ter), the genetic testing of the proband’s offspring identified the same mutation Italy (2021) [ 69 ] 46 M Abdominal pain Mucocutaneous lesions, oral papules, acral keratoses, macrocephaly GI hamartoma Family history: Colon and breast cancer in his mother Colonoscopy, IHC, EGD, genetic test Surgical history: NA Medical observations: Macrocephaly; polypoid lesions in GI 38 F Abdominal pain Thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma FDB, Fibroma Family history: Negative Endoscopy, colonoscopy, IHC, EGD, uterus US, genetic test Surgical history: Thyroidectomy & mastectomy Medical observations: Thyroid carcinoma, FDB with lobular carcinoma in situ, uterine fibroids and squamous polyp of uterine cervix Laboratory result & detailed information Case 1 (M). colonoscopy: more than 20 sessile and pedunculated polyposis lesions throughout the entire colon and the terminal ileum; IHC: large cistically dilated tortuous intestinal glands surrounded by stroma; EGD: multiple small carpeting lesions; Genetic test: heterozygous variant c.306del, p.Lys102Asnfs*11 ( NM_000314.8 ) was detected in the exon 5 of the PTEN gene Case 2 (F): Endoscopy: Gastrointestinal polyposis lesions; Colonoscopy: more than 20 sessile polyps involving the entire colon; IHC: simultaneous presence of enlarged lymphoid follicles and hyperplastic polyps; EGD: numerous millimetric sessile lesions covering all the esophageal mucosa and gastric mucosa; Genetic test: heterozygous variant c.253 + 1G > A; p.? ( NM_000314.8 ) (rs587776667) Iran (2022) [This study] 39 F Rectorrhagia refractory dyspepsia Breast carcinoma Thyroid lesion Family history: Gastric cancer in her father & breast cancer in her cousin Endoscopy, colonoscopy, laboratory test, genetic test, breast UC, histopathological examination, endometrial biopsy, abdominal CT scan, thyroid sonography Surgical history: Partial mastectomy Medical observations: Polyps in stomach, duodenum, rectosigmoid Laboratory result & Detailed information Hematology: WBC = 2.2 × 10 3 / μL, RBC = 4.141 × 10 6 / μL, HGB = 9.2 g/dl, PLT = 443 × 10 3 / μL; Chemistry: T3, T4, and TSH were within thenormal limits; Genetic test: RefSeq = NM_00314.7, Nucleic acid alteration = c.697C > T, Amino acid alteration = (p.Arg233Ter) rs121909219, Zigosity = Heterozygous, Ch. Location = Chr10 Mutation: Pathogenic APAM Atypical polypoid adenomyoma, CT Computerized tomography, CCA Clear cell acanthoma, D&C Dilatation and curettage, DSA Digital subtraction angiography, ERCP Endoscopic retrograde cholangio-pancreatography, ECG Electroencephalography, FDG-PET F-fluorodeoxyglucose-positron emission tomography, FA Fluorescein angiography, FDP Familial defective apolipoprotein, FDB Fibrocystic disease of the breast, GI Gastrointestinal, HMA Heteroduplex mobility analysis, IHC Immunohistochemistry, LDD Lhermitte-Duclos disease, MRI Magnetic resonance imaging, PCR Polymerase chain reaction, PET Positron emission tomography, RCC Renal cell carcinoma, SSCP Single strand conformation polymorphism, SEAVF Spinal epidural arteriovenous fistulas, SLA Sebaceous lymphadenoma, US Ultrasonography a Shows the chief complains of each patient b Shows the major criteria considered to diagnose PHTS c Shows the major criteria considered to diagnose PHTS d Shows the family, surgical and medical history of each patient e Shows the diagnostic measures applied for each patient f Shows the detailed results of each diagnostic measures performed Fig. 3 a Clinical criteria considered for diagnosing PHTS patients; and b Medical observations reported for these cases according to the literature review Fig. 4 PTEN pathogenic variants found in tumours and PHTSs in the case reports reviewed; mutated sites of the pathogenic variants are shown in the exons and introns of the PTEN gene Results of the literature review USA (2012) [ 38 ] Colon cancer Lipomas Colonoscopy, genetic test, histology Laboratory results & detailed information f : Colonoscopy & microscopic examination: ganglioneuromatous polyposis , specimen contained an adenomatous polyp in addition to multiple, finger-like polyps and mesenteric lipomas; Genetic test: pathologic non-sense mutation at the PTEN locus Spain (2016) [ 2 ] Breast carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Brain and chest CT, MRI of spine, genetic test Laboratory results & detailed information CT: left sphenoid wing meningioma with extra-conal extension and resultant left optic nerve impingement and proptosis; right breast lesions MRI: thoracolumbar scoliosis with spondylosis and multilevel disc disease; Genetic test: pathogenic variants in the PTEN gene: (c.697C > T) (pArg233*) Tunisia (2012) [ 6 ] Altered bowel habits Macrocephaly, thyroid carcinoma, mucocutaneous lesions, acral keratosis FDB, thyroid lesion, gastrointestinal hamartomas Laboratory result & detailed information Breast US: bilateral nodules compatible with fibrocystic disease; Endoscopy: esophageal, duodenal, and gastric sessile polyps; Colonoscopy : multiple lesions in the sigmoid and rectum USA (2013) [ 14 ] Menorrhagia refractory to intravenous estrogen Endometrial carcinoma, Macrocephaly, mucocutaneous lesions, oral papules, trichilemmoma Lipomas, fibroma Endometrial curettage & pathological examination, PET/MRI of ovaries, colonoscopy, genetic test Laboratory result & detailed information Endometrial curettage & Pathological examination: focal grade 1 endometriosis adenocarcinoma; PET/MRI: concerning for significant myometrium invasion, showed no involvement of the ovaries at age 14; Colonoscopy: multiple polyposis lesions in transverse and sigmoid colon; Genetic test: Arg335X (1003C > T) mutation in the PTEN gene Brazil (2015) [ 13 ] Macrocephaly, thyroid carcinoma, mucocutaneous lesions, oral papules Laboratory result & detailed information histopathologic evaluation: epithelial hyperplasia as a histological finding of biopsy from the gingival nodule Croatia (2019) [ 18 ] Thyroid carcinoma (follicular), mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma FDB, Lipoma, Fibroma, Vascular anomalies Laboratory result & detailed information Gynecological US: polyp in the endometrium and multiple myomas of the myometrium; Cardiological examination: pericardial effusion USA (2017) [ 39 ] Lesions on calf,abdomen, clavicle & elbow Laboratory result & detailed information CT: Nodular lesions in the right parotid gland; IHC: Sebaceous lymph adenoma, Clear Cell Acanthoma, Czech (2011) [ 40 ] Macrocephaly, thyroid carcinoma, mucocutaneous lesions Intellectual disability, Thyroid lesion, GI hamartomas Laboratory result & detailed information Endoscopy : hundreds of polyps in the stomach, duodenum and colon; CT : frontal lesion; IHC : invasive follicular carcinoma benign meningioma; Genetic test : heterozygous deletion mutation at (c.438delT), exon 5 Japan (2020) [ 41 ] Breast carcinoma, thyroid carcinoma, LDD Laboratory result & detailed information Breast US: irregular marginated hypoechoic mass measuring 15.1 × 15 × 9.4 mm in the 12 o’clock region of the right breast; Pathological examination: ductal carcinoma in situ (DCIS) in the right mammary gland and invasive ductal carcinoma in the left mammary gland; Chest MRI: Primary tumour of the right mammary gland to be a mass 15 mm and early phase linear enhancement for the left side =  > stage 0 (cTisN0M0) right breast cancer and stage IIA (cT2N0M0) for the left side; Brain MRI: alternative isointense and hyper intense bands in the left cerebellar hemisphere; Chest CT : no lymph node metastases or distant metastases Portugal (2020) [ 42 ] Macrocephaly, thyroid carcinoma, breast carcinoma, Mucocutaneous lesions: acral keratosis Breast CT & IHC, thyroid & breast US, genetic test Laboratory result & detailed information Breast CT and IHC: breast lump, high metastatic breast sarcoma; Thyroid US: 5.6-cm hypoechogenic nodule and anecogenic areas fine-needle biopsy and was diagnosed with follicular lesion of undetermined significance (FLUS) (Bethesda category III); Genetic test: a change in heterozygote, pathogenic variant c.405dupA (p. (Cys136Metfs * 44) in the PTEN gene India (2015) [ 43 ] Macrocephaly, mucocutaneous lesions, oral papules, acral keratosis Medical observations: Syndactyly and polydactyly, cobblestone tongue with coalesced papules Laboratory result & detailed information Imaging studies (ultrasound abdomen and pelvis, chest x-ray, ECG, MRI brain and echocardiography) and upper GI endoscopy, colonoscopy and mammography were normal USA (2017) [ 44 ] Breast carcinoma, mucocutaneous lesions, oral papules, acral keratosis Medical observations: Malignancy of GI tract, anemia, asthma, breast cancer Laboratory result & detailed information Intraoral examination: papules, pebbles on the case of the tongue and maxillary; IHC: Superficial keratinized squamous epithelium overlying a mass of dense fibrous connective tissue composed of interlacing bundles of collagen fibers interspersed by fibroblasts and blood vessels Japan (2014) [ 45 ] Intellectual disability, Vascular anomalies Laboratory result & detailed information Brain CT & MRI: hematoma diameter 27 mm & circular area of heterogeneous intensity in the pons; DSA: no abnormal vessels & no tumour staining; IHC: dura mater contained abnormal vessels & ectatic cortical veins presented in the arachnoid space; Genetic test: PTEN mutation Italy (2018) [ 46 ] Breast carcinoma, thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Medical observations: Breast & Thyroid carcinoma, periodontal disease Laboratory result & detailed information IHC: hyper plastic epidermoid covering and parakeratosis on the surface; Since the diagnosis of the disease had already been made, there was no information about the diagnostic methods Japan (2020) [ 47 ] Breast carcinoma, Macrocephaly, Endometriosis carcinoma Laboratory result & Detailed information: Pelvic US: thickening of the endometrium and a cystic mass in the left ovary; Abdominopelvic CT: endometrial thickening and a 5-cm cystic mass in the left adnexal region; IHC: grade 1 endometriosis carcinoma component presenting cribriform glands; Genetic test: Pathogenic variants of PTEN (c.C1003T, p.R335X) in both the patient and her mother Spain (2019) [ 48 ] Medical observations: Bilateral cholesteatoma, trigeminal schwannoma, uterine fibroids, finger fibroma, tracheal fibrotic nodules, trichilemmoma, oral fibroma Laboratory result & Detailed information: GI endoscopy: glycogenic acanthosis and ten colorectal inflammatory and hyperplastic polyps; Genetic test: a heterozygous mutation = a four-nucleotide deletion (c.510_513del) resulting in a premature stop codon (p.Ser170Argfs*12) Lebanon (2017) [ 49 ] Breast carcinoma, Macrocephaly, Endometrial, carcinoma Lipomas, Fibroma Laboratory result & Detailed information: Axilla MRI: not demonstrate any suspicious lymph nodes; IHC : high grade ductal carcinoma in situ; Brian MRI: no lesions suggestive of meningioma; Genetic test: PTEN c.209 + 5G > A alteration confirming the clinical impression of CS Japan (2019) [ 15 ] Macrocephaly, Endometriosis carcinoma Thyroid lesions, Lipoma, Fibroma, GI hamartomas Colonoscopy, IHC, GI endoscopy, MRI of pelvic, CT, FDG-PET Laboratory result & Detailed information: Colonoscopy: colorectal polyposis lesions; IHC: hamartoma polyps and ectopic endometrial implants; GI endoscopy: multiple esophageal papillomas and glycogenic acanthosis; MRI: gluteal subcutaneous lipoma CT: heterogeneously enhanced mass, 9 cm; FDG-PET: abnormal uptake by the ovarian tumour (SUVmax: 8.33) Japan (2015) [ 50 ] Hoarseness & dysphagia Thyroid lesions, Vascular anomalies MRI, histology & IHC, GI endoscopic, genetic test Laboratory result & Detailed information: MRI: cerebellar dysplastic gangliocytoma; IHC : lung adenocarcinoma (T4N2M1b, Stage IV); GI endoscopic: Gastrointestinal polyposis; Genetic test: PTEN gene mutation, a point mutation ( TGT to CGT ) at exon 5 in codon 136 was detected in his serum USA (2016) [ 51 ] Macrocephaly, thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma Lipomas, Thyroid lesions Chest, abdomen & pelvis CT& PET-CT, pathological evaluation, IHC, Endoscopic sonography, genetic test Medical observations: Macrocephaly, thyroid carcinoma, mucocutaneous, multiple intestinal polyps Laboratory result & Detailed information: CT: large (9 × 8 × 4 cm) ill-defined mass of the head and neck of the pancreas, invading the celiac axis; encasing the celiac artery, superior mesenteric, and splenic arteries and veins; and compressing the portal vein confluence; PET-CT: large central lesion in the abdomen; IHC& pathological evaluation: cytoplasmic staining of tumour cells, grade 1 NET with a Ki-67 < 2% and involved margins; Endoscopic sonography: stage uT4N1Mx determined Genetic test: nonsense mutation c.697C3T (p.R233*) causing a premature stop codon in exon 7 Japan (2018) [ 16 ] GI hamartomas, Thyroid lesions, Fibroma, Vascular anomalies Laboratory result & Detailed information: US: adenomatous goiter in the thyroid gland; GI endoscopy: numerous polyposis lesions; CT angiography: vascular malformation in the wall of the sigmoid colon; Pathological examination: vascular malformations expanded from the submucosal layer to the mesocolon USA (2019) [ 52 ] LDD, Macrocephaly Brain MRI, IHC Laboratory result & Detailed information: MRI: cerebellar tumour and progression of the left cerebellar gangliocytoma IHC: expansion of the cerebellar folia, with near complete replacement of the small neurons of the internal granular layers by larger, ganglionic neurons USA (2016) [ 53 ] Macrocephaly, Mucocutaneous lesions, trichilemmoma Thyroid lesion, Lipoma, Colon cancer Histopathologic examination, IHC, breast US Laboratory result & Detailed information: Histopathological examination: a circumscribed, lobulated, proliferative glandular lesion with areas of expanded fibromyxoid stroma and epithelial hyperplasia with apocrine and columnar cell changes, arranged in a papillary, micropapillary and cribriform architecture; IHC: loss of PTEN expression in the epithelial component of the lesion. USA (2020) [ 54 ] Cerebral MRI, IHC Laboratory result & Detailed information: MRI: lesion in the cerebellum suggesting dysplastic gangliocytoma; IHC: EMA and vimentin, consistent with World Health Organization (WHO) grade I meningioma margin. The patient had already been diagnosed with the CS Italy (2012) [ 55 ] Macrocephaly, Mucocutaneous lesions, oral papules, acral keratosis Autism, Intellectual disability Cerebral MRI, ECG, IHC, genetic test, laboratory test Laboratory result & Detailed information MRI: right periventricular hyperintensity probably due to a remote hypoxic-ischemic insult; ECG: focal spike-wave complexes over the left temporal regions. IHC: focal prominent epidermal hyperplasia that at its periphery is demarcated by elongated rete ridges; Genetic test: an exon 2 deletion was detected; Laboratory test: moderate increase of thyrotrophin-stimulating hormone and free triiodothyronine and uncertain values for anti-endomysial antibodies with positivity for human leukocyte antigen (HLA) haplotypes (HLADQ2 and HLA-DQ8) associated with celiac disease USA (2018) [ 56 ] Breast carcinoma, Macrocephaly RCC, Lipomas, Vascular anomalies Laboratory result & Detailed information MRI: longitudinally extensive myelopathy; Spinal angiography: 2 SEAVFs; Genetic test: A deleterious mutation (209 + 4_209 + 7delAGTA) was found in intron 3 of the PTEN Korea (2021) [ 57 ] Endometrial carcinoma, Mucocutaneous lesions Thyroid lesion, Vascular anomalies Colonoscopy, endoscopy, genetic test Laboratory result & Detailed information Colonoscopy: multiple colon polyps (biopsy: lymphoidpolyps) were detected; Capsule endoscopy : scattered small bowel polyps; Genetic test: variant in which cytosine, the 289th base of the PTEN gene, was changed to thymine (c.289C > T). Consequently, glutamine, the 97th amino acid, was replaced with a stop codon (p.Gln97*) Italy (2014) [ 58 ] asymptomatic keratotic lesions of the maxillary & mandibular gingiva Laboratory tests, IHC, GI endoscopy, genetic test Laboratory result & Detailed information Hematology and chemistry: hematologic tests, including BS, Na, K, Ca, AST, ALP, LDH, Cr, HCT, RBC, HB, MCV, Plt, WBC, HIV, hepatitis B, C; All Laboratory test values were normal; IHC: proliferation of multiple benign fibromas with overlying hyperkeratosis; GI endoscopy: gastric polyposis lesions; Genetic test: germline mutation in exon 8 Brazil (2012) [ 59 ] Macrocephaly, Mucocutaneous lesions, oral papules Histopathologic evaluation, endoscopy, Skull x-ray Laboratory result & Detailed information Hematology and chemistry ; including Ca, ALP and AST and urinalysis were normal; Histopathologic analysis: nodular hyperplasia of the thyroid; Endoscopy: polyposis in the GI tract Japan (2018) [ 60 ] Macrocephaly, Mucocutaneous lesions, oral papules Brain MRI, CT-scan GI endoscopy, genetic test, PCR Laboratory result & Detailed information Blood tests: for autoantibodies, amino acids, lactate, pyruvate, pituitary hormone, tumour markers, and infectious agents showed no abnormalities; Brain MRI: focal cortical dysplasia; CT: hypometabolism of cortical dysplasia; GI endoscopy: multiple polyps Genetic test: heterozygous deletion in exon 5 (c.486delC) Portugal (2016) [ 61 ] Headache & visual blurring bilaterally Thyroid cancer, mucocutaneous lesions, acral keratosis, LDD CT, MRI, OCT, genetic test Laboratory result & Detailed information CT: unilateral cerebellar mass in the right hemisphere; MRI: right cerebellar mass with secondary hypertrophy of the cerebellar folia with a striated or tigroid pattern characteristic of LDD; OCT : thickening of peripapillary retinal nerve fiber layer; FA: leakage from the optic discs and confirmed papilledema; Genetic test: PTEN mutation c.493G > T USA (2018) [ 62 ] Genetic test, colonoscopy, endoscopy Laboratory result & Detailed information Genetic test: non-synonymous c.17_18delAA frameshift mutation in exon 1 of PTEN and a c.116G > T (p.R39L) missense mutation of serine/threonine kinase 11(STK11) of unknown significance; Colonoscopy & Pathological examination : 75–100 polyp and ganglioneuromas in splenic flexure, descending and sigmoid colon Portugal (2017) [ 63 ] Fibromas on the trunk and hyperkeratotic lesions on the hands Mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma, thyroid carcinoma, penile melanosis, macrocephaly Fibroma, Lipomas, GI hamartomas Genetic test, laboratory tests Laboratory result & Detailed information Genetic test: PTEN mutation; Laboratory test & renal ultrasound : no significant changes Japan (2018) [ 64 ] Thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratoses FDB, Vascular anomalies Mammography, genetic test, Ileocolonoscopy Laboratory result & Detailed information Mammography : carcinoma of the left breast; Genetic test: a heterozygous c.1003C > T (p.R335X) mutation of the phosphatase and tensing homolog ( PTEN ) gene; Ileocolonoscopy: hemispherical or drumstick-shaped multiple polyps in the terminal ileum USA (2020) [ 65 ] Laboratory result & Detailed information MRI: non-enhancing cerebellar lesion, the patient was previously diagnosed with CD and we can exclude it USA (2015) [ 66 ] Macrocephaly, Breast carcinoma Chest CT, thyroid US, abdominal CT, genetic test Laboratory result & Detailed information Chest CT: mediastinal mass; Genetic test: heterozygous missense variant (c.103A > G; p.Met35Val) was observed in the PTEN gene; Thyroid US: multiple nodules; Colonoscopy: sessile polyps Singapore (2021) [ 67 ] Breast carcinoma, LDD Laboratory result & Detailed information Brain CT : large hypodense lesion at the right cerebellum with resulting hydrocephalus; MRI: tiger-striped pattern of cerebellar folia in the right cerebellum; IHC: ganglion cells were positive for synaptophysin and neurofilament Korea (2012) [ 68 ] EGD, colonoscopy, genetic test Laboratory result & Detailed information EGD: gastric, duodenal polyps and esophageal acanthosis; colonoscopy: hamartomatous polyps in the rectum and oral mucosal papillomatosis Genetic test: heterozygous transition of C to A at nucleotide 633 in exon 6 ( NM_000314.4 c.633C > A), which is a nonsense mutation, making a stop codon (p.Cys211*) Iran (2010) [ 19 ] PCR-SSCP, HMA, genetic test Laboratory result & Detailed information PCR-SSCP: all identified mutations were present in exon 5; HMA: heteroduplex bands with mobility shifts in lanes 2,5&6 are mutant samples Genetic test : nucleic acid alteration = c.341 T > G UK (2015) [ 17 ] Laboratory result & Detailed information IHC: for neurofilament protein showed residual nerve fibers infiltrated by the tumour; MRI and CT: brain and neck showed a mass (4.2*2.9 cm) at the cerebellopontine angle; Genetic test: Nucleic acid alteration = c.1003C > T, amino acid alteration = p.(Arg335Ter), the genetic testing of the proband’s offspring identified the same mutation Italy (2021) [ 69 ] Mucocutaneous lesions, oral papules, acral keratoses, macrocephaly Colonoscopy, IHC, EGD, genetic test Thyroid carcinoma, mucocutaneous lesions, oral papules, acral keratosis, trichilemmoma FDB, Fibroma Endoscopy, colonoscopy, IHC, EGD, uterus US, genetic test Laboratory result & detailed information Case 1 (M). colonoscopy: more than 20 sessile and pedunculated polyposis lesions throughout the entire colon and the terminal ileum; IHC: large cistically dilated tortuous intestinal glands surrounded by stroma; EGD: multiple small carpeting lesions; Genetic test: heterozygous variant c.306del, p.Lys102Asnfs*11 ( NM_000314.8 ) was detected in the exon 5 of the PTEN gene Case 2 (F): Endoscopy: Gastrointestinal polyposis lesions; Colonoscopy: more than 20 sessile polyps involving the entire colon; IHC: simultaneous presence of enlarged lymphoid follicles and hyperplastic polyps; EGD: numerous millimetric sessile lesions covering all the esophageal mucosa and gastric mucosa; Genetic test: heterozygous variant c.253 + 1G > A; p.? ( NM_000314.8 ) (rs587776667) Iran (2022) [This study] Endoscopy, colonoscopy, laboratory test, genetic test, breast UC, histopathological examination, endometrial biopsy, abdominal CT scan, thyroid sonography Medical observations: Polyps in stomach, duodenum, rectosigmoid Laboratory result & Detailed information Hematology: WBC = 2.2 × 10 3 / μL, RBC = 4.141 × 10 6 / μL, HGB = 9.2 g/dl, PLT = 443 × 10 3 / μL; Chemistry: T3, T4, and TSH were within thenormal limits; Genetic test: RefSeq = NM_00314.7, Nucleic acid alteration = c.697C > T, Amino acid alteration = (p.Arg233Ter) rs121909219, Zigosity = Heterozygous, Ch. Location = Chr10 Mutation: Pathogenic APAM Atypical polypoid adenomyoma, CT Computerized tomography, CCA Clear cell acanthoma, D&C Dilatation and curettage, DSA Digital subtraction angiography, ERCP Endoscopic retrograde cholangio-pancreatography, ECG Electroencephalography, FDG-PET F-fluorodeoxyglucose-positron emission tomography, FA Fluorescein angiography, FDP Familial defective apolipoprotein, FDB Fibrocystic disease of the breast, GI Gastrointestinal, HMA Heteroduplex mobility analysis, IHC Immunohistochemistry, LDD Lhermitte-Duclos disease, MRI Magnetic resonance imaging, PCR Polymerase chain reaction, PET Positron emission tomography, RCC Renal cell carcinoma, SSCP Single strand conformation polymorphism, SEAVF Spinal epidural arteriovenous fistulas, SLA Sebaceous lymphadenoma, US Ultrasonography a Shows the chief complains of each patient b Shows the major criteria considered to diagnose PHTS c Shows the major criteria considered to diagnose PHTS d Shows the family, surgical and medical history of each patient e Shows the diagnostic measures applied for each patient f Shows the detailed results of each diagnostic measures performed a Clinical criteria considered for diagnosing PHTS patients; and b Medical observations reported for these cases according to the literature review PTEN pathogenic variants found in tumours and PHTSs in the case reports reviewed; mutated sites of the pathogenic variants are shown in the exons and introns of the PTEN gene

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.

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 [ 72 ]. 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% [ 34 ]. Hence, women with PHTS are recommended to self-examine their breasts and undergo regular mammography [ 13 ]. 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 [ 74 ]. Compared to previously reported rates [ 2 , 9 , 34 , 73 , 75 – 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 – 82 ]. While the clinical and laboratory diagnostic criteria serve as the foundation for diagnosis [ 9 ], 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% [ 38 ]. However, the risks and benefits of early intervention should be carefully weighed against the financial expenses and health risks associated with increased endoscopic surveillance [ 38 ]. Innella et al. [ 69 ] 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 – 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 [ 13 ]. 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 ].

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 [ 1 ]. 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) [ 4 ]. 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 [ 5 ]. 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 [ 7 ]. Early detection is crucial, as the best potential prognosis for patients with PHTS rests on accurate clinical observation plus ongoing surveillance of affected individuals [ 2 ]. 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 – 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 – 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) [ 19 ]. 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 – 23 ]. IHCCR confirms these cases through whole-exome sequencing (WES), a comprehensive genetic test that sequences all of the protein-coding gene regions [ 24 ]. 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.