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Table 3 Results of the literature review

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

Country

(Year)

[Ref]

Age

Sex

Chief

complaintsa

Major criteriab

Minor criteriac

History and other clinical manifestationsd

Diagnostic measurese

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 informationf:

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: Hemiparesis, 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 × 103/ μL, RBC = 4.141 × 106/ μL, HGB = 9.2 g/dl, PLT = 443 × 103/ 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

  1. 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
  2. aShows the chief complains of each patient
  3. bShows the major criteria considered to diagnose PHTS
  4. cShows the major criteria considered to diagnose PHTS
  5. dShows the family, surgical and medical history of each patient
  6. eShows the diagnostic measures applied for each patient
  7. fShows the detailed results of each diagnostic measures performed