PTEN Hamartoma Tumour Syndrome (PHTS) encompasses diverse clinical phenotypes, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This autosomal dominant genetic predisposition with high penetrance arises from heterozygous germline variants in the PTEN tumour suppressor gene, leading to dysregulation of the PI3K/AKT/mTOR signalling pathway, which promotes the overgrowth of multiple and heterogenous tissue types. Clinical presentations of CS range from benign and malignant disorders, affecting nearly every system within the human body. CS is the most diagnosed syndrome among the PHTS group, notwithstanding its weak incidence (1:200,000), for which it is considered rare, and its precise incidence remains unknown among other important factors. The literature is notably inconsistent in reporting the frequencies and occurrences of these disorders, adding an element of bias and uncertainty when looking back at the available research. In this review, we aimed to highlight the significant disparities found in various studies concerning CS and to review the clinical manifestations encountered in CS patients. Furthermore, we intended to emphasize the great significance of early diagnosis as patients will benefit from a longer lifespan while being unceasingly advised and supported by a multidisciplinary team.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) represents the initial tumor suppressor gene identified to possess phosphatase activity, governing various cellular processes including cell cycle regulation, migration, metabolic pathways, autophagy, oxidative stress response, and cellular senescence. Current evidence suggests that PTEN is critical for stem cell maintenance, self-renewal, migration, lineage commitment, and differentiation. Based on the latest available evidence, we provide a comprehensive overview of the mechanisms by which PTEN regulates activities of different stem cell populations and influences neurological disorders, encompassing autism, stroke, spinal cord injury, traumatic brain injury, Alzheimer\'s disease and Parkinson\'s disease. This review aims to elucidate the therapeutic impacts and mechanisms of PTEN in relation to neurogenesis or the stem cell niche across a range of neurological disorders, offering a foundation for innovative therapeutic approaches aimed at tissue repair and regeneration in neurological disorders. This review unravels novel therapeutic strategies for tissue restoration and regeneration in neurological disorders based on the regulatory mechanisms of PTEN on neurogenesis and the stem cell niche.

MicroRNAs (miRNA) are small and conserved noncoding RNA molecules that regulate gene expression at the posttranscriptional level. These groups of RNAs are crucial in various cellular processes, especially in mediating disease pathogenesis, particularly cancer. The dysregulation of miRNAs was reported in many cancer types, including nasopharyngeal cancer (NPC), which is a malignant tumor of the nasopharynx. In this review, miRNAs involvement in crucial signaling pathways associated with NPC such as PTEN/PI3K/AKT, TGFβ/SMAD, RAS/MAPK, Wnt/β-catenin and pRB-E2F was investigated. miRNAs could function as tumor suppressor-miR or onco-miR in NPC profoundly influenced cell cycle, apoptosis, proliferation, migration, and metastasis. This comprehensive review of current literature provided a thorough profile of miRNAs and their interplay with the aforementioned signaling pathways in NPC. Understanding these molecular interactions could remarkably impact the diagnosis, prognosis, and therapeutic strategies for NPC.

Treating advanced thyroid cancer presents challenges due to its resistance to various treatment modalities, thereby limiting therapeutic options. To our knowledge, this study is the first to report the efficacy of temsirolimus in conjunction with dual immunotherapy of nivolumab/ipilimumab to treat heavily treated advanced PDTC. A 50-year-old female initially presented with a rapidly enlarging mass on her right neck. Subsequent diagnosis revealed poorly differentiated thyroid carcinoma, leading to a total thyroidectomy followed by post-operative radioablation therapy. After four years, an examination for persistent cough revealed a recurrence of the disease within multiple mediastinal nodes. Genetic analysis of blood samples uncovered somatic mutations in the tumor, specifically involving PTEN and TP53. The disease progressed despite palliative radiation, lenvatinib, and nivolumab/ipilimumab therapy. Consequently, temsirolimus, functioning as an mTOR inhibitor, was introduced as an adjunct to the nivolumab/ipilimumab regimen. This combination approach yielded remarkable clinical improvement and disease control for a duration of approximately six months. Temsirolimus likely suppressed the aberrantly activated PI3K/AKT/mTOR signaling pathway, facilitated by the PTEN genetic alteration, thus engendering an effective treatment response. This synergy between targeted agents and immunotherapy presents a promising therapeutic strategy for advanced PDTC patients with limited treatment alternatives. In previous clinical trials, mTOR inhibitors have demonstrated the ability to maintain stable disease (SD) in 65% to 74% for advanced thyroid cancer patients, including those with PDTC. When combined with other targeted therapies, the observed SD or partial response rates range from 80% to 97%. Many of these trials primarily involved differentiated thyroid carcinoma, with diverse genetic mutations. Thyroid cancer patients with alterations in the PI3K/mTOR/Akt appeared to benefit most from mTOR inhibitors. However, no clear association between the efficacy of mTOR inhibitors and specific histologies or genetic mutations has been established. Future studies are warranted to elucidate these associations.

Cowden syndrome (CS) is a rare disease that was first described in 1963 and later included in the large group of genodermatoses. It is the most common syndrome among the PTEN-associated hamartomatous tumor syndromes (PHTS). CS has an autosomal dominant inheritance pattern, with increased penetrance and variable expressivity, making early diagnosis difficult. Mutations in the PTEN gene (phosphatase and TENsin homolog) are involved in its pathogenesis, involving many organs and systems originating in the three embryonic layers (ectodermum, endodermum, and mesodermum). The consequence is the development of hamartomatous lesions in various organs (brain, intestines, thyroid, oropharyngeal cavity, colon, rectum, etc.). Multiple intestinal polyps are common in patients with CS, being identified in over 95% of patients undergoing colonoscopy. The authors describe the case of a patient who presented the first signs of the disease at 3 ½ years (tonsil polyp) but was diagnosed only at the age of 20 following a colonoscopy that revealed hundreds of intestinal polyps, suggesting further molecular testing. A heterozygous frameshift mutation was identified in the PTEN gene, classified as a potentially pathogenic variant (c.762del.p(Val255*)). The authors present this case to highlight the path taken by the patient from the first symptoms to the diagnosis and to emphasize the clinical aspects of this mutational variant that have still not been identified in other patients with this syndrome.

Breast cancer (BC) is the most common malignancy in women in western countries. A significant part of malignant cases is caused by genetic mutation. Mutations in the gene phosphatase and tensin homologue deleted on chromosome (PTEN) have been proven in various malignancies. The present study was conducted with the aim of investigating the prevalence of BC due to PTEN gene mutation, as well as estimating the chance of developing BC due to the occurrence of PTEN gene mutation. The present study was conducted using a systematic review method based on PRISMA 2020 statements. The search was done in PubMed, Web of Science (WOS), Scopus, and direct scientific databases. The search was performed using the keywords breast cancer, breast malignancy, PTEN, polymorphism, mutation, variant, and their equivalents. Statistical analysis was performed using the second version of Comprehensive Meta-Analysis Software. A total of 2138 articles were collected. After removing duplicate articles, checking the title and abstract, and then checking the full text of the documents, finally 64 articles were approved and entered the systematic review process. Analysis of these studies with a sample size of 231,179 showed the prevalence of breast cancer patients with PTEN mutations. The combined results of 64 studies showed that the prevalence of PTEN mutations has a 3.3 (95% CI 2.2-5) in BC patients, and an analysis of 6 studies showed that the odds ratio of developing BC due to PTEN mutation is 3.7 (95% CI 1.1-11.9). The results of this study show that mutation in the PTEN gene increases the chance of developing BC. However, it was found that a small part of patients gets BC due to the occurrence of mutation in this gene.

暂无摘要。

PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples.
Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome.
This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) is a rare hereditary disorder caused by germline pathogenic mutations in the PTEN gene. This study presents a case of PHTS referred for genetic evaluation due to multiple polyps in the rectosigmoid area, and provides a literature review of PHTS case reports published between March 2010 and March 2022.
METHODS: A 39-year-old Iranian female with a family history of gastric cancer in a first-degree relative presented with minimal bright red blood per rectum and resistant dyspepsia. Colonoscopy revealed the presence of over 20 polyps in the rectosigmoid area, while the rest of the colon appeared normal. Further upper endoscopy showed multiple small polyps in the stomach and duodenum, leading to a referral for genetic evaluation of hereditary colorectal polyposis. Whole-exome sequencing led to a PHTS diagnosis, even though the patient displayed no clinical or skin symptoms of the condition. Further screenings identified early-stage breast cancer and benign thyroid nodules through mammography and thyroid ultrasound.
UNASSIGNED: A search of PubMed using the search terms \"Hamartoma syndrome, Multiple\" [Mesh] AND \"case report\" OR \"case series\" yielded 43 case reports, predominantly in women with a median age of 39 years. The literature suggests that patients with PHTS often have a family history of breast, thyroid and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Gastrointestinal polyps are one of the most common signs reported in the literature, and the presence of acral keratosis, trichilemmomas and mucocutaneous papillomas are pathognomonic characteristics of PHTS.
CONCLUSIONS: When a patient presents with more than 20 rectosigmoid polyps, PHTS should be considered. In such cases, it is recommended to conduct further investigations to identify other potential manifestations and the phenotype of PHTS. Women with PHTS should undergo annual mammography and magnetic resonance testing for breast cancer screening from the age of 30, in addition to annual transvaginal ultrasounds and blind suction endometrial biopsies.

PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients.
A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca\' Granda Ospedale Maggiore Policlinico.
We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years.
Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance.