Phosphatase and Tensin Homolog Immunohistochemical Staining and Clinical Criteria for Cowden Syndrome in Patients With Trichilemmoma or Associated Lesions

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment.

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Cowden Syndrome: report of a case and brief review of literature

Anais Brasileiros de Dermatologia ◽

10.1590/abd1806-4841.20132578 ◽

2013 ◽

Vol 88 (6 suppl 1) ◽

pp. 52-52 ◽

Cited By ~ 8

Author(s):

Ana Carolina Souza Porto ◽

Elisabeth Roider ◽

Thomas Ruzicka

Keyword(s):

Cell Cycle Progression ◽

Cowden Syndrome ◽

Pten Gene ◽

Benign Tumors ◽

Cutaneous Lesions ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Increased Risk ◽

History Of ◽

Risk Of Cancer

We present the case of a female patient with facial cutaneous lesions, a cobblestone-like pattern of the oral mucosa, and verruciform lesions on the hand since her youth. She reported a history of breast cancer, endometrial cancer, melanoma and multiple benign tumors and cysts. PTEN gene analysis was performed and confirmed Cowden Syndrome, a rare genodermatosis with an autosomal dominant pattern of inheritance, characterized by multiple hamartomas. The phosphatase and tensin homolog (PTEN) gene negatively regulates cell proliferation and cell cycle progression. Loss of PTEN function contributes to an increased risk of cancer. We emphasize the importance of early detection and accurate management of Cowden Syndrome.

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The Skin in Cowden Syndrome

Frontiers in Medicine ◽

10.3389/fmed.2021.658842 ◽

2021 ◽

Vol 8 ◽

Author(s):

Agnes Lim ◽

Joanne Ngeow

Keyword(s):

Targeted Therapies ◽

Autosomal Dominant ◽

Malignant Tumors ◽

Skin Lesions ◽

Cowden Syndrome ◽

Differential Diagnoses ◽

Phosphatase And Tensin Homolog ◽

Autosomal Dominant Condition ◽

Tensin Homolog ◽

Dominant Condition

Cowden syndrome (CS) is an autosomal dominant condition caused by mutations in the phosphatase and tensin homolog (PTEN) gene, and is characterized by multiple hamartomas and a predisposition to malignant tumors. Characteristic skin lesions include trichilemmomas, acral keratosis, mucocutaneous neuromas, oral papillomas, and penile macules, and are often the first clues to the underlying diagnosis. Here, we discuss the mucocutaneous manifestations of CS, differential diagnoses of genetic causes of each cutaneous finding, genetic analyses for patients with skin manifestations, management of patients with CS, and potential new targeted therapies for CS.

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Testicular pain as a presentation of Cowden syndrome

Annals of The Royal College of Surgeons of England ◽

10.1308/147870811x582819 ◽

2011 ◽

Vol 93 (5) ◽

pp. e51-e52 ◽

Cited By ~ 3

Author(s):

Hussain M Alnajjar ◽

Arun Sahai ◽

Andrew Keane ◽

Stephen Gordon

Keyword(s):

Cowden Syndrome ◽

Limited Information ◽

Nodular Goitre ◽

Phosphatase And Tensin Homolog ◽

Testicular Pain ◽

Left Testicle ◽

Tensin Homolog ◽

History Of ◽

Multiple Hamartoma Syndrome

This case report outlines a rare case in Cowden syndrome and PTEN (phosphatase and tensin homolog) gene mutation and how it may initially present to the urologist. Also known as multiple hamartoma syndrome, Cowden syndrome is a rare disorder associated with the development of several types of malignancy. A thorough search of the literature reveals limited information regarding its presentation to the urologist. We report the case of a 47-year-old gentleman with a two-week history of worsening pain and swelling in his left testicle. Testicular ultrasound revealed multiple hyperechoic areas bilaterally suggestive of multiple lipomas. He was also found to have macrocephaly, freckling of his glans and foreskin and an enlarged nodular goitre and the geneticist diagnosed Cowden syndrome. The disease is discussed and guidance is given on its management and follow up.

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PTEN-Related Overgrowth Syndromes

Overgrowth Syndromes ◽

10.1093/med/9780190944896.003.0009 ◽

2019 ◽

pp. 163-186

Author(s):

Lamis Yehia ◽

Joanne Ngeow ◽

Charis Eng

Keyword(s):

Autosomal Dominant ◽

Vascular Malformations ◽

Treatment Strategies ◽

Suppressor Gene ◽

Cowden Syndrome ◽

Loss Of Function ◽

Autosomal Dominant Disorder ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Cell Growth And Proliferation

Individuals carrying germline mutations in the tumor suppressor gene phosphatase and tensin homolog (PTEN) may present with diverse clinical phenotypes, grouped under the term of PTEN hamartoma tumor syndrome (PHTS). This chapter will focus on two PHTS conditions: Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome. The first condition is an autosomal dominant disorder characterized by macrocephaly, intestinal hamartomatous polyposis, vascular malformations, lipomas, hemangiomas, and genital freckling. Other features include developmental delay, hypotonia, and scoliosis. Cowden syndrome is also an autosomal dominant disorder, mainly characterized by multiple hamartomas and high risk of breast, thyroid, and other cancers. PTEN encodes the main inhibitor of the PI3K-AKT pathway, regulating cell growth and proliferation, and protein synthesis. Therefore, germline loss-of-function mutations in this gene lead to excessive growth, particularly affecting connective tissues. Detection of PTEN mutations is critical for clinical management and treatment strategies.

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Screening for germline phosphatase and tensin homolog-mutations in suspected Cowden syndrome and Cowden syndrome-like families among uterine cancer patients

Oncology Letters ◽

10.3892/ol.2015.2890 ◽

2015 ◽

Vol 9 (4) ◽

pp. 1782-1786 ◽

Cited By ~ 2

Author(s):

GERASIMOS TZORTZATOS ◽

CHRISTOS ARAVIDIS ◽

ANNIKA LINDBLOM ◽

MIRIAM MINTS ◽

EMMA THAM

Keyword(s):

Cancer Patients ◽

Uterine Cancer ◽

Cowden Syndrome ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

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A Pediatric Case of Cowden Syndrome with Graves’ Disease

Case Reports in Pediatrics ◽

10.1155/2017/2750523 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4

Author(s):

Cláudia Patraquim ◽

Vera Fernandes ◽

Sofia Martins ◽

Ana Antunes ◽

Olinda Marques ◽

...

Keyword(s):

Treatment Options ◽

Antithyroid Drug ◽

Human Tumor ◽

Suppressor Gene ◽

Cowden Syndrome ◽

Graves Disease ◽

Multisystem Disorder ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Coarse Facies

Cowden syndrome (CS) is a rare dominantly inherited multisystem disorder, characterized by an extraordinary malignant potential. In 80% of cases, the human tumor suppressor gene phosphatase and tensin homolog (PTEN) is mutated. We present a case of a 17-year-old boy with genetically confirmed CS and Graves’ disease (GD). At the age of 15, he presented with intention tremor, palpitations, and marked anxiety. On examination, he had macrocephaly, coarse facies, slight prognathism, facial trichilemmomas, abdominal keratoses, leg hemangioma, and a diffusely enlarged thyroid gland. He started antithyroid drug (ATD) therapy with methimazole and, after a 2-year treatment period without achieving a remission status, a total thyroidectomy was performed. Diagnosis and management of CS should be multidisciplinary. Thyroid disease is frequent, but its management has yet to be fully defined. The authors present a case report of a pediatric patient with CS and GD and discuss treatment options.

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Phosphatase and Tensin Homolog (PTEN) Gene Mutations and Autism: Literature Review and a Case Report of a Patient With Cowden Syndrome, Autistic Disorder, and Epilepsy

Journal of Child Neurology ◽

10.1177/0883073811420296 ◽

2011 ◽

Vol 27 (3) ◽

pp. 392-397 ◽

Cited By ~ 41

Author(s):

Sara Conti ◽

Maria Condò ◽

Annio Posar ◽

Francesca Mari ◽

Nicoletta Resta ◽

...

Keyword(s):

Case Report ◽

Literature Review ◽

Autistic Disorder ◽

Gene Mutations ◽

Cowden Syndrome ◽

Pten Gene ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

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High Throughput Screen Identifies the DNMT1 (DNA Methyltransferase-1) Inhibitor, 5-Azacytidine, as a Potent Inducer of PTEN (Phosphatase and Tensin Homolog)

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314458 ◽

2020 ◽

Vol 40 (8) ◽

pp. 1854-1869

Author(s):

Keith A. Strand ◽

Sizhao Lu ◽

Marie F. Mutryn ◽

Linfeng Li ◽

Qiong Zhou ◽

...

Keyword(s):

Protein Expression ◽

High Throughput ◽

Knockout Mice ◽

Vascular Remodeling ◽

Dna Methyltransferase ◽

Dna Methyltransferase 1 ◽

Protective Effects ◽

High Throughput Screen ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog

Objective: Our recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Ang II (angiotensin II)-induced pathological vascular remodeling, suggesting that pharmacological PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Approach and Results: To identify novel PTEN activators, we conducted a high-throughput screen using a fluorescence based PTEN promoter-reporter assay. After screening ≈3400 compounds, 11 hit compounds were chosen based on level of activity and mechanism of action. Following in vitro confirmation, we focused on 5-azacytidine, a DNMT1 (DNA methyltransferase-1) inhibitor, for further analysis. In addition to PTEN upregulation, 5-azacytidine treatment increased expression of genes associated with a differentiated SMC phenotype. 5-Azacytidine treatment also maintained contractile gene expression and reduced inflammatory cytokine expression after PDGF (platelet-derived growth factor) stimulation, suggesting 5-azacytidine blocks PDGF-induced SMC de-differentiation. However, these protective effects were lost in PTEN-deficient SMCs. These findings were confirmed in vivo using carotid ligation in SMC-specific PTEN knockout mice treated with 5-azacytidine. In wild type controls, 5-azacytidine reduced neointimal formation and inflammation while maintaining contractile protein expression. In contrast, 5-azacytidine was ineffective in PTEN knockout mice, indicating that the protective effects of 5-azacytidine are mediated through SMC PTEN upregulation. Conclusions: Our data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.

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