The Clinical Spectrum of PTEN Hamartoma Tumor Syndrome: Exploring the Value of Thyroid Surveillance

2021 ◽  
pp. 1-9
Author(s):  
Julia A. Baran ◽  
Steven D. Tsai ◽  
Amber Isaza ◽  
Garrett M. Brodeur ◽  
Suzanne P. MacFarland ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Nodules ◽  
Autism Spectrum ◽  
Clinical Feature ◽  
Phosphatase And Tensin Homolog ◽  
Pten Hamartoma Tumor Syndrome ◽  
Tensin Homolog ◽  
Thyroid Screening ◽  
Clinical Advantage ◽  
Benign Histology

<b><i>Introduction:</i></b> Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) comprises a collection of clinical features characterized by constitutional variants in <i>PTEN</i>. Several guidelines recommend thyroid screening, beginning at the pediatric age at the time of PHTS diagnosis; however, the benefits of early surveillance has not been well defined. <b><i>Methods:</i></b> We conducted a retrospective investigation of patients followed up at the Children’s Hospital of Philadelphia with a diagnosis of PHTS between January 2003 and June 2019. In total, 81 patients younger than 19 years were identified. <b><i>Results:</i></b> The most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%). A total of 58 of 81 patients underwent thyroid surveillance, with 30 patients (51.7%) found to have a nodule(s). Ultimately, 16 patients underwent thyroidectomy, with 7.4% (6/81) diagnosed with thyroid cancer. All thyroid cancer patients were older than 10 years at diagnosis, and all displayed low-invasive behavior. Of the patients younger than 10 years at the time of thyroid ultrasound (US) surveillance, 71.4% (15/21) had a normal US. The remaining 6 patients had thyroid nodules, including 4 undergoing thyroid surgery with benign histology. <b><i>Discussion/Conclusion:</i></b> Patients with macrocephaly, impaired cognitive development and thyroid nodules, and/or early-onset gastrointestinal polyps should undergo constitutional testing for PHTS. There does not appear to be a clinical advantage to initiating thyroid US surveillance before 10 years of age. In PHTS patients with a normal physical examination, thyroid US surveillance can be delayed until 10 years of age.

scholarly journals A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotypes relationships

2018 ◽  
Author(s):  
Taylor L. Mighell ◽  
Sara Evans-Dutson ◽  
Brian j. O’Roak
Keyword(s):  
Phosphatase Activity ◽  
Autism Spectrum ◽  
Saturation Mutagenesis ◽  
Single Amino Acid ◽  
Pten Protein ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Lipid Phosphatase ◽  
Functional Scores

ABSTRACTPhosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). These data uncovered novel insights into PTEN protein structure, biochemistry, and mutation tolerance. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16×10-5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data.

scholarly journals OR22-02 PTEN Hamartoma Tumor Syndrome in Pediatrics: Triggers for Evaluation and the Value of Surveillance

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Julia Baran ◽  
Steven Tsai ◽  
Daniel Singleton ◽  
Amber Isaza ◽  
Garrett Brodeur ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Clinical Features ◽  
Early Onset ◽  
Gastrointestinal Disease ◽  
Suppressor Gene ◽  
Clinical Feature ◽  
Oral Lesions ◽  
Thyroid Ultrasound ◽  
Pten Hamartoma Tumor Syndrome ◽  
Invasive Behavior

Abstract Context: PTEN Hamartoma Tumor Syndrome (PHTS) comprises a collection of rare clinical disorders characterized by germline mutations in the tumor suppressor gene PTEN. Current guidelines recommend screening for thyroid tumors beginning in pediatric age at the time of PHTS diagnosis; however, the benefit of early surveillance has not been well defined. Patients/Objective: We conducted a retrospective, single-site cohort investigation of patients followed at the Children’s Hospital of Philadelphia with diagnosis of PHTS between January 2003 - June 2019. In total, 81 patients under 18 years of age were identified. Clinical features, PTEN mutation codon, thyroid and gastrointestinal (GI) features were extracted from the electronic health record. The aim of the study is to assess genotype-phenotype, the incidence of thyroid and gastrointestinal disease, and to determine whether current recommendations for thyroid surveillance are improving outcomes. Results: The most common clinical feature at presentation was macrocephaly (85%) followed by impaired development (42%), skin/oral lesions (31%), and autistic spectrum disorder (27%). GI polyps were the presenting feature in 5 patients, with 14 of 81 patients ultimately diagnosed secondary to constipation (71%), rectal bleeding (64%), and/or abdominal pain (50%). All polyps were benign. A total of 58 of 81 patients underwent thyroid surveillance, with 30 patients (52%) found to have a nodule(s). Ultimately, 16 patients underwent thyroidectomy, with 31% (5/16) diagnosed with thyroid cancer. All thyroid cancer patients were greater than 10 years of age at diagnosis and all displayed low-invasive behavior (ATA low-risk). Of the patients &lt 10 years at the time of thyroid ultrasound (US) surveillance, 74% (14/19) had a normal US. The remaining five patients who underwent thyroid surgery all had benign histology. No genotype-phenotype relations were found; however, patients with identical mutations were found to have similar clinical features. Conclusions: Patients with macrocephaly associated with impaired development, skin/oral lesions, thyroid nodules and/or early onset GI polyps should undergo germline testing for PHTS. There does not appear to be a clinical advantage to initiating thyroid US surveillance prior to 10 years of age. Early detection may not improve outcome of thyroid cancer as the majority of thyroid cancers display low-invasive behavior. In PHTS patients with a normal physical exam, thyroid ultrasound surveillance can be delayed until after 10 years of age. Early onset GI polyps may be the presenting diagnosis of PHTS.

The Accuracy of ACR TI-RADS Classification of Neck Ultrasound as a First-Line Diagnostic Approach for Thyroid Neoplasms in Pediatric Patients: A Retrospective Study

2018 ◽  
Vol 5 (1) ◽  
pp. 13-23
Author(s):  
Nikolai S. Grachev ◽  
Elena V. Feoktistova ◽  
Igor N. Vorozhtsov ◽  
Natalia V. Babaskina ◽  
Ekaterina Yu. Iaremenko ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Predictive Value ◽  
Thyroid Nodules ◽  
Pediatric Patients ◽  
Thyroid Neoplasms ◽  
Diagnostic Methods ◽  
Diagnostic Approach ◽  
First Line ◽  
Neck Ultrasound

Background.Ultrasound (US)-guided fine-needle aspiration biopsy (FNAB) is the gold standard in diagnosing the pathological nature of undetermined thyroid nodules. However, in some instances limitations and shortcomings arise, making it insufficient for determining a specific diagnosis.Objective.Our aim was to evaluate the effectiveness of ACR TI-RADS classification of neck ultrasound as a first-line diagnostic approach for thyroid neoplasms in pediatric patients.Methods.A retrospective analysis was made of FNA and US protocols in 70 patients who underwent the examination and treatment at Dmitry Rogachev National Research Center between January 2012 and August 2017. In the retrospective series 70% (49/70) of patients undergone FNA and 43% (30/70) of them undergone repeated FNA. All US protocols were interpreted according to ACR TI-RADS system by the two independent experts. The clinical judgment was assessed using the concordance test and the reliability of preoperative diagnostic methods was analized.Results.According to histologic examination protocols, benign nodules reported greater multimorbidity 29% (20/70), compared with thyroid cancer 17% (12/70), complicating FNA procedure. A statistically significant predictor of thyroid cancer with a tumor size ACR TI-RADS showed a significant advantage of ACR TI-RADS due to higher sensitivity (97.6 vs 60%), specificity (78.6 vs 53.8%), positive predictive value (87.2 vs 71.4%), and negative predictive value (95.7 vs 41.2%). Concordance on the interpreted US protocols according to ACR TI-RADS classification between two experts was high, excluding accidental coincidence.Conclusion.The data support the feasibility of US corresponding to the ACR TI-RADS classification as a first-line diagnostic approach for thyroid neoplasm reducing the number of unnecessary biopsies for thyroid nodules.

On the Classification of TI-RADS and Stratification of Signs of Thyroid Cancer According to Ultrasound Data

2017 ◽  
pp. 29-38 ◽  
Author(s):  
E. P. Fisenko ◽  
J. P. Sich ◽  
N. N. Vetsheva
Keyword(s):  
Thyroid Cancer ◽  
Retrospective Analysis ◽  
Thyroid Nodules ◽  
Thyroid Ultrasound ◽  
High Reproducibility ◽  
System 1

Objective:a comparative “blind” assessment of the thyroid nodules identified by ultrasound, according to the TI-RADS scale in various modifications.Materials and methods.Retrospective analysis of 149 echograms  of thyroid nodules by three independent experts was performed (the  experience of ultrasound of thyroid ultrasound for more than 7 years).Results. In solid nodules, high-specific large (more than 94%) and  small (more than 90%) ultrasound signs of thyroid cancer have been identified. The nodes are stratified according to the TI-RADS system: 1 – in the modification J.Y. Kwak et al. (2011), 2 – according to the  proposed system, taking into account small ultrasound signs of  thyroid cancer. High reproducibility of both systems are obtained. In the first system 13.7% of cancer nodes fell into the category of TI- RADS 3 (benign formations), in the second system only 5% of  cancers fell into the category of TI-RADS 3, which is important for  biopsy selection. The sensitivity of the first system was TI-RADS  82.05%, of the second system – 94.87%.Conclusions.Classification of TI-RADS can be used to interpret the  ultrasound results of thyroid nodules, taking into account both the  main large and small ultrasound signs of cancer. For its validation in  our country, it is necessary to further broad discussion of the proposed TI-RADS system.

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

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.

miR-139-5p promotes neovascularization in diabetic retinopathy by regulating the phosphatase and tensin homolog

2021 ◽  
Vol 44 (2) ◽  
pp. 205-218
Author(s):  
Zhongwei Zhang ◽  
Caiping Song ◽  
Tao Wang ◽  
Lei Sun ◽  
Ling Qin ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

scholarly journals The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1525
Author(s):  
Chunling Huang ◽  
Ji Bian ◽  
Qinghua Cao ◽  
Xin-Ming Chen ◽  
Carol A. Pollock
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Kidney Diseases ◽  
Mitochondrial Protein ◽  
Physiological Role ◽  
Close Link ◽  
Promising Alternative ◽  
Diabetic Kidney ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.

scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Mi Tian ◽  
Jingjing Wang ◽  
Shangming Liu ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Mrna ◽  
Normal Chow ◽  
Mice Liver

AbstractThe liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuRLKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3′ untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuRLKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

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