PTEN hamartoma tumor syndrome: An overview

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 7.33). 09/2009; 11(10):687-94. DOI: 10.1097/GIM.0b013e3181ac9aea
Source: PubMed


PTEN hamartoma tumor syndrome (PHTS) encompasses four major clinically distinct syndromes associated with germline mutations in the tumor suppressor PTEN. These allelic disorders, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome are associated with unregulated cellular proliferation leading to the formation of hamartomas. Thus far, an increased risk of malignancy has only been documented in Cowden syndrome; however, current recommendations advise that all individuals with PTEN hamartoma tumor syndrome follow the cancer surveillance strategies suggested for Cowden syndrome until further data indicate otherwise. Because any individual phenotypic feature of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome are frequently present in the general population, many individuals often go undiagnosed and consequently do not benefit from available cancer surveillance strategies. Therefore, it is critical for clinicians to recognize the phenotypic features associated with these syndromes to accurately diagnose and provide preventative care. This overview details the clinical description of the PTEN hamartoma tumor syndrome and associated disorders, their diagnosis and molecular/genetic testing, as well as differential diagnosis for assessment of other hamartoma-associated syndromes.

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Available from: Charis Eng, May 19, 2014
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    • "Among other possible overgrowth candidate genes, germ-line mutations in the PTEN gene have been previously associated with a group of disorders called PTEN hamartoma tumor syndrome, which are characterized by macrocephaly, intellectual disability and overgrowth [Yin and Shen, 2008; Hobert and Eng, 2009; Tan et al., 2011]. They include Cowden syndrome [OMIM 158350; Tan et al., 2011], with 85% of patients carrying a PTEN mutation; Bannayan-Riley-Ruvalcaba syndrome, with 65% of patients with PTEN mutation, and Proteus syndrome (OMIM 176920), with 20% of patients with a mutation in the PTEN gene [Zhou et al., 2001, Eng, 2003; Orloff and Eng, 2008]. "
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    ABSTRACT: Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the NSD1 gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of NSD1 defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the NSD1 and PTEN genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical NSD1 microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo PTEN gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies PTEN in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in NSD1 molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).
    Molecular syndromology 01/2015; 6(1). DOI:10.1159/000370169
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    • "There are a number of disorders associated with PTEN mutations, including Cowden syndrome, Bannayan–Riley– Ruvalcaba syndrome, and autism spectrum disorders with macrocephaly . Of note, Proteus syndrome (PS) recently correlated with AKT1 mutations in a majority of patients [Lindhurst et al., 2011], has in the past also been associated with PTEN mutations [Zhou et al., 2000; Smith et al., 2002; Hobert and Eng, 2009; Lindhurst et al., 2011]; however, it is unclear whether these patients have PS or a different condition. Cowden syndrome (CS) is the phenotype most commonly associated with detectable PTEN mutations, reported in 80% of those with a clinical diagnosis of CS [Marsh et al., 1998]. "
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    ABSTRACT: We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities. The phenotype of PHTS may include MRI abnormalities such as multifocal periventricular white matter abnormalities and enlarged perivascular spaces. These neuroimaging findings, in association with macrocephaly and developmental delay, should prompt consideration of PTEN as a diagnostic possibility. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2014; 164(3). DOI:10.1002/ajmg.a.36309 · 2.16 Impact Factor
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    • "Phosphatase and tensin homolog deleted on chromosome 10 was originally identified as a tumor suppressor gene, which negatively regulates cell survival and proliferation and is mutated in several cancers (99, 100). PTEN germline mutations are associated with several hereditary disorders characterized by hamartomas and increased cancer risk such as Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome, collectively classified as PTEN hamartoma tumor syndrome (PHTS) (101). PTEN predominantly acts as a 3′ lipid phosphatase to oppose PI3K signaling by dephosphorylating PI(3,4,5)P3, a product of PI3K, at its 3′ hydroxyl position to yield PI(4,5)P2 (102). "
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    ABSTRACT: T lymphocytes play a critical role in host defense in all anatomical sites including mucosal surfaces. This not only includes the effector arm of the immune system, but also regulation of immune responses in order to prevent autoimmunity. Genetic targeting of PI3K isoforms suggests that generation of PI(3,4,5)P3 by PI3K plays a critical role in promoting effector T cell responses. Consequently, the 5'- and 3'-inositol poly-phosphatases SHIP1, SHIP2, and phosphatase and tensin homolog capable of targeting PI(3,4,5)P3 are potential genetic determinants of T cell effector functions in vivo. In addition, the 5'-inositol poly-phosphatases SHIP1 and 2 can shunt PI(3,4,5)P3 to the rare but potent signaling phosphoinositide species PI(3,4)P2 and thus these SHIP1/2, and the INPP4A/B enzymes that deplete PI(3,4)P2 may have precise roles in T cell biology to amplify or inhibit effectors of PI3K signaling that are selectively recruited to and activated by PI(3,4)P2. Here we summarize recent genetic and chemical evidence that indicates the inositol poly-phosphatases have important roles in both the effector and regulatory functions of the T cell compartment. In addition, we will discuss future genetic studies that might be undertaken to further elaborate the role of these enzymes in T cell biology as well as potential pharmaceutical manipulation of these enzymes for therapeutic purposes in disease settings where T cell function is a key in vivo target.
    Frontiers in Immunology 09/2013; 4:288. DOI:10.3389/fimmu.2013.00288
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