Article

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: 6.44). 09/2009; 11(10):687-94. DOI: 10.1097/GIM.0b013e3181ac9aea
Source: PubMed

ABSTRACT 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%).
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    • "Volume 4, Number 3, June 2013 114 thyroid and endometrial cancer, as well as multiple neurological features [8] [9]. Neuronal patterning in the central nervous system is controlled by a variety of signaling pathways that guide neuronal migration to form laminae. Directed migration of neuronal precursor cells or immature neurons to the proper positions is critical during the lamination. "
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    ABSTRACT: PTEN plays an important role not only in tumorigenesis but also in the normal development of central nervous system. PTEN loss in neural progenitor cells during embryogenesis disrupts migration and proper formation of the brain laminar structure. We generated a conditional PTEN knockout mouse by crossing mice that express Cre recombinase driven by the human GFAP promoter to a floxed PTEN gene to investigate the role of astroglial PTEN signaling pathway in neuronal patterning and lamination. We found PTEN loss not only in astroglial cells, but also in radial glia-derived neurons in hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mice. Homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mice showed progressive brain enlargement with cellular disorganization that occurred predominantly in hippocampus and cerebellum and died by postnatal day 20. Confocal images show that nestin-positive radial glial cells were observed in the hippocampus, cortex, and cerebellum at postnatal day 0 in homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp), but not in heterozygous hGFAP-Cre(+/-)/PTEN(loxp/-) and hGFAP-Cre(-/-)/PTEN(loxp/loxp) mice. Homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mouse eyes, which lack radial glial lineage, were able to develop normal architectonics after birth. In addition, we also found that neuronal progenitor migration was defected at postnatal day 0 in homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) mice. These results suggest that PTEN has a critical role in regulating radial glial differentiation, proliferation, maturation, and eventually neuronal patterning in central nervous system in a spatio-temporal dependent manner.
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    • "Conversely, cancer screening in regard to breast and thyroid malignancies is well defined and recommended for CS patients beginning at 18 years of age or 5 years before the family's earliest age of cancer diagnosis (Hobert and Eng, 2009; Gammon et al., 2009). This case illustrates the importance of recognizing both the features of CS and the clinical manifestations of its associated cancers, which may present during adolescence. "
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