Considerations on diagnosis and surveillance measures of PTEN hamartoma tumor syndrome: clinical and genetic study in a series of Spanish patients

PHTS Working Group

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Background: The limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease. Results: We reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research. Conclusions: This study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines.

Original languageEnglish
Article number85
JournalOrphanet Journal of Rare Diseases
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the European Regional Development Fund in the framework of project PI14/00459, and by a grant from the Federación Española de Enfermedades Raras (FEDER). FPI fellowship BES‐2015‐071383 to LP-C, funded by MINECO and the European Social Fund (ESF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2022, The Author(s).


  • Cowden syndrome
  • Exome
  • NGS
  • PTEN gene
  • PTEN hamartoma tumor syndrome


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