title: Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies.
abstract: BACKGROUND
  Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is caused by germ line mutations in the PTEN gene. Symptoms include cancer predisposition, immune deviations, and lipomas/lipomatosis. No causal standard therapy is available. We describe a therapeutic attempt with the mammalian target of rapamycin (mTOR) inhibitor sirolimus for a PHTS patient suffering from thymus hyperplasia and lipomatosis. We furthermore assessed the in vitro effects of sirolimus and other inhibitors on lipoma cells of the patient.
  
  
  METHODS
  The patient underwent clinical and blood examinations and whole-body magnetic resonance imaging to assess tumor sizes. Lipoma cells of the patient were incubated with inhibitors of the phosphoinositide-3-kinase (PI3K)/AKT/mTOR signaling pathway to analyze the effects on proliferation, adipocyte differentiation, and survival in vitro.
  
  
  RESULTS
  Sirolimus treatment improved somatic growth and reduced thymus volume. These effects diminished over the treatment period of 19 mo. Sirolimus decreased lipoma cell proliferation and adipocyte differentiation in vitro but did not cause apoptosis. PI3K and AKT inhibitors induced apoptosis significantly.
  
  
  CONCLUSIONS
  Sirolimus treatment led to an improvement of the patient's clinical status and a transient reduction of the thymus. Our in vitro findings point to PI3K and AKT inhibitors as potential treatment options for patients with severe forms of PHTS.
authors.affiliation: 1] Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany [2] Leipzig University Medical Center, IFB Adiposity Diseases, Leipzig, Germany.
authors.forename: Gordian L
authors.initials: GL
authors.lastname: Schmid
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kässner
authors.affiliation: John Radcliffe Hospital, Translational Gastroenterology Unit and Children's Hospital, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
authors.forename: Holm H
authors.initials: HH
authors.lastname: Uhlig
authors.affiliation: 1] Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany [2] Leipzig University Medical Center, IFB Adiposity Diseases, Leipzig, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kratzsch
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Norman
authors.initials: N
authors.lastname: Händel
authors.affiliation: Department of Paediatrics, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Fred-P
authors.initials: FP
authors.lastname: Zepp
authors.affiliation: Department of Paediatrics, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Kowalzik
authors.affiliation: Medical Genetics Center, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Laner
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Starke
authors.affiliation: 1] Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany [2] Leipzig University Medical Center, IFB Adiposity Diseases, Leipzig, Germany.
authors.forename: Franziska K
authors.initials: FK
authors.lastname: Wilhelm
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schuster
authors.affiliation: Department of Paediatric Radiology, University of Leipzig, Leipzig, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Viehweger
authors.affiliation: Department of Paediatric Radiology, University of Leipzig, Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hirsch
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Kiess
authors.affiliation: Hospital for Children & Adolescents, Department of Women and Child Health, Center for Pediatric Research Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Garten
mesh_terms: D002675:Child, Preschool; D006223:Hamartoma Syndrome, Multiple / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007231:Infant, Newborn; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D020123:Sirolimus / Q000627:therapeutic use*
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus