Haematologica (Dec 2013)

Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

  • Anne Rensing-Ehl,
  • Ales Janda,
  • Myriam R. Lorenz,
  • Beryl P. Gladstone,
  • Ilka Fuchs,
  • Mario Abinun,
  • Michael Albert,
  • Karina Butler,
  • Andrew Cant,
  • Anna-Maria Cseh,
  • Martin Ebinger,
  • Sigune Goldacker,
  • Sophie Hambleton,
  • Holger Hebart,
  • Leonora Houet,
  • Karim Kentouche,
  • Ingrid Kühnle,
  • Kai Lehmberg,
  • Ester Mejstrikova,
  • Charlotte Niemeyer,
  • Milen Minkov,
  • Olaf Neth,
  • Gregor Dückers,
  • Stephan Owens,
  • Joachim Rösler,
  • Freimut H. Schilling,
  • Volker Schuster,
  • Markus G. Seidel,
  • Petr Smisek,
  • Martina Sukova,
  • Peter Svec,
  • Thomas Wiesel,
  • Benjamin Gathmann,
  • Klaus Schwarz,
  • Werner Vach,
  • Stephan Ehl,
  • Carsten Speckmann

DOI
https://doi.org/10.3324/haematol.2012.081901
Journal volume & issue
Vol. 98, no. 12

Abstract

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Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3+TCRα/β+CD4−CD8− “double negative” T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool.