title: Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia.
abstract: 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.
authors.affiliation: stephan.ehl@uniklinik-freiburg.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.forename: Ales
authors.initials: A
authors.lastname: Janda
authors.forename: Myriam R
authors.initials: MR
authors.lastname: Lorenz
authors.forename: Beryl P
authors.initials: BP
authors.lastname: Gladstone
authors.forename: Ilka
authors.initials: I
authors.lastname: Fuchs
authors.forename: Mario
authors.initials: M
authors.lastname: Abinun
authors.forename: Michael
authors.initials: M
authors.lastname: Albert
authors.forename: Karina
authors.initials: K
authors.lastname: Butler
authors.forename: Andrew
authors.initials: A
authors.lastname: Cant
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Cseh
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.forename: Sigune
authors.initials: S
authors.lastname: Goldacker
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.forename: Holger
authors.initials: H
authors.lastname: Hebart
authors.forename: Leonora
authors.initials: L
authors.lastname: Houet
authors.forename: Karim
authors.initials: K
authors.lastname: Kentouche
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kühnle
authors.forename: Kai
authors.initials: K
authors.lastname: Lehmberg
authors.forename: Ester
authors.initials: E
authors.lastname: Mejstrikova
authors.forename: Charlotte
authors.initials: C
authors.lastname: Niemeyer
authors.forename: Milen
authors.initials: M
authors.lastname: Minkov
authors.forename: Olaf
authors.initials: O
authors.lastname: Neth
authors.forename: Gregor
authors.initials: G
authors.lastname: Dückers
authors.forename: Stephan
authors.initials: S
authors.lastname: Owens
authors.forename: Joachim
authors.initials: J
authors.lastname: Rösler
authors.forename: Freimut H
authors.initials: FH
authors.lastname: Schilling
authors.forename: Volker
authors.initials: V
authors.lastname: Schuster
authors.forename: Markus G
authors.initials: MG
authors.lastname: Seidel
authors.forename: Petr
authors.initials: P
authors.lastname: Smisek
authors.forename: Martina
authors.initials: M
authors.lastname: Sukova
authors.forename: Peter
authors.initials: P
authors.lastname: Svec
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiesel
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gathmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Werner
authors.initials: W
authors.lastname: Vach
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
mesh_terms: D000293:Adolescent; D001327:Autoimmune Diseases / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D053222:Fas Ligand Protein / Q000097:blood* / Q000235:genetics*; D005260:Female; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D014805:Vitamin B 12 / Q000097:blood*
chemical_list: D015415:Biomarkers; D053222:Fas Ligand Protein; D014805:Vitamin B 12