Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation.
Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care.
Pediatric Hematology/Oncology and Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address: shoshanav@hadassah.org.il.
Shoshana
S
Revel-Vilk
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Ute
U
Fischer
Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
Bärbel
B
Keller
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Schafiq
S
Nabhani
Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
Laura
L
Gámez-Díaz
Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
Anne
A
Rensing-Ehl
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Michael
M
Gombert
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Andrea
A
Hönscheid
Pediatric Hemato-Oncology Unit, Augusta Victoria Hospital, Jerusalem, Israel.
Hani
H
Saleh
Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Avraham
A
Shaag
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
Arndt
A
Borkhardt
Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
Bodo
B
Grimbacher
Center for Chronic Immunodeficiency, University Medical Center and University of Freiburg, Freiburg, Germany.
Klaus
K
Warnatz
Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel.
Orly
O
Elpeleg
Pediatric Hematology/Oncology and Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Polina
P
Stepensky
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA
D048868:Adaptor Proteins, Signal Transducing; C428703:LRBA protein, human
Autoimmune lymphoproliferative disorder; Immunodeficiency