A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects

Deniz Cagdas, Sevil Oskay Halaçlı, Çağman Tan, Bernice Lo, Pınar Gür Çetinkaya, Saliha Esenboğa, Betül Karaatmaca, Helen Matthews, Burcu Balcı-Hayta, Tuba Arıkoğlu, Fatih Ezgü, Elifcan Aladağ, İnci N. Saltık-Temizel, Hülya Demir, Barış Kuşkonmaz, Visal Okur, Fatma Gümrük, Hakan Göker, Duygu Çetinkaya, Kaan BoztuğMichael Lenardo, Özden Sanal, İlhan Tezcan

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3 Citations (Scopus)


Introduction: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. Methods: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). Results: The median age on admission and age of diagnosis were 7 years (0.3–16.5) and 11 years (5–44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαβ+CD4CD8) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1–3). In total, one patient died from sepsis during adulthood before HSCT. Conclusion: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell’s important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.

Original languageEnglish
JournalJournal of Clinical Immunology
Publication statusAccepted/In press - 1 Jan 2019



  • Hsct
  • LRBA deficiency
  • Malignancy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Cagdas, D., Halaçlı, S. O., Tan, Ç., Lo, B., Çetinkaya, P. G., Esenboğa, S., Karaatmaca, B., Matthews, H., Balcı-Hayta, B., Arıkoğlu, T., Ezgü, F., Aladağ, E., Saltık-Temizel, İ. N., Demir, H., Kuşkonmaz, B., Okur, V., Gümrük, F., Göker, H., Çetinkaya, D., ... Tezcan, İ. (Accepted/In press). A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects. Journal of Clinical Immunology. https://doi.org/10.1007/s10875-019-00677-6