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A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects.
J Clin Immunol 2019; 39(7):726-738JC

Abstract

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+CD4-CD8-) 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.

Authors+Show Affiliations

Department of Pediatrics, Division of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey. deniz.ayvaz@hacettepe.edu.tr.Institute of Child Health, Immunology, Hacettepe University, Ankara, Turkey.Institute of Child Health, Immunology, Hacettepe University, Ankara, Turkey.Sidra Medical and Research Center, Al Rayyan, Qatar.Department of Pediatrics, Division of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey.National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.Department of Medical Biology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Allergy and Immunology, Mersin University Medical School, Mersin, Turkey.Department of Pediatrics, Division of Pediatric Inborn Metabolic Disorders, Metabolism and Genetics, Gazi University Medical School, Ankara, Turkey.Department of Internal Medicine, Division of Hematology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Gastroenterology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Gastroenterology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Hematology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Hematology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Hematology, Hacettepe University Medical School, Ankara, Turkey.Department of Internal Medicine, Division of Hematology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Hematology, Hacettepe University Medical School, Ankara, Turkey.CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.Department of Pediatrics, Division of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey.Department of Pediatrics, Division of Pediatric Immunology, Hacettepe University Medical School, Ankara, Turkey.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31432443

Citation

Cagdas, Deniz, et al. "A Spectrum of Clinical Findings From ALPS to CVID: Several Novel LRBA Defects." Journal of Clinical Immunology, vol. 39, no. 7, 2019, pp. 726-738.
Cagdas D, Halaçlı SO, Tan Ç, et al. A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects. J Clin Immunol. 2019;39(7):726-738.
Cagdas, D., Halaçlı, S. O., Tan, Ç., Lo, B., Çetinkaya, P. G., Esenboğa, S., ... Tezcan, İ. (2019). A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects. Journal of Clinical Immunology, 39(7), pp. 726-738. doi:10.1007/s10875-019-00677-6.
Cagdas D, et al. A Spectrum of Clinical Findings From ALPS to CVID: Several Novel LRBA Defects. J Clin Immunol. 2019;39(7):726-738. PubMed PMID: 31432443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Spectrum of Clinical Findings from ALPS to CVID: Several Novel LRBA Defects. AU - Cagdas,Deniz, AU - Halaçlı,Sevil Oskay, AU - Tan,Çağman, AU - Lo,Bernice, AU - Çetinkaya,Pınar Gür, AU - Esenboğa,Saliha, AU - Karaatmaca,Betül, AU - Matthews,Helen, AU - Balcı-Hayta,Burcu, AU - Arıkoğlu,Tuba, AU - Ezgü,Fatih, AU - Aladağ,Elifcan, AU - Saltık-Temizel,İnci N, AU - Demir,Hülya, AU - Kuşkonmaz,Barış, AU - Okur,Visal, AU - Gümrük,Fatma, AU - Göker,Hakan, AU - Çetinkaya,Duygu, AU - Boztuğ,Kaan, AU - Lenardo,Michael, AU - Sanal,Özden, AU - Tezcan,İlhan, Y1 - 2019/08/20/ PY - 2019/04/05/received PY - 2019/07/25/accepted PY - 2019/8/23/pubmed PY - 2019/8/23/medline PY - 2019/8/22/entrez KW - Hsct KW - LATAIE KW - LRBA deficiency KW - Malignancy SP - 726 EP - 738 JF - Journal of clinical immunology JO - J. Clin. Immunol. VL - 39 IS - 7 N2 - 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+CD4-CD8-) 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. SN - 1573-2592 UR - https://www.unboundmedicine.com/medline/citation/31432443/A_Spectrum_of_Clinical_Findings_from_ALPS_to_CVID:_Several_Novel_LRBA_Defects L2 - https://doi.org/10.1007/s10875-019-00677-6 DB - PRIME DP - Unbound Medicine ER -