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 Boztuğ & 3 others Michael Lenardo, Özden Sanal, İlhan Tezcan

Research output: Contribution to journalArticle

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+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
DOIs
Publication statusAccepted/In press - 1 Jan 2019

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Autoimmune Lymphoproliferative Syndrome
Common Variable Immunodeficiency
Lipopolysaccharides
Hematopoietic Stem Cell Transplantation
B-Lymphocytes
Patient Admission
Respiratory Tract Infections
Western Blotting
Exome
T-Lymphocytes
Autoimmune Thyroiditis
Protein Deficiency
Agammaglobulinemia
Lymphopenia
Splenomegaly
Eosinophilia
Splenectomy
Regulatory T-Lymphocytes
Missense Mutation

Keywords

  • Hsct
  • LATAIE
  • 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., ... 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

A Spectrum of Clinical Findings from ALPS to CVID : Several Novel LRBA Defects. / Cagdas, Deniz; Halaçlı, Sevil Oskay; Tan, Çağman; Lo, Bernice; Çetinkaya, Pınar Gür; Esenboğa, Saliha; Karaatmaca, Betül; Matthews, Helen; Balcı-Hayta, Burcu; Arıkoğlu, Tuba; Ezgü, Fatih; Aladağ, Elifcan; Saltık-Temizel, İnci N.; Demir, Hülya; Kuşkonmaz, Barış; Okur, Visal; Gümrük, Fatma; Göker, Hakan; Çetinkaya, Duygu; Boztuğ, Kaan; Lenardo, Michael; Sanal, Özden; Tezcan, İlhan.

In: Journal of Clinical Immunology, 01.01.2019.

Research output: Contribution to journalArticle

Cagdas, D, Halaçlı, SO, Tan, Ç, Lo, B, Çetinkaya, PG, Esenboğa, S, Karaatmaca, B, Matthews, H, Balcı-Hayta, B, Arıkoğlu, T, Ezgü, F, Aladağ, E, Saltık-Temizel, İN, Demir, H, Kuşkonmaz, B, Okur, V, Gümrük, F, Göker, H, Çetinkaya, D, Boztuğ, K, Lenardo, M, Sanal, Ö & Tezcan, İ 2019, '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
Cagdas, Deniz ; Halaçlı, Sevil Oskay ; Tan, Çağman ; Lo, Bernice ; Çetinkaya, Pınar Gür ; Esenboğa, Saliha ; Karaatmaca, Betül ; Matthews, Helen ; Balcı-Hayta, Burcu ; Arıkoğlu, Tuba ; Ezgü, Fatih ; Aladağ, Elifcan ; Saltık-Temizel, İnci N. ; Demir, Hülya ; Kuşkonmaz, Barış ; Okur, Visal ; Gümrük, Fatma ; Göker, Hakan ; Çetinkaya, Duygu ; Boztuğ, Kaan ; Lenardo, Michael ; Sanal, Özden ; Tezcan, İlhan. / A Spectrum of Clinical Findings from ALPS to CVID : Several Novel LRBA Defects. In: Journal of Clinical Immunology. 2019.
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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.",
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author = "Deniz Cagdas and Hala{\cc}lı, {Sevil Oskay} and {\cC}ağman Tan and Bernice Lo and {\cC}etinkaya, {Pınar G{\"u}r} and Saliha Esenboğa and Bet{\"u}l Karaatmaca and Helen Matthews and Burcu Balcı-Hayta and Tuba Arıkoğlu and Fatih Ezg{\"u} and Elifcan Aladağ and Saltık-Temizel, {İnci N.} and H{\"u}lya Demir and Barış Kuşkonmaz and Visal Okur and Fatma G{\"u}mr{\"u}k and Hakan G{\"o}ker and Duygu {\cC}etinkaya and Kaan Boztuğ and Michael Lenardo and {\"O}zden Sanal and İlhan Tezcan",
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TY - JOUR

T1 - A Spectrum of Clinical Findings from ALPS to CVID

T2 - 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

PY - 2019/1/1

Y1 - 2019/1/1

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.

AB - 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.

KW - Hsct

KW - LATAIE

KW - LRBA deficiency

KW - Malignancy

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