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The plethora, clinical manifestations and treatment options of autoimmunity in patients with primary immunodeficiency.

Abstract

Aim: Although the association between primary immunodeficiency and autoimmunity is already well-known, it has once again become a topic of debate with the discovery of newly-defined immunodeficiencies. Thus, investigation of the mechanisms of development of autoimmunity in primary immunodefficiency and new target-specific therapeutic options has come to the fore. In this study, we aimed to examine the clinical findings of autoimmunity, autoimmunity varieties, and treatment responses in patients who were genetically diagnosed as having primary immunodeficiency.

Material and Methods: The files of patients with primary immunodeficiency who had clinical findings of autoimmunity, who were diagnosed genetically, and followed up in our clinic were investigated. The demographic and clinical features of the patients and their medical treatments were evaluated.

Results: Findings of autoimmunity were found in 30 patients whose genetic mutations were identified. The mean age at the time of the first symptoms was 8.96[+ or -]14.64 months, and the mean age of receiving a genetic diagnosis was 82.55[+ or -]84.71 months. The most common diseases showing findings of autoimmunity included immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (16.7%); autoimmune lymphoproliferative syndrome (10%); lipopolysaccharide-responsive beige-like anchor protein deficiency (10%); and DiGeorge syndrome (10%). Twelve (40%) patients showed findings of autoimmunity at the time of first presentation. The most common findings of autoimmunity included inflammatory bowel disease, inflammatory bowel disease-like findings (n=14, 46.7%), immune thrombocytopenic purpura (n=11, 36.7%), and autoimmune hemolytic anemia (n=9, 30.0%). A response to immunosupressive agents was observed in 15 (50%) patients. Ten patients underwent hematopoietic stem cell transplantation. Six patients were lost to follow-up due to a variety of complications.

Conclusion: Autoimmunity is frequently observed in patients with primary immunodeficiency. The possibility of primary immunodeficiency should be considered in patients with early-onset manifestations of autoimmunity, and these patients should be carefully monitored in terms of immunodeficiency development. Early diagnosis of primary immunodeficiency may provide favorable outcomes in terms of survival. (Turk Pediatri Ars 2016; 51: 186-92)

Keywords: Autoimmunity, autoimmune hemolytic anemia, inflammatory bowel disease, primary immunodeficiency

Introduction

Primary immune deficiency disorders (PID) are a group of genetic diseases characterized by recurrent infections. To date, at least 300 diferrent gene mutations have been found to lead to morbidity resulting in PID (1). Although they are known as rare diseases, recent investigations have shown that they occur more commonly than expected (2). In Turkey, the prevalence was found as 30.5/100 000 in a two-center study conducted in the Marmara and Egean regions (3). Autoimmunity is also frequently observed in additon to recurrent infections in PID (1). Disruption in central or peripheral regulatory mechanisms in T and/or B cells, increased antigen load due to recurrent infections, and inability to eliminate dead cells are blamed for the development of autoimunity (4-6). Briefly stated, disruptions in the steps of development of the immune system may lead to autoimmuntiy by disupting the mechanism of recognition and tolerance of self.

In some immune deficiencies, the first sign of disease may be autoimmunity. Especially in infancy, findings of autoimmunity should raise suspicion for primary immune deficiency even though infection has not yet been observed (7). Observation of autoimmunity alone in the beginning may prolong the time for making the diagnosis or may lead to the use of inappropriate therapeutic methods. In this context, pediatricians' awareness, especially of the relationship of early-onset autoimmunity with PID will improve the chances of early diagnosis of PID. In addition, knowledge of disease-specific mechanisms of autoimmunity will provide establishment of specific treatment. In this study, the autoimmunity variety, treatment options, and survival were evaluated in patients with PID who were genetically diagnosed and who had autoimmunity findings.

Material and Methods

In this study, the demographic properties and autoimmunity findings of PID patients who were diagnosed genetically and who had autoimmunity findings were examined retrospectively. Patients who had no genetic diagnosis, but who had autoimmunity findings and were being followed up with diagnoses of common variable immune deficiency, selective IgA deficiency, and combined immune deficiency were excluded from this study. Verbal consent was obtained from the patients and written informed consent was obtained from the parents for the recording of data. Ethics committee approval was obtained from the ethics committee of our university (09.04.2015, number: 09.2015.249).

Demographic and clinical properties

The current age, age at the time of diagosis, age at the time of the first symptoms, sex, consanguineous marriage, genetic diagnoses, clinical and laboratory findings, treatment methods, treatment responses, and survival data were examined.

Autoimmunity findings

The main autoimmunity findings examined included autoimmune hemolytic anemia (AHA), immune thrombocytopenic purpura (ITP), autoimmune thyroiditis, eczema, arthritis, lupus-like rash, inflammatory bowel disease (IBD)/IBD-like findings, adrenal failure, diabetes mellitus (DM), gastritis, hepatis, nephrotic syndrome, psoriasis, vitiligo, pericarditis, hypoparathyroidism, alopesia, cutaneous granuloma, and vasculitis. In addition, autoantibody positivity was also investigated.

Statistical analysis

Data were analyzed using Statistical Package for the Social Sciences version 22.0 (SPSS Inc.; Chicago, IL, USA). Continuous variables among the descriptive statistics are expressed as mean[+ or -]standard deviation (SD). Frequency analyses,, are expressed as number (n) and percentage (%).

Results

A total of 30 patients who were being followed up in our division because of immune deficiency, who were diagnosed genetically, and who had autoimmunity findings were evaluated. The demographic and clinical properties of the patients are shown in Table 1.

Genetic diagnoses

Eighteen different genetic diagnoses were observed in the patients. These included X-linked immune dysregulation, polyendocrinopathy, enteropathy syndrome (IPEX) (n=5, 16.7%), autoimmune lymphoproliferative syndrome (ALPS) (n=3, 10.0%), lipopolysaccharide-responsive beigelike anchor protein deficiency (LRBA) (n=3, 10.0%), DiGeorge syndrome (DGS) (n=3, 10.0%), atypical RAG1 deficiency (n=2, 6.7%), DOCK8 deficiency (n=2, 6.7%), CD 19 deficiency (n=1, 3.3%), loss of function mutation of the PI3KR1 gene (n=1, 3.3%), gain of function mutation of the PIK3CD gene (n=1, 3.3%), interleukin (IL)-10 receptor deficiecny (n=1, 3.3%), autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) (n=1, 3.3%), excessive gain of function mutation of the STAT1 gene (n=1, 3.3%), protein kinase C, delta (PRKCD) deficiecny (n=1, 3.3%), IL-21 receptor deficiency (n=1, 3.3%), chronic granulomatous disease (CGD) (n=1, 3.3%), Wiskott-Aldrich syndrome (WAS) (n=1, 3.3%), ataxia telengiectasia (n=1, 3.3%), and RAG2 deficiency (n=1, 3.3%). Autoimmune findings were observed in 12 of 30 (40%) patients at the initial presentation. The diagnoses of these patients were as follows: IPEX, ALPS, LRBA deficiency, RAG1 deficiency, DGS, PRKCD deficiency, IL-10 receptor deficiency, and RAG2 deficiency.

Autoimmunity findings, treatment, and survival

The autoimmuninty properties observed through the diagnoses of the patients are shown in Table 2. The most common autoimmunity findings included IBD/IBD-like findings (n=14, 46.7%), ITP (n=11, 36.7%) and AHA (n=9, 30.0%) (Figure 1). The cutaneous findings observed in the patients are shown in Figure 2. Laboratory findings revelead that the direct Coombs test was positive in 9 (30.0%) patients, antinuclear antibiody (ANA) was positive in 5 (16.7%) patients, and thyroid autoantibodies were positive in 4 (13.3%) patients. Antiplatelet antibodies were tested in one of eleven patients who had thrombocytopenia, and were found positive. Autoantibody positivity was not found in 10 patients (33.3%). The agents used to treat autoimmunity findings varied in each patient and these included intravenous immunoglobulin, corticosteroids, sirolimus, rituximab, cyclophosphamide, hydroxychloroquine, azathioprine, mycophenolate mofetil, cyclosporin, methotrexate, etanercept, and thyroid hormone. Splenectomy was performed in a patient who had treatment-resistant chronic thrombocytopenia. The survival rate was 70% (n=7) in 10 patients who underwent bone marrow transplantation. The causes of death in six patients who were lost included graft versus host disease (GvHD), sepsis, acute respiratory distress syndrome (ARDS), intracranial hemorrhage, and intracranial mycotic aneursm. The therapies, treatment responses, and clinical prognoses of the patients are presented in Table 2.

Discussion

Although the typical characteristic of primary immunodeficiencies is recurrent infections, autoimmunity is observed as a predominant finding in some immune deficiencies (8). Among these diseases, APECED, ALPS, IPEX, IPEX-like syndromes (CD25 and STAT5b deficiency, LRBA deficiency, CTLA4 deficiency, gain of function mutation of the STAT1 gene), IL-10/IL-10 receptor deficiency and newly defined Phospholipase C-gamma-2-related autoantibody deficiency and immune dysregulation (PLAID) are characterized by autoimmunity. In addition, autoimmunity findings may also be observed during the course of the disease in common variable immune deficiency (CVID), hyper IgM syndrome, X-linked agammaglobulinemia, selective IgA deficiency, CKGD, severe combined immune deficiencies, WAS, and complement deficiencies. The main mechanisms blamed for autoimmunity in primary immune deficiencies include escape of T cells, which react to cells of the organism from central and peripheral supressive steps; disruption in pathways that affect programmed cell death; abnormal function of regulatory T cells; and the inability to eliminate abnormal B cells in the bone marrow or in peripheral tissues (4, 5, 9).

Among our patients, autoimmunity was observed most commonly in IPEX. In IPEX, autoimmunity may be observed in many organs before the age of one year as a result of regulator T cell disruption (10). Autoimmunity findings, which may be observed in IPEX, include type 1 DM, thyroiditis, autoimmune cytopenias, eczema, autoimmune enteropathy, hepatitis, nephrotic syndrome, interstitial nephritis, and arthritis (11). In our patients, eczema, hemolytic anemia, hypothyroidism, diarrhea, Type 1 DM, gastritis, hepatitis, and nephrotic syndrome were observed. In four of five patients, autoimmunity was observed in the early months of life as the first finding. In 45% of the cases of IPEX described in the literature, the findings occured in the neonatal period, and even at birth in 11 patients (11). Therefore, autoimmune involvement, especially of multiple organs in the early period necessitates the suspicion of IPEX, which is one of the primary immune deficiencies even if infection has not yet developed. In STAT5b deficiency, which is defined as similar to IPEX, IL-2 receptor mutation, gain of protein function mutation of the STAT1 and STAT3 genes, CTLA4 deficiency and LRBA deficiency, disruptions in signal pathways responsible for regulatory T cell function have also been identified (12-16). In our patients who had LRBA deficiency and gain of protein function mutation of the STAT1 gene, hemolytic anemia, IBD/IB-like findings, alopecia, thrombocytopenia, and hypothyroidism were detected.

In autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy, autoimmune involvement of many organs is observed because of the inability to eliminate T cells, which react to the organism during development in the thymus as a result of mutation in the autoimmune regulatory gene (AIRE) (17, 18). Hypoparathyroidism, hypothyroidism, adrenal failure, chronic atrophic gastritis, pernicious anemia, autoimmune hepatitis, and vitiligo are among the findings observed in this disease in which au toimmune reaction is observed against many endocrine organs (19). Hypoparathyroidsm, hypothyroidism, adrenal failure, and vitiligo were observed in our patients.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

It is thought that autoimmunity observed in DiGeorge syndrome is caused both by disruption in expression of the AIRE gene, and decreased variety and number of regulatory T cells as a result of abnormal thymus development (20). Autoimmune disease may be observed with a rate of 8.5% in DiGeorge syndrome. The most common autoimmune findings include reduction in cell counts (ITP, AHA, neutropenia), hypothyroidism and arthritis, respectively (21). In our patients, hematologic disorders also predominated as an autoimmunity finding.

Programmed cell death is very important in terms of the balance of the immune system and development of tolerance. Autoimmune lymphoproliferative syndrome (ALPS) is characterized by disruption in cell death. Autoimmunity is observed in approximately 70% of patients (22). The most common findings include autoimmune hemolytic anemia and autoimmune thrombocytopenia. Direct Coombs test-positive hemolytic anemia was found in all three of our patients who had a diagnosis of autoimmune lymphoproliferative syndrome and thrombocytopenia was found in two. Antiplatelet and anti-neutrophil antibodies, together with anti-erythrocyte antibodies detected with a positive direct Coombs test are the most common autoantibodies found in ALPS (23, 24).

Autoimmunity observed in CGD is thought to be triggered by a prolonged inflammatory response related with the inability of phagocytes with disrupted oxidative function to eliminate cellular remnants and antigens (25, 26). The most common autoimmunity finding in these patients is IBD. In addition, discoid lupus, arthritis, and ITP may be observed (4). In our patient, recurrent pericarditis and hepatitis were observed (27).

It is known that early-onset IBD is related with immune deficiencies. CGD, IL-10/IL-10 receptor deficiency, WAS, IPEX and IPEX-like diseases, and severe combined immune deficiencies are among these immune deficiencies (28). An underlying immune deficiency should be kept in mind, especially in the presence of very early-onset IBD (below age six months), consanguineous marriage or multiple family members affected, and in patients with unresponsiveness to treatment and accompanying autoimmunity, because stem cell transplantation will be among the therapeutic options other than ordinary IBD treatment, if immune deficiency is found (11, 29). In addition, therapeutic interventions directed to prevent infections may also affect survival. The initial finding in our patient with IL-10 receptor deficiency was diarrhea. The symptoms started at the age of one month in this patient and stem cell transplantation was performed when no response to drugs used for IBD (azatyoprine, steroid, cyclosporin) was observed.

Cutaneous findings are frequently observed in primary immune deficiencies. The most common cutaneous finding is skin infections. In addition, eczema, erythrodermia, pigment changes, granuloma, vasculitic formations, and urticaria may also be observed (30). The main cutaneous findings observed in our patients included eczema, lupus-like cutaneous eruptions, vitiligo, granuloma, alopecia, and psoriasis. Although eczema is a frequent finding observed in childhood, severe eczema in early infancy may be a sign of DOCKS mutation, IPEX, and severe combined immune deficiencies. Cutaneous granulomas may be caused by infectious agents or occur as sterile granuloma in PID (30-33). Granuloma was observed in two of our patients who had ataxia telangiectasia and RAG2 mutation.

Rapid genetic diagnosis of primary immune deficiencies in recent years has enabled development of specific therapies for new and present gene disorders. For example, use of CTLA4 protein (abatacept) has provided great benefit in controlling intestinal findings and other autoimmine diseases, because CTLA4 protein is also reduced in cases of LRBA deficiency (34). Sirolimus is another specific drug and has increased the survival rates to a great extent in patients with IPEX, PI3KR1, PIK3CD, LRBA and ALPS (35, 36). In our patients, both autoimmune findings and organomegaly (liver, lymph node, and spleen) were controlled with sirolimus treatment. Almost complete regression was observed in cutaneous findings with hydroxychloroquine in our patient with PRKCD deficiency in association with cutaneous involvement (37). Anti-CD20 (rituximab) treatment was found more successful than corticosteroid in our patient with DOCK8 in association with hemolytic anemia. Finally, it has been reported that autoimmunity findings could be controlled with ruxolitinib (Janus kinase inhibitor) in patients with gain of function STAT1 mutation (38). As the mechanism of development of autoimmunity becomes clear, target-specific therapeutic opitions will increase gradually as observed in these examples.

In conclusion, autoimmunity occurs with different findings in various immune deficiencies independent of the mechanism. It should be kept in mind that early-onset autoimmunity findings and multiple autoimmunity may even be a sign of primary immune deficiency in patients who have not yet developed infection. This approach will increase the chance of early and accurate treatment and survival in these patients.

Ethics Committee Approval: Ethics committee approval was received for this study from the ethics committee of Marmara University School Medicine (04.09.2015- 09.2015.249).

Informed Consent: Verbal informed consent was obtained from patients and parents of patients who participated in this study.

Peer-review: Externally peer-reviewed.

Author Contributions: Concept - A.O.O, E.K.A., S.B.; Design - S.B.; Supervision - A.O.O, E.K.A., S.B.; Funding - A.O.O, E.K.A., S.B.; Materials - H.E.B., E.N., A.K.; Data Collection and/or Processing - H.E.B., E.N., A.K., A.O.O, E.K.A., S.B.; Analysis and/or Interpretation - H.E.B., S.B.; Literature Review - H.E.B., S.B.; Writing -H.E.B., S.B.; Critical Review - H.E.B., E.N.,A.K., A.O.O, E.K.A., S.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

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Hatice Ezgi Bans (1), Ayca Kiykim (2), Ercan Nain (2), Ahmet Oguzhan Ozen (2), Elif Karakoc-Aydiner (2), Safa Baris (2)

(1) Department of Peditarics, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey (2) Department of Peditarics, Division of Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey

Address for Correspondence: Safa Baris E-mail: safabaris@hotmail.com

Received: 30.01.2016

Accepted: 24.06.2016
Table 1. Demographic and clinical properties of the patients

Demographic and clinical properties

Sex, n, (%)                                    Female
                                                 Male
Current age (Mean[+ or -]SD) (years)
Age at the time of first symptoms
(Mean[+ or -]SD) (months)
                                            IPEX(n=5)
                                           ALPS (n=3)
                                      Di George (n=3)
                                            LRBA(n=3)
                                          DOCK8 (n=2)
                                           RAG1 (n=2)
Age at the time of genetic
diagnosis (Mean[+ or -]SD) (months)
Consanguineous marriage, n, (%)
Treatment response of
autoimmune findings, n, (%)
Bone marrow transplantation, n, (%)
Mortality, n, (%)

Demographic and clinical properties

Sex, n, (%)                                5(16.7)
                                          25 (83.3)
Current age (Mean[+ or -]SD) (years)  10.56[+ or -]8.02
Age at the time of first symptoms      8.96[+ or -]14.64
(Mean[+ or -]SD) (months)
                                       4.40[+ or -]4.72
                                       4.33[+ or -]3.21
                                       2.33[+ or -]2.30
                                       6.00[+ or -]0.00
                                       6.00[+ or -]0.00
                                      34.00[+ or -]36.76
Age at the time of genetic
diagnosis (Mean[+ or -]SD) (months)   82.55[+ or -]84.71
Consanguineous marriage, n, (%)            16(53.3)
Treatment response of
autoimmune findings, n, (%)               15 (50.0)
Bone marrow transplantation, n, (%)        10(33.3)
Mortality, n, (%)                          6 (20.0)

ALPS: autoimmune lymphoproliferative syndrome; DOCKS: dedicator of
cytokinesis S; IPEX: immune dysregulation, polyendocrinopathy,
enteropathy, X-linked; LRBA: lipopolysaccharide-responsive beige-like
anchor protein; RAG: recombination-activating gene

Table 2. Autoimmunity findings, treatment methods and prognoses by the
diagnoses of the patients

Diagnosis              Autoimmunity properties

CD 19 deficiency       Psoriasis
PI3KR1 mutation        UP, arthritis, IBD/IBD-like findings

PIK3CD mutation        IBD/IBD-like findings
IL-10 receptor         IBD/IBD-like findings
deficiency
APECED                 Hypothyroidism, adrenalitis, vitiligo
STAT1 mutation         ITP, Hypothyroidism
PRKCD deficiency       Eczema, ITP, SLE-like eruption,
                       IBD/IBD like findings
LRBA deficiency        AHA, ITPI

LRBA deficiency        ITP, IBD/IBD-like findings
LRBA deficiency        IBD/IBD-like findings, alopecia
IL-21 receptor         SLE-like eruption
deficiency
DOCK8 deficiency       Eczema, AHA
DOCK8 deficiency       Eczema, Vasculitis
DGS                    AHA, ITP
DGS                    ITP
DGS                    ITP
KGH                    Pericarditis, hepatitis

RAG1 deficiency        AHA, SLE-like eruption,
                       IBD/IBD-like findings
RAG1 deficiency        Hypothyroidism, DM, vitiligo
IPEX                   Eczema, AHA, IBD/IBD-like
                       findings
IPEX                   IBD/IBD-like findings, hepatitis,
                       nephrotic syndrome
IPEX                   Eczema, AHA, hypothyroidism, DM

IPEX                   IBD/IBD-like findings

IPEX                   IBD/IBD-like findings, gastritis
WAS                    Eczema, ITP, IBD/IBD-like findings
ALPS                   AHA, ITP
ALPS                   AHA, ITP
ALPS                   AHA, IBD/IBD-like findings
RAG2 deficiency        IBD/IBD-like findings
Ataxia telangiectasia   Cutaneous granuloma

Diagnosis              Autoimmune tests

CD 19 deficiency       ANA
PI3KR1 mutation

PIK3CD mutation
IL-10 receptor
deficiency
APECED                 AntiTPO
STAT1 mutation         AntiTPO
PRKCD deficiency       ANA, anti SSA,
                       antiribosomal p protein
LRBA deficiency        ANA, direct Coombs

LRBA deficiency
LRBA deficiency
IL-21 receptor         Lupus anticoagulant
deficiency
DOCK8 deficiency       Direct Coombs
DOCK8 deficiency
DGS                    Direct Coombs
DGS                    ANA
DGS
KGH

RAG1 deficiency        Direct Coombs

RAG1 deficiency        ATG, anti-islet cell antibody
IPEX                   Direct Coombs, anti-
                       enterocyte cell antibody
IPEX                   ANA

IPEX                   Anti-TPO, direct Coombs

IPEX                   Anti-enterocyte
                       cell antibody
IPEX                   Antiparietal cell antibody
WAS                    Anti-platelet antibody
ALPS                   ANA, direct Coombs
ALPS                   Direct Coombs
ALPS                   Direct Coombs
RAG2 deficiency
Ataxia telangiectasia

Diagnosis              Treatment

CD 19 deficiency       IVIG,PUVA
PI3KR1 mutation        IVIG, steroid, methotrexate,
                       etanercept, splenectomy, sirolimus
PIK3CD mutation        IVIG, steroid, sirolimus
IL-10 receptor         Azathioprine, steroid,
deficiency             cyclosporin
APECED                 Steroid, Levotyroxine
STAT1 mutation         Levothyroxine, IVIG
PRKCD deficiency       IVIG, hydroxychloroquine

LRBA deficiency        Steroid, cyclosporin,
                       mikofenolat mofetil, IVIG
LRBA deficiency        Steroid, IVIG
LRBA deficiency        Steroid, IVIG
IL-21 receptor         IVIG, hydroxychloroquine
deficiency
DOCK8 deficiency       IVIG, steroid, rituximab
DOCK8 deficiency       Steroid, cyclophosphamide
DGS                    IVIG
DGS                    IVIG
DGS                    IVIG
KGH                    Steroid

RAG1 deficiency        Rituximab, hydroxychloroquine,
                       IVIG, colchicine
RAG1 deficiency        Levothyroxine, IVIG
IPEX                   Steroid, cyclosporin

IPEX                   Azathioprine, steroid

IPEX                   Steroid, sirolimus

IPEX                   Steroid, sirolimus

IPEX                   Sirolimus
WAS                    IVIG, rituximab, eltrombopag
ALPS                   Steroid, IVIG, sirolimus
ALPS                   Steroid, cyclosporin
ALPS                   IVIG,G-CSF
RAG2 deficiency        Subcutaneous IVIG, steroid
Ataxia telangiectasia  IVIG, hydroxychloroquine

Diagnosis              Prognosis

CD 19 deficiency       Living
PI3KR1 mutation        Living

PIK3CD mutation        Living
IL-10 receptor         BMT/living
deficiency
APECED                 Living
STAT1 mutation         Bdtus/intracranial mycotic aneurism
PRKCD deficiency       Living

LRBA deficiency        BMT/living

LRBA deficiency        Living
LRBA deficiency        Living
IL-21 receptor         Exitus/sepsis
deficiency
DOCK8 deficiency       BMT/living
DOCK8 deficiency       BMT/living
DGS                    Living
DGS                    Living
DGS                    Living
KGH                    BMT/Exitus/
                       GVHH
RAG1 deficiency        Living

RAG1 deficiency        BMT/living
IPEX                   BMT/living

IPEX                   Exitus/ARDS

IPEX                   BMT/intracranial
                       hemorrhage/exitus
IPEX                   BMT/ARDS/exitus

IPEX                   Living
WAS                    Living
ALPS                   Living
ALPS                   Living
ALPS                   Living
RAG2 deficiency        BMT/living
Ataxia telangiectasia  Living

ALPS: autoimmune lymphoproliferative syndrome; ANA: anti-nuclear
antibody; APECED: autoimmune polyendocrinopathy, candidiasis,
ectodermal dystrophy; ATG: antithyroglobulin antibody; DGS: DiGeorge
syndrome; DM: diabetes mellitus; DOCKS: dedicator of cytokinesis 8;
GVHH: graft versus host disease; IL: interleukin; IPEX: immune
disregulation, polyendocrinopathy, enteropathy, X-linked; IVIG:
intravenous immunglobulin; CGD: chronic granulomatous disease;
BMT: bone marrow transfer; LRBA: lipopolysaccha ride-responsive
beige-like anchor protein; PIK3CD: phosphatidylinositol 3-kinase,
catalytic, delta; PI3KR1: phosphatidylinositol 3-kinase, regulatory
subunit 1; PRKCD: protein Kinase C, Delta deficiency; PUVA: psoralen
Ultra-Violet A; RAG: recombination-activating gene; SLE: systemic
lupus erythematosus; STAT1: signal transducer and activator of
transcription 1; TPO: thyroid peroxidase; WAS: Wiskott-Aldrich syndrome
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Title Annotation:Original Article
Author:Bans, Hatice Ezgi; Kiykim, Ayca; Nain, Ercan; Ozen, Ahmet Oguzhan; Karakoc-Aydiner, Elif; Baris, Saf
Publication:Turkish Pediatrics Archive
Article Type:Report
Date:Dec 1, 2016
Words:4581
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