RÉSUMÉ
Objective@#To investigate the clinical, immunological, and molecular manifestations of nuclear factor kappa-B subunit 2 (NFκB2) gene mutation associated common variable immunodeficiency (CVID) .@*Methods@#A 14-month-old boy diagnosed with NFκB2-mutated CVID was admitted into Children's Hospital of Chongqing Medical University in December 2015. The clinical manifestations, biochemical tests, immunological function, molecular features, treatment, and follow-up of the patient were analyzed. The Chinese and PUBMED databases were searched with the key words "NFκB2" and "immune deficiency" and related literatures were reviewed.@*Results@#The patient had 4 episodes of pneumonias and one otitis media since the age of 6 months. The serum immunoglobulin levels were IgG 2.73 g/L, IgA<0.07 g/L, and IgM 0.12 g/L. The percentage of peripheral lymphocyte subsets demonstrated increased CD3+T lymphocyte (81.8%), increased CD4+ naïve T cell (39.1%), normal B cell (14.1%), low switched memory B and plasmablast B (respectively 0.1% and 0), and lightly diminished natural killer(NK) cell (4.13%). Within the peripheral CD4+T cells, the percentage of regulatory T cells (1.49% (control 4.08%)), T follicular helper (3.66% (control 11.0%)), and T helper 17 (9.65% (control 15.7%)) were decreased, while the percentage of T helper 2 (60.9% (control 46.5%)) was elevated. T lymphocyte proliferative response and T cell receptor repertoire diversity were normal. NK-cell cytotoxic activity was impaired. The whole-exome sequencing harbored a de novo heterozygous nonsense mutation in exon 22 (c.2557C>T; p. Arg853X) in the C-terminus of NF-κB2. The western blotting confirmed the decreased expression of NF-κB2 (p52) protein. The patient received intravenous immunoglobulin infusion monthly (400-600 mg/kg), followed by improvement of pulmonary infection. After searching the databases, a total of 28 cases (1 Chinese and 27 non-Chinese) were identified. There were 12 cases of nonsense mutation (5 were gain-of-function mutation), and 8 cases of missense and frameshift mutations, respectively. The main clinical manifestation was respiratory infection, followed by autoimmune diseases such as alopecia and trachyonychia. Fifteen cases developed adrenocorticotrophic hormone (ACTH) deficiency.@*Conclusions@#NF-κB2 signaling pathway played an important role in T and B lymphocyte differentiation, and NK-cell cytotoxic activity. NFκB2 mutation should be considered in cases with recurrent infections, hypogammaglobulinemia, and decreased memory B cells and plasma cells, especially when combined with ACTH deficiency.
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Objective@#To investigate the clinical and immunological laboratory features, mutations in SH2D1A gene and SAP protein expression in four children of two families with X-linked lymphoproliferative disease type 1(XLP-1).@*Method@#Four patients (Family A including Patient 1 and Patient 2, Family B including Patient 3 and Patient 4) and their maternal relatives were enrolled in this study. The clinical manifestation, EBV infection status and chest CT scan were analyzed. The absolute and relative numbers of lymphocyte subsets, T lymphocyte proliferative response, SAP protein expression were assessed by flow cytometry. Quantification of signal joint TCR rearrangementexcision circle (sjTRECs), CDR3 spectratyping of TCRvβ and gene mutation of SH2D1A were detected by PCR based on genomic DNA or cDNA.@*Result@#Four male patients from two families were diagnosed with XLP-1. The ages of disease onset were more than 1 year, more than 1 year, more than 1 month and 6 months. The ages at diagnosis were nine years and ten months, sixteen years and eight months, fourteen years and ten months, four years and nine months. All patients had recurrent infections and EBV infection. Patients 1, 2, and 3 had agammaglobulinemia and Patient 4 had hypogammaglobulinemia. Chest CT scan showed all patients had atelectasis and pneumonia, and Patient 3 had bronchiectasis. Patient 3 was diagnosised as Burkitt lymphoma. For immunological function, all patients exhibited reduced CD4/CD8 ratios, increased numbers of exhausted T lymphocyte, decreased number of NK cell. The numbers of total B lymphocyte and naïve B lymphocyte were normal, but the number of memory B lymphocyte declined in all cases. Four patients′ copy numbers of sjTRECs were low and CDR3 spectratypings of TCRvβ showed mildly skewed. But their T lymphocyte proliferative response was normal. SAP protein expression in four cases were measured by flow cytometry. Two patients from Family A were absent and two patients from Family B showed decreased values. SH2D1A gene sequence analysis showed that the patients of Family A harbored a nonsense mutation (c.163 C>T; p.R55X) in exon 2. Their mother and two sisters were carriers. A missense mutation of SH2D1A gene (c.278 G>A; p.G93D) in exon 3 was found in the patients of Family B. The mother was carrier. Four patients remain survived, Patient 3 gave up treatment, other three patients received IVIG therapy.@*Conclusion@#Four patients with XLP-1 from two families characterized by agammaglobulinemia have an extreme vulnerability to Epstein-Barr virus (EBV) infection. The functions of T cell, B cell and NK cell are impaired at different stages. The detection of SAP protein and SH2D1A gene are the key methods for diagnosis of XLP-1.
RÉSUMÉ
Objective@#To investigate the clinical and immunological laboratory features and gene mutation in a female patient who carried a germline gain-of-function mutation in STAT3.@*Method@#A patient with lymphadenopathy and pancytopenia, visited the Department of Rheumatology and Immunology of Children′s Hospital of Chongqing Medical University in May 2016. The clinical and laboratory characteristics, results of immunophenotyping and exome sequencing were analyzed retrospectively and related literature was reviewed.@*Result@#The patient was a four years old girl. The clinical manifestation consisted of autoimmune pancytopenia, lymphadenopathy and recurrent infections. Multiple exams showed that peripheral blood leukocyte count was (2.2-4.9)×109/L, red blood cell count was (2.09-5.75)×109/L, hemoglobin level was 64-165 g/L, platelet count was (52-138) ×109/L. Percentages of lymphocyte subsets showed that CD3+ T lymphocyte was 0.716 0 (CD4+ T lymphocyte was 0.326 0, CD8+ T lymphocyte was 0.323 0 and CD4- CD8-T TCRαβ+ lymphocyte was 0.029 0), CD19+ B lymphocyte was 0.235 0 (transitional B was 0.004 3), NK was 0.032 0. Percentages of CD4+ T lymphocyte release IL-4, IFN-γ, IL-17 and IL-21 were 0.014 9, 0.213, 0.024 0 and 0.021 0, respectively. Lymphocyte proliferation function and TCRVβ diversity were normal. The serum immunoglobulin levels were 16.4 g/L (IgG), 1.53 g/L (IgA), 3.99 g/L (IgM) and 3.20 kU/L (IgE). The patient carried a missense variant in the 21st exon of STAT3, c. 1974G>C, p.K658N, which was previously described as a gain-of-function mutation. The patient was treated with methylprednisolone and prednisone intermittently. There were significant improvements of hepatosplenomegaly, lymphadenopathy and pancytopenia. We searched internal database and literature for cases with gain-of-function mutations in STAT3. A total of 19 cases were identified, all were non-Chinese. Among 16 cases who had clinical data, age of onset of 11 patients was less than 5 years. 14 cases had autoimmune hemolytic anemia, autoimmune thrombocytopenia or autoimmune neutropenia. Twelve patients had lymphadenopathy while 11 had infections and 5 had endocrine abnormalities.@*Conclusion@#The patient with Primary immunodeficiency disease (PID) due to gain-of-function mutation in STAT3 gene often has early-onset autoimmune disorders, lymphadenopathy and recurrent infections. Since the routine immunological examination may be normal or slightly abnormal, comprehensive evaluation of immune function should be done. Genetic testing ultimately helps to confirm the diagnosis.