-
The Netherlands Journal of Medicine Nov 2007In this report we present four patients with reversible hypogammaglobulinaemia who required immunoglobulin substitution for several years. One patient had documented...
In this report we present four patients with reversible hypogammaglobulinaemia who required immunoglobulin substitution for several years. One patient had documented systemic lupus erythematosus (SLE), the other three patients had primary hypogammaglobulinaemia without known cause. Whereas the cessation of azathioprine therapy may have contributed to the recovery in the patient with SLE, the restoration of the immunoglobulin production in the other three patients occurred spontaneously. All four patients were IgA deficient when the hypogammaglobulinaemia was first detected and remained so after IgM and IgG production had recovered. Two of the three patients who also had anti-IgA antibodies started to produce anti-IgA again after stopping the immunoglobulin substitution. We conclude that recovery of hypogammaglobulinaemia is possible but rare. When recovery is suspected, we recommend that immunoglobulin substitution is stopped and the antibody response to vaccination is tested.
Topics: Adolescent; Agammaglobulinemia; Child, Preschool; Female; Humans; IgA Deficiency; Infant; Male; Middle Aged; Risk Factors
PubMed: 18057460
DOI: No ID Found -
Journal of Clinical Immunology Aug 2023To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States...
PURPOSE
To understand the natural history and clinical outcomes for patients with X-linked agammaglobulinemia (XLA) in the United States utilizing the United States Immunodeficiency Network (USIDNET) patient registry.
METHODS
The USIDNET registry was queried for data from XLA patients collected from 1981 to 2019. Data fields included demographics, clinical features before and after diagnosis of XLA, family history, genetic mutation in Bruton's tyrosine kinase (BTK), laboratory findings, treatment modalities, and mortality.
RESULTS
Data compiled through the USIDNET registry on 240 patients were analyzed. Patient year of birth ranged from 1945 to 2017. Living status was available for 178 patients; 158/178 (88.8%) were alive. Race was reported for 204 patients as follows: White, 148 (72.5%); Black/African American, 23 (11.2%); Hispanic, 20 (9.8%); Asian or Pacific Islander, 6 (2.9%), and other or more than one race, 7 (3.4%). The median age at last entry, age at disease onset, age at diagnosis, and length of time with XLA diagnosis was 15 [range (r) = 1-52 years], 0.8 [r = birth-22.3 years], 2 [r = birth-29 years], and 10 [r = 1-56 years] years respectively. One hundred and forty-one patients (58.7%) were < 18 years of age. Two hundred and twenty-one (92%) patients were receiving IgG replacement (IgGR), 58 (24%) were on prophylactic antibiotics, and 19 (7.9%) were on immunomodulatory drugs. Eighty-six (35.9%) patients had undergone surgical procedures, two had undergone hematopoietic cell transplantation, and two required liver transplantation. The respiratory tract was the most affected organ system (51.2% of patients) followed by gastrointestinal (40%), neurological (35.4%), and musculoskeletal (28.3%). Infections were common both before and after diagnosis, despite IgGR therapy. Bacteremia/sepsis and meningitis were reported more frequently before XLA diagnosis while encephalitis was more commonly reported after diagnosis. Twenty patients had died (11.2%). The median age of death was 21 years (range = 3-56.7 years). Neurologic condition was the most common underlying co-morbidity for those XLA patients who died.
CONCLUSIONS
Current therapies for XLA patients reduce early mortality, but patients continue to experience complications that impact organ function. With improved life expectancy, more efforts will be required to improve post-diagnosis organ dysfunction and quality of life. Neurologic manifestations are an important co-morbidity associated with mortality and not yet clearly fully understood.
Topics: Humans; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Quality of Life; Agammaglobulinaemia Tyrosine Kinase; Genetic Diseases, X-Linked; Agammaglobulinemia; Mutation
PubMed: 37219739
DOI: 10.1007/s10875-023-01502-x -
Frontiers in Immunology 2023Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the gene, which...
BACKGROUND
Bruton's tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (XLA) is caused by mutation in the gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in XLA.
RESULTS
Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were . Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.
CONCLUSION
This report provides the first overview of demographic, clinical, immunological and genetic data of XLA in Malaysia. The combination of flow cytometric assessment and genetic analysis provides a definitive diagnosis for XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.
Topics: Male; Pregnancy; Female; Humans; Protein-Tyrosine Kinases; Malaysia; COVID-19; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia
PubMed: 37809070
DOI: 10.3389/fimmu.2023.1252765 -
Frontiers in Immunology 2020X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase () gene and is the most common genetic mutation in patients with congenital...
X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase () gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ≦2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for expression and genetic analysis. Nineteen (from 16 families) out of 29 patients had mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with mutations had obviously decreased expressions. sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.
Topics: Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Diseases, X-Linked; Humans; Infant; Male; Membrane Transport Proteins; Mitochondrial Precursor Protein Import Complex Proteins; Mutation; Pedigree; Phenotype; Pseudomonas; Respiratory Tract Infections; Sepsis; Taiwan; Young Adult
PubMed: 33013854
DOI: 10.3389/fimmu.2020.02001 -
Frontiers in Immunology 2022Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo... (Review)
Review
Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo reticularis. The clinical phenotype of DADA2 is, however, very broad and may involve several organ systems. Apart from vasculitis, children may present with i) Hematological manifestations (ii) Lymphoproliferation and iii) Immunodeficiencies. Patients with DADA2 can have variable patterns of cytopenias and bone marrow failure syndromes. Patients with DADA2 who have predominant haematological manifestations are associated with ADA2 gene variants that result in minimal or no residual ADA2 activity. Lymphoproliferation in patients with DADA2 may range from benign lymphoid hyperplasia to lymphoreticular malignancies. Patients may present with generalized lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome (ALPS) like phenotype, Hodgkin lymphoma, T-cell large granular lymphocytic infiltration of bone marrow and multicentric Castleman disease. Immunodeficiencies associated with DADA are usually mild. Affected patients have variable hypogammaglobulinemia, decrease in B cells, low natural killer cells, common variable immunodeficiency and rarely T cell immunodeficiency. To conclude, DADA2 has an extremely variable phenotype and needs to be considered as a differential diagnosis in diverse clinical conditions. In this review, we describe the evolving clinical phenotypes of DADA2 with a special focus on haematological and immunological manifestations.
Topics: Adenosine Deaminase; Agammaglobulinemia; Humans; Immunologic Deficiency Syndromes; Intercellular Signaling Peptides and Proteins; Polyarteritis Nodosa; Severe Combined Immunodeficiency
PubMed: 35592317
DOI: 10.3389/fimmu.2022.869570 -
Cleveland Clinic Journal of Medicine Feb 2006If a patient has frequent or recurrent bronchopulmonary or sinus infections, they may be due to low levels of immunoglobulins. This article describes common primary... (Review)
Review
If a patient has frequent or recurrent bronchopulmonary or sinus infections, they may be due to low levels of immunoglobulins. This article describes common primary (idiopathic) and secondary forms of hypogammaglobulinemia and how to evaluate and manage them.
Topics: Agammaglobulinemia; Diagnosis, Differential; Humans; Immunoglobulins, Intravenous
PubMed: 16478038
DOI: 10.3949/ccjm.73.2.133 -
The Journal of Allergy and Clinical... Jan 2020Primary antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies. More severe forms of PADs-common variable immunodeficiency (CVID) and X-linked...
BACKGROUND
Primary antibody deficiencies (PADs) are the most prevalent primary immunodeficiencies. More severe forms of PADs-common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA)-require immunoglobulin replacement therapy (IRT) and may have serious complications. Differentiating severe PAD from milder hypogammaglobulinemia not requiring IRT can involve prolonged evaluations and treatment discontinuation. Severe PAD is defined by plasma cell deficiency, but this requires a biopsy to establish. Serum B-cell maturation antigen (sBCMA) is elevated in multiple myeloma, but levels are reduced among patients with myeloma in remission who have hypogammaglobulinemia.
OBJECTIVE
To measure the sBCMA level in 165 subjects to determine whether it differentiates severe PAD-CVID and XLA-from less severe forms not requiring IRT and those without PAD.
METHODS
sBCMA, B cells, and tissue plasma cells were measured among subjects with and without PAD, and correlated to clinical and laboratory data.
RESULTS
Subjects with an IgG level of less than 600 mg/dL had reduced sBCMA levels compared with subjects with PAD with IgG levels of greater than or equal to 600 mg/dL and controls without PAD. sBCMA level was lower in patients with CVID and XLA compared with patients with IgA or IgG deficiency and controls. sBCMA level correlated with gastrointestinal plasma cells. sBCMA level of less than 15 ng/mL had 97% positive predictive value for CVID or XLA, whereas 25 ng/mL or more had an 88% negative predictive value.
CONCLUSIONS
sBCMA level is profoundly reduced in patients with severe PAD, including those with CVID and XLA and those with IgG levels of less than 600 mg/dL. sBCMA level measurement has potential to augment clinical evaluation of PAD. Prospective studies are needed to evaluate sBCMA for new PAD diagnosis and determine the necessity of IRT.
Topics: Agammaglobulinemia; B-Cell Maturation Antigen; Common Variable Immunodeficiency; Humans; Primary Immunodeficiency Diseases; Prospective Studies
PubMed: 31430592
DOI: 10.1016/j.jaip.2019.08.012 -
Brazilian Journal of Medical and... 2019Humoral immunological defects are frequent and important causes of hypogammaglobulinemia, leading to recurrent infections, autoimmunity, allergies, and neoplasias.... (Observational Study)
Observational Study
Humoral immunological defects are frequent and important causes of hypogammaglobulinemia, leading to recurrent infections, autoimmunity, allergies, and neoplasias. Usually, its onset occurs in childhood or during the second and third decades of life; however, the diagnosis is made, on average, 6 to 7 years afterwards. As a consequence, antibody defects can lead to sequelae. Here we describe the clinical-laboratory characteristics, treatment, and prognoses of patients with hypogammaglobulinemia. An observational, cross-sectional, and retrospective study of patients attending the recently established outpatient group of Clinical Immunology between 2013 and 2018 was carried out. Patients with IgG levels below 2 standard deviations from the mean values for the age and/or impaired antibody response were included. Eight patients (3 F and 5 M; median age=41 years (16-65), average symptom onset at 25 years (1-59), and time to diagnosis of 10 years were included. The main infections were: sinusitis in 7/8, pneumonia in 6/8, otitis in 2/8, tonsillitis and diarrhea in 2/8, and diarrhea in 2/8 patients. Hypothyroidism was identified in 4/8 (50%) patients. Rhinitis was found in 7/8 (87.5%) and asthma in 3/8 (37.5%) patients. The tomographic findings were consolidations, atelectasis, emphysema, ground glass opacity, budding tree, bronchial thickening, and bronchiectasis. Immunoglobulin reposition was used between 466 and 600 mg/kg monthly (514.3 mg·kg-1·dose-1). Prophylactic antibiotic therapy was included in 7/8 (87.5%) patients. Airway manifestations prevailed in patients with hypogammaglobulinemia. There is a need for educational work to reduce the time of diagnosis and initiation of treatment, avoiding sequelae.
Topics: Adolescent; Adult; Agammaglobulinemia; Aged; Cross-Sectional Studies; Female; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Retrospective Studies; Time Factors; Young Adult
PubMed: 31618370
DOI: 10.1590/1414-431X20198926 -
Blood Dec 2017Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections,... (Review)
Review
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections, and myelokathexis, which describes degenerative changes of mature neutrophils and hyperplasia of bone marrow myeloid cells. Some patients present with hypogammaglobulinemia and/or refractory warts of skin and genitalia. Congenital cardiac defects constitute uncommon manifestations of the disease. The disorder, which is inherited as an autosomal dominant trait, is caused by heterozygous mutations of the chemokine receptor CXCR4. These mutations lead to an increased sensitivity of neutrophils and lymphocytes to the unique ligand CXCL12 and to an increased accumulation of mature neutrophils in the bone marrow. Despite greatly improved knowledge of the disease, therapeutic choices are insufficient to prevent some of the disease outcomes, such as development of bronchiectasis, anogenital dysplasia, or invasive cancer. The available therapeutic measures aimed at preventing the risk for infection in WHIM patients are discussed. We critically evaluate the diagnostic criteria of WHIM syndrome, particularly when WHIM syndrome should be suspected in patients with congenital neutropenia and lymphopenia despite the absence of hypogammaglobulinemia and/or warts. Finally, we discuss recent results of trials evaluating plerixafor, a selective antagonist of CXCR4, as a mechanism-oriented strategy for treatment of WHIM patients.
Topics: Agammaglobulinemia; Biomarkers; Child; Child, Preschool; Disease Progression; Female; Humans; Immunologic Deficiency Syndromes; Infections; Neutropenia; Phenotype; Primary Immunodeficiency Diseases; Treatment Outcome; Warts
PubMed: 29066537
DOI: 10.1182/blood-2017-02-708552 -
Acta Reumatologica Portuguesa 2008Primary immunodeficiencies are defined as genetically determined functional and/or quantitative abnormalities in one or more of the components of the immune system....
Primary immunodeficiencies are defined as genetically determined functional and/or quantitative abnormalities in one or more of the components of the immune system. Immunodeficiency and arthritis can be related, although the mechanisms are not always clear. Different causes for immunodeficiency can secondarily be found in patients with arthritis; on the other hand, arthritis can be a manifestation of primary immunodeficiency. Arthritis occurs chiefly in humoral primary immunodeficiencies, namely in X-linked agammaglobulinemia and common variable immunodeficiency, and may be one of the warning signs for primary immunodeficiency. We report a case of arthritis as the presenting feature of X-linked agammaglobulinemia. In X-linked agammaglobulinemia, arthritis may be a consequence of infection, most notably by Mycoplasma, or of immune dysfunction itself. In children, and occasionally in young adults, a combination of arthritis and hypogammaglobulinemia should suggest primary immunodeficiency, although other causes of hypogammaglobulinemia must be excluded. Physicians evaluating patients with arthritis should be aware of this fact so that an early diagnosis can be pursued as it is of extreme importance in the optimal management and prognosis of these patients.
Topics: Adult; Agammaglobulinaemia Tyrosine Kinase; Agammaglobulinemia; Child, Preschool; Codon, Nonsense; Diagnosis, Differential; Genetic Diseases, X-Linked; Humans; Immunoglobulins, Intravenous; Male; Protein-Tyrosine Kinases
PubMed: 19078863
DOI: No ID Found