Bruton's agammaglobulinemia

A 23-year-old man with Bruton's X-linked agammaglobulinemia (XLA), who required intravenous immunoglobulin G (IgG) every 3 weeks, presented with an erythematous scaly eruption adjacent to the chest port for antibiotic therapy (Figures 1A,B). His past medical history included Helicobacter cinaedi cellulitis in 2015 that was treated with intravenous vancomycin and ertapenem with no improvement after several months. The therapy was switched to ertapenem and amikacin, which was also unsuccessful after 1 year. Subsequently, on switching to oral doxycycline for 6 months, he had a 2-year period without skin lesions...

No abstract text is available yet for this article.

Despite several reports and small case series on the disease course of SARS-CoV-2 infection in patients with inborn errors of immunity (IEI), including X-linked agammaglobulinemia (XLA), this topic remains incompletely described. Here we present the case of a 38-year-old unvaccinated man with XLA, who acquired SARS-CoV-2 infection and experienced a protracted disease course with 47 days of SARS-CoV-2 positivity, critical COVID-19 with respiratory insufficiency necessitating intensive care and ventilatory support, and prompting repeated intensified treatments with remdesivir, dexamethasone, and monoclonal antibodies to eventually control infection...

Agammaglobulinemia is a rare inherited immunodeficiency disorder. Mutations in the BLNK gene cause low levels of mature B lymphocytes in the peripheral blood leading to recurrent infections. We present a four-year-old Turkish boy who had recurrent respiratory tract infections in the last six months. He had very low IgG (81 mg/dl) and IgA levels (<5 mg/dl) with high IgM (258 mg/dl). Flow cytometric analysis of lymphocyte subsets showed low CD19+ B cells (0.05%). Homozygous c.790C > T (p...

PURPOSE: To report a case of a male patient with a severe corneal and conjunctival immunopathy likely caused by an X-linked agammaglobulinemia. METHODS: A clinical case report with observation results from 2001-2021. RESULTS: A severe corneal immunopathy of both eyes is reported in a retrospective long-term observation of nearly twenty years in a 32-year-old male patient with X-linked agammaglobulinemia (XLA). A chronic progressive corneal scarring with a loss of visual acuity and typical symptoms of a phlyctenular keratoconjunctivitis were observed...

Background: Fragment analysis of exon 1 of the human androgen receptor, known as HUMARA, is a polymerase chain reaction (PCR)-based method for detecting X-linked agammaglobulinemia (XLA) carriers. This method takes advantage of X-chromosome inactivation (XCI) in female cells. XLA is caused by mutations in the Bruton tyrosine kinase ( BTK ) gene, located in Xq22.1. In this study, XCI is nonrandom or skewed in B cells. B cells with an active X-chromosome carrying a BTK mutation do not mature. Peripheral B cells in XLA carriers inactivate the mutated X-chromosome...

X-linked agammaglobulinemia (XLA) is an X-linked recessive primary immunodeficiency disorder caused due to a pathogenic variant in the Bruton tyrosine (BTK) gene with an incidence of 1:379,000 live births and 1:190,000 male births. Patients affected with XLA present with recurrent infections of the gastrointestinal and respiratory tracts. Here we report the first case series of 17 XLA patients of 10 South Indian families with a wide spectrum of clinical and genetic features. In our cohort, patients presented mainly with recurrent pneumonia, gastrointestinal infection, otitis media, pyoderma, abscesses, empyema, arthritis, and osteomyelitis...

Gene editing utilizing homology-directed repair has advanced significantly for many monogenic diseases of the hematopoietic system in recent years but has also been hindered by decreases between in vitro and in vivo gene integration rates. Homology-directed repair occurs primarily in the S/G2 phases of the cell cycle, whereas long-term engrafting hematopoietic stem cells are typically quiescent. Alternative methods for a targeted integration have been proposed including homology-independent targeted integration and precise integration into target chromosome, which utilize non-homologous end joining and microhomology-mediated end joining, respectively...

X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton tyrosine kinase) BTK) gene. Affected patients have severely reduced amounts of circulating B cells. Patients with atypical XLA may have residual circulating B cells, and there are few studies exploring these cells' repertoire. We aimed to study the B cell repertoire of a novel hypomorphic mutation in the BTK gene, using the next generation sequencing (NGS) technology. Clinical data was collected from our clinical records. Real-time PCR was used to determine KREC copies, and NGS was used to determine the immunoglobulin (Ig) heavy chain (IgH) repertoire diversity...

Bacterial infections are a major cause of morbidity and mortality in chronic lymphocytic leukemia (CLL), and infection risk increases in patients treated with the Bruton's tyrosine kinase (Btk) inhibitor, ibrutinib. Btk and related kinases (like Tec) are expressed in non-leukemic hematopoietic cells and can be targeted by ibrutinib. In platelets, ibrutinib therapy is associated with bleeding complications mostly due to off-target effects. But the ability of platelets to respond to bacteria in CLL, and the potential impact of ibrutinib on platelet innate immune functions remain unknown...

This is the first report of meningoencephalitis in an adult male with X-linked agammaglobulinemia caused by a probable Torque teno virus (TTV) infection. TTV was detected in the cerebrospinal fluid samples of the patient by high-throughput sequencing technology. The patient was treated successfully. Abstract X-linked agammaglobulinemia (XLA) is a rare primary immunodeficiency disease caused by mutations in the Bruton's tyrosine kinase (Btk) gene, characterized by recurrent infections and low or undetectable immunoglobulin levels...

Common variable immunodeficiency (CVID) is characterized by profound primary antibody defects and frequent infections, yet autoimmune/inflammatory complications of unclear origin occur in 50% of individuals and lead to increased mortality. Here, we show that circulating bacterial 16S rDNA belonging to gut commensals was significantly increased in CVID serum (P < 0.0001), especially in patients with inflammatory manifestations (P = 0.0007). Levels of serum bacterial DNA were associated with parameters of systemic immune activation, increased serum IFN-γ, and the lowest numbers of isotype-switched memory B cells...

PURPOSE OF REVIEW: The clinical outcomes from COVID-19 in monogenic causes of predominant antibody deficiency have pivotal implications for our understanding of the antiviral contribution of humoral immunity. This review summarizes the lessons learned from COVID-19 infection in X-linked agammaglobulinemia (XLA) due to genetic defects in Bruton's tyrosine kinase (BTK). RECENT FINDINGS: Key molecular pathways underlying the development of severe COVID-19 are emerging, highlighting the possible contribution of BTK to hyperinflammation...

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in the gene for Bruton's tyrosine kinase (Btk) , with affected males most commonly presenting with recurrent bacterial infections during the first few years of life. Here we present a 17-month-old male with a chief complaint of worsening rash and fever, whose history of streptococcal pneumonia meningitis at 5 months of age prompted suspicion for an underlying immunodeficiency and subsequent diagnosis of XLA. Bacterial meningitis is a rare initial presentation of XLA, and therefore physicians may easily overlook any underlying immunodeficiency...

INTRODUCTION: The Bruton tyrosine kinase (BTK) regulates B cell and macrophage signaling, development, survival, and activation. Inhibiting BTK has been hypothesized to ameliorate lung injury in patients with severe COVID-19, however clinical outcome data is inconclusive. OBJECTIVE: To evaluate the clinical outcomes of BTK inhibitors (BTKinibs) in patients with COVID-19. EVIDENCE REVIEW: We searched PubMed, Embase, and Web of Science:Core on December 30, 2020...

X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency caused by mutations in the Bruton Tyrosine Kinase ( BTK ) gene. Marked neutropenia can be the initial abnormal laboratory finding in patients with XLA who are presenting with their first illness. The two cases presented herein support early consideration of evaluation for primary humoral immune deficiency in previously healthy male patients under the age of 12 months who present with neutropenia in the setting of infection shortly after passively acquired maternal antibody has sufficiently waned...

Since Dr. Ogden Bruton's 1952 paper describing the first human primary immunodeficiency disease, the peripheral membrane binding signaling protein, aptly named Bruton's tyrosine kinase (BTK), has been the target of intense study. Dr. Bruton's description of agammaglobulinemia set the stage for ultimately understanding key signaling steps emanating from the B cell receptor. BTK is a multidomain tyrosine kinase and in the decades since Dr. Bruton's discovery it has become clear that genetic defects in the regulatory domains or the catalytic domain can lead to immunodeficiency...

Interruptions or alterations in the B cell development pathway can lead to primary B cell immunodeficiency with resultant absence or diminished immunoglobulin production. While the most common cause of congenital agammaglobulinemia is X-linked agammaglobulinemia (XLA), accounting for approximately 85% of cases, other genetic forms of agammaglobulinemia have been identified. Early recognition and diagnosis of these conditions are pivotal for improved outcomes and prevention of sequelae and complications. The diagnosis of XLA is often delayed, and can be missed if patient has a mild phenotype...

X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by pathogenic variants in the BTK gene, resulting in impaired B cell differentiation and maturation. Over 900 variants have already been described in this gene, however, new pathogenic variants continue to be identified. In this report, we describe 22 novel variants in BTK, associated with B cell deficiency with hypo- or agammaglobulinemia in male patients or in asymptomatic female carriers. Genetic data was correlated with BTK protein expression by flow cytometry, and clinical and family history to obtain a comprehensive assessment of the clinico-pathologic significance of these new variants in the BTK gene...

Since the first clinical description in 1952, immunoglobulin replacement therapy remains the mainstay of treatment of patients with X-linked agammaglobulinemia (XLA). However, this therapy only replaces IgG isotype and does not compensate for the loss of Bruton tyrosine kinase in non-B-lymphocytes. Patients may still therefore develop complications despite current standard of care. Here, we describe an XLA patient with persistent chronic norovirus infection, refractory to treatment and causing intestinal failure...