X-linked agammaglobulinemia typically presents in infancy or childhood with microbial infections as a consequence of low to absent mature B cells and pan-hypogammaglobulinemia, caused by mutations in BTK. However, atypical presentation in some cases may delay the diagnosis as well as the implementation of appropriate replacement therapy.

Primary immunodeficiencies (PID) can present with recurrent infections, autoimmunity, inflammation, or malignancy and each of these conditions can be associated with elevated immunoglobulin. A high level of immunoglobulin G (IgG) is an uncommon finding, especially in pediatrics, and does not rule out primary immunodeficiency. Deficiencies in varied aspects of immune response have been described with high IgG. Reported PID conditions with elevated IgG include defects in humoral, cellular, and innate immunity. Some of these immunodeficiencies can have fatal outcomes, some require hematopoetic stem cell transplantation, and some require systemic medications. The mechanisms driving elevated IgG are not well understood, but in some cases abnormal cytokine production has been proposed. The evaluation of a patient with high IgG is guided by the patient's history and a physical examination, with special attention to autoimmunity in pediatrics and malignancy and liver disease in adults. In the setting of autoimmunity, chronic gastrointestinal disease, or chronic infections, the measurement of specific antibodies to evaluate the function of the IgG should be considered. An increased appreciation of elevation in IgG reflecting immune dysregulation may lead to earlier PID diagnoses.

X-linked agammaglobulinemia (XLA) is a rare immunodeficiency caused by defects in the Bruton tyrosine kinase (BTK) gene, characterized by impaired B-cell development, reduced immunoglobulin production, and increased susceptibility to bacterial infections at an early age. Some XLA patients show atypical presentations, with most reports concentrating on the diagnosis at a relatively old age. They presented with infections at late age or with unusual pathogens; however, other atypical manifestations have only rarely been reported. Methods: Description of patients with XLA and novel mutations in BTK who presented with atypical manifestations or developed noninfectious complications. Results: Four patients presented unique manifestations unusual for XLA. The first with Granulomatous Dermatitis, the second with acute demyelinating encephalomyelitis, the third with “Crohn's disease like” localized protein-losing enteropathy, and the last patient with idiopathic thrombocytopenic purpura, which is an unexpected finding in a patient devoid of endogenous immunoglobulins. Mutations in BTK were found in all domains of the gene; 1 resulted in a stop codon and 3 were missense mutations. Conclusions: Early recognition of atypical presentations and manifestations of patients with XLA is crucial for timely initiation of life-saving therapy, which may include anti-bacterial and anti-inflammatory treatments in addition to immunoglobulin. Statement of novelty: In this study we present unique inflammatory and autoimmune phenomenons in XLA patients that were not described previously and are somewhat unexpected. These should alert the immunologist for the possibility of XLA diagnosis.

GATA2-associated disorders include: (i) monocytopenia with mycobacterial infections (MonoMAC); (ii) dendritic cell, monocyte, B and NK lymphoid deficiency; (iii) familial myelodysplastic syndrome (MDS) and acute myeloid leukemia; and (iv) congenital deafness with lower limb lymphedema deficiency (Emberger syndrome). Markedly reduced or absent monocytes have been considered as the hallmark of the disease. Here we report on a patient that presented in infancy with hearing loss and lymphedema. By 4 years of age the patient developed acne, disseminated warts, lymphadenopathy, and MDS, yet with increased monocyte as well as normal NK- and B-cell numbers. The patient was found to have a novel mutation in GATA2 that was predicted to disrupt the C-terminal zinc finger. Importantly, and in contrast to common concepts, GATA2-associated syndromes might present with monocytosis. Statement of novelty: We describe a novel mutation in GATA2 associated with monocytosis.

This is a prospective outcome study of patients with profound combined immunodeficiency (P-CID) (study number DRKS00000497). Combined immunodeficiencies (CID) are a heterogeneous group of inherited immune disorders with impaired T-cell development and (or) function manifesting through increased susceptibility to infections and (or) immune dysregulation. They can be delineated from severe CID (SCID) by their manifestation beyond the first year of life. Profound CID (P-CID) is a potentially life-threatening form of CID, in which stem cell transplant (SCT) is a relevant consideration at diagnosis. The primary objective of the study is to provide natural history data on patients with P-CID, irrespective of whether they undergo hematopoietic stem cell transplant (HSCT) or not. The goals are to determine survival, the frequency of severe events, and quality of life (QOL) 5 years after study inclusion. The secondary objective is to develop a risk model for P-CID patients. The model is developed from a set of clinical and laboratory parameters obtained at diagnosis, at study inclusion, and yearly thereafter. The tertiary objectives of this study are to determine the effects of donor, recipient, and treatment factors on the outcome of HSCT. The goal is to determine the quality of engraftment and immunological reconstitution and to determine the effects of these parameters on clinical outcome. The main hypothesis is that P-CID patients undergoing early HSCT have a better 5-year survival rate than patients who undergo late HSCT or are not transplanted. This is a prospective multi-centre international cohort study (observational study). Enrolled patients will be evaluated and treated according to local institutional protocols. They will receive comparable baseline and follow-up evaluations across all participating centres, irrespective of the therapeutic strategy at the individual site. There will be at least 6 study visits (scheduled yearly) for all patients. Because of the variable history prior to study inclusion, a morbidity score is determined for each patient at study visit 1. For those patients undergoing HSCT, an additional 6 month post-HSCT visit will be scheduled. The study visits will document immunological parameters, severe events including major infections, and major manifestations of immune dysregulation, severe transplant-related events, and QOL.