Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment and an understanding of the human immune response. We identified six unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with three different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, five patients had somatic variants in TLR8 with less than 30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in three patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and three patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain-of-function to TLR8 protein, and immune phenotyping demonstrated a pro-inflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B cell maturation. Differentiation of myeloid cells from patient-derived induce pluripotent stem cells demonstrated increased responsiveness to TLR8. Together these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B and T cell defects, and in some cases bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.
Purpose of review Here we review the rheumatologic and autoimmune features of primary immune deficiencies with a focus on recently recognized genetic diseases, the spectrum of autoimmunity in PID, and targeted therapies. Recent findings Primary immune deficiencies (PIDs) were initially described as genetic diseases of the immune system leading to susceptibility to infection. It is now well recognized that immune dysfunction and dysregulation also cause noninfectious complications including autoimmunity. The increased application of molecular testing for PID has revealed the diversity of clinical disease. Recent discoveries of diseases with prominent autoimmunity include activated phosphoinositide 3-kinase δ syndrome and PIDs caused by gain-of-function in STAT1 and STAT3. Similarly, identification of larger cohorts of patients with molecular diagnoses in more common PIDs, such as common variable immune deficiency (CVID), has led to increased understanding of the range of autoimmunity in PIDs. Understanding the molecular basis of these PIDs has the potential to lead to targeted therapy to treat associated autoimmunity. Summary Autoimmunity and rheumatologic disease can be presenting symptoms and/or complicating features of primary immunodeficiencies. Evaluation for PIDs in patients who have early-onset, multiple, and/or atypical autoimmunity can enhance diagnosis and therapeutic options.
Scurvy is rare in developed countries but is known to cause lower-extremity pain and refusal to ambulate in children. Since the discovery of the link between scurvy and dietary deficiency of ascorbic acid, there has been a substantial decrease in its prevalence and recognition. Here we describe 3 cases of scurvy in young children presenting with difficulty walking. Only 1 of 3 patients had gingival lesions at the initial presentation. Two cases underwent an extensive evaluation for hematologic and rheumatologic diseases before the diagnosis of scurvy was made. Dietary histories eventually revealed that all 3 patients had sharply limited intake of fruits and vegetables secondary to oral aversion, and 1 patient had autism. Radiographic changes of long bones were observed in all patients. Interestingly, all patients had concomitant vitamin D deficiency. After replacement with vitamin C, all patients recovered and started to walk again with improved leg pain. These clinical manifestations and radiologic findings highlight the importance for rheumatologists to have a higher index of suspicion for scurvy in nonambulatory children.
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