Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.

BACKGROUND: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. METHODS: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. RESULTS: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSIONS: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

BACKGROUND: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. OBJECTIVE: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. METHODS: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. RESULTS: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. CONCLUSIONS: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.

Early Identification of Lung Fungal Infections in Chronic Granulomatous Disease (CGD) Using Multidetector Computer Tomography.

PURPOSE: The purpose of this study is to evaluate the possibility of early detection of pulmonary fungal infections by lung CT scan in chronic granulomatous disease (CGD). METHODS: A retrospective study on 14 patients affected with CGD for a total of 18 infectious episodes was performed. Revision of clinical data and CT scan analysis before and after treatment was performed. RESULTS: The presence of lung nodules <30 mm was evaluated in 18 infectious episodes in 14 patients. A total of 125 nodules in 18 CT scans were identified. Identification of the infectious agent through biopsy and in vitro culture resulted positive only in 3/18 cases. The remaining cases received clinical/radiologic diagnosis of suspected pulmonary fungal infection. In all cases, the introduction of empirical antifungal treatment resulted in reduction in size or complete resolution of the pulmonary lung nodules in all patients affected with CGD. CONCLUSIONS: Lung CT scan allows for early detection of pulmonary fungal infection in CGD. Pulmonary nodules (<30 mm), single or multiple, uni- or bilateral, with or without a halo sign may represent the first radiologic sign of pulmonary fungal infection in CGD.

STAT mutations as program switchers: turning primary immunodeficiencies into autoimmune diseases.

STAT proteins are a family of transcription factors that mediate cellular response to cytokines and growth factors. Study of patients with familial susceptibility to pathogens and/or autoimmune diseases has led to the identification of 7 inherited disorders that are caused by mutations of 4 STAT family genes. Homozygous or compound heterozygous mutations of STAT1 lead to complete or partial forms of STAT1 deficiency that are associated with susceptibility to intracellular pathogens and herpetic infections. Patients with heterozygous STAT1 gain-of-function (GOF) mutations usually present with chronic mucocutaneous candidiasis (CMC) but may also experience bacterial and viral infections, autoimmune manifestations, lymphopenia, cerebral aneurysms, and increased risk to develop tumors. STAT2 deficiency has been described in 5 family members and is characterized by selective susceptibility to viral infections, whereas STAT3 loss-of-function (LOF) mutations are causative of the autosomal-dominant hyper-IgE syndrome (HIES), a condition that is characterized by cutaneous and respiratory infections in association with mucocutaneous candidiasis, eczema, skeletal and connective tissue abnormalities, eosinophilia, and high levels IgE. STAT5B LOF and STAT3 GOF mutations are both associated with disorders characterized by autoimmune or allergic manifestations, together with increased risk of infections. Particularly, STAT5b deficiency results in growth hormone (GH) insensitivity, immunodeficiency, diarrhea, and generalized eczema, whereas STAT3 GOF mutations result in autoimmune cytopenia, lymphadenopathy, short stature, infections, enteropathy, and multiorgan autoimmunity, including early-onset type I diabetes, thyroiditis, hepatitis, arthritis, and interstitial lung disease.

Correlation of bone marrow abnormalities, peripheral lymphocyte subsets and clinical features in uncomplicated common variable immunodeficiency (CVID) patients.

B cell developmental defects in CVID were recently described in a limited number of cases. To date, a detailed correlation between this maturational defect and the clinical presentation of affected patients has not been reported. In this study, we correlated bone marrow B cell evaluation, peripheral B and T lymphocyte subsets and clinical findings in 15 CVID patients. Early B cell developmental defects were observed in one third of patients. Combined bone marrow and peripheral lymphocytes evaluation allowed to further subdivide CVID patients in three groups with shared clinical features at diagnosis and during follow-up. These data broaden the number of CVID patients with early B cell developmental defects and, together with the peripheral lymphocytes evaluation, offer insight into the related clinical features in affected patients.