A Nationwide Study of the Delayed Diagnosis and the Clinical Manifestations of Predominantly Antibody Deficiencies and CTLA4-Mediated Immune Dysregulation Syndrome in Greece.

Background and Objectives: Predominantly antibody deficiencies (PAD) represent the most common type of primary immunodeficiencies in humans, characterized by a wide variation in disease onset, clinical manifestations, and outcome. Considering that the prevalence of PAD in Greece is unknown, and there is limited knowledge on the clinical and laboratory characteristics of affected patients, we conducted a nationwide study. Materials and Methods: 153 patients (male/female: 66/87; median age: 43.0 years; range: 7.0-77.0) diagnosed, and followed-up between August 1979 to September 2023. Furthermore, we classified our cohort into five groups according to their medical history, immunoglobulin levels, and CTLA4-mutational status: 123 had common variable immunodeficiency (CVID), 12 patients with "secondary" hypogammaglobulinemia due to a previous B-cell depletion immunotherapy for autoimmune or malignant disease several years ago (median: 9 years, range 6-14) displaying a typical CVID phenotype, 7 with combined IgA and IgG subclass deficiencies, 5 patients with CVID-like disease due to CTLA4-mediated immune dysregulation syndrome, and 6 patients with unclassified hypogammaglobulinemia. Results: We demonstrated a remarkable delay in PAD diagnosis, several years after the onset of related symptoms (median: 9.0 years, range: 0-43.0). A family history of PAD was only present in 11.8%, with the majority of patients considered sporadic cases. Most patients were diagnosed in the context of a diagnostic work-up for recurrent infections, or recurrent/resistant autoimmune cytopenias. Interestingly, 10 patients (5.6%) had no history of infection, diagnosed due to either recurrent/resistant autoimmunity, or during a work-up of their medical/family history. Remarkable findings included an increased prevalence of lymphoproliferation (60.1%), while 39 patients (25.5%) developed bronchiectasis, and 16 (10.5%) granulomatous disease. Cancer was a common complication in our cohort (25 patients, 16.3%), with B-cell malignancies representing the most common neoplasms (56.7%). Conclusion: Our findings indicate the necessity of awareness about PAD and their complications, aiming for early diagnosis and the appropriate management of affected patients.

A Case of Idiopathic First Bite Syndrome, Possibly Linked to Type I Diabetes Mellitus.

We present a rare case of a 34-year-old male with poorly regulated type I diabetes and three-month history of excruciating pain in the right condylar process of the mandible, occurring only during the first bite of each meal. The patient had no history of surgery or trauma in the head and neck region. Clinical and imaging examination revealed no tumor or pathology deriving from the dentures, the temporomandibular joint (TMJ), or the salivary glands. Idiopathic first bite syndrome (FBS) was suspected and treated with pregabalin and glycemic control. This case highlights how a detailed pain history and clinical examination can lead to a rare diagnosis and indicates the potential involvement of diabetic neuropathy in idiopathic FBS, as well as the importance of glycemic regulation in treatment.

TNFRSF13B/TACI Mutations in Patients with Chronic Rhinosinusitis with Nasal Polyps.

BACKGROUND: The pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) remains still inconclusive. Recent studies identified an increased expression of BAFF (a B cell-activating factor) and its receptor TACI (Transmembrane Activator and cAML Interactor) in nasal polyp samples, while TNFRSF13B/TACI mutations have been found in patients with benign lymphoproliferative disorders and primary antibody deficiencies. OBJECTIVE: The aim of our study was to evaluate the possible contribution of TNFRSF13B/TACI mutations in CRSwNP pathogenesis. METHODS: Forty-four (44) patients with CRSwNP (male/female: 33/11, mean age: 52.5 years, range: 16-83) were analyzed for TNFRSF13B/TACI mutations by PCR-sequencing. RESULTS: No pathogenic TNFRSF13B/TACI mutations were identified in our cohort study of CRSwNP patients. We detected two common missense mutations (p.P251L and p.V220A), along with other common silent mutations and intronic polymorphisms in an identical prevalence to healthy control population. CONCLUSION: TNFRSF13B/TACI mutations might not play a role in the pathogenesis of CRSwNP.

TACI Mutations in Primary Antibody Deficiencies: A Nationwide Study in Greece.

Background and objectives: Monoallelic (heterozygous) or biallelic (homozygous or compound heterozygous) TACI mutations have been reported as the most common genetic defects in patients with common variable immunodeficiency (CVID), which is the most common clinically significant primary immunodeficiency in humans. The aim of our study was to evaluate the prevalence and any correlations of TACI defects in Greek patients with primary antibody deficiencies. Materials and Methods: 117 patients (male/female: 53/64) with CVID (110) and a combined IgA and IgG subclass deficiency (7) with a CVID-like clinical phenotype were enrolled in the study. Genomic DNA was extracted from peripheral blood and the molecular analysis of the TACI gene was performed by PCR (Polymerase Chain Reaction) and sequencing of all 5 exons, including exon-intron boundaries. Results: Seventeen patients (14.5%) displayed TACI defects, four (23.5%) carried combined heterozygous mutations and 13 (76.5%) carried single heterozygous mutations. The most frequently detected mutation was C104R (58.8%), followed by I87N (23.5%) and A181E (11.8%), while R20C, C62Y, P151L, K188M and E236X mutations were present in only one patient each. Patients with TACI defects were more frequently male (p = 0.011) and displayed a benign lymphoproliferation (splenomegaly and lymph node enlargement, p = 0.047 and p = 0.002, respectively), had a history of tonsillectomy (p = 0.015) and adenoidectomy (p = 0.031) and more frequently exhibited autoimmune cytopenias (p = 0.046). Conclusions: Considering that accumulating evidence suggests several CVID patients have a complex rather than a monogenic inheritance, our data further support the notion that TACI mutations, particularly as monoallelic defects, should be primarily considered as susceptibility co-factors and/or modifiers of primary antibody deficiencies.