Concerns about physician deskilling in AI-enabled medicine usually ask how automated systems substitute for, attenuate, or distort clinical capacities. This article argues that precision medicine introduces a distinct object-side problem. Its dominant classificatory operation is not simply finer nosological classification but stratification for action: patients are grouped and regrouped for treatment selection, risk allocation, surveillance, trial eligibility, and prediction. In doing so, precision medicine fragments established disease categories, connects conditions across former boundaries, temporalizes disease into trajectories and thresholds, and produces actionable risk states and algorithmic subgroups. If clinical expertise is acquired through relatively stable nosological categories, then preserved skills may become insufficient when those categories no longer organize the clinical object in the same way. I call this failure of fit ontological deskilling. The article distinguishes it from technological deskilling, diagnostic uncertainty, overdiagnosis, medicalization, plastic diagnostics, and ordinary adaptive-learning demands. Drawing on Canguilhem, Mol, phenomenological intentionality, and accounts of expertise, it argues that ontological deskilling changes the conditions of clinical judgment, uncertainty, and responsibility. The appropriate response is critical nosological awareness: the ability to use disease categories competently while recognizing their contingency, plurality of functions, and susceptibility to transformation.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disease characterized by unpredictable episodes of tissue swelling (angioedema), which, in most cases, occur first under the age of 18 years, and entail a significant burden of disease not only for the patients but also for their families. Clinical symptoms of HAE are not specific, which may cause difficulties in differential diagnosis. Additionally, if not appropriately treated, HAE attacks can be life-threatening. The international HAE guidelines published so far have focused mainly on adults. A guideline that refers to the age-specific characteristics of pediatric patients, both in terms of diagnosis and management, was therefore needed. The International Steering Committee and Taskforce developed recommendations and provided evidence-based grading based on expert opinion and strength of evidence. Recommendations were presented to, discussed, and electronically voted by healthcare professionals during the 14th C1 Inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary, 2025. This international guideline will ensure early diagnosis, standardized and up-to-date treatment, and promote the availability of effective therapies for all pediatric patients affected with this rare disease. It also draws attention to the importance of establishing HAE centers and registries, which solicit specialist care and research of the disease.

Hereditary angioedema is a rare but potentially life-threatening disorder in which outcomes depend not only on correct diagnosis and effective medicines, but also on how health systems organize referral, laboratory confirmation, emergency pathways, reimbursement, home treatment, and long-term follow-up. Selected health systems in the Balkan Peninsula area provide a particularly informative setting for health-system comparison because neighboring countries with active hereditary angioedema expertise differ substantially in rare-disease governance, registry maturity, diagnostic infrastructure, treatment coverage, and patient-organization capacity. This Policy and Practice Review synthesizes international guidance, published regional literature, comparative country information from the Balkan Experts in Angioedema: Consensus and Ongoing Navigation (BEACON) initiative, and advocacy-informed implementation insights to assess current care delivery in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Greece, Romania, Serbia, Slovenia, and Türkiye. Across the region, the most consistent problems are prolonged diagnostic delay, unequal access to complement and genetic testing, approved-but-not-reimbursed modern therapies, hospital-only access to rescue medication, uneven use of home treatment and self-administration, incomplete emergency preparedness, and variable registry and advocacy infrastructure. Countries with stronger alignment between policy frameworks, specialist centers, registries, reimbursement pathways, and patient organizations appear better positioned to deliver guideline-concordant care, whereas fragmentation at any point in the care pathway reduces the practical value of therapeutic advances. The review argues that the main barriers to equitable hereditary angioedema care across the included health systems are now predominantly regulatory, financing, organizational, and educational rather than scientific. We therefore propose actionable recommendations for ministries and payers, specialist centers and professional societies, emergency-care systems, registry stakeholders, and patient organizations, with the goal of converting regional heterogeneity into a structured quality-improvement agenda.

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell–mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH.

In contrast to hereditary angioedema (HAE) due to C1-inhibitor deficiency, the detection of pathogenic variants in genes linked to HAE with normal C1 inhibitor levels (HAE-nC1INH) is required for the diagnosis of the corresponding types of the disease. The mainstreaming of genomic technology and the increasing use of next generation sequencing have increased the possibility of an unintentional detection of HAE-nC1INH pathogenic variants and allowed the incidental finding of variants of uncertain significance (VUS) in the relevant genes. Apart from F12 and PLG pathogenic variants, the current level of evidence on the prevalence and penetrance of variants associated with HAE-nC1INH does not support the reporting of their incidental finding. On the other hand, although VUS should not be used in clinical decision-making, further consideration is warranted (a) for VUS found in exon 9 of the F12 gene after a diagnostic genetic analysis of individuals either with or without personal or family history of angioedema, and (b) for VUS found in any of the other genes linked to HAE-nC1INH, after genetic analysis performed in the context of differential diagnosis of angioedema cases. Given the complexity of interpreting, reporting and communicating incidental findings, a close partnership between patients, clinicians, laboratory geneticists and genetic counsellors is essential to optimize the management of these results.

Natural antibodies (NAbs) occurring in individuals without prior exposure to specific antigens, provide direct first barrier protection against pathogens, and exert immunoregulation thus actively contributing to the maintenance of immune homeostasis, controlling inflammatory processes and preventing autoimmunity. Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by a compromised immune function that brings into focus the role of NAbs. Our aim was to explore whether NAb levels could serve as potential key indicators in CVID for monitoring disease progression and predicting outcomes. In this study, we analyzed a Hellenic cohort of 56 patients with CVID (31 newly diagnosed and 25 under immunoglobulin replacement therapy-IgRT) and 33 healthy controls, for total Ig levels and serum IgM and IgG NAb levels against five informative target-antigens of NAbs, namely, actin, DNA, carbonic anhydrase, F(ab΄)2 fragments of human IgG and TriNitroPhenyl. In addition, follow-up pre- and post- IgRT samples were analyzed in ten (10) patients of our cohort. Results showed that Ig-treated patients exhibited significantly lower IgM NAb levels than untreated patients and healthy controls against all panel antigens. In the follow-up samples, pre-treatment IgM NAb levels negatively correlated with total serum IgM. This imbalance was only partially restored after IgRT, with a significant decrease in IgM NAb levels observed in nine out of ten patients. Moreover, post-treatment patients with recurrent infections presented significantly lower IgM NAb levels, a reduction also observed in patients with bronchiectasis independently of treatment status. On the contrary, post-treatment patients with enteropathy had significantly higher IgM NAb levels against all panel antigens, an increase also noted in patients with autoimmune diseases. Regarding IgG NAbs, replacement therapy restored levels to those of healthy controls. In conclusion, impaired NAb levels are found in CVID patients, particularly related to certain phenotypes. Moreover, the significant decrease in IgM NAb levels after IgRT suggests a potential association with disease course and complications. The results suggest that administration of human IgM NAbs may be an effective combinatorial treatment in selected patients. Further research is needed to understand the functional roles of NAbs in CVID and its complex clinical phenotypes.

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.

Hereditary angioedema is a rare disease manifesting with recurrent attacks of disabling and potentially life -threatening angioedema, for which early diagnosis and effective therapy are critical. Recent scientific progress and the development of novel therapeutic options has engendered multiple important changes in the diagnosis and management of the disease. In an attempt to encourage and facilitate the use of this progress for all patients, the Hellenic Society of Angioedema has undertaken the effort to develop consensus recommendations for the diagnosis, treatment, and management of hereditary angioedema in special patients' groups. To this aim, a panel of 11 experts was assembled and a modified Delphi method was used. After a comprehensive review of relevant literature from the last five years retrieved from Medline, the initial text of the recommendations was formulated and consensus was sought among the experts. The consensus included statements that were agreed by more than 80% of the experts. This article presents the 24 consensus recommendations that were finally formulated.

ObjectiveTo assess the impact conferred by NOD2 variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece.MethodsConsecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one NOD2 gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded.ResultsIn total, 24 rare NOD2 variants in 23/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than NOD2. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the NOD2 variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7/9), colchicine (n=6/8) and/or anti-TNF treatment (n=3/4), while a complete response was observed in 6/10 patients receiving steroids and 3/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment.ConclusionNOD2 variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.

Background: Hereditary angioedema (HAE) is a potentially life-threatening disorder characterized by recurrent episodes of subcutaneous or submucosal swelling. HAE with normal C1 inhibitor (HAE-nC1-INH) is an underdiagnosed condition. Although the association with genetic variants has been identified for some families, the genetic causes in many patients with HAE-nC1-INH remain unknown. The role of genes associated with bradykinin catabolism is not fully understood. Objective: We sought to investigate the biological parameters and the genes related to kallikrein-kinin system in families with a clinical phenotype of HAE-nC1-INH and presenting with a carboxypeptidase N (CPN) deficiency. Methods: This study includes 4 families presenting with HAE-nC1-INH and CPN deficiency. Patients’ clinical records were examined, biological parameters of kallikrein-kinin system were measured, and genetics was analyzed by next-generation sequencing and Sanger sequencing. Predictive algorithms (Human Splicing Finder, Sorting Intolerant From Tolerant, Polymorphism Phenotyping v2, MutationTaster, and ClinPred) were used to classify variants as affecting splicing, as benign to deleterious, or as disease-causing. Results: Patients presented with angioedema and urticaria, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Affected patients displayed low CPN activity—30% to 50% of median value in plasma. We identified 3 variants of the CPN1 gene encoding the catalytic 55-kDa subunit of CPN: c.533G>A, c.582A>G, and c.734C>T. CPN deficiency associated with genetic variants segregated with HAE-nC1-INH symptoms in affected family members. Conclusions: CPN1 gene variants are associated with CPN deficiency and HAE-nC1-INH symptoms in 4 unrelated families. Genetic CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, with synergistic effects in angioedema and urticarial symptoms.

Background: Carboxypeptidase N (CPN) plays a major role in anaphylatoxin inactivation and is critical for bradykinin catabolism. CPN deficiency is a rare and underdiagnosed condition. Its pathophysiology has been shown as a function of anaphylatoxin and kinin accumulation, prone to mast cell and endothelium activation and sustaining inflammatory processes. We aimed to study families with homogeneous presentations for clinical and biological observations and genetics. Methods: Four families presenting with a CPN deficiency have been included. The study comprised clinical records of patients, biological parameters of anaphylatoxin/kinin metabolism, analysis of variants by next-generation sequencing and Sanger sequencing. Variants were classified as affecting splicing, benign to deleterious or disease causing according to algorithms (HSF , SIFT , Polyphen-2 , MutationTaster ). Results: Patients had chronic spontaneous urticaria and swellings, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Plasma samples from affected patient displayed low CPN activity, mostly below 50% of median value. We detected 3 variants in CPN1 gene encoding the catalytic 85-kDa subunit of CPN, c.533G>A, c.582A>G and c.734C>T. The families carried these variants in combination, e.g. [c.533G>A];[c.533G>A] (n=2), [c.533G>A(;)c.582A>G] (n=1) and [c.533G>A(;)c.734C>T] (n=1). Family studies revealed that variant combinations associated with CPN deficiency segregated with both symptoms and CPN activity. Conclusions: CPN deficiency has been found associated with combinations of CPN1 variants, with c.533G>A when present on both alleles or in combination with c.582A>G or c.734C>T. It is associated with a high risk of chronic spontaneous urticaria and/or swellings, consistently with anaphylatoxin and bradykinin accumulation.

BACKGROUND:Limited evidence suggests that variants in TNFRSF11A gene, encoding RANK, may contribute to systemic autoinflammatory disease (SAID). AIM/METHODS:To estimate the prevalence of TNFRSF11A variants in a cohort of patients with SAIDs screened for 26 related genes and describe the disease phenotypic expression. RESULTS:A total of 12 out of 167 patients, 7 males, aged (median) 38 years at disease onset, yielded at least one TNFRSF11A rare variant. All patients carried a coexisting variant in at least one other SAID-related gene, most frequently MEFV (6 patients), but also TNFRSF1A, NOD2, NLRP3, NLRP7, MVK, IL36RN, RBCK1, PLCG2 and PSMB8. SAID episodes lasting (median) 9 days manifested with high grade fever (91%), myalgias (75%), malaise (67%), serositis (58%), arthralgias/arthritis (58%), gastrointestinal involvement (33%), and rash (25%), and responded to corticosteroids. The most common initial clinical diagnosis was TNF-associated periodic fever syndrome (TRAPS), which was, however, confirmed, in only one patient. The emergence of MEFV variations supported the diagnosis of atypical Familial Mediterranean Fever in two cases, whereas the diagnosis of Yao syndrome was speculated in two patients with NOD2 variants. The presence of atypical disease and the inability of defining diagnosis in the remaining 7 patients, supported the possible involvement of TNFRSF11A variants in the phenotypic expression of SAIDs. CONCLUSION:TNFRSF11A variants, occurring in 7% of SAID patients always in combination with other SAID-related gene variants, contribute to the development of an autoinflammatory syndrome resembling to TRAPS. Additional studies to confirm novel pathogenic SAID pathways are clearly warranted.

Supplementary Table S2. Scaffold 'Sample view' of all proteins and protein clusters identified in protein band 1 to 5.

We report here the identification by next-generation sequencing of a novel HLA allele, DRB1*11:308, in a Greek individual as a part of a research project investigating diagnostic and prognostic biomarkers in head and neck cancer (BIOKARETRA).

Advances in next generation sequencing technologies, as well as their expanded accessibility and clinical use over the past 2 decades, have led to an exponential increase in the number of identified single gene disorders. Among these are primary atopic disorders-inborn errors of immunity resulting in severe allergic phenotypes as a primary presenting feature. Two cardinal aspects of type I immediate hypersensitivity allergic reactions are hives and angioedema. Mast cells (MCs) are frequent primary drivers of these symptoms, but other cells have also been implicated. Even where MC degranulation is believed to be the cause, mediator-induced symptoms may greatly vary among individuals. Angioedema-particularly in the absence of hives- may also be caused by hereditary angioedema conditions resulting from aberrant regulation of contact system activation and excessive bradykinin generation or impairment of vascular integrity. In these patients, swelling can affect unpredictable locations and fail to respond to MC-directed therapies. Genetic variants have helped delineate key pathways in the etiology of urticaria and nonatopic angioedema and led to the development of targeted therapies. Herein, we describe the currently known inherited and acquired genetic causes for these conditions, highlight specific features in their clinical presentations, and discuss the benefits and limitations of biomarkers that can help distinguish them. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2023;11:2286-301)

We report here the identification by next-generation sequencing of a novel HLA allele, DRB1*11:308, in a Greek individual as a part of a research project investigating diagnostic and prognostic biomarkers in head and neck cancer (BIOKARETRA).

EDITORIAL article Front. Allergy, 09 November 2022Sec. Skin Allergy Volume 3 - 2022 | https://doi.org/10.3389/falgy.2022.1065400

Existing evidence indicates that modifier genes could change the phenotypic outcome of the causal SERPING1 variant and thus explain the expression variability of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). To further examine this hypothesis, we investigated the presence or absence of 18 functional variants of genes encoding proteins involved in the metabolism and function of bradykinin, the main mediator of C1-INH-HAE attacks, in relation to three distinct phenotypic traits of patients with C1-INH-HAE, i.e., the age at disease onset, the need for long-term prophylaxis (LTP), and the severity of the disease. Genetic analyses were performed by a validated next-generation sequencing platform. In total, 233 patients with C1-INH-HAE from 144 unrelated families from five European countries were enrolled in the study. Already described correlations between five common functional variants [F12-rs1801020, KLKB1-rs3733402, CPN1-rs61751507, and two in SERPING1 (rs4926 and rs28362944)] and C1-INH-HAE severity were confirmed. Furthermore, significant correlations were found between either the age at disease onset, the LTP, or the severity score of the disease and a series of other functional variants (F13B-rs6003, PLAU-rs2227564, SERPINA1-rs28929474, SERPINA1-rs17580, KLK1-rs5515, SERPINE1-rs6092, and F2-rs1799963). Interestingly, correlations uncovered in the entire cohort of patients were different from those discovered in the cohort of patients carrying missense causal SERPING1 variants. Our findings indicate that variants other than the SERPING1 causal variants act as independent modifiers of C1-INH-HAE severity and could be tested as possible prognostic biomarkers.

A number of blood parameters (formed elements of blood, acute phase reactant proteins, activation of complement, fibronectin level and some factors of the coagulation-fibrinolytic system) have been studied in 10 patients suffering from anxiety neurosis before and after a stressfull condition (cold pressor test) for 30 s. Our results showed that, at least in some instances, stress can induce an acute phase reaction, C3 activation and a moderate increase of factor VIII-related antigen. Additional research into the impact of emotional stress on blood components is needed.