Sule Haskologlu

Introduction: Inborn errors of immunity (IEI) may manifest with infections, immune dysregulation, syndromic features, and multisystem involvement. Critically ill neonates and children admitted to intensive care units (ICUs) with severe or atypical presentations may harbor underlying IEI, posing significant diagnostic challenges. This study aimed to evaluate the clinical characteristics, consultation indications, immunological findings, warning signs, and diagnostic outcomes of patients assessed for suspected IEI in neonatal and pediatric intensive care units. Methods: We retrospectively reviewed patients from the neonatal intensive care unit (NICU) and pediatric intensive care unit (PICU) of our hospital who were referred to the Department of Pediatric Immunology and Allergy because of clinical and/or laboratory suspicion of IEI between January 2017 and September 2025. Consultation indications, final diagnoses, IEI categories, and traditional Jeffrey Modell Foundation (JMF) and additional warning signs were evaluated. The diagnostic performance of individual warning signs for confirmed IEI was assessed, and the incremental contribution of additional warning signs beyond the traditional JMF criteria was examined at the patient level. Results: A total of 172 patients were referred from the NICU and PICU, corresponding to 0.8% and 2.6% of all admissions, respectively; 40 (23.3%) were diagnosed with IEI. Syndromic features with systemic involvement were the most frequent indication for consultation in the NICU, whereas severe infection/sepsis predominated in the PICU. Combined immunodeficiencies with syndromic features were most frequent in the NICU, while predominantly antibody deficiencies were most common in the PICU. Deep-seated infection/septicemia, chronic diarrhea/enteropathy, and syndromic features were significantly associated with confirmed IEI, with ORs of 2.21 (95% CI, 1.08–4.53), 2.57 (95% CI, 1.08–6.07), and 2.41 (95% CI, 1.06–5.48), respectively. Overall, 38/40 (95.0%) patients with IEI fulfilled at least one traditional JMF warning sign. Both JMF-negative patients with IEI had at least one additional warning sign; therefore, considering traditional and additional warning signs together retrospectively identified all 40 patients with IEI in this referral cohort. Mortality among patients with IEI was 32.5%. Conclusion: IEI was diagnosed in 23.3% of critically ill patients referred for immunological evaluation because of suspected IEI. Deep-seated infection/septicemia, chronic diarrhea/enteropathy, and syndromic features were significantly associated with confirmed IEI. Traditional JMF warning signs identified most patients with IEI; however, additional warning signs captured two IEI patients who did not fulfill any traditional JMF criteria. These findings support considering additional non-infectious and syndromic manifestations alongside traditional warning signs when evaluating critically ill children for IEI.

The Nuclear Factor Kappa B (NF‐kB) signalling pathway is essential for regulating inflammation, cell survival, and adaptive immune responses through its canonical (NF‐κB1‐associated) and noncanonical (NF‐κB2‐associated) branches. The canonical pathway mediates rapid and broad reactions to immune stimuli, whereas the noncanonical pathway is activated by specific signals and contributes to lymphoid organ development, B‐cell maturation including germinal centre activity, T‐cell differentiation, thymic selection and antiviral defence. NF‐κB transcription factors consist of five subunits: NF‐kB1 (p105/p50), NF‐kB2 (p100/p52), RelA, RelB and c‐Rel—and heterozygous variants in NFKB1 or NFKB2 genes result in a wide range of immune dysregulation. NFKB1 mutations have been associated with common variable immunodeficiency, autoinflammatory or rheumatologic manifestations, Epstein–Barr virus–related lymphoproliferation, gastrointestinal involvement and susceptibility to recurrent or opportunistic infections. Clinical features of NFKB2 deficiency show considerable variability depending on mutation location, but recurrent infections and hypogammaglobulinemia remain the most frequently reported findings. Despite growing recognition of NF‐κB–related inborn errors of immunity, the phenotypic spectrum continues to expand and genotype–phenotype correlations remain challenging. In this study, we describe seven individuals from five families with NFKB1 or NFKB2 variants and demonstrate considerable clinical and immunological heterogeneity, including marked intrafamilial variability.

Background: Inborn errors of immunity (IEI) predispose patients to malignancy, particularly lymphoma, but data on diagnostic sequence and outcomes are limited. Methods: We retrospectively analyzed IEI-associated malignancies diagnosed at a single center between January 2004 and December 2025. Results: Among 1,668 patients with IEI, 67 (4.0%) developed malignancy. Median ages at IEI and malignancy diagnosis were 8 and 10 years, respectively. Malignancy-first presentation occurred in 45 patients (67%), especially adolescents, and was associated with advanced-stage disease (p = 0.007). Lymphoid malignancies accounted for 90% of cases; non-Hodgkin lymphoma and Hodgkin lymphoma comprised 54% and 36%, respectively, and 84.7% presented with stage III-IV disease. Median event-free and overall survival were 66 and 155 months, respectively. In a clinically selected multivariable Cox model, NHL, solid/plasma cell tumors, older age at malignancy diagnosis, and DNA repair defect status were associated with worse OS. Twelve patients underwent allogeneic HSCT; one died early, and no post-transplant relapses occurred. Conclusion: Early immunologic evaluation and timely, individualized consideration of HSCT may support optimized management in children and adolescents, in whom cancer may be the first manifestation of IEI.

Introduction: Delayed-type cutaneous adverse drug reactions (CADRs) are T-cell-mediated hypersensitivity reactions that may present with variable clinical severity in children. They range from mild maculopapular exanthema (MPE) to severe, life-threatening mucocutaneous syndromes such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Data on pediatric delayed-type CADRs remain limited. They represent an important cause of morbidity in pediatric patients and require careful diagnostic evaluation. This study aimed to describe the clinical characteristics, etiologic agents, management strategies, and outcomes of pediatric patients with delayed-type CADR followed at a tertiary pediatric center. Methods: This retrospective case series included 33 pediatric patients diagnosed with delayed-type CADR between January 2013 and December 2024. Demographic features, suspected culprit drugs, clinical manifestations, laboratory and histopathologic findings, treatment approaches, and outcomes were reviewed. RegiSCAR, EuroSCAR, and SCORTEN criteria were applied for diagnostic classification and severity assessment of DRESS, AGEP, and SJS/TEN, respectively. Results: The median age was 9 years (range: 9 days–16 years); 17 patients were female. The most frequent diagnosis was MPE (n = 18, 54.5%), followed by DRESS (n = 5, 15.1%), SJS/TEN (n = 3, 9.1%), AGEP/ALEP (n = 3, 9.1%), erythema multiforme (n = 2, 6.0%), and symmetric drug-related intertriginous and flexural exanthem (n = 2, 6.0%). Antibiotics and antiepileptic drugs were the most commonly implicated drug classes. Systemic corticosteroids were administered in moderate-to-severe cases, and intravenous immunoglobulin was used in selected patients with DRESS and SJS/TEN. Four patients died due to underlying primary diseases; no CADR-related mortality was observed. Conclusion: This retrospective case series describes the heterogeneous clinical spectrum of delayed-type CADRs in children in a tertiary referral setting. In our cohort, MPE was the most frequent phenotype, while antibiotics and antiepileptic drugs were the most commonly implicated agents. A high burden of comorbidities, including immunosuppression and polypharmacy, was notable and may have influenced the observed clinical spectrum. Severe reactions required multidisciplinary management.

Introduction: The severity and incidence of invasive pneumococcal infections increase in inborn errors of immunities. However, there are limited number of studies in the literature evaluating pneumococcal antibody levels in patients with a prediagnosis of transient hypogammaglobulinemia (THI) and unclassified hypogammaglobulinemia (UH). The aim of our study was to serologically evaluate pneumococcal antibody levels in children aged 24–72 months with THI or UH who had completed the primary PCV schedule, and to compare these levels with those of age-matched healthy control. Methods: Patients aged between 24 and 72 months who were admitted to the Pediatric Immunology Allergy Department Outpatient Clinic between January 2024 and July 2024 and who were considered to have transient or unclassifiable hypogammaglobulinemia. Healthy children of similar age group, without signs of infection or chronic disease and with complete vaccination according to their age were included in the study as a healthy control group. Serum samples obtained were separated and stored at −20 C0 until the day anti-PNP IgG levels were studied by ELISA method. Results: No statistically significant difference was found when anti-PCP IgG levels were compared according to the diagnosis of THI and UH in the patient group (p = 0.410). It was determined that both patient groups produced similar antibody levels. There were no statistically significant differences in anti-PCP IgG levels between patients and control group (p = 0.427). When the correlation between the time elapsed since the last dose of PCV13 and anti-PCP IgG levels was evaluated in the patient group (both in all patients and age groups) and in the control group, no statistically significant correlation was found. In the patient group, anti-PNP IgG levels were found to be lower in the group in which both IgG and IgM values were low compared to the other groups. No statistically significant difference was found between the clinical characteristics of the patients and anti-PCP IgG levels. Conclusion: This study is one of the few to evaluate pneumococcal antibody levels in children with THI and UH who have completed the primary PCV13 vaccination series. Further prospective studies involving serotype-specific tests and different pneumococcal vaccine formulations are needed.

Background: Major histocompatibility complex (MHC) class II deficiency is a rare, life-threatening primary immunodeficiency that presents in early infancy with a SCID phenotype. However, emerging data indicate substantial clinical and immunological heterogeneity, including atypical presentations and neurological involvement. Methods: We retrospectively evaluated the clinical, immunological, genetic, and treatment-related characteristics and outcomes of 22 patients from 19 unrelated families diagnosed with MHC class II deficiency at a single referral center (2000–2019). Ten patients underwent HSCT at our center; transplant-related outcomes were evaluated, and long-term follow-up data were available for the six surviving patients through 2025. Results: The median age at symptom onset and diagnosis was 9 and 12 months, respectively. Pneumonia, chronic diarrhea, and failure to thrive were the most common presenting features; neurological manifestations and developmental delay were observed in a subset of patients. Two patients showed residual HLA-DR expression and survived with a milder clinical course. CD4 ⁺ T cell lymphopenia and humoral dysfunction were consistent, while total lymphocyte counts were variable. RTE levels were mildly to moderately reduced in all tested patients, suggesting impaired thymic output. Severe viral infections were frequent and could be rapidly fatal. Fourteen patients required PICU admission, associated with high mortality. Genetic analysis (n:15) identified homozygous pathogenic variants in RFXANK (n=5), RFXAP (n=4), RFX5 (n=3), and CIITA (n=3). Ten patients underwent HSCT, with superior survival compared to non-transplanted patients (60% vs. 18%). Among transplanted patients, survival appeared higher following RTC than MAC (75% vs. 50%). Post-transplant mortality was observed in association with severe pre-transplant disease, delayed diagnosis, graft failure, and infectious complications. At ≥10 years post-HSCT, all survivors were IVIG-independent; CD4 ⁺ T cell recovery was higher after MAC than RTC, while T-cell chimerism remained mixed in both groups. Conclusion: MHC class II deficiency is a SCID-like pediatric immunological emergency that is fatal without HSCT in most patients. Early diagnosis is critical, as initial infections may be rapidly progressive. HSCT provides durable engraftment and sustained clinical stability in long-term survivors. Incorporating HLA-DR expression analysis into first-line immunological screening, even in the absence of profound lymphopenia, may facilitate earlier diagnosis, prompt HSCT referral, and improve survival.

Purine nucleoside phosphorylase (PNP) deficiency causes inadequate purine metabolite detoxification, which leads to combined immunodeficiency and variable neurologic symptoms. Hematopoietic stem cell transplantation (HSCT) cures the immunodeficiency, but large studies on the long-term outcomes are lacking. In a retrospective study of the European Society for Blood and Marrow Transplantation, we investigated 46 patients with PNP deficiency from 21 centers. We analyzed the presenting clinical signs and outcomes after HSCT. Cognition (0-3), hearing (0-3), interaction (0-4), movement (0-4), and occupation (0-3) (CHIMO) were scored at the last follow-up (FU) visit (no impairment, 17; mild, 15-16; moderate, 12-14; and severe impairment, 50%-100%)/low-level donor chimerism (11%-50%) was observed in 85%/15% of patients, respectively, leading to resolution of T lymphopenia. The median overall CHIMO score was 14 (6-17), while the median scores for each component were 3 (0-3), 3 (1-3), 4 (1-4), 3 (1-4), and 2 (0-3), respectively. Patients who underwent HSCT before 24 months after the initial presentation demonstrated superior OS (P = .049). Neurological symptoms that occurred before 11 months of age were associated with reduced OS (P = .027). While the overall results were satisfactory, earlier diagnosis could further improve outcomes.

Inborn errors of immunity (IEI) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer (NK) cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment and HSCT as approach curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years. From 2000 to 2025, 30 HLH cases with primary HLH/IEI who were diagnosed and treated at the departments of pediatric hematology, immunology and oncology of Ankara University School of Medicine Children Hospital and Bone Marrow Transplantation Unit were included in this study. Of the 30 patients, 18 were boys and 12 were girls. The mean age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the mean age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than five days, with a mean duration of 13.30±14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%), and hepatomegaly in 25 patients (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 patients (76.6%), and thrombocytopenia in 30 patients (100%). Genetic evaluation was performed in all patients, and a causative gene was identified in 19 out of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26,6%), followed by UNC13D gene defect (FHLH3) in 4 patients (13,3%). HSCT was performed in 17 patients (56,6%), with 6 receiving transplants from matched related donors (MRD), 4 from matched sibling donors (MSD), 5 from matched unrelated donors (MURD), and 2 from mismatched related donors (MMRD). 13 patients remain alive, with a mean survival of 119.89 months. 17 patients (56.6%) died, primarily from mortality included multi-organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), HLH reactivation, septic shock, and heart failure. HSCT patients had a significantly longer survival (mean 165.6 months) compared to non-HSCT patients (45.36 months, p <0.01). PICU admission, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p < 0.05). Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with national and international cohorts, confirm that HSCT remains the only curative option for familial HLH, and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.