We aimed to evaluate the sensitivity and specificity of Recent Thymic Emigrant (RTE) levels for diagnostic discrimination among various Inborn Errors of Immunity (IEI) subgroups. We analysed 205 paediatric patients diagnosed with IEI at the Paediatric Immunology and Allergy Department of Başakşehir Çam and Sakura City Hospital in Istanbul between January 2021 and January 2024. An age- and sex-matched control group consisting of 31 healthy children was also included for comparison. Demographic, clinical and laboratory data were evaluated. Reduced RTE levels were identified in 39% of all patients. Low RTE levels were most pronounced in patients with syndromic combined immunodeficiency (77%) and immune dysregulation (100%), and were also observed at high frequencies in combined immunodeficiency (CID) (60%) and autoinflammatory disorders (57.1%). For the syndromic CID group, the diagnostic performance of RTE yielded an area under the curve (AUC) of 0.80, with a sensitivity of 92% and a specificity of 52%. In the immune dysregulation group, the AUC was 0.79, with a sensitivity of 83.5% and a specificity of 57.1%. Assessment of RTE levels represents a valuable diagnostic biomarker, particularly for patients within the syndromic CID and immune dysregulation categories. This parameter may contribute meaningfully to clinical practice by facilitating early diagnosis, guiding genetic testing and enabling assessment of thymic function. Incorporating thymic output assessment into routine immunophenotyping panels may shorten the diagnostic timeline for IEI and allow earlier initiation of appropriate therapies.

Hematopoietic stem cell transplantation (HSCT) provides definitive treatment for many inborn errors of immunity (IEI). Although most children achieve full immune reconstitution, long-term psychosocial and quality-of-life outcomes in medically stable survivors remain insufficiently understood. Children aged 8–18 years with IEI who achieved complete immune recovery and had no chronic complications were included. Quality of life and psychological status were evaluated using the Pediatric Quality of Life Inventory (PedsQL-C) and the Revised Children’s Anxiety and Depression Scale (RCADS). Healthy children matched for age, sex, and sociodemographic background served as controls. Thirty-six patients and 41 controls participated. Children post-HSCT had significantly lower physical, psychosocial, and total quality-of-life scores (p = 0.022, 0.015, 0.006) and higher depression scores (p = 0.027). One-quarter of school-aged patients were not attending school, and one-third of families restricted exposure to crowded environments. Despite immune recovery, children remain vulnerable to psychosocial challenges. These findings support incorporation of routine psychological assessment and family counseling into long-term post-HSCT follow‑up.

Recombination-activating genes (RAG1 and RAG2) encode lymphoid-specific proteins that are essential for V(D)J recombination during early T- and B-lymphocyte development. Biallelic mutations in these genes result in a broad spectrum of primary immunodeficiency phenotypes, ranging from classical severe combined immunodeficiency (SCID) to combined immunodeficiency, immune dysregulation, autoimmunity, and inflammatory complications. The immunological phenotype varies widely, from T-B-NK+ severe combined immunodeficiency (SCID) to combined immunodeficiency (CID), or near-normal T and B cell counts, and even antibody deficiencies despite preserved pathogen-specific antibody responses. In this cohort, we aimed to characterize the clinical, immunological, and genetic features, as well as the disease course, of patients diagnosed with RAG1 and RAG2 deficiencies.

BACKGROUND:Inborn errors of immunity (IEI), previously referred to as primary immunodeficiencies, are a heterogeneous group of genetic disorders affecting immune development and function. While once considered rare, IEIs are increasingly recognized, particularly in regions with high consanguinity rates. Cutaneous manifestations, as well as ocular and hair abnormalities, may provide early and clinically relevant diagnostic clues. This study aimed to assess the prevalence, types, and diagnostic value of cutaneous, ocular and hair manifestations in patients with IEI. METHODS:A total of 386 patients with confirmed IEI, classified according to the 2024 IUIS criteria, were retrospectively analyzed. Cutaneous, ocular (e.g., conjunctivitis, keratitis, scleral telangiectasia), and hair manifestations (e.g., alopecia areata, pigmentary abnormalities) were systematically reviewed from medical records. Skin findings were categorized as infectious, immune-allergic (eczema, alopecia areata, urticaria, erythroderma), disease-specific, or other. RESULTS:Cutaneous, ocular, and/or hair manifestations were identified in 198 patients (51.3%), with 59.1% present at diagnosis. Infectious manifestations were the most common (71.8%), followed by immune-allergic findings (34.8%), including eczema (30.3%), and disease-specific manifestations (17.7%). Ocular findings were observed in 15.7% of patients, while hair abnormalities were present in 4.04%. Skin infections were predominantly bacterial (53.1%) and were most frequent in phagocytic and innate immunity defects. Eczema was most frequent in hyper-IgE syndrome (85.8%), while non-eczematous allergic findings were most common in immune dysregulation. Ocular involvement, including viral retinitis and scleral telangiectasia, and hair abnormalities, such as syndromic hair shaft defects and alopecia areata, were observed across multiple IEI subgroups. CONCLUSION:Cutaneous, ocular, and hair abnormalities are frequent in IEI and may support early diagnosis. Recognition of recurrent, atypical, or treatment-resistant skin, eye, or hair findings should prompt immunological evaluation, particularly in pediatric patients.

Phosphoglucomutase 3 deficiency (PGM3 deficiency) is a rare congenital disorder of glycosylation classically associated with severe immunodeficiency, skeletal abnormalities, and neurodevelopmental impairment. However, emerging evidence suggests that PGM3 deficiency may also present with attenuated or milder clinical phenotypes. In this study, we describe patients with a novel PGM3 variant exhibiting a less severe immunological and clinical presentation, thereby expanding the known phenotypic spectrum of PGM3 deficiency. Demographic-data and Wechsler Intelligence Scale for Children profiles were evaluated alongside laboratory data, including complete blood cell counts, lymphocyte subsets, serum immunoglobulin levels, vaccine antibody titers, and lymphocyte cytokine profiles. Whole exome sequencing was conducted, and phospho-flow assays were utilized for the analysis of p-STATs. Five patients with a mild form of PGM3 deficiency were described, exhibiting a Hyper-IgE Syndrome phenotype without severe skeletal dysplasia or dysmorphism, with the exception of one patient displaying very mild skeletal dysplasia and three patients exhibiting mild to moderate intellectual disability. All patients demonstrated an increase in Natural Killer T cells and a decrease in B cells, alongside an increase in activated CD4 + T cells (CD45RO+), a decrease in naïve CD4 + and CD8 + T cells (CD45RA+ CCR7+), and an increase in TEMRA CD8 + T cells (CD45RA+CCR7–). Functional analysis of all patients revealed impaired PGM3 function, as evidenced by decreased surface expression of gp130 and p-STAT3. Defective glycosylation in PGM3 deficiency leads to reduced gp130 expression and attenuated gp130-dependent STAT3 phosphorylation. The resulting cellular features partially overlap with those observed in STAT3 loss-of-function and gp130 deficiency, supporting a shared signaling mechanism while remaining clinically distinct.

Gain-of-function (GOF) mutations in the STAT1 gene result in heightened interferon signaling and impaired IL-17 immunity. While chronic mucocutaneous candidiasis (CMC) remains the hallmark feature, affected individuals often display a broader phenotype including viral infections, mycobacterial susceptibility, and autoimmune diseases. We describe a 4-year-old girl who initially presented with abdominal pain and was diagnosed with acute appendicitis. During surgery, marked mesenteric lymphadenopathy was discovered, and histopathology revealed acid-fast bacilli. Mycobacterium tuberculosis was confirmed by gastric fluid PCR, prompting initiation of anti-tuberculosis therapy. Her past medical history included hospitalization for herpes zoster and recurrent episodes of oral candidiasis during febrile illnesses. Immunologic evaluation showed normal immunoglobulin levels, vaccine responses, oxidative burst, and lymphocyte proliferation. However, low NK cells, reduced recent thymic emigrants, and decreased class-switched memory B cells were noted. Genetic testing revealed a previously unreported heterozygous STAT1 variant (p.Thr387Arg), classified as likely pathogenic according to ACMG criteria with a CADD score of 23.4. Parental genetic testing was negative, suggesting a de novo mutation. Although STAT1 phosphorylation could not be assessed, the proportion of IL-17–producing CD4⁺ T cells was markedly reduced, supporting impaired Th17 immunity. Based on clinical, immunologic, and genetic findings, a clinical and immunological phenotype consistent with STAT1 GOF was established. One year later, the patient developed arthritis and was diagnosed with systemic lupus erythematosus (SLE) based on autoantibody positivity and low complement levels. During follow-up, she also developed hemophagocytic lymphohistiocytosis (HLH), further reflecting severe immune dysregulation. Ruxolitinib was initiated as bridging therapy, resulting in partial clinical improvement, and hematopoietic stem cell transplantation (HSCT) was planned as definitive therapy. This report describes a novel STAT1 variant consistent with a gain-of-function phenotype associated with disseminated tuberculosis and early-onset SLE, expanding the clinical and molecular spectrum of this disorder. In children presenting with overlapping infectious and autoimmune features, underlying inborn errors of immunity should be considered.

Background: Atopic dermatitis (AD) and food allergy (FA) are common allergic diseases in early childhood. AD may be concomitant with FA, particularly in young children. Although studies report the prevalence of FA in children with AD, there is insufficient data regarding different phenotypes of FA. Objective: The aim of our research was to determine the prevalence and clinical predictors of different phenotypes of concomitant FA in children with AD. Methods: This cross-sectional multicenter study included patients younger than 24 months old diagnosed with AD, recruited from 14 pediatric allergy centers. Patients were categorized into two groups using skin testing, allergen-specific IgE, and ultimately food challenge testing (FCT): those with FA and those without. Individuals with FA were classified into three distinct phenotypes: IgE-mediated, non-IgE-mediated, and concurrent IgE- and non-IgE-mediated. Results: The data of 530 children [59% male, median-age 7 months (IQR: 5–11)] were analyzed. IgE-mediated FA was found in 28.1% of participants, whereas 22.4% (n = 119/530) exhibited non-IgE-mediated FA. Concurrent IgE- and non-IgE-mediated FA was reported in 12.1% (n = 64/530) of patients. Cow’s milk (69.6%) and egg-white (68.9%) were identified as the most prevalent allergens. Cow’s milk was primarily responsible for non-IgE-mediated and egg-white for IgE-mediated FA. The most significant predictors of FA were severe AD and the presence of blood in stool with odds ratios of 8.25 (95% Cl: 3.04–22.39) and 10.04 (95% CI: 2.03–49.59), respectively (p < 0.01) (p < 0.005). Conclusions: The study’s findings indicate that children with early-onset and mild-to-moderate AD deserve to be comprehensively assessed for FA symptoms. The most significant indicators of concomitant FA in AD patients were the presence of blood in stool and severe AD. It is important to consider that those who exhibit IgE-mediated FA may also have concurrent non-IgE-mediated FA. We underline that it is important to consider that children with AD who exhibit IgE-mediated FA may also have concurrent non-IgE-mediated FA. Addressing these symptoms may assist healthcare practitioners in clinical practice to improve the quality of care for AD patients having FA.

The group of patients with DNA-repair-defects increases susceptibility to infections due to impaired repertoire diversity. In this context, we aimed to investigate the TCRv beta-repertoire by flow cytometric analysis and its correlation with clinical entities in a group of IEI patients with DNA repair defects. Peripheral lymphocyte subset and TCRv beta-repertoire analyses were performed by flow cytometric analysis. The aim was to explore the changing TCR-V beta-repertoire that can predict some clinical entities by investigating the repertoire using flow-cytometric-analysis-based TCR-V beta and its interaction with clinical entities in a group of IEI patients with DNA repair defects. TCR-repertoire of the patients with DNA-repair-defects and healthy controls was analysed with flow-cytometer. The potential of flow-cytometric analysis of the TCR repertoire as a practical and easily accessible clinical prediction method was investigated. Thirty-nine-IEI patients with DNA-repair-defects and 15 age-matched healthy-controls were included in this study. Peripheral lymphocyte subset and TCR-V beta repertoire analyses were performed by flow cytometry. Compared to the control group, 9 out of 24 clones (37.5%) exhibited a statistically significant reduction, while only 3 clones showed a statistically significant increase (p < 0.05). Preferential use of v beta-genes was associated with some clinical entities. Lower TCR-v beta-9 and TCR-v beta 23, higher TCR-v beta 7.2 were found in the patients with pneumonia (n = 13) (p = 0.018, p = 0.044 p = 0.032). AT patients with pneumonia had lower TCR-v beta-9 clone than patients without pneumonia (p = 0.008). Skewed proliferation of most TCR-v beta clones was seen DNA-repair-defects, especially AT. In addition, this study showed that preferential use of TCR-v beta genes could be predictive for some clinical entities.

BACKGROUND:Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) insufficiency are rare primary immune dysregulation disorders. Both conditions result from impaired maintenance of CTLA-4, a critical inhibitory checkpoint molecule. Despite the known benefits of abatacept (a CTLA-4-Ig fusion protein) treatment, its precise immunologic effects remain unclear. OBJECTIVE:We comprehensively investigated the effect of abatacept therapy on patients with LRBA deficiency and CTLA-4 insufficiency using an integrative multiomics approach. METHODS:The study combined longitudinal flow cytometry, targeted and single-cell transcriptomics, and plasma proteomics in patients receiving abatacept treatment. RESULTS:Abatacept treatment increased thymic output and expansion of naive T and B cells while reducing memory T-cell subsets, CD4+ T-cell cytokine production, and CD21low B cells. Multimodal transcriptomic and proteomic analyses revealed previously unrecognized immunopathogenic mechanisms, including increased CD28 and T-cell receptor signaling as well as compensatory upregulation of inhibitory checkpoint proteins (LAG3, TIGIT, ADORA2A, VSIR, HAVCR2) in response to CTLA-4 insufficiency. Proteomic profiling confirmed the upregulation of inflammatory mediators, including CHI3L1, CXCL13, and CSF1. Most of these transcriptomic and proteomic abnormalities were reversed after abatacept therapy; notably, gene signatures derived from lymphocytes exhibited greater normalization than those associated with myeloid cells. Furthermore, identified shared and disease-specific molecular signatures distinguished LRBA-deficient patients from those with CTLA-4 insufficiency, revealing more severe immune dysregulation in LRBA deficiency. Single-cell RNA sequencing validated the reversal of checkpoint dysregulation and the expression of inflammation-related genes across lymphoid and myeloid lineages. CONCLUSION:Abatacept effectively corrects key immune circuits in both diseases. This integrative systems-level approach offers new mechanisms and therapeutic targets, supporting personalized intervention strategies.

PURPOSE:We aimed to investigate allergic sensitization and associated factors in pediatric patients with selective immunoglobulin A deficiency (SIgAD) and to evaluate differences between allergic and nonallergic groups. METHODS:We analyzed 110 patients (aged 4-18 years) diagnosed with SIgAD at Çam and Sakura City Hospitals, Istanbul, between 2021 and 2024. Their demographic, clinical, and laboratory data were assessed. RESULTS:Allergic sensitization was detected in 62.7% of patients. Patients with allergic sensitization, family history of allergic diseases, eosinophilia, and elevated total immunoglobulin E (IgE) levels were significantly higher (P < 0.05). Immunglobulin M (IgM) levels were higher in the allergic group (P = 0.01), and they had lower neutrophil counts (P = 0.03). Allergic sensitization was lower in patients with autoimmune diseases (P = 0.03). In 60% of the patients, the main reason for presentation was recurrent infection. CONCLUSION:Allergic sensitization with SIgAD is associated with genetic and immunological factors. A family history of allergic disease, eosinophilia, and elevated total IgE levels are important markers for the development of allergy. These findings highlight the need to closely monitor allergies in people with SIgAD.

Bruton’s tyrosine kinase (BTK) is expressed by innate immune cells, and it has been suggested that a lack of BTK may affect monocytes, impacting infection susceptibility and inflammatory response in patients with X-linked agammaglobulinemia (XLA). This study aimed to explore the role of monocyte subsets and monocyte human leucocyte antigen DR (mHLA-DR) expression in patients with XLA. Fifty-nine patients diagnosed with XLA and 37 age-matched healthy subjects were enrolled, and their demographic and clinical features were recorded. Three monocyte subsets were identified—classical (CL) (CD14++CD16−), intermediate (INT) (CD14++CD16+), and non-classical (NC) (CD14lowCD16++)—and their mHLA-DR expressions (mean fluorescence intensity, MFI) were determined by flow cytometry. We evaluated monocyte plasticity as the classical/intermediate monocyte (CMIM) ratio. Patients with XLA comprised 38 children (mean age, 10.46 ± 4.81 years) and 21 adults (25.09 ± 6.18 years). Compared to the control group, patients had decreased classical (p = .012) but increased intermediate and non-classical monocytes (p < .001 and p = .048, respectively). They also presented with increased mHLA-DR expression of total monocytes and their subsets compared to the healthy subjects (p < .05). There were 17 patients with bronchiectasis (28.8

Background:Adenosine deaminase 2 deficiency (DADA-2) is an autoinflammatory syndrome caused by mutations in the ADA2 gene. ADA-2 functions as an enzyme in purine metabolism and is presumed to play roles in immune regulation. The clinical spectrum of DADA2varies widely, from vascular inflammation and immune dysregulation to hematological abnormalities, including pure red cell aplasia and hemophagocytic lymphohistiocytosis (HLH). This study aimed to describe the clinical, demographic, and immunological profiles of seven DADA-2 patients to broaden the understanding of its hematological and immunological manifestations and provide insight for early diagnosis and treatment strategies. Methods:Data were collected from patient medical records at the Department of Pediatric Allergy and Clinical Immunology, Basaksehir Cam and Sakura City Hospital. The study included genetic analysis, flow cytometry for lymphocyte subpopulations, and ADA-2 enzyme activity measurement. Results:Seven patients from five families were included, predominantly male, with an average symptom onset at 15 months. Hematological findings were present in all patients, with neutropenia observed at the initial presentation (100%). HLH developed in two patients, contributing to a higher mortality rate of 42.8%. Bone marrow analysis in affected patients revealed hypocellularity and marked T-cell infiltration, with fibrosis detected in one. Despite no evidence of viral triggers (EBV, CMV, VZV, Parvovirus B19), HLH occurred in two patients, suggesting a primary immune dysregulation. Inflammatory and immunodeficiency-related findings were also observed, suggesting a mixed phenotype as the most common presentation. Genotype-phenotype analysis showed that patients with undetectable ADA2 enzyme activity or loss-of-function mutations had more severe hematological involvement. In contrast, a patient with residual enzyme activity exhibited a mixed phenotype. Three patients underwent successful hematopoietic stem cell transplantation (HSCT), reversing disease manifestations. Conclusion:Our findings reinforce that DADA2 can initially present as isolated neutropenia, and frequently exhibits a mixed phenotype encompassing hematologic, immunologic, and inflammatory features. HLH is a severe complication that may arise without infectious triggers. Genetic testing for ADA2 should be incorporated into diagnostic panels for congenital neutropenia to avoid delays in diagnosis. Genotype-phenotype correlations offer some prognostic insights, but residual enzyme activity may not fully predict disease severity, underscoring the need for individualized management.

Janus kinase-3 (JAK3) deficiency, first described in 1995, is an autosomal recessive inborn error of immunity that mostly results in variants of severe combined immunodeficiency (SCID). The frequency is estimated to account for 7-14% of heritable SCID, with sporadic cases in the Western world. Neither preferential “hot spots” nor founder effects have yet been documented. Hereby, we aim to describe the global experience of JAK3-related diseases regarding clinical spectrum, genetic landscape, including founder variants and treatment strategies. We extracted clinical, genetic, and immunological data from published cases on patients with СID/SCID phenotype caused by defects in the JAK3 gene. The literature search included unpublished cases from collaborators, reports from meetings of the European Society for Immunodeficiencies (ESID), of the Clinical Immunology Society (CIS), and published data in the biomedical research search engine (PubMed) from 1995 to 2024. Our cohort includes 132 patients with 47 unique genetic defects, including 35 novel variants (18 homozygous, 17 heterozygous). The patients were from 5 continents with majority of Asian ancestry. Country of diagnosis included North America (USA [n = 42]); South America (Brazil [n = 3]); Europe (Turkey [n = 8], Hungary [n = 1], Poland [n = 6], UK [n = 5], Italy [n = 5], Israel [n = 4], Belarus [n = 4], Russian Federation [n = 3], Georgia [n = 3], Spain [n = 1], Germany [n = 1]); Asia (India [n = 16], Iran [n = 6],China [n = 4], Pakistan [n = 1], Japan [n = 1]); and Africa (Egypt [n = 16], Saudi Arabia [n = 1], Sudan [n = 1]). Forty-five (35%) of patients from the cohort were born to consanguineous parents in 31 families from Georgia (n = 3, 1-family), Russian Federation (n = 3/2-family), Sudan (n = 1), Turkey (n = 8, 5-family), Israel (n = 4, 2-family), India (n = 3, 2-family), Egypt(n = 13, 8-family), UK (n = 5, 4-family), China (n = 1), Brazil (n = 1), Spain (n = 1), Italy (n = 1), Pakistan (n = 1), and Saudi (n = 1). 13 novel founder variants are identified. The same founder variant was seen in several countries. The majority of genetic defects were homozygous (68%); 40/132 compound were heterozygous, and 2 patients had germline heterozygous gain-of-function. The variants occurred across the entire JAK3 gene with no hotspots. Only 6 (5%) of 132 cases developed Omenn syndrome. 61 patients were transplanted, 17 died at the age of 9 months (mean age 9-18 months), and 44 are alive. We describe for the first time a global cohort of JAK3 with 132 patients with founder effects in a subgroup. Patients were identified in four continents but are most common in countries with a high rate of consanguinity. Founder effect was identified in 14 regions.

X-linked agammaglobulinemia (XLA) is caused by Bruton tyrosine kinase gene mutations, leading to B-cell deficiency. This study aimed to investigate myeloid-derived suppressor cells (MDSCs) frequency, lymphocyte apoptosis and clinical significance in patients with XLA. The study comprised 46 paediatric (mean age: 9.9 ± 4.8 years) and 21 adult patients (24.6 ± 5.9 years). Total MDSCs (HLA-DR-CD33+CD11b+) were subdivided into CD15+ polymorphonuclear (PMN-MDSCs) and CD14+ monocytic (M-MDSCs) and analysed by flow cytometry. The paediatric XLA patients had increased M-MDSCs and early apoptotic lymphocyte frequency compared to healthy subjects. The mean diagnostic delay was positively correlated with early apoptotic CD3+ and CD4+ T-cells. Seventeen patients (14 adults and 3 children) had bronchiectasis. PMN-MDSCs were higher in adult patients than in paediatric patients. Increased PMN-MDSCs in adults with XLA suggest the presence of chronic inflammation in patients with bronchiectasis. The study findings broaden understanding of XLA's complex immunopathology and highlight the need for more comprehensive immune monitoring of these patients beyond antibody production.

BACKGROUND:Dedicator of cytokinesis protein 8 (DOCK8) is a guanine nucleotide exchange factor highly expressed in, and critical for, the function of various innate and adaptive immune cells. DOCK8 deficiency leads to combined immunodeficiency characterized by susceptibility to infections, autoimmunity, and a severe Th2-type immune response. While dysfunction in various T cell subsets has been implicated in these phenotypes, a comprehensive analysis of the T-cell receptor (TCR) repertoire in these patients has not yet been documented. This study investigates the αβ TCR repertoire in DOCK8-deficient patients to identify features related to disease pathogenesis and explore the potential role of TCR repertoire alterations in disease development. METHODS:We compared immune repertoire profiles determined by high-throughput TCR sequencing of circulating CD4+ and CD8+ T cells from patients with DOCK8 deficiency (n = 10) to healthy controls (n = 7) and patients with ataxia-telangiectasia (AT) (n = 5). RESULTS:Different diversity analyses revealed a restricted TRA and TRB repertoire in both CD4+ and CD8+ T cells from DOCK8-deficient patients, with the restriction being more pronounced in CD8+ T cells. Skewed usage of individual variable (V) and joining (J) genes and potentially self-reactive CD8+ T cell clones, as determined by hydrophobicity and cysteine indices, were identified in DOCK8-deficient patients. CONCLUSION:Our study represents the most comprehensive immune repertoire analysis in DOCK8 deficiency. The identification of a significantly restricted αβ TCR repertoire, along with the detection of potentially autoreactive clones, highlights the crucial role of immune repertoire profiling in elucidating the pathogenesis of DOCK8 deficiency.

Primary immunodeficiency disorders (PIDDs) comprise a heterogeneous group of genetic conditions characterised by recurrent infections, immune dysregulation and increased susceptibility to malignancies. While clinical evaluation remains essential for diagnosis, genetic testing plays a pivotal role in confirming the diagnosis and guiding management. This cross-sectional study evaluates the diagnostic yield and clinical utility of targeted gene panel testing in patients with a strong clinical suspicion of PIDDs, within the framework of the Jeffrey Modell Foundation's 'Jeffrey's Insights' programme. Between 2022 and 2024, 104 patients without a prior genetic diagnosis were evaluated at the Department of Paediatric Allergy and Clinical Immunology, Başakşehir Çam and Sakura City Hospital, Türkiye. In 72 of 104 patients, the identified variants were consistent with clinical phenotypes. Pathogenic or likely pathogenic variants were identified in 41.3% of patients, increasing to 57.7% when including variants of uncertain significance (VUS) with high CADD scores. Genetic findings prompted reclassification of International Union of Immunological Societies (IUIS) categories in 25% of cases. Autosomal recessive inheritance and parental consanguinity were notable, reflecting regional genetic patterns. Failure to thrive and low switched memory B cell percentages were significantly associated with confirmed genetic diagnoses, while food allergy, viral skin infections and eczema were more common in genetically undiagnosed patients. These findings support the clinical value of targeted gene panels as an effective, accessible and informative tool in the diagnosis and classification of PIDDs, enhancing precision in patient care and enabling tailored therapeutic strategies.

BACKGROUND:Trichohepatoenteric syndrome (THES) is characterized by neonatal-onset intractable diarrhea. It often requires long-term total parenteral nutrition (TPN). In addition, other characteristic findings of the syndrome include growth retardation, facial dysmorphism, hair abnormalities, various immunological problems and other rare system findings. Two genes and their associated pathogenic variants have been associated with this syndrome: SKIC3 and SKIC2. METHODS AND RESULTS:In this case series, the clinical findings and molecular analysis results of a total of 8 patients from 5 different families who presented with persistent diarrhea and were diagnosed with THES were shared. Pathogenic variants were detected in the SKIC3 gene in 6 of our patients and in the SKIC2 gene in 2 patients. It was planned to compare the clinical findings of our patients with other patients, together with literature data, and to present yet-undefined phenotypic features that may be related to THES. In our case series, in addition to our patients with a novel variant, patient number 2 had a dual phenotype (THES and Spondyloepimetaphyseal dysplasia, sponastrime type) that has not been reported yet. Delay in gross motor skills, mild cognitive impairment, radioulnar synostosis, osteoporosis, nephropathy and cystic lesions (renal and liver) were observed as unreported phenotypic findings. CONCLUSIONS:We are expanding the clinical and molecular repertoire of the syndrome regarding patients diagnosed with THES. We recommend that the NGS (next-generation sequencing) multigene panel should be used as a diagnostic tool in cases with persistent diarrhea.