Tetratricopeptide repeat domain 7A (TTC7A) deficiency is a primary immunodeficiency due to mutations in the TTC7A gene. It causes intestinal disease and a poorly characterized immunodeficiency, with poor long-term survival. We describe the clinical and immunological characteristics, management, and outcomes of an international cohort of patients with genetically confirmed TTC7A deficiency. Data from 61 patients from 13 countries were retrospectively analyzed. Overall survival was 64% (median follow-up 4.2 years), significantly higher in the inflammatory bowel disease than in the hereditary multiple intestinal atresia group (80 vs. 48%, P < 0.05). Infections represent the leading cause of death. Allogeneic stem cell transplantation was performed in 16 patients to correct the immunodeficiency but was associated with a significant transplant-related mortality (44%). Solid organ transplantation of the small bowel remains exceptionally rare (two patients). Malignancy/autoimmune disorders developed in 4 (6.5%) and 17 (28%) patients, respectively. TTC7A remains difficult to treat, and prognosis is dismal for affected patients. Further understanding of the disease mechanisms and development of innovative treatment approaches are required.

BACKGROUND:Immunocompromised children with hematologic malignancies or undergoing allogeneic haematopoietic stem cell transplantation (HSCT) are at high risk for invasive fungal diseases (IFDs). Reported incidence varies considerably due to heterogeneous diagnostic criteria, antifungal strategies and environmental conditions. Environmental preventive measures, although highly relevant, remain underrecognised determinants of IFD incidence. METHODS:This retrospective, single-centre trial included paediatric cancer or transplant patients at high risk for IFD treated before (Cohort 1) and after (Cohort 2) relocation of a paediatric cancer centre from a 1990s building to a state-of-the-art facility with improved environmental protection standards (observation periods: 56 and 12 months, respectively). Antifungal prophylaxis continuously followed local standards. IFD was diagnosed according to 2019 EORTC/MSGERC criteria. Primary endpoint was IFD incidence; secondary endpoints included prophylaxis use, IFD management and mortality. RESULTS:This study included 186 patients (Cohort 1: n = 140; Cohort 2: n = 46). Baseline characteristics were comparable between both cohorts. Adherence to prophylaxis standards exceeded 98%, with liposomal amphotericin B being the most common agent. In Cohort 1, 25 possible, probable, or proven IFD occurred, mainly pulmonary aspergillosis, whereas no cases were observed following implementation of environmental measures in Cohort 2 (17.9% vs. 0%, p = 0.002). Most IFD cases occurred in HSCT recipients. IFD was associated with increased mortality (p < 0.0001). CONCLUSIONS:In this contemporary paediatric cancer and transplant setting, environmental protective measures were associated with a marked reduction in IFD incidence, complementing consistent pharmacologic prophylaxis. These findings underscore environmental protection as essential for IFD prevention in high-risk paediatric populations.

Prunotto et al. describe clinical presentation, immunological status, treatment, and long-term outcomes of a large cohort of pediatric and adult patients affected by an extremely complex and rare immunodeficiency known as TTC7A deficiency for which no clear therapeutic pathway is currently available.

Background: Children with profound combined immunodeficiency (P-CID) are at high risk of severe infections, immune dysregulation, organ damage, and death. Clinical factors that may inform hematopoetic-stem-cell-transplantation (HSCT) decisions remain poorly defined because evidence is limited to retrospective studies. Methods: We conducted a prospective, multicenter cohort study of 139 children aged 1–16 years with impaired T-cell immunity and at least one disease-related manifestation. Patients were recruited from 31 centers in 14 countries between 2011 and 2018 and followed for 5–12 years regardless of subsequent HSCT. Disease severity at study entry was classified pragmatically as severe or non-severe according to the treating physician’s integrated assessment during HSCT decision-making. Outcomes included death, recurrent severe events, and chronic organ damage. We used joint frailty models to identify predictors of outcome and marginal structural models to explore the association between HSCT and mortality across cumulative disease burden. As treatment was not randomized, results may be affected by residual confounding. Findings: Most patients continued accumulating events during follow-up. Poor outcomes were more frequent among patients classified as severe. In multivariable analyses, severe infections predicted recurrent disease-related events and death, while chronic organ damage and malignancy predicted death. Autoimmune cytopenia, lymphoproliferation, and organ-specific immune dysregulation were not independently associated with outcome. Genetic diagnosis, CD4 counts, and naïve CD4 percentages were not informative for risk stratification. In univariable analyses, low post-neonatal TREC/KREC levels and impaired T-cell proliferation were associated with poor outcome. In observational analyses, HSCT was associated with lower mortality at higher pre-transplant event burden, with wide confidence intervals. Interpretation: In P-CID, selected clinical parameters are more informative than genotype or T-cell counts for risk assessment. Our findings support repeated reassessment of disease burden and organ damage when considering HSCT rather than reliance on a fixed transplant threshold. Whether earlier transplantation improves outcome remains uncertain.

Schwere kombinierte Immundefekte (SCID) sind seltene, aber lebensbedrohliche angeborene Erkrankungen, die unbehandelt im Säuglingsalter zu schweren, häufig letal verlaufenden Infektionen führen. Da betroffene Neugeborene bei Geburt in der Regel klinisch unauffällig sind, ist eine frühzeitige Diagnosestellung entscheidend. Dieser Beitrag gibt einen Überblick über das „T-cell-receptor-excision-circle“-basierte Neugeborenenscreening (TREC-NBS) auf SCID, das seit 2019 in Deutschland flächendeckend Bestandteil des erweiterten Neugeborenenscreenings ist. Bis September 2024 wurden rund 4,5 Mio. Neugeborene mittels TREC-Quantifizierung untersucht; dabei konnten etwa 170 Kinder mit einer primären schweren T‑Zell-Lymphozytopenie identifiziert werden. Der Beitrag beschreibt die wissenschaftlichen Grundlagen des Screenings, den in Deutschland etablierten Algorithmus sowie das strukturierte diagnostische und klinische Vorgehen bei auffälligen Screeningbefunden und fasst die bisherigen Erfahrungen aus der Screeningpraxis zusammen.

BACKGROUND:Inborn errors of immunity (IEI) associated with gain of function (GOF) in the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways (JAK-STAT-GOF IEI) are rare disorders characterized by immune dysregulation, autoimmunity, malignancy, and increased infection susceptibility. To date, no JAK inhibitors (JAKi) are licensed for these conditions, but they are frequently prescribed off-label, even though high-quality evidence and treatment guidelines remain limited. OBJECTIVE:We developed evidence- and consensus-based recommendations for JAKi treatment in JAK-STAT-GOF IEI across all age groups on the basis of a systematic literature review and expert consensus. METHODS:An international expert group conducted a systematic literature review and developed recommendations on JAKi treatment in JAK-STAT-GOF IEI using a modified Delphi approach. Recommendations were developed based on published evidence, data from an international retrospective cohort study, and patient representative input. These statements were then tested for consensus in a 2-round Delphi survey procedure in a larger, interdisciplinary expert panel. RESULTS:Consensus- and evidence-based guidance is presented across 5 thematic areas: (1) JAKi indications/contraindications, (2) pretreatment assessment, (3) pharmacology/dosing, (4) monitoring, and (5) use in the context of hematopoietic stem cell transplantation. A total of 51 statements were established and contextualized with the available evidence. CONCLUSION:This consensus provides structured guidance for clinicians managing JAK-STAT-GOF IEI with JAKi. While prospective trials will further refine these strategies, this guidance represents the current international standard of care, reflecting the synthesis of clinical experience and the best available evidence.

Biallelic loss-of-function variants in capping protein regulator and myosin 1 linker 2 (CARMIL2) cause a complex disorder of immune dysregulation hallmarked by susceptibility to infections, inflammatory bowel and skin disease, and Epstein-Barr virus-positive smooth muscle tumors (EBV+ SMTs). We report a multicenter retrospective study to evaluate hematopoietic cell transplantation (HCT) outcomes in CARMIL2-deficient patients. 17 patients underwent 19 HCTs, with a total follow-up of 768 mo and a median follow-up of 37 mo (range 1-195). Three patients died during the early posttransplant period (overall survival, 82.4%), and two required a second HCT for graft failure. Despite limitations due to cohort size and high pre-transplant morbidity in individual patients, HCT improved all major disease manifestations, including infections, inflammatory disease, and previously treatment-refractory EBV+ SMTs. No patient required immunoglobulin replacement after HCT, and no detrimental effects of mixed chimerism were noted. Allogeneic HCT is therefore a curative option for patients with CARMIL2 deficiency, which should be offered upon diagnosis.

Allogeneic HCT substantially addresses immunodeficiency, immune dysregulation, and Epstein-Barr virus–positive smooth muscle tumors in patients with CARMIL2 deficiency and should be offered shortly following diagnosis.

TREC-NBS identifies patients with inborn errors of immunity (IEI) and syndromic features, but uncertainty remains regarding their immunological management. To address this, syndromic patients detected by TREC-NBS in Germany between August 2019 and April 2024 were systematically analyzed, including phenotype, treatment, and outcomes. National registries were screened, and data were completed by the treating centres. A total of 77 syndromic patients were identified, with 22 different gene defects found in 72 individuals (93.5

PURPOSE:Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/Microcephalic osteodysplastic primordial dwarfism type I, Roifman, and Lowry-Wood syndromes, which are characterized by variable microcephaly, short stature, neurodevelopmental impairment, skeletal dysplasia, and immunodeficiency. Two-thirds of the reported individuals present with Taybi-Linder syndrome, the first-described and most severe form. METHODS:We collected clinical and molecular data from individuals with biallelic RNU4ATAC variants through various French and European networks and clinics to refine the phenotypic spectrum of RNU4ATAC-opathies. RESULTS:We enrolled 69 participants and identified 18 new pathogenic variants. We report a significant proportion of attenuated or atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune or inflammatory manifestations, affecting nearly half of the participants. Integrating our data with the 109 published cases, we propose a novel classification based on the main manifestations, immunodeficiency, and microcephalic primordial dwarfism. Using computer-assisted facial analysis, we also demonstrated the existence of a specific dysmorphic pattern in RNU4ATAC-opathies that is distinct among some sub-syndromes. CONCLUSION:We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to paucisymptomatic forms, indicating that these diseases are likely to remain underdiagnosed.

Lymphoproliferation in autoimmune lymphoproliferative syndrome (ALPS) due to FAS deficiency is driven by highly proliferative FAS-controlled T cells (FCT) with a distinct molecular signature. Activating signals and metabolic fuels of their proliferation are poorly understood. Lymphoproliferation caused by proliferative T cells is also a hallmark of acute EBV infection. In these antiviral T cells, a metabolic switch to glycolysis underpins effector differentiation and IFNγ translation. Here, we used EBV-induced CD8 effector T cells as a benchmark to characterize FCT metabolism. Metabolic assays, RNA sequencing, and in silico computational analysis revealed that FCT are as highly glycolytic as EBV-induced effector T cells, but this metabolic program is uncoupled from T-BET expression and IFNγ production. In contrast to virus-activated T cells, FCT showed mitochondrial hyperpolarization and elevated reactive oxygen species production. These findings support a model of FCT lymphoproliferation, in which activating signals strongly enhance glycolysis but do not induce classical effector differentiation.

Initiation of newborn screening (NBS) programs in Europe dates back to the 1960s. One of the most recent expansions of NBS programs was the addition of severe combined immunodeficiency (SCID) based on detection of T-cell receptor excision circles (TRECs). In this review, we present an overview of the current situation in Europe. To avoid a biased overview based on only published results, a 37-item survey on TREC-based NBS was sent to representatives of 46 European countries. With a response rate of 83%, we collected data of 38 countries. Seventeen of the 38 European countries that have completed the survey have nationally or regionally implemented TREC-based NBS. The survey results emphasize similarities and differences as well as common practices and challenges in TREC-based NBS. Because TRECs are a general surrogate marker for severe T lymphocytopenia, conditions other than SCID are also identified. Therefore, the initial definition of the target disease as "SCID" might need to be reconsidered and extended to "SCID and severe T lymphocytopenia." Even though complete harmonization of TREC-based NBS programs across Europe will remain challenging, collaboration and close partnerships will help in the move toward universal TREC-based screening for all newborns, resulting in more infants with SCID and severe T lymphocytopenia being detected each year.

BACKGROUND:Inborn errors of immunity are traditionally understood as monogenic germline disorders. However, somatic mosaicism can also result in immune-mediated diseases, mimicking inborn errors of immunity. While early postzygotic mosaicism is the predominant mechanism, genetic variants causing a selective advantage to hematopoietic progenitors and/or mature immune cells may cause immune dysregulation and initiate disease at any age. Somatic mosaicism for STAT5BN642H was linked to severe allergic disease in infancy, but its full clinical spectrum and underlying mechanisms remain incompletely defined. OBJECTIVE:We elucidated how somatic N642H mutations of the STAT5B gene shape lineage-specific mosaicism, immune cell function, and clinical phenotypes. METHODS:We investigated 3 new patients-including one adult-with STAT5BN642H mosaicism using deep sequencing, flow and mass cytometry, and functional immune assays. Mutant cell distribution was mapped across blood lineages. A mouse model with mosaic STAT5BN642H mutation in hematopoietic stem cells was generated to study clonal dynamics and immune phenotypes. RESULTS:Patients displayed variable lineage mosaicism correlating with two predominant clinical outcomes: early-onset severe atopy with hypereosinophilia, and autoimmune-lymphoproliferative immunodeficiency with expansions of CD8 and γδ T cells. Functional studies revealed enhanced IL-2-mediated proliferation, effector differentiation, and oligoclonal T-cell expansions. In mice, a few mutant hematopoietic stem cells reproduced the patient lineage-skewed immune landscapes with variable growth advantage of mutant cells across hematopoietic development and recapitulated patient T-cell phenotypes. Targeted mTOR inhibition successfully controlled lymphoproliferation in patients. CONCLUSION:A single somatic variant in a few stem cells can remodel hematopoiesis, generating variable immune mosaics and heterogeneous immune disease.

Transfusion management of Kx- individuals with McLeod phenotype (MLP) is highly challenging, particularly as cryopreservation affects red blood cell (RBC) concentrate quality. We developed a concept to provide non-cryopreserved Kx- RBCs over the complete period of hematopoietic stem cell transplantation (HSCT) for treatment of X-linked chronic granulomatous disease (X-CGD) with MLP. An infant with a large deletion affecting 12 protein-coding genes, including DMD, PRRG1, LANCL3, XK, CYBB, and DYNLT3, leading to CGD, Duchenne muscular dystrophy, and MLP, was scheduled for HSCT with the need of Kx- blood supply. No Kx- and RhD compatible donors were identified by rare donor programs, and autologous blood collection was not possible. In an interdisciplinary multicenter effort pre- and post-HSCT blood management, including procurement of non-cryopreserved allogeneic Kx- RBCs from an individual with MLP, was orchestrated, balancing donations, storage, pediatric RBC preparation, and irradiation with the clinical schedule. Our concept ensured compatible blood supply from 100 days prior HSCT to the peritransplant phase. The patient received 5 non-cryopreserved Kx- pediatric RBCs and was discharged with complete chimerism at day +68. The screen was repeatedly negative for antibodies to high frequency RBC antigens. After 2.8 years, the patient remained independent of transfusions and was without signs of graft-versus-host disease. Close coordination between institutions and disciplines and process optimization allow readily available provision of non-cryopreserved Kx- RBCs to support HSCT to a patient with unique contiguous gene deletion syndrome of X chromosome.

Ukraine’s healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)–purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on a neonatal dried blood spot (DBS) by real-time PCR, which showed remarkably reduced T-cell receptor and kappa-deleting recombination excision circles (TREC/KREC). Retesting was delayed due to communication difficulties with the family. Whole exome sequencing on a new DBS confirmed the diagnosis. The newborn was a candidate for allogeneic hematopoietic stem cell transplantation (HSCT), the only curative treatment. HSCT is a complex procedure still ongoing in Ukraine despite the conflict. However, due to the psychosocial strain, the family sought medical support in Germany, where HSCT was performed successfully at 6 months. As part of a collaborative initiative with Italy, PNP biomarkers were quantified on the same DBSs using tandem mass spectrometry, according to the protocols established for SCID NBS in Tuscany, serving as a proof of concept of its diagnostic performance. This case highlights the importance of sustaining preventive and life-saving healthcare services, and reflects the key role of international partnerships in upholding the right to healthcare in times of crisis.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.