Issues

A report in this issue of JHI deepens our understanding of human disease associated with loss of CTLA-4.

In this News & Views, we discuss two studies reporting autosomal recessive OSMRβ deficiency as a new inborn error of immunity marked by severe atopy, hyper-IgE, and eosinophilia, thereby refining the genetic dissection of STAT3-dependent hyper-IgE syndrome.

This review article considers the utility of calculated globulin as an unbiased and inexpensive screening tool for immunodeficiency. The benefits and practicalities of its clinical implementation and current challenges and limitations are discussed.

Down syndrome (DS) is characterized by lifelong immune dysregulation leading to high rates of autoimmune disorders, complications from infections, immune hypersensitivity, and a unique form of immunodeficiency. Here within, we describe clinical considerations toward monitoring, management, and therapeutic opportunities. We highlight recent research advances that illuminate diagnostic approaches to evaluate immune dysregulation in DS.

Wouters et al. review the clinical and genetic landscape of DADA2, a multisystem inborn error of immunity. It examines expanding phenotypes, emerging pathophysiological mechanisms, treatment strategies, and newly described dominant-negative variants that challenge classical recessive inheritance—suggesting DADA2 is considerably more prevalent than previously recognized.

APDS is a rare inborn error of immunity classified as a group of combined immunodeficiency; however, because specific treatments—such as rapamycin and p110δ inhibitors—for APDS are available, early diagnosis and therapeutic intervention are crucial for improving patient prognosis.

Yanes et al. presents evidence-based guidelines from the Australasian Society of Clinical Immunology and Allergy to support clinicians in selecting patients with suspected inborn errors of immunity for genomic testing. The work provides practical recommendations to improve clinical decision-making, delivery of diagnostic genomic testing, and patient outcomes.

O’Connell et al. demonstrate that negative functional studies can meaningfully guide care. In a neonate with a DOCK11 variant of uncertain significance, negative functional studies guide clinical care and highlight the broader value of publishing instructive negative findings in immunology and genomic medicine.

This case report describes progressive multifocal leukoencephalopathy in a patient with ADA-SCID who received early gene therapy, highlighting the importance of lifelong monitoring after early gene therapy protocols. Further research in ADA-SCID and advances in gene therapy approaches may improve long-term immune reconstitution and reduce the risk of late complications.

We report a deep intronic FOXP3 pathogenic variant that was investigated by RNA sequencing in heterozygous female carriers.

We report the first detailed immunological characterization of a DEGCAGS patient, showing that biallelic ZNF699 loss-of-function variants can cause syndromic combined immunodeficiency and that DNA methylation profiling improves diagnostic precision in selected inborn errors of immunity.

Peters et al. describe genetics and phenotypes of n = 48 DADA2 patients from Germany, Austria, and Switzerland. The data support the hypothesis that patients with low residual ADA2 activity are prone to bone marrow failure, while high residual ADA2 activity correlates with vasculitis.

Catak et al. describe the first case of homozygous CTLA-4 deficiency, which drives severe early-onset autoimmunity through profound T and B cell dysregulation. They show that the variant impairs protein stability, yet targeted therapy with abatacept successfully restores immune balance, highlighting new clinical strategies for CTLA-4–related disorders.

In this first randomized, placebo-controlled trial, thalidomide demonstrated potential efficacy and acceptable safety in patients aged 1 year or older with chronic granulomatous disease–related inflammatory bowel disease, suggesting potential as a therapeutic option without increasing the risk of infection.

Winestone et al. demonstrate that in 796 children with SCID transplanted with nonsibling donors between 1982 and 2020, survival was 18.8% lower among Black patients, 14.4% lower among Asian/Pacific Islander patients, and 6.9% lower among Hispanic patients compared with non-Hispanic White patients (P < 0.01). Newborn screening for SCID mitigates wide disparities between Black and non-Hispanic White patients.

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.

A subset of patients evaluated for immune dysregulation presents with increased proportions of TCR γδ cells despite normal total lymphocyte counts. Corresponding to this phenotype, the authors report a case of a somatic TCR γδ–specific STAT5B mutation that is molecularly amenable to tailored immune modulation. This raises awareness of druggable TCR γδ–intrinsic, genetically determined immune dysregulation.

Kienapfel et al. report the characterization of two novel mutations underlying STAT2 deficiency in three patients with viral infections and hyperinflammation following live viral vaccines. Beneficial use of ruxolinitib in one patient with vaccine-triggered hemophagocytic lymphohistiocytosis is also reported.

Al-Tamemi et al. describe that autosomal recessive CGD represents a significant disease in the MENA region associated with significant morbidity and mortality. Regional challenges are related to universal newborn BCG vaccine, lack of newborn screening programs, and limitation of curative interventions such as hematopoietic stem cell transplantation and gene therapy.

Hematopoietic stem cell transplantation is a curative option for children with MSMD. Outcomes improve when conditioning is tailored to genetic defects: Flu/Treo for IL-12 deficiency and Flu/Treo/TT with pretransplant immunosuppression for IFN-γ defects. Multidisciplinary infection management and long-term follow-up are essential to optimize survival and quality of life.

This study demonstrates that second-tier genetics improves newborn screening accuracy for SCID and other T cell deficiencies. A safety net algorithm maintains high sensitivity for SCID while substantially increasing the PPV from 22.1% to 55.2%.

The authors identify three novel mutations in AIRE and detect T cell defects in patients with APS-1. Furthermore, they review the literature and identify additional clinical features, and define mutational hotspots suitable for targeted sequencing. These parameters could facilitate the timely identification of APS-1, which impacts the early initiation of treatment.

Gkantaras et al. analyzed 7,525 ESID Registry patients clinically diagnosed with CVID and show enrichment of monogenic inborn errors of immunity in pediatric cases. Their findings challenge pediatric CVID as a definite diagnosis and support systematic genetic evaluation in pediatric CVID-like cases, especially those with disease onset before 4 years and/or immune dysregulation at presentation.

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.

Nishinosono et al. show that nationwide TREC/KREC newborn screening in Japan demonstrates that large-scale programs can achieve favorable outcomes while revealing practical implementation challenges. Public funding expands coverage, whereas interlaboratory variability highlights the need for standardized cutoffs and repeat-sampling algorithms for equitable nationwide implementation.

Baba et al. demonstrate the utility of multidisciplinary genetic evaluation for identifying inborn errors of immunity in adult rheumatology practice. They establish a workflow that improves diagnostic precision and management for patients with atypical rheumatic and musculoskeletal diseases.

STAT1 gain-of-function mutations cause chronic mucocutaneous candidiasis and broad immune dysregulation, yet African data are limited. In a Moroccan cohort, Baghad et al. describe clinical and genetic features of 12 patients, highlighting infectious predominance, phenotypic diversity, and the need for improved molecular diagnosis and targeted therapies.