Yellow fever vaccine (YFV) is a live attenuated vaccine that can cause a mild infection in immunocompetent patients. However, it may not be self-limiting in patients with inborn errors of immunity (IEI) and may be the first and most severe presentation in these patients. A 10-month-old female infant sought emergency care presenting fever for three days and diffuse exanthema. She was a previous healthy child of consanguineous parents. The child had received YFV 28 days before the onset of symptoms. Upon hospital admission, petechial rash on the limbs and hepatosplenomegaly were noted on physical exam. Laboratory tests showed thrombocytopenia, increased serum aminotransferases and elevated gamma-glutamyl transferase (GGT) and alkaline phosphatase levels. During hospitalization she developed hypoactivity, drowsiness, and hypotonia. The possibility of viscerotropic and neurotropic vaccine associated disease was suspected and a possible primary immunodeficiency disease considered. The patient was tested for antibodies against the yellow fever virus (MAC ELISA) on serum and cerebrospinal fluid (CSF) samples, showing positive IgM results. Immunophenotyping showed low levels of lymphocytes and absence of T-cell receptor excision circles (TREC), leading to diagnose of severe combined immunodeficiency disease (SCID). Despite treatment, after 35 days of hospitalization, she evolved to cardiorespiratory arrest and death. Serious adverse events after administration of the YFV are rare and associated with neurological or visceral involvement in most cases. The unfavorable outcome highlights the importance of neonatal screening for SCID and the clinical suspicion of primary immunodeficiencies in infants who have serious adverse events to live virus vaccines.

Inborn errors of immunity (IEI) are a diverse group of disorders caused by defects in immune system structure or function, involving both innate and adaptive immunity. The 2022 update of the IEI classification includes 485 distinct disorders, categorized into ten major disease groups. With the rapid development of molecular biology, the specific pathogenesis of many IEI has been revealed, making gene therapy possible in preclinical and clinical research of this type of disease. This article reviews the advancements in gene therapy for IEI, aiming to increase awareness and understanding of these disorders.
免疫出生错误（inborn errors of immunity, IEI）是由遗传因素导致免疫结构或功能障碍所致的一类疾病，可累及固有免疫和适应性免疫。2022年IEI新分类包含485种IEI，分为十大类疾病。近年来随着分子生物学的快速发展，许多IEI的具体发病机制得以揭示，使得基因治疗在该类疾病的临床前和临床研究成为可能。该文综述基因治疗在IEI中的研究和应用，以进一步提高临床医生对IEI诊治的认知。.

BACKGROUND: Severe combined immunodeficiency (SCID) is a life-threatening genetic disorder caused by critical defects of the immune system. Almost all cases are lethal if not treated within the first two years of life. Early diagnosis and intervention are thus essential for improving patient outcomes. In 2013, Ontario became the first Canadian province to perform newborn screening (NBS) for SCID by T cell receptor excision circles (TRECs) analysis, a surrogate marker of thymic function and lymphocyte maturation.
METHODS: This retrospective study reports on nearly 10 years of NBS for SCID at a quaternary referral centre.
RESULTS: From August 2013 to April 2023, our centre\'s densely populated catchment area flagged 162 newborns with low TRECs levels, including 10 cases with SCID. Follow-up revealed other causes of low TRECs, including non-SCID T cell lymphopenia (secondary/reversible or idiopathic causes, and syndromic conditions) and prematurity. A small number of cases with normal repeat TRECs levels and/or T cell subsets were also flagged. Province-wide data from around this period revealed at least 24 diagnosed cases of SCID or Leaky SCID.
CONCLUSIONS: This is the first report of NBS outcomes in a Canadian province describing the causative genetic defects, and the non-SCID causes of a positive NBS for SCID.

Heterozygous autosomal dominant mutations in the CXCR4 gene cause WHIM syndrome, a severe combined immunodeficiency disorder. The mutations primarily affect the C-terminal region of the CXCR4 chemokine receptor, specifically several potential phosphorylation sites critical for agonist (CXCL12)-mediated receptor internalization and desensitization. Mutant receptors have a prolonged residence time on the cell surface, leading to hyperactive signaling that is responsible for some of the symptoms of WHIM syndrome. Recent studies have shown that the situation is more complex than originally thought, as mutant WHIM receptors and CXCR4 exhibit different dynamics at the cell membrane, which also influences their respective cellular functions. This review examines the functional mechanisms of CXCR4 and the impact of WHIM mutations in both physiological and pathological conditions.

Early diagnosis and effective management of Primary immunodeficiency diseases (PIDs), particularly severe combined immunodeficiency (SCID), play a crucial role in minimizing associated morbidities and mortality. Newborn screening (NBS) serves as a valuable tool in facilitating these efforts. Timely detection and diagnosis are essential for swiftly implementing isolation measures and ensuring prompt referral for definitive treatment, such as allogeneic hematopoietic stem cell transplantation. The utilization of comprehensive protocols and screening assays, including T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC), is essential in facilitating early diagnosis of SCID and other PIDs, but their successful application requires clinical expertise and proper implementation strategy. Unfortunately, a notable challenge arises from insufficient funding for the treatment of PIDs. To address these issues, a collaborative approach is imperative, involving advancements in technology, a well-functioning healthcare system, and active engagement from stakeholders. The integration of these elements is essential for overcoming the existing challenges in NBS for PIDs. By fostering synergy between technology providers, healthcare professionals, and governmental stakeholders, we can enhance the efficiency and effectiveness of early diagnosis and intervention, ultimately improving outcomes for individuals with PIDs.

OBJECTIVE: In this review, an update is provided on the current knowledge and pending questions about human adenosine deaminase type 2 deficiency. Patients have vasculitis, immunodeficiency and some have bone marrow failure. Although the condition was described ten years ago, the pathophysiology is incompletely understood RECENT FINDINGS: Endothelial instability due to increased proinflammatory macrophage development is key to the pathophysiology. However, the physiological role of ADA2 is a topic of debate as it is hypothesized that ADA2 fulfils an intracellular role. Increasing our knowledge is urgently needed to design better treatments for the bone marrow failure. Indeed, TNFi treatment has been successful in treating DADA2, except for the bone marrow failure. Major advances have been made in our understanding of DADA2. More research is needed into the physiological role of ADA2.

BACKGROUND: Many newborn screening programs worldwide have introduced screening for diseases using DNA extracted from dried blood spots (DBS). In Germany, DNA-based assays are currently used to screen for severe combined immunodeficiency (SCID), spinal muscular atrophy (SMA), and sickle cell disease (SCD).
METHODS: This study analysed the impact of pre-analytic DNA carry-over in sample preparation on the outcome of DNA-based newborn screening for SCID and SMA and compared the efficacy of rapid extraction versus automated protocols. Additionally, the distribution of T cell receptor excision circles (TREC) on DBS cards, commonly used for routine newborn screening, was determined.
RESULTS: Contaminations from the punching procedure were detected in the SCID and SMA assays in all experimental setups tested. However, a careful evaluation of a cut-off allowed for a clear separation of true positive polymerase chain reaction (PCR) amplifications. Our rapid in-house extraction protocol produced similar amounts compared to automated commercial systems. Therefore, it can be used for reliable DNA-based screening. Additionally, the amount of extracted DNA significantly differs depending on the location of punching within a DBS.
CONCLUSIONS: Newborn screening for SMA and SCID can be performed reliably. It is crucial to ensure that affected newborns are not overlooked. Therefore a carefully consideration of potential contaminating factors and the definition of appropriate cut-offs to minimise the risk of false results are of special concern. It is also important to note that the location of punching plays a pivotal role, and therefore an exact quantification of TREC numbers per μl may not be reliable and should therefore be avoided.

A cell\'s ability to survive and to evade cancer is contingent on its ability to retain genomic integrity, which can be seriously compromised when nucleic acid phosphodiester bonds are disrupted. DNA Ligase 1 (LIG1) plays a key role in genome maintenance by sealing single-stranded nicks that are produced during DNA replication and repair. Autosomal recessive mutations in a limited number of individuals have been previously described for this gene. Here we report a homozygous LIG1 mutation (p.A624T), affecting a universally conserved residue, in a patient presenting with leukopenia, neutropenia, lymphopenia, pan-hypogammaglobulinemia, and diminished in vitro response to mitogen stimulation. Patient fibroblasts expressed normal levels of LIG1 protein but exhibited impaired growth, poor viability, high baseline levels of gamma-H2AX foci, and an enhanced susceptibility to DNA-damaging agents. The mutation reduced LIG1 activity by lowering its affinity for magnesium 2.5-fold. Remarkably, it also increased LIG1 fidelity > 50-fold against 3\' end 8-Oxoguanine mismatches, exhibiting a marked reduction in its ability to process such nicks. This is expected to yield increased ss- and dsDNA breaks. Molecular dynamic simulations, and Residue Interaction Network studies, predicted an allosteric effect for this mutation on the protein loops associated with the LIG1 high-fidelity magnesium, as well as on DNA binding within the adenylation domain. These dual alterations of suppressed activity and enhanced fidelity, arising from a single mutation, underscore the mechanistic picture of how a LIG1 defect can lead to severe immunological disease.

Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4+ and/or CD8+ cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.

UNASSIGNED: Forkhead box protein N1 (FOXN1) transcription factor plays an essential role in the development of thymic epithelial cells, required for T-cell differentiation, maturation, and function. Biallelic pathogenic variants in FOXN1 cause severe combined immunodeficiency (SCID). More recently, heterozygous variants in FOXN1, identified by restricted gene panels, were also implicated with causing a less severe and variable immunodeficiency.
UNASSIGNED: We undertook longitudinal follow-up and advanced genetic investigations, including whole exome sequencing and whole genome sequencing, of newborns with a heterozygous variant in FOXN1.
UNASSIGNED: Five patients (3 female, 2 male) have been followed since they were first detected with low T-cell receptor excision circles during newborn screening for SCID. Patients underwent immune evaluation as well as genetic testing, including a primary immunodeficiency panel, whole exome sequencing, and whole genome sequencing in some cases.
UNASSIGNED: Median follow-up time was 6.5 years. Initial investigations revealed low CD3+ T lymphocytes in all patients. One patient presented with extremely low lymphocyte counts and depressed phytohemagglutinin responses leading to a tentative diagnosis of SCID. Over a period of 2 years, CD3+ T-cell counts rose, although in some patients it remained borderline low. One of 5 children continues to experience recurrent upper respiratory infections and asthma episodes. The remaining are asymptomatic except for eczema in 2 of 5 cases. Lymphocyte proliferation responses to phytohemagglutinin were initially low in 3 patients but normalized by age 10 months. In 3 of 5 cases, T lymphocyte counts remain low/borderline low.
UNASSIGNED: In cases of monoallelic FOXN1 variants, using whole exome sequencing and whole genome sequencing to rule out possible other significant pathogenic variants allowed us to proceed with confidence in a conservative manner, even in extreme cases consistent with newborn screen-positive early presentation of SCID.