Introduction:Reticular dysgenesis (RD), caused by biallelic variants in AK2, represents the most severe and rare form of Severe Combined Immunodeficiency, characterized by profound defects in lymphoid and myeloid lineages; however, data on its clinical spectrum and hematopoietic stem cell transplantation (HSCT) outcomes remain scarce. Methods:In this retrospective single-center study, we analyzed genetically confirmed AK2-related RD cases managed at King Faisal Specialist Hospital and Research Centre between 2005 and 2025, reviewing clinical, immunologic, genetic, and transplant-related data. Results:Ten patients from eight unrelated families were included, most with parental consanguinity, all presenting in the neonatal period with severe infections, neutropenia unresponsive to granulocyte colony-stimulating factor, and bilateral sensorineural hearing loss. A recurrent homozygous missense variant (AK2: NM_001625.4: c.524G>C; p. Arg175Pro) was identified in nine patients, while one patient harbored a start-loss variant. Seven patients underwent HSCT at a median age of 4 months using matched sibling, haploidentical, or cord blood donors; six survived, yielding a post-transplant survival of 85.7% with a median follow-up of 10 years, and achieved full donor myeloid and lymphoid engraftment with robust immune reconstitution. Discussion:These findings demonstrate that AK2-related RD presents with a distinctive neonatal phenotype and carries high pre-transplant mortality, while early HSCT enables durable engraftment and favorable long-term outcomes, supporting the importance of early diagnosis and newborn screening in high-consanguinity populations.

BackgroundInterleukin-2 receptor alpha chain (IL2RA, CD25) deficiency is a rare autosomal recessive inborn error of immunity characterized by profound immune dysregulation, susceptibility to infections, and autoimmunity. Only 13 cases of IL2RA deficiency have been reported worldwide since its first description in 1997, and experience with allogeneic hematopoietic stem cell transplantation (HSCT) for this condition remains very limited. This study aimed to describe the clinical, immunological, genetic, and HSCT outcomes of two siblings with IL2RA deficiency with a novel homozygous frameshift mutation and to review previously reported cases.MethodsThe clinical course, laboratory findings, genetic diagnosis, and transplant outcomes of two patients managed at King Faisal Specialist Hospital & Research Centre were retrospectively reviewed. A comprehensive literature review was conducted to contextualize these cases.ResultsBoth patients presented with severe enteropathy, eczema, recurrent respiratory infections, growth failure, and features of allergic disease in early childhood. Immunological evaluation revealed hypergammaglobulinemia, impaired T-cell proliferation, reduced CD19+ B cells, inverted CD4/CD8 ratio, and absence of CD25 expression. Genetic analysis revealed a novel homozygous frameshift variant in IL2RA (c.166delC; p.R56fs). Both patients underwent HSCT with myeloablative conditioning. The younger sibling received marrow from a matched unrelated donor and achieved full donor chimerism with complete clinical and immunological recovery, remaining well 6 years after HSCT. The older sibling received marrow from a matched related donor and is alive and stable at 5 years of follow-up, with sustained donor chimerism and resolution of autoimmunity, complicated only by transient mild chronic graft-versus-host disease.DiscussionThe two cases expand the mutational and clinical spectrum of IL2RA deficiency and provide long-term evidence that HSCT can cure immune dysregulation and susceptibility to infection. The findings underscore the importance of early genetic diagnosis and timely consideration of HSCT as definitive therapy for this rare but life-threatening disorder.

Background Reticular dysgenesis (RD) is the most severe and rarest form of severe combined immunodeficiency (SCID), characterized by profound defects in both lymphoid and myeloid lineages and caused by biallelic pathogenic variants in AK2. Due to its rarity, data on the clinical spectrum and hematopoietic stem cell transplantation (HSCT) outcomes remain limited. Methods We conducted a retrospective single-center study of ten patients with genetically confirmed AK2-related RD managed at King Faisal Specialist Hospital and Research Center between 2005 and 2025. Clinical features, immunologic and hematologic findings, genetic results, transplant characteristics, immune reconstitution, and outcomes were systematically reviewed. Results Ten patients from eight unrelated families were included; parental consanguinity was present in eight cases. All patients presented in the neonatal period with severe bacterial infections and profound neutropenia refractory to granulocyte colony-stimulating factor, and all had bilateral sensorineural hearing loss. Nine patients shared the same homozygous missense variant (AK2 c.524G>C; p.Arg175Pro), suggesting a founder effect, while one patient carried a start-loss mutation (c.1A>G). Seven patients underwent HSCT at a median age of 4 months using matched sibling, haploidentical, or umbilical cord blood donors. Six of seven transplanted patients survived, with a post-transplant survival rate of 85.7% after a median follow-up of 9 years. All transplanted survivors achieved full engraftment of donor myeloid and lymphoid cells, with robust immune reconstitution. Conclusion AK2-related RD presents with a distinctive neonatal phenotype and high pre-transplant mortality. Early HSCT enables durable engraftment and favorable long-term outcomes. These findings highlight the critical importance of early diagnosis and support newborn screening for SCID in high-consanguinity populations.

To achieve consensus on the definition and clinical approach of Monogenic Inflammatory Immune Dysregulation Disorders (MIIDDs), a collective term for rare conditions marked by inflammation, immune dysregulation, and infection susceptibility. These consensus guidelines specifically apply to pathogenic (or likely pathogenic) gene mutations affecting both innate and adaptive immunity, excluding variants of unknown significance (VUS). A multi-step, evidence-based, multidisciplinary consensus process was employed, consisting of: (1) a systematic literature review across four electronic databases (Cochrane Library, Web of Science, Scopus, and MEDLINE via PubMed), updated through December 31, 2024; (2) a pre-Delphi electronic survey completed by 95 international adult and pediatric immunologists and rheumatologists; and (3) a modified online Delphi process with an international multidisciplinary expert panel, where statements were iteratively analyzed and refined until achieving consensus (≥ 80

Phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric lipid kinases that are involved in a diverse array of cellular functions such as growth, metabolism, and migration. Mutations in PIK3CD, which encodes an immune-specific catalytic subunit of PI3K, cause both dominant (activating) and recessive (loss of function) immune deficiencies in humans. Here we report a family with three affected children carrying a novel bi-allelic, truncating mutation in PIK3CD. All three patients exhibited chronic diarrhea and recurrent sinopulmonary infections. Immunoblot confirmed loss of protein along with reduced expression of the associated p85α regulatory subunit. Immune phenotyping showed B cell dysregulation with abnormally high levels of naïve cells. In vitro functional testing of CD19 + and enriched naïve B cells revealed impaired proliferation, and reduction in class-switch recombination upon CD40L and IL-21 stimulation. Our data raise the possibility that PI3K-related dysregulation in human B cells may be broader than in mouse models, where class-switch recombination can still occur with external T cell help. Our study substantially increases the limited number of patients known to have immune deficiency due to loss of PIK3CD.

Background:Zeta-chain-associated protein kinase 70 (ZAP70) deficiency is a rare autosomal recessive T+B+NK+ combined immunodeficiency characterized by heterogeneous clinical and immunologic phenotypes. Because of the limited number of reported cases, data guiding optimal management and hematopoietic stem cell transplantation (HSCT) strategies remain scarce. Methods:We retrospectively reviewed all patients with genetically confirmed ZAP70 deficiency treated at King Faisal Specialist Hospital and Research Centre. Data on pre-HSCT clinical and immunologic features, transplant characteristics, post-HSCT complications, immune reconstitution, and long-term outcomes were recorded. Results:Thirteen patients with a median age at symptom onset of 1 month were identified. The most frequent initial presentations were recurrent respiratory infections and cutaneous manifestations. Autoimmune complications and lymphoproliferation were observed in several patients. Eleven of thirteen patients (84.6%) exhibited profound CD8+ T-cell lymphopenias and two had near-normal CD8+ T-cell counts with impaired T-cell function. Eleven patients underwent HSCT, including seven from Human Leukocyte Antigen (HLA)-matched family donors, two from one-antigen mismatched related donors, one from a haploidentical mother (matched for graft-versus-host disease risk but mismatched for rejection), and one from an unrelated cord blood donor. Two patients required a second transplant because of poor immune reconstitution. Of the 11 patients who underwent HSCT, 8 (73%) remain alive with a median follow-up of 7 years (range, 1-15), and most demonstrated resolution of clinical manifestations. Conclusion:HSCT remains the only curative treatment for ZAP70 deficiency. Myeloablative conditioning regimens appear to promote more robust and durable immune reconstitution. In critically ill patients with severe infections or end-organ damage, reduced-intensity or unconditioned HSCT can be considered as a life-saving approach, although subsequent interventions might be necessary.

IntroductionThe Bacillus Calmette–Guérin (BCG) vaccine is widely used to prevent tuberculosis but is associated with significant complications in patients with severe combined immunodeficiency (SCID). Considering the high incidence of SCID in Saudi Arabia, the Ministry of Health revised its national vaccination schedule in 2019, postponing BCG administration from birth to 6 months of age, aiming to enable time for the diagnosis of primary immunodeficiency diseases before vaccination. This study evaluated the consequences of this policy change on the incidence of BCG-related complications in SCID patients.MethodsThis retrospective study included 178 SCID patients diagnosed at King Faisal Specialist Hospital and Research Center, Riyadh, between 2015 and 2023. Patients were divided into two cohorts: Era 1 (2015–2019), when BCG vaccination was administered at birth, and Era 2 (2019–2023), when BCG vaccination was administered at 6 months of age. Data on demographics, clinical presentations, BCG-related complications, genetic testing, treatment, and outcomes were analyzed.ResultsA total of 49 SCID patients developed BCGitis, of which 65.3% experienced disseminated disease. The incidence of BCG-related complications dropped significantly after the policy change, from 46.1% in Era 1 to 2.6% in Era 2. Patients required stem cell transplantation and a median of 17.6 months of anti-mycobacterial therapy. The crude mortality rate was high (36.7%; 18/49), with 66.7% (12/18) of these fatalities linked to disseminated BCGitis.ConclusionsPostponing BCG vaccination to 6 months of age significantly decreases the incidence of BCG-related complications in SCID patients and highlights the importance of tailoring vaccination schedules for high-risk populations. Early newborn screening and timely diagnosis of immunodeficiencies are essential to further minimize complications. The revised vaccination policy of Saudi Arabia provides a model for optimizing immunization strategies in regions with a high prevalence of inborn errors of immunity.

Zeta chain-associated protein kinase 70 (ZAP-70) deficiency is an exceptionally rare autosomal recessive form of T+B+NK+ combined immunodeficiency (CID), associated with a heterogeneous clinical and immunological phenotype. Due to the scarcity of reported cases, outcome data to guide therapeutic strategies, particularly hematopoietic stem cell transplantation (HSCT), are limited. Here, we describe the clinical, immunological, and genetic features, as well as transplantation outcomes and post-HSCT immune reconstitution, in thirteen novel patients managed at a single tertiary care center. We retrospectively reviewed clinical, immunologic, genetic characteristics, HSCT outcome, and immune reconstitution for 13 patients who were diagnosed with ZAP-70 deficiency at King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. A total of thirteen patients were included, with a mean age at diagnosis of 4 months. The most common initial presentations were recurrent chest infections and skin abnormalities. Autoimmune manifestations and lymphoproliferation were also observed. Immunological evaluation revealed absent or severely reduced CD8+ T cell counts in most patients; however, two patients deviated from this pattern, demonstrating nearly normal CD8+ counts. Three ZAP-70 mutations in homozygous states were identified. Eleven patients underwent HSCT, with seven from fully matched sibling donors, three from mismatched related donor, and one from umbilical cord. Two patients required a second transplant for poor immune reconstitutions. At last follow-up, eight patients were alive with reasonable immune reconstitution. Early recognition and timely HSCT are critical for improving outcomes in ZAP-70-deficient patients. Despite challenges in immune reconstitution, mixed lymphoid chimerism was sufficient to achieve clinical stability in the majority of patients.

Receptor Interacting Serine/Threonine Kinase 1 (RIPK1) is widely expressed and integral to inflammatory and cell death responses. Autosomal recessive RIPK1-deficiency, due to biallelic loss of function mutations in RIPK1, is a rare inborn error of immunity (IEI) resulting in uncontrolled necroptosis, apoptosis and inflammation. Although hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy, the extent to which disease may be driven by extra-hematopoietic effects of RIPK1-deficiency, which are non-amenable to HSCT, is not clear. We present a multi-centre, international review of an additional 5 RIPK1-deficient children who underwent HSCT. All patients presented with very early onset inflammatory bowel disease, 2 also suffered from inflammatory arthritis. Median age at transplant was 3 years (range 1—5 years); 1 received matched sibling marrow, 1 matched unrelated peripheral blood stem cells (PBSC), 2 TCRαβ/CD19-depleted PBSC from maternal-haploidentical donors, and 1 had TCRαβ/CD19-depleted PBSC from a mismatched unrelated donor. All received reduced-toxicity conditioning, based on treosulfan (n = 4) or busulfan (n = 1); 1 patient underwent a successful second transplant following autologous reconstitution. Four of five patients (80

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.

Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics.

Vaccination with Bacillus Calmette–Guérin (BCG) can be harmful to patients with combined primary immunodeficiencies. We report the outcome of BCG vaccination in a series of twelve patients affected by adenosine deaminase deficiency (ADA-SCID). BCG vaccination resulted in a very high incidence of complications due to uncontrolled replication of the mycobacterium. All patients who developed BCG-related disease were treated successfully and remained free from recurrence of disease. We recommend the prompt initiation of enzyme replacement therapy and secondary prophylaxis to reduce the risk of BCG-related complications in ADA-SCID patients.

Background: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2(-/-) mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. Objective: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies.Methods: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro.Results: The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2(V205fs) mutant failed to suppress T-cell proliferation.Conclusions: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient. (J Allergy Clin Immunol 2023;151:572-8.)

Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG. In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG. Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0–14 years). The patients’ diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5–125 months). The QoL score showed a significant improvement in the patients’ global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients’ general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively). This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20

Human inborn errors of immunity (IEI) are a group of 485 distinct genetic disorders affecting children and adults. Signs and symptoms of IEI are heterogeneous, and accurate diagnosis can be challenging and depends on the available human expertise and laboratory resources. The Middle East and North Africa (MENA) region has an increased prevalence of IEI because of the high rate of consanguinity with a predominance of autosomal recessive disorders. This area also exhibits more severe disease phenotypes compared with other regions, probably due to the delay in diagnosis. The MENA-IEI registry network has designed protocols and guidelines for the diagnosis and treatment of IEI, taking into consideration the variable regional expertise and resources. These guidelines are primarily meant to improve the care of patients within the region, but can also be followed in other regions with similar patient pop-ulations. (c) 2022 American Academy of Allergy, Asthma & Immunology

Saudi Genome program is a revolutionary nationwide transformation initiative of Saudi Vision 2030. The program goals are to recognize and reduce the incidence of genetic diseases in the Kingdom of Saudi Arabia (KSA). Accordingly, the program will establish the foundation for personalized and genomic medicine in the KSA. Epilepsy has a high prevalence in KSA reaching around 6.54 of 1000 individuals with a subsequent massive financial burden. One of the main risk factors for this high prevalence and associated with increased risk of epilepsy development is consanguinity marriage, which is traditional in KSA. In this review, we executed a comprehensive state-of-art literature review regarding epilepsy genetics to offer a perception into the genes associated with epilepsy recognized in Saudi epileptic patients. Several genes' mutations were incorporated in this review including AFG3L2, ASPM, ATN1, ATP1A2, BMP5, CCDC88A, C12orf57, DNAJA1, EML1, ERLIN2, FRRS1L, GABRG3, NRXN3, MDH1, KCNJ10, KCNMA1, KCNT1, KIAA0226, OPHN1, PCCA, PCCB, PEX, PGAP2, PI4K2A, PODXL, PRICKLE1, PNKP, RELN, SCN2A, SCN1B, SLC2A1, SLC19A3, SLC25, SIAH1, SYNJ1, SZT2, TBCK, TMX2, TSC1, TSC2, TSEN, WDR45B, WWOX, UBR, UGDH, and YIF1B. For each of these genes, we tried to explain a little about the gene associated proteins and their roles in epilepsy development.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant disorder affecting roughly 1:50,000 individuals. It is commonly characterized by swelling of the larynx, gastrointestinal tract, extremities, and skin. There is growing genetic heterogeneity associated with this disease but more than 95% of mutations are found in SERPING1, the gene which encodes complement 1 inhibitor (C1-INH). HAE cohorts from several populations have been published but no large scale study has been reported from the Arab world to date. Here we document the clinical and genetic findings of HAE patients from a single Saudi institution, which is a major referral center at the national level. A total of 51 patients across 17 unrelated families were recruited including two large multi-generational families, of which one contained an in-frame exonic deletion that was resolved through MLPA. Two cases were negative for all the genes we tested (including F12, PLG, ANGPT1, MYOF, KNG1, and HS3ST6). The predominant HAE subtype in our cohort was type I, at 76%. We were able to uncover a mutation in 49 patients (96%). No type III (normal C1-INH) patients were encountered in the clinic, suggesting that this subtype does not play a major role in HAE pathogenesis in Saudi Arabia. Additionally, the existence of four patients with consistently normal complement 4 (C4) levels alongside abnormal C1-INH profiles highlights the utility of dual screening for both proteins in suspected patients.