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Middle East and North Africa region (MENA) populations are of different ethnic origins. Consanguineous marriages are common practice with an overall incidence ranging between 20 and 50%. Primary immunodeficiency diseases (PIDs) are a group of heterogeneous genetic disorders caused by defects in the immune system that predisposes patients to recurrent infections, autoimmune diseases, and malignancies. PIDs are more common in areas with high rates of consanguineous marriage since most have an autosomal recessive mode of inheritance. Studies of PIDs in the region had contributed into the discovery and the understanding of several novel immunodeficiency disorders. Few MENA countries have established national registries that helped in estimating the prevalence and defining common PID phenotypes. Available reports from those registries suggest a predominance of combined immunodeficiency disorders in comparison to antibody deficiencies seen in other populations. Access to a comprehensive clinical immunology management services is limited in most MENA countries. Few countries had established advanced clinical immunology service, capable to provide extensive genetic testing and stem cell transplantation for various immunodeficiency disorders. Newborn screening for PIDs is an essential need in this population considering the high incidence of illness and can be implemented and incorporated into existing newborn screening programs in some MENA countries. Increased awareness, subspecialty training in clinical immunology, and establishing collaborating research centers are necessary to improve patient care. In this review, we highlight some of the available epidemiological data, challenges in establishing diagnosis, and available therapy for PID patients in the region.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3–47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

Interleukin-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 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 deficiency with a novel homozygous frameshift mutation and to review previously reported cases. The 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. Both 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 (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. The two cases expand the mutational and clinical spectrum of 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.

Severe combined immunodeficiency disease (SCID) is the most severe form of primary immunodeficiency disorders (PID). T-cell receptor excision circle (TREC) copy number analysis is an efficient tool for population-based newborn screening (NBS) for SCID and other T cell lymphopenias. We sought to assess the incidence of SCID among Saudi newborn population and examine the feasibility of using targeted next generation sequencing PID gene panel (T-NGS PID) on DNA isolated from dried blood spots (DBSs) in routine NBS programs as a mutation screening tool for samples with low TREC count. Punches from 8,718 DBS collected on Guthrie cards were processed anonymously for the TREC assay. DNA was extracted from samples with confirmed low TREC count, then screened for 22q11.2 deletion syndrome by real-time polymerase chain reaction and for mutations in PID-related genes by T-NGS PID panel. Detected mutations were confirmed by Sanger sequencing. Sixteen out of the 8,718 samples were confirmed to have low TREC copy number. Autosomal recessive mutations in were confirmed in three samples. Two additional samples were positive for the 22q11.2 deletion syndrome. In this study, we provide evidence for high incidence of SCID among Saudi population (1/2,906 live births) and demonstrate the feasibility of using T-NGS PID panel on DNA extracted from DBSs as a new reliable, rapid, and cost-effective mutation screening method for newborns with low TREC assay, which can be implemented as part of NBS programs for SCID.

Reticular dysgenesis (RD), caused by biallelic variants in , 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. In this retrospective single-center study, we analyzed genetically confirmed -related RD cases managed at King Faisal Specialist Hospital and Research Centre between 2005 and 2025, reviewing clinical, immunologic, genetic, and transplant-related data. 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 ( : 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. These findings demonstrate that -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.

The 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. This 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. A 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. Postponing 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.

Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846S ) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient T counts were significantly depressed, and that CD4 T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date.

Zeta-chain-associated protein kinase 70 ( ) 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. We retrospectively reviewed all patients with genetically confirmed 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. 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. HSCT remains the only curative treatment for 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.

Objective 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). Methods 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% agreement among panelists). Results Fifteen experts from 12 countries participated in two rounds of the Delphi process, resulting in the development of eight overarching principles and 10 consensus statements. These were categorized into five domains: (1) definitions and conceptual framework, (2) diagnostic and monitoring considerations, (3) treatment and therapeutic strategies, (4) multidisciplinary and collaborative care, and (5) patient education and support. Conclusion This consensus defines MIIDDs and provides a structured clinical framework to streamline research efforts and improve patient outcomes.

Purpose Autosomal recessive hyper-IgE syndrome is a rare combined immunodeficiency characterized by susceptibility to viral infections, atopic eczema, high serum IgE and defective T cell activation. The genetic etiologies are diverse. Null mutations in DOCK8 and TYK2 are responsible for many cases. This study aims to provide a detailed clinical and immunological characterization of the disease and explore the underlying genetic defects among a large series of patients followed by a single center. The available data might improve our understanding of the disease pathogenesis and prognosis. Methods Clinical data of twenty-five patients diagnosed with AR-HIES were collected. Seventeen patients screened for STAT3, TYK2 and DOCK8 mutations. Results Sinopulmonary infections, dermatitis, hepatic disorders, cutaneous and systemic bacterial, fungal and viral infections were the most common clinical features. The rate of hepatic disorders and systemic infections were high. Twelve patients died with a median age of 10 years. CMV infection was the only statistically significant predicting factor for poor prognosis (early death). Three novel DOCK8 mutations and two large deletions were found in thirteen patients. No mutations found in STAT3 or TYK2 genes. Conclusion Autosomal recessive hyper-IgE syndrome is a combined immunodeficiency disease characterized by high morbidity and mortality rate. The different genetic background and environmental factors may explain the more severe phenotypes seen in our series. DOCK8 defect is the most common identified genetic cause. Patients with no identified genetic etiology are likely to carry mutations in the regulatory elements of genes tested or in novel genes that are yet to be discovered.