Epidemiology of combined immunodeficiencies affecting cellular and humoral immunity- a multicentric retrospective cohort study from the Arabian Peninsula.

AIMS: To understand the characteristics of combined immunodeficiency disorders that affect cellular and humoral immunity (CID) in the Arabian Peninsula. METHODS: Retrospective study of 236 patients with CID from the region were enrolled from 2004 to 2022. RESULTS: 236 patients were included with a majority being profound CID. Among patients with a family history of CID, the ages at onset and diagnosis, and the delay in diagnosis were lower compared to those with no family history of CID, but this did not affect time to transplant. HSCT was performed for 51.27% of the patients with median time from diagnosis to HSCT of 6.36 months. On multivariate analysis, patients who underwent early transplant had increased odds of having CD3 count ≤1000 cell/µl, diagnosed by screening or erythroderma. CONCLUSION: There is a delay in diagnosis and treatment of CID in our region. Establishing newborn screening programs and HSCT units in our region are the urgent need.

Hermansky-Pudlak Syndrome: Spectrum in Oman.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder, characterized by oculocutaneous albinism, a hemorrhagic diathesis secondary to storage pool-deficient platelets, and in some patients' pulmonary fibrosis, granulomatous colitis, and immunodeficiency. To date, 11 different types of Hermansky-Pudlak syndrome were identified. HPS type 2 is distinctively characterized by severe neutropenia and recurrent sinopulmonary infections. HPS is more common in Puerto Rico, and this is the first report deciphering the genotypic spectrum of HPS in Oman. Between 2001 and 2021, 8 Omani cases with HPS (3 HPS type 2, 1 HPS type 3, and 4 HPS type 6) had been suspected clinically and confirmed through genetic mutation analysis. Patients had mild hemorrhagic phenotype, and variable platelet aggregation defects with different platelet agonists. All patients had characteristic eye manifestations. In addition, patients with HPS type 2 had severe neutropenia. Novel mutations in AP3B1(c.205-1G>C, c.12_13delTA (p.Asn4Lysfs*6) and HPS6 (c.19_20delCT (p. Leu7Alafs*168) were not reported in population variant databases. Diagnosis of HPS had markedly improved in Oman; however, increased clinician awareness is needed. A high index of suspicion and early referral for diagnosis and initiation of proper treatment might help improve outcomes.

Predictors of early death risk among untransplanted patients with combined immunodeficiencies affecting cellular and humoral immunity: A multicenter report.

BACKGROUND: There is an increased demand for hematopoietic stem cell transplant (HSCT) to treat various diseases including combined immunodeficiencies (CID), with limited worldwide availability. Variables affecting the decision regarding CID patients' prioritization for HSCT are not known. We aimed to determine general, clinical, and immunologic factors associated with the higher risk of early death (≤6 months after diagnosis) in untransplanted CID patients. METHODS: Data collection was done retrospectively from five centers and included general patients' information, and clinical and laboratory variables. Inclusion criteria were untransplanted patients who are either dead or alive with a follow-up period ≥6 months after diagnosis. RESULTS: Two hundred and thirty-six CID patients were reported by participating centers, of whom 111 were included in the study with a cumulative follow-up period of 278.6 years. Seventy-two patients died with the median age of death of 10.5 months. 35.1% of the patients succumbed within 6 months after the diagnosis. Having a history of Candida infections, sepsis or hepatomegaly was associated with an increased risk of early death. None of the other general or clinical variables was associated with such risk. Bivariate analysis of lymphocyte subsets showed that patients with the following counts: CD3+  < 100, CD4+  < 200, CD8+  < 50, or CD16+ CD56+ <200 cells/µl had increased risk of early death. In adjusted analysis, increased risk of early death was observed among patients with CD3+ count <100 cells/µl. CONCLUSION: Combined immunodeficiencies patients with a history of Candida infections, sepsis, hepatomegaly, or severe T-lymphopenia should be given priority for HSCT to avoid early death.

Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities.

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense changes, two variants predicted to result in complete protein loss through nonsense-mediated decay, and two frameshift changes that likely introduce a truncation. Our findings (i) independently confirm the role of ZNFX1 in primary genetic immunodeficiency, (ii) expand the genetic and clinical spectrum of ZNFX1-related disease, and (iii) illustrate the utility of large, well-curated, and continually updated genotype-phenotype databases in resolving molecular diagnoses of patients with initially negative genetic testing findings.

Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. OBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. METHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. RESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. CONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.

Bacillus Calmette-Guérin vaccine-related complications in children in Oman.

BACKGROUND: Bacillus Calmette-Guérin (BCG) vaccine-related complications are frequently observed in children in Oman. There are a few regional studies on BCG complications, but none from Oman. OBJECTIVE: Evaluate the spectrum of BCG-vaccine related complications and immune status in Omani children. DESIGN: Retrospective cross-sectional study. SETTING: Referral tertiary hospital. METHODS: Children aged younger than 13 years old and with complications of BCG vaccination recorded from 2006-2018 were included in this study. Clinical characteristics, treatment, immune workup and outcome were reviewed from hospital records. MAIN OUTCOME MEASURES: Different BCG vaccine-related complications categorized by the site of involvement. SAMPLE SIZE: 226. RESULTS: Of the 226 children had BCG-vaccine related complications, 99% received BCG vaccine immediately after birth. The median age of presentation was 4 months. The most common complication was isolated BCG lymphadenitis (85%, n=192), followed by BCG-related osteomyelitis (10.2%, n=23) and disseminated BCG infection (4.9%, n=11). The median age of presentation of disseminated BCG was 5 months, with different organs involved. Out of 11 children with disseminated BCG infection, 72.7% (n=8) had primary immune deficiency (PID), including chronic granulomatous disease (CGD, n=5), severe combined immunodeficiency (SCID) (n=2); 1 patient had Mendelian susceptibility to mycobacterial disease (IFNGR2 deficiency); 2 patients with PID not yet identified and the 1 with a non-specific PID had blood or saliva samples sent for whole-exome sequencing. CONCLUSION: Because of the spectrum of BCG vaccine-related complications, including the most severe in children with PID, we suggest that delaying the BCG vaccine from birth to 6 months may prevent disseminated BCG diseases and their complications in children with PID because any PID will have been identified before 6 months. Further studies are needed to guide this recommendation. LIMITATIONS: Single center-based study that may not provide a full overview of all BCG vaccine-related complications in Oman. Unavailability of details of some microbiological results and an inability to determine the detailed management for all patients. CONFLICT OF INTEREST: None.

A Decade Experience on Severe Combined Immunodeficiency Phenotype in Oman, Bridging to Newborn Screening.

Introduction: Severe combined immunodeficiency (SCID) results from various monogenic defects that impair immune function and brings on early severe and life-threatening infections. The main stay of treatment for SCID is hematopoietic stem cell transplant (HSCT) with near normal survival at 5 years for an early transplant done at or before the age of 3.5 months of life and the patient is maintained free of infections. Although overall rare, it constitutes a major burden on affected children, their families and on the health system especially in communities with a high rate of consanguinity where incidence and prevalence of recessive inborn errors of immunity (IEI) are expected to be high. Method: Here, we report the clinical, immunological, and molecular findings in 36 children diagnosed with SCID from a single tertiary center in Oman for the last decade. Results: We observed a median annual incidence rate of 4.5 per 100,000 Omani live births, and 91.7% of affected children were born to consanguineous parents. Twenty-three children (63.9%) fulfilled the criteria for typical SCID. The median age at onset, diagnosis and diagnostic delay were 54, 135, and 68 days, respectively. The most common clinical manifestations were pneumonia, septicemia, and chronic diarrhea. Eleven children (30.6%) have received hematopoietic stem cell transplant (HSCT) with a survival rate of 73%. The most frequent genetic cause of SCID in this cohort (n = 36) was (RAG-1), encoding for recombination activating gene (n = 5, 13.9%). Similarly, Major histocompatibility complex type II deficiency accounted for (n = 5, 13.9%) of our cohort. Conclusion: Our report broadens the knowledge of clinical and molecular manifestations in children with SCID in the region and highlights the need to initiate newborn based screening program (NBS) program.