Algerian Registry for Inborn Errors of Immunity in Children: Report of 887 Children (1985-2021).

INTRODUCTION: Inborn errors of immunity (IEI) represent a heterogeneous large group of genetic disorders characterized by susceptibility of affected individuals to recurrent infections, autoimmune/inflammatory diseases, allergy, and malignancy. We aimed to report for the first time the Algerian registry for IEI in children. METHODS: We described the characteristics of IEI in Algerian children from the data collected in the Algerian registry for IEI between 1985 and 2021. RESULTS: Over a period of 37 years, we included 887 children (530 male, 59.6%) with a mean age at diagnosis of 3.23 years and a mean diagnosis delay of 2 years. The prevalence rate was estimated at 1.97/100,000 inhabitants or 5.91/100,000 children. The parental consanguinity was found in 52.6%. The most prevalent category was combined immunodeficiencies (CID) (35.5%), followed by predominantly antibody deficiencies (24.5%) and CID with syndromic features (18.3%). The most predominant diseases were severe CID (134 cases), MHC II deficiency (99 cases), agammaglobulinemia (82 cases), common variable immunodeficiency (78 cases), hyper IgE syndromes (61 patients), ataxia-telangiectasia (46 patients), Wiskott-Aldrich syndrome (40 patients) and chronic granulomatous disease (39 cases). The clinical presentation was dominated by lower respiratory tract infections (69%), failure to thrive (38.3%), and chronic diarrhea (35.2%). Genetic analysis was performed in 156 patients (17.6%). The global mortality rate was 28.4% mainly caused by CID. CONCLUSION: This is the first report of the Algerian registry for IEI in children. Data is globally similar to that of the Middle East and North African (MENA) registries with high consanguinity, predominance of CID, and significant mortality. This registry highlights the weak points that should be improved in order to provide better patient care.

Does omeprazole improve asthma-control in poorly-controlled asthmatic children with gastro-esophageal reflux.

OBJECTIVES: The role of gastro-esophageal reflux disease (GERD) in poorly controlled asthma is often mentioned, but published studies have presented discordant results. Our main objective was to assess the effectiveness of GERD treatment in controlling asthma in children. METHODS: We conducted a prospective study including poorly controlled asthmatic children aged 4 to 16 years. We checked the presence of acid reflux using pH monitoring. Patients with GERD were randomized into two groups; one received omeprazole for 6 months and the control group was not treated. The outcome was the score of the children asthma control test at the end of 6 months. The acid suppression was checked at the end of treatment with pH monitoring. After treatment, children with persistent acid reflux received high PPI doses and therefore were reevaluated 6 months later. RESULTS: We included 102 children with poorly controlled asthma among which 59 (57.8%) had acid reflux. Gastroesophageal reflux (GER) was significantly more common in boys (p = 0.04). Treatment with omeprazole in sufficient doses improved the control of asthma in 5 children out of 6 (84.8 vs 11.5; p<.0001). Three factors appeared to be statistically associated with asthma control improvement after PPI therapy: male sex (p=.04), normal birth weight (p=.05) and a positive Prick-test (p=.05). These factors were not confirmed or were not sufficiently precise in multivariate analysis. The likelihood of a causal relationship between acid reflux and asthma, difficult to highlight with pH monitoring, was poor. CONCLUSIONS: This study confirmed the high prevalence of GER in poorly controlled asthmatic children and showed the possible benefit of an efficient GER treatment in improving asthma control.

X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations.

PURPOSE: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients. METHODS: Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing. RESULTS: We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed. CONCLUSIONS: This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia.

X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections, profound decrease of all immunoglobulin isotypes and very low level of B lymphocytes in peripheral blood. The disorder is caused by mutations in the Bruton's Tyrosine Kinase (BTK). Nine male patients suspected to have XLA from nine unrelated families were enrolled in this study. We performed sequencing of the BTK gene in all nine patients, and in the patients' relatives when possible. The XLA diagnosis was confirmed for six patients with six different mutations; we identified a novel mutation (c.1522G>A) and five known mutations. One third of nine unrelated patients do not have mutations in BTK and thus likely suffer from autosomal recessive agammaglobulinemia in the setting of consanguinity. Our results support that the autosomal recessive agammaglobulinemia can be more common in Algeria.

Clinical, immunological and genetic features in eleven Algerian patients with major histocompatibility complex class II expression deficiency.

Presenting processed antigens to CD4+ lymphocytes during the immune response involves major histocompatibility complex class II molecules. MHC class II genes transcription is regulated by four transcription factors: CIITA, RFXANK, RFX5 and RFXAP. Defects in these factors result in major histocompatibility complex class II expression deficiency, a primary combined immunodeficiency frequent in North Africa. Autosomal recessive mutations in the RFXANK gene have been reported as being the principal defect found in North African patients with this disorder. In this paper, we describe clinical, immunological and genetic features of 11 unrelated Algerian patients whose monocytes display a total absence of MHC class II molecules. They shared mainly the same clinical picture which included protracted diarrhoea and respiratory tract recurrent infections. Genetic analysis revealed that 9 of the 11 patients had the same RFXANK founder mutation, a 26 bp deletion (named I5E6-25_I5E6+1, also known as 752delG26). Immunological and genetic findings in our series may facilitate genetic counselling implementation for Algerian consanguineous families. Further studies need to be conducted to determine 752delG26 heterozygous mutation frequency in Algerian population.

Children hypertension in Northern Africa.

OBJECTIVES: To assess factors associated with prehypertension and hypertension among children in North Africa. METHODS: An epidemiological observational, school- and college-based study among 3562 healthy children and adolescents to assess factors associated with blood pressure categories (normal, prehypertensive, hypertensive), including perinatal (gestational age, birth weight, breastfeeding) and current lifestyle characteristics (body mass index, time spent watching a screen and time spent exercising). RESULTS: Prevalence of hypertension increased with age from 8.7% between 6-10 years to 14.7% between 11-15 years, and 15.6% above 15 years. Prevalence of prehypertension and hypertension increased with body mass index from 9.9% and 11.5% among children not overweight to 15.6% (RR 1.58, 95% CI 1.24-2.02, P<0.001) and 17.2% (RR 1.50, 95% CI 1.22-1.85, P<0.001) among those overweight and to 26.8% (RR 2.72, 95% CI 2.04-3.64, P<0.01) and 32.3% (RR 2.82, 95% CI 2.27-3.50, P<0.01) among obese children. There was a trend of association of prehypertension with the time spent watching Television, internet and electronic games. Children whose mother or father had a history of hypertension had a trend to be prehypertensive or hypertensive. A parental hypertension was found in 33.6% of normotensive, 38.2% of prehypertensive, and 42.6% of hypertensive children (P=0.05). Children with prehypertension or hypertension were more likely to have a diabetic father or mother (22.8% and 22.6% vs 15.8%, respectively, P=0.01). Also, prehypertension and hypertension were associated with shorter gestational age, early birth, reduced birth weight, and shorter breastfeeding. CONCLUSION: Prehypertension and hypertension have a high prevalence among children in North Africa. They are associated with overweight, obesity, diabetes, a shorter gestational age, a lower birth weight and a shorter breastfeeding.

Diagnostic and Predictive Contribution of Autoantibodies Screening in a Large Series of Patients With Primary Immunodeficiencies.

Objectives: To evaluate the diagnostic and predictive contribution of autoantibodies screening in patients with primary immunodeficiencies (PIDs). Methods: In the present study, PID patients and healthy controls have been screened for 54 different autoantibodies. The results of autoantibodies screening in PID patients were correlated to the presence of autoimmune diseases. Results: A total of 299 PID patients were included in this study with a predominance of antibody deficiencies (27.8%) followed by immunodeficiencies affecting cellular and humoral immunity (26.1%) and complement deficiencies (22.7%). Autoimmune manifestations were present in 82 (27.4%) patients. Autoimmune cytopenia (10.4%) was the most common autoimmune disease followed by gastrointestinal disorders (10.0%), rheumatologic diseases (3.7%), and endocrine disorders (3.3%). Autoantibodies were found in 32.4% of PID patients and 15.8% of healthy controls (P < 0.0005). Anti-nuclear antibodies (ANA) (10.0%), transglutaminase antibody (TGA) (8.4%), RBC antibodies (6.7%), anti-smooth muscle antibody (ASMA) (5.4%), and ASCA (5.0%) were the most common autoantibodies in our series. Sixty-seven out of the 82 patients with autoimmune manifestations (81.7%) were positive for one or more autoantibodies. Eleven out of the 14 patients (78.6%) with immune thrombocytopenia had positive platelet-bound IgM. The frequencies of ASCA and ANCA among patients with IBD were 47.4% and 21.0% respectively. All patients with celiac disease had TGA-IgA, while six out of the 11 patients with rheumatologic diseases had ANA (54.5%). Almost one third of patients (30/97) with positive autoantibodies had no autoimmune manifestations. ANA, rheumatoid factor, ASMA, anti-phospholipid antibodies and ANCA were often detected while specific AID was absent. Despite the low positive predictive value of TGA-IgA and ASCA for celiac disease and inflammatory bowel disease respectively, screening for these antibodies identified undiagnosed disease in four patients with positive TGA-IgA and two others with positive ASCA. Conclusion: The present study provides valuable information about the frequency and the diagnostic/predictive value of a large panel of autoantibodies in PIDs. Given the frequent association of some AIDs with certain PIDs, screening for corresponding autoantibodies would be recommended. However, positivity for autoantibodies should be interpreted with caution in patients with PIDs due to their low positive predictive value.