Clinical, immunological, and molecular characterization of hyper-IgM syndrome due to CD40 deficiency in eleven patients.

PURPOSE: Hyper-IgM syndrome due to CD40 deficiency (HIGM3) is a rare form of primary immunodeficiency with few reported cases. In this study, we further characterize the clinical, immunological, and molecular profiles of the disease in a cohort of 11 patients. METHODS: Molecular genetic analysis and a comprehensive clinical review of patients diagnosed with HIGM3 at our tertiary care center from 1994 to 2011 were undertaken. RESULTS: Eleven patients from seven families were enrolled. The patients had a median age of 9 years [ranging from 2 to 22 years old]. All 11 patients had recurrent chest infections at presentation. Pneumocystis jiroveci pneumonia was confirmed in three patients. Five patients had sclerosing cholangitis, and five patients had Cryptosporidium isolated from their stool. Six patients had nasal and sinus infections, and two of these patients had destructive nasal fungal infections. Eight patients had neutropenia. All of the patients had low IgG and normal or high IgM levels. IgA was undetectable in all but three patients. Two novel mutations were found: a splice site for intron 3 and a missense mutation located in the coding region of exon 3. Two patients underwent successful stem cell transplantation from a matched donor. Four patients are doing well on prophylaxis; two are very sick, one with protracted diarrhea and persistent Cryptosporidium and the other with neurological complications. Three patients died early in life as a result of severe sepsis. CONCLUSIONS: To our knowledge, this report provides the largest cohort of patients with this disease with a very long follow-up period. Our cohort showed variable disease severity

Clinical, immunological and molecular characterization of DOCK8 and DOCK8-like deficient patients: single center experience of twenty-five patients.

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.