Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey.

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.

Autoimmune hemolytic anemia and common variable immunodeficiency: a case-control study of 18 patients.

To describe the main characteristics and treatment of autoimmune hemolytic anemia (AHA) in patients with common variable immunodeficiency (CVID), we analyzed data from 18 patients, 4 from an earlier study and 14 from the French DEF-I cohort on adult patients with primary hypogammaglobulinemia. To be included, patients had to have CVID and a previous history of AHA with a hemoglobin level < or =90 g/L at onset. To determine whether AHA is associated with a particular clinical phenotype of CVID, we conducted a case-control study from the DEF-I cohort. The estimated frequency of AHA in CVID patients from the DEF-I cohort was 5.5% (14/252). Median age at AHA diagnosis was 26 years (range, 1-57 yr), and 27.5 years (range, 5-61 yr) at CVID diagnosis. CVID was diagnosed before the onset of AHA in only 2 patients (11%). CVID was diagnosed more than 6 months after AHA in 10 cases (55.5%), and the 2 conditions were diagnosed concomitantly in 6 cases. The 14 patients included in the DEF-I cohort were compared with 238 control patients with CVID but without AHA. Corticosteroids were used as initial treatment for all patients in the current study. An initial response was obtained in 15 of 18 (83%) patients. Overall, 9 of these (60%) achieved a lasting response with steroids alone (7 patients) or in combination with intravenous immunoglobulin (2 patients). Seven patients underwent splenectomy, and 5 additional splenectomies were performed for associated autoimmune thrombocytopenic purpura. After splenectomy, a lasting response was obtained in 3 of the 7 patients with AHA. However, 5 of the 12 splenectomized patients experienced life-threatening infection. Severe infection occurred in 2 of 4 patients receiving immunosuppressive drugs. At the end of follow-up, 13 of 18 (72%) patients were in treatment-free remission (13 complete responses), and 4 of 18 (22%) were in remission while on prednisone < or =20 mg/d. One patient had died, of cancer.