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

Abstract

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.

Figure 1

Pedigrees of the 9 kindreds with STAT3 deficiency (familial cases) identified. Each kindred with STAT3 deficiency is designated by a capital letter (K), each generation is designated by a Roman numeral (I) and each individual is designated by an Arabic numeral (from left to right). Patients with a clinical phenotype are indicated by closed symbols. In each family, the proband is indicated by an arrow. Individuals whose genetic status could not be evaluated are indicated by “E?”. Patient age at last follow-up and NIH score are also provided.

Figure 2

Schematic representation of the STAT3 gene. Positions of the STAT3 mutations in the DNA binding (DNA) domain, the Src homology 2 (SH2) domain, the transactivation (TA) domain, amino-terminal (AT) domain, or coiled-coil (CC) domain. Underlined mutations were identified in patients from the current study; mutations not underlined were identified in previous studies. [–4,28,29,33,35,36,41,47,52,55,60-62,70,71] The positions of all known mutations are indicated in amino acid nomenclature, with the exception of mutations starting with c. at the bottom, which are shown in nucleotide nomenclature.

Figure 3

A, B-cell immunophenotyping in 55 STAT3-deficient patients. Percentage of CD27+CD19+ B cells in STAT3-deficient patients, with the gray area representing the normal values for these cells according to age. In the gray circle, the only patient (Patient 3) with a high percentage of CD27+CD19+ cells displayed global lymphopenia, including B-cell lymphopenia. B, IgE levels in 56 STAT3-deficient patients (KUI/L). The gray area indicates the normal values of IgE as a function of age.

Figure 4

Survival curve of the 60 STAT3-deficient patients.

Figure 5

A, Documented skin infections. Skin bacterial infections were caused by Staph. aureus in 204 episodes and by other bacteria in 13 episodes (E. coli in 3, Proteus mirabilis in 2, P. aeruginosa in 2, Enterobacter aerogenes in 1, Serratia marcescens in 1, [alpha] or [beta]-hemolytic Streptococcus in 3, and Propionibacterium acnes in 1). Skin fungal infections were caused by C. albicans in 23 episodes and by other fungi in 6 episodes (C. parapsilosis in 2, C. glabrata in 1, T. rubrum in 1, T. mentagrophytes in 1, and Cryptococcus laurentii in 1). Skin viral infections were caused by varicella zoster virus in 16, herpes simplex virus in 8, human papillomavirus in 9, and the Molluscum contagiosum poxvirus in 4 episodes. Isolated Sarcoptes scabiei pediculosis was reported in 1 episode. B, Documented lung infections. S. pneumoniae and Staph. aureus were the most frequently involved, in 25 and 24 episodes of documented infections, respectively. Three cases of M. pneumoniae infections were also reported. The other bacteria isolated were H. influenzae isolated in 11, P. aeruginosa in 8, Stenotrophomonas maltophilia in 2, E. coli in 2, K. pneumoniae in 2, Serratia marcescens in 2, Fusobacterium species in 1, Bacteroides fragilis in 1, Prevotella oralis in 1, and Moraxella catarrhalis in 2 episodes. Lung fungal infections were secondary aspergillosis in 13 episodes, and 2 cases of pneumocystosis were also identified. Two patients also presented respiratory infections caused by respiratory syncytial virus (RSV), and 1 displayed a respiratory infection caused by varicella zoster virus (VZV).