Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome: Molecular, Cellular, and Clinical Features From a French National Survey.

Marie-Olivia Chandesris (1, 2, 3) , Isabelle Melki (3) , Angels Natividad (3) , Anne Puel (3) , Claire Fieschi (4, 5) , Ling Yun (3) , Caroline Thumerelle (6) , Eric Oksenhendler (5) , David Boutboul (4) , Caroline Thomas (7) , Cyrille Hoarau (8) , Yvon Lebranchu (8) , Jean-Louis Stephan (9) , Celine Cazorla (10) , Nathalie Aladjidi (11) , Marguerite Micheau (11) , François Tron (12) , André Baruchel (13) , Vincent Barlogis (14) , Gilles Palenzuela (15) , Catherine Mathey (16) , Stéphane Dominique (17) , Gérard Body (18) , Martine Munzer (19) , Fanny Fouyssac (20) , Rolland Jaussaud (21) , Brigitte Bader-Meunier (22) , Nizar Mahlaoui (2, 22) , Stéphane Blanche (22) , Marianne Debré (22) , Muriel Le Bourgeois (23) , Virginie Gandemer (24) , Nathalie Lambert (25) , Virginie Grandin (25) , Stéphanie Ndaga (25) , Corinne Jacques (25) , Chantal Harre (25) , Monique Forveille (25) , Marie-Alexandra Alyanakian (22) , Anne Durandy (2, 26) , Christine Bodemer (27) , Felipe Suarez (1, 2) , Olivier Hermine (2, 1) , Olivier Lortholary (2, 28) , Jean-Laurent Casanova (3, 22, 29) , Alain Fischer (2, 22, 26) , Capucine Picard (2, 3, 22, 25)

1 ERL 8254 - Equipe Inserm U1163 - Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
2 CEREDIH - Centre de Référence Déficits Immunitaires Héréditaires
3 Inserm U980 - Génétique Humaine des Maladies Infectieuses
4 Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale
5 Service d'immunologie clinique
6 Service de pneumologie pédiatrique
7 Hématologie et oncologie pédiatrique
8 Unité Transversale d'Allergologie, Néphrologie et Immunologie Clinique
9 Service d'hématologie pédiatrique
10 Service de maladies infectieuses
11 Service d'Hémato-oncologie Pédiatrique
12 Laboratoire d'immunologie et biothérapies [Rouen]
13 Service d'hématologie et immunologie pédiatrique
14 Service d'hématologie pédiatrique
15 Service de pédiatrie
16 Service de pédiatrie
17 Service de pneumologie, oncologie thoracique et soins intensifs respiratoires [Rouen]
18 Service de pneumologie pédiatrique
19 Service d'hématologie-oncologie pédiatrique
20 Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy]
21 Médecine interne, maladies infectieuses, immunologie clinique
22 Service d'immuno-hématologie pédiatrique [CHU Necker]
23 Service de Pneumologie Allergologie [CHU Necker]
24 Service d'hématologie-oncologie pédiatrique
25 Centre d'étude des déficits immunitaires
26 Developpement Normal et Pathologique du Système Immunitaire
27 Service de dermatologie pédiatrique
28 Centre d'infectiologie Necker-Pasteur [CHU Necker]
29 St. Giles Laboratory of Human Genetics of Infectious Diseases

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.

Domaines: Immunologie; Génétique

Marie-Olivia Chandesris, Isabelle Melki, Angels Natividad, Anne Puel, Claire Fieschi, et al.. Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome: Molecular, Cellular, and Clinical Features From a French National Survey.. Medicine, 2012, 91 (4), pp.e1-e19. ⟨10.1097/MD.0b013e31825f95b9⟩. ⟨inserm-00717018⟩