%0 Journal Article
%T Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
%A Woellner C
%A Gertz EM
%A Schäffer AA
%A Lagos M
%A Perro M
%A Glocker EO
%A Pietrogrande MC
%A Cossu F
%A Franco JL
%A Matamoros N
%A Pietrucha B
%A Heropolitańska-Pliszka E
%A Yeganeh M
%A Moin M
%A Español T
%A Ehl S
%A Gennery AR
%A Abinun M
%A Breborowicz A
%A Niehues T
%A Kilic SS
%A Junker A
%A Turvey SE
%A Plebani A
%A Sánchez B
%A Garty BZ
%A Pignata C
%A Cancrini C
%A Litzman J
%A Sanal O
%A Baumann U
%A Bacchetta R
%A Hsu AP
%A Davis JN
%A Hammarström L
%A Davies EG
%A Eren E
%A Arkwright PD
%A Moilanen JS
%A Viemann D
%A Khan S
%A Maródi L
%A Cant AJ
%A Freeman AF
%A Puck JM
%A Holland SM
%A Grimbacher B
%J J Allergy Clin Immunol
%V 125
%N 2
%D Feb 2010
%M 20159255
%F 14.29
%R 10.1016/j.jaci.2009.10.059
%X <B>BACKGROUND: </B>The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.<BR><B>OBJECTIVE: </B>To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients.<BR><B>METHODS: </B>We collected clinical data, determined T(H)17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation.<BR><B>RESULTS: </B>In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) T(H)17 cells but were distinct by markedly reduced IFN-gamma-producing CD4(+)T cells.<BR><B>CONCLUSIONS: </B>We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.