Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Immunology and Molecular Pathology, Royal Free Hospital, University College London, London NW3 2QG, United Kingdom.
Cristina
C
Woellner
E Michael
EM
Gertz
Alejandro A
AA
Schäffer
Macarena
M
Lagos
Mario
M
Perro
Erik-Oliver
EO
Glocker
Maria C
MC
Pietrogrande
Fausto
F
Cossu
José L
JL
Franco
Nuria
N
Matamoros
Barbara
B
Pietrucha
Edyta
E
Heropolitańska-Pliszka
Mehdi
M
Yeganeh
Mostafa
M
Moin
Teresa
T
Español
Stephan
S
Ehl
Andrew R
AR
Gennery
Mario
M
Abinun
Anna
A
Breborowicz
Tim
T
Niehues
Sara Sebnem
SS
Kilic
Anne
A
Junker
Stuart E
SE
Turvey
Alessandro
A
Plebani
Berta
B
Sánchez
Ben-Zion
BZ
Garty
Claudio
C
Pignata
Caterina
C
Cancrini
Jiri
J
Litzman
Ozden
O
Sanal
Ulrich
U
Baumann
Rosa
R
Bacchetta
Amy P
AP
Hsu
Joie N
JN
Davis
Lennart
L
Hammarström
E Graham
EG
Davies
Efrem
E
Eren
Peter D
PD
Arkwright
Jukka S
JS
Moilanen
Dorothee
D
Viemann
Sujoy
S
Khan
László
L
Maródi
Andrew J
AJ
Cant
Alexandra F
AF
Freeman
Jennifer M
JM
Puck
Steven M
SM
Holland
Bodo
B
Grimbacher
D000293:Adolescent; D000328:Adult; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007223:Infant; D020381:Interleukin-17 / Q000276:immunology; D007589:Job Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D017410:Practice Guidelines as Topic; D050796:STAT3 Transcription Factor / Q000235:genetics*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D055815:Young Adult
D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007073:Immunoglobulin E