Destructive pulmonary staphylococcal infection in a boy with hyper-IgE syndrome: a novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene (p.Y657S).
Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder, characterized by eczema, recurrent skin and lung infections, and significantly elevated serum IgE level. It was previously diagnosed based on clinical manifestations and laboratory markers that were not specific to the disease. Recent studies have demonstrated that mutations in signal transducer and activator of transcription 3 (STAT3) cause the autosomal dominant or sporadic HIES, which make the disease definitively characterized at molecular level. Here, we reported a 3-year old Chinese boy with neonatal-onset rash and multiple serious Staphylococcus aureus infections including recurrent skin abscesses, liver abscess, sepsis, and destructive pulmonary infection (pneumonia, multiple pulmonary abscesses, pyopneumothorax, and finally, pneumatocele). Genetic study revealed a heterozygous mutation in exon 21 of STAT3 gene (g.66583 A > C, c.1970A > C) in the boy, which resulted in a substitution of tyrosine at the amino acid position 657 to serine (p.Y657S) in the Src homology 2 (SH2) domain of STAT3. Functional prediction with bioinformatics programs of the Sorting Intolerant from Tolerant (SIFT) and the Polymorphism Phenotyping (PolyPhen) reported "deleterious (SIFT score 0.02)" and "probably damaging (PSIC score difference 2.94)" values, respectively. Further study of family members revealed that neither his parents, nor his twin brother carried the mutation, indicating the mutation was likely to occur de novo in our patient.


CONCLUSIONS
The mutation,p.Y657S,in SH2 domain of STAT3 is a disease-causing mutation in the boy with HIES.
Department of Pediatric Hematology/Immunology, West China Second University Hospital, Sichuan University, No.20, Section 3, Renmin Nan Lu, Chengdu 610041, China.
Jin-yan
JY
Liu
Qiang
Q
Li
Ting-ting
TT
Chen
Xia
X
Guo
Jiao
J
Ge
Li-xing
LX
Yuan
D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004200:Diseases in Twins / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007589:Job Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D008171:Lung Diseases / Q000209:etiology; D008297:Male; D017354:Point Mutation; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013203:Staphylococcal Infections / Q000209:etiology; D014429:Twins, Dizygotic
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human