Correspondence
STAT3 Mutation in the Original Patient with Job's Syndrome
N Engl J Med 2007; 357:1667-1668October 18, 2007
- Article
To the Editor:
In 1966, a report on two unrelated young girls who had had recurrent staphylococcal abscesses since infancy was introduced with the biblical quote, “So went Satan forth from the presence of the Lord, and smote Job with sore boils from the sole of his foot unto his crown” (Job 2:7).1 The authors called this disorder the Job syndrome because of the phenotypic similarity to the biblical figure Job. Subsequently, similar patients were recognized and noted to have markedly elevated IgE levels, leading to the name “hyper-IgE syndrome” (HIES). (Details about the second girl, who died at the age of 19 years, are provided in the Supplementary Appendix, available with the full text of this letter at www.nejm.org.)
The cause of the syndrome remained elusive until 2006, when a homozygous mutation in the tyrosine kinase 2 (TYK2) gene was discovered in a patient with a variant form of HIES, which suggested that defects in signaling between Janus kinase (JAK) and signal transducer and activator of transcription (STAT) may cause the Job syndrome.2 We and other investigators3,4 have recently identified heterozygous hypomorphic mutations in the STAT3 gene in a majority of patients with the classic autosomal dominant form of Job's syndrome.
The protocol for our research was approved by the institutional review board at the University of Washington School of Medicine and Children's Hospital, Seattle. All subjects in the study provided written informed consent.
One of the two original patients with the Job syndrome1 remains alive in our cohort of patients with classic HIES. This patient (Subject II-3),1 who is now 50 years of age, has had lifelong eczema, multiple atraumatic fractures, hyperkeratotic fingernails owing to candida infection, recurrent Staphylococcus aureus abscesses, and pneumonia with lung abscesses and formation of pneumatoceles. She gave birth to three boys by two fathers (Figure 1Figure 1
Pedigree of the Original Patient.). Her first son (Subject III-1) died 3 days after birth from pneumonia and sepsis with Pseudomonas aeruginosa and acinetobacter. Her second son (Subject III-3) was hospitalized shortly after birth with S. aureus pneumonia. Later, eczema developed, along with rising IgE levels (104,000 IU per milliliter in his second year of life [normal value, <64]), multiple skin abscesses, candidiasis, pneumonia with formation of pneumatoceles, and spontaneous rib factures; he also retained his primary teeth. At 28 years of age, he underwent lobectomy because of multiple pneumatoceles and persistent S. aureus and aspergillus infections. He died at the age of 29 years from respiratory failure. His 8-month-old son (Subject IV-1) was hospitalized at 3 months of age with failure to thrive, pneumothorax, S. aureus pneumonia with abscess formation, empyema, and multiple rib fractures. His current IgE level is 45 IU per milliliter (normal value, <15).Mutation analysis of the STAT3 gene revealed a heterozygous point mutation in exon 12 (1144C→T; protein, R382W) in the index patient and her two affected descendants (Subjects III-3 and IV-1). R382W is not reported as a single-nucleotide polymorphism and was not observed in the unaffected relatives of the index patient (Subjects II-1, II-2, II-5, II-6, III-2, and III-4) or in 200 ancestrally matched chromosomes.
Arginine at position 382 is highly conserved and directly involved in DNA binding.5 This amino acid substitution is the most common STAT3 mutation identified in classic autosomal dominant HIES. It accounts for nearly half the identified mutations.3,4 Since all these mutations are hypomorphic (missense mutations or in-frame deletions) and involve only one allele of STAT3, this finding suggests a dominant negative effect.
5 ReferencesEllen D. Renner, M.D.
Troy R. Torgerson, M.D., Ph.D.
Stacey Rylaarsdam, A.A.A.S.
Stephanie Añover-Sombke, B.S.
Karin Golob
Taylor LaFlam
Qili Zhu, M.D.
Hans D. Ochs, M.D.
University of Washington School of Medicine, Seattle, WA 98195
allgau@u.washington. edu 1
Davis SD ,Schaller J ,Wedgwood RJ . Job's syndrome: recurrent, “cold,” staphylococcal abscesses. Lancet 1966;1:1013-1015
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Minegishi Y ,Saito M ,Morio T , et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 2006;25:745-755
CrossRef | Web of Science | Medline3
Minegishi Y ,Saito M ,Tsuchiya S , et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007;448:1058-1062
CrossRef | Web of Science | Medline4
Holland SM ,DeLeo FR ,Elloumi HZ , et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007;357:1608-1619
Full Text | Web of Science | Medline5
Becker S ,Groner B ,Muller CW . Three-dimensional structure of the Stat3beta homodimer bound to DNA. Nature 1998;394:145-151
CrossRef | Web of Science | Medline
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