Hyper IgE syndrome diagnosed in early infancy by gene analysis of STAT3 mutation

ARTICLE

ejd.2010.1245

Auteur(s) : Akira WATARAI¹ watarai@med.kitasato-u.ac.jp, Shiro NIIYAMA¹, Miho MORITA¹, Yuki BANDO², Yoshiyuki MINEGISHI³, Kensei KATSUOKA¹

¹ Departments of Dermatology, Japan

² Pediatrics, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Minamiku, Kanagawa, 252-0374 Japan

³ Department of Immune Regulation, Tokyo Medical and Dental University, Tokyo, Japan

A baby was delivered at 40 weeks gestation and the birth weight was 3,186 g. There was no family history of Hyper IgE syndrome (HIES). Five days after birth, reddish papules with pustules appeared on the head and trunk, which rapidly worsened (figure 1A). Laboratory findings revealed a white blood cell count of 80800/μL with a normal differential. The eosinophil count was high, at 24%. The serum IgE level was 5,590 IU/mL (normal range 0-100 IU/mL). Bacteriological cultures from the pustule grew methicillin-resistant Staphylococcus aureus (MRSA). Afterwards, he suffered from recurrent eczema and uncontrolled infections, including mucocutaneous candidiasis, omphalitis, otitis media and hordeolum. Eighty days after birth, skin abscesses, which were not accompanied by the usual signs of inflammation, appeared on his scalp (figure 1B). These abscesses were so-called cold abscesses. At this point, the National Institutes of Health (NIH) score of this patient was 42. From this observation, HIES was suspected and we performed a genetic analysis. The mutation V637M [1] in the SH2 domain of the STAT3 protein was detected. The STAT3 mutation was not detected in his family. He was started on daily trimethoprim-sulfamethoxazole for treatment and prophylaxis. There was partial clearing of his dermatitis with the intermittent use of topical corticosteroids. Antibiotics and topical corticosteroids resulted in alleviation of his dermatitis. At the age of 2.5 years, the patient had symptoms of slight eczema and mucocutaneous candidiasis, accompanied by characteristic facial features including a prominent forehead and a broad nasal bridge. There was no recurrence of abscesses. There were no skeletal abnormalities but the patient had a short stature of −3 standard deviations.

HIES is a rare primary immunodeficiency, characterized by eczema associated with extremely high serum IgE levels and eosinophilia, along with recurrent skin abscesses and pneumonia. Recently, the causative genes of HIES were discovered. Type 1 HIES, that is, sporadic inheritance, is mainly due to mutations in the Janus-activated kinase/signal transducer and activator of transcription (JAK-STAT)-mediated cytokine signals [2]. A null mutation in tyrosine kinase 2 (TYK2) was identified in a patient with type 2 HIES, which is autosomally recessively inherited [3]. STAT3 and TYK2 mutations lead to impaired Th17 cell function. Engelhardt reported that patients with severe combined immunodeficiency detected to a homozygous dedicator of cytogenesis 8 protein (DOCK8) fulfilled the criteria of HIES, and this was autosomally recessively inherited [4]. Grimbacher et al. reported the incidence of various features of HIES: the occurrence of eczema was 100%, a peak IgE > 2,000 IU/mL was present in 97% of cases, eosinophilia was 93%, cold abscess was 87%, mucocutaneous candidiasis was 83%, and characteristic facial features were present in 83% of cases. These features were also present in our case. Pneumonia, lung cyst and bone fractures also had comparatively high incidences; these features were absent in our case. It is necessary to observe the clinical course and detect the characteristic facial features and skeletal abnormalities to reach a definitive diagnosis. However, with the identification of STAT3 mutations and the development of molecular diagnostic techniques, a definite diagnosis can be made earlier. The early diagnosis of type 1 HIES by genetic analysis of STAT3 mutations has seldom been reported [5]. Recently, a PCR-based high-resolution DNA-melting assay to scan selected exons of the STAT3 gene for mutations responsible for HIES has been reported [6], and may prove to be a useful diagnostic test in the future. However, molecular tests are not widely available at present. As the early manifestation of HIES is mainly a cutaneous eruption, the diagnosis has to be made carefully, with an index of suspicion if there are features of immunodeficiency.

Disclosure

Financial support: none. Conflict of interest: none.

References

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2 Y Minegishi, M Saito, S Tsuchiya et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome Nature 2007; 448: 1058-1062.

3 Y Minegishi, M Saito, T Morio 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.

4 KR Engelhardt, S McGhee, S Winkler et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome J Allergy Clin Immunol 2009; 124: 1289-1302.

5 BZ Garty, A Ben-Baruch, A Rolinsky et al. Pneumocystis jirovecii pneumonia in a baby with hyper-IgE syndrome Eur J Pediatr 2010; 169: 35-37.

6 A Kumánovics, CT Wittwer, RJ Pryor et al. Rapid Molecular Analysis of the STAT3 Gene in Job Syndrome of Hyper-IgE and Recurrent Infectious Diseases J Mol Diagn 2010; 12: 213-219.