Case Report 2500 www.thelancet.com Vol 379 June 30, 2012 Lancet 2012; 379: 2500 Department of Infectious and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary (B Tóth PhD, L Méhes MD, S Taskó, Prof L Maródi MD); Department of Dermatology, Heim Pál Children’s Hospital, Budapest, Hungary (Z Szalai MD); 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary (Prof Z Tulassay MD); St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA (S Cypowyj PhD, Prof J-L Casanova MD); and Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM U980 and University Paris Descartes, Paris, France (Prof J-L Casanova MD, A Puel PhD) Correspondence to: Prof László Maródi, Department of Infectious and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary lmarodi@dote.hu See Online for appendix Herpes in STAT1 deficiency Beáta Tóth, Leonóra Méhes, Szilvia Taskó, Zsuzsanna Szalai, Zsolt Tulassay, Sophie Cypowyj, Jean-Laurent Casanova, Anne Puel, László Maródi In July, 2011, a 47-year-old woman and her 16-year-old daughter presented to our services because of persistent and recurrent oral candidosis. The mother began experiencing genital candidosis at the age of 3 years and her nails became affected when she was 4 (see appendix). From the age of 5 years, she presented with herpetic vesicles two to four times per year, mainly affecting her face. She had chickenpox when she was 5 years old and 1 year later had shingles. At 21 years, she developed cutaneous herpes lesions over an 8×5 cm area on the right side of her face. At 30 years, she had another episode of shingles on her right trunk. At 45 years, retrosternal discomfort and pain on swallowing solid food developed. Gastroscopy showed 6 cm long narrowing of the oesophagus. Candida albicans was isolated. Except for one episode of pneumococcal pleuro- pneumonia with confluent lobar consolidation at the age of 38 years, no causal organisms of pneumonia were identified. The daughter had had recurrent oral and pharyngeal candidosis since infancy, and genital and nail candidosis from the ages of 12 and 16 years. She had chickenpox when she was 3 years old, but no primary episode of HSV infection had been reported. Recurrent infections with HSV and varicella began when she was 6. From that time, she had recurrent HSV infections mainly affecting the lips and mouth, mouth ulcers every 1–3 months since infancy, and two episodes of cutaneous varicella infection affecting the right thigh and knee. Both patients carried the heterozygous germline mutation detected by genomic DNA sequencing in the STAT1 gene, which encodes signal transducer and acti- vator of transcription (STAT) 1 (see figure, appendix). In contrast to previously reported patients with STAT1 mutations and chronic mucocutaneous disease only, our patients presented with recurrent shingles and cutaneous lesions due to the reactivation of varicella and HSV infection. 1,2 These unusual reactivations followed the normal courses of chickenpox and uneventful primary HSV infections in childhood. Both patients had normal serum concentrations of immunoglobulin isotypes, specific antibody responses, and normal counts of white blood cells. In response to stimulation with heat-killed Candida, both patients showed normal interferon-γ release but no release of interleukin 17 (controls, 210–255 ng/L and impaired release of interleukin 22 (208 and 69 ng/L; controls, 506–525). Treatment with nystatin, itraconazole, and aciclovir, alone or in combination, resulted in clinical improvement and local pain relief in both patients. Dilation of the narrow segment of the mother’s oesophagus greatly relieved her pain. Both patients were started on prophylactic fluco- nazole 150 mg twice a week, and at the last follow-up in April, 2012 they were free of candidal or viral disease. An impairment of the development or function of interleukin-17-producing T cells is common to all known inborn errors of immunity underlying chronic mucocu- taneous candidosis. 3,4 The clinical phenotype of such patients, including those with STAT1 mutations, has never been thoroughly described. Our patients’ cases show that individuals carrying STAT1 gain-of-function mutations might also be susceptible to viral diseases. The mechanism underlying reactivation disease in patients with STAT1 mutations and chronic muco- cutaneous candidosis could involve the impairment of memory T cells, as reported in patients with hyper-IgE syndrome and STAT3 deficiency. 5 The effect of recurrent viral infections on the prognosis of chronic mucocu- taneous candidosis remains to be elucidated. Contributors All authors looked after the patients. LM wrote the report. Written consent to publication was obtained. References 1 Liu L, Okada S, Kong X, et al. Gain-of-function human STAT1 mutations impair IL- 17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011; 208: 1635–48. 2 van der Veerdonk FL, Plantinga TS, Hoischen A, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 2011; 365: 54–61. 3 Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011; 332: 65–68. 4 Tóth B, Wolff AS, Halász Z, et al. Novel sequence variation of AIRE and detection of interferon-omega antibodies in early infancy. Clin Endocrinol 2010; 72: 641–47. 5 Siegel AM, Heimall J, Freeman AF, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity 2011; 35: 806–18. Figure: Pedigree of STAT1 R247W mutation Red/m=mutant; green/wt=wild type. wt/wt wt/wt wt/wt m/wt m/wt