Introduction
Chronic mucocutaneous candidiasis (CMC) is a disorder characterized by recurrent or persistent symptomatic infections caused by Candidaspecies affecting the nails, skin, oral cavity, and genital mucosa [1]. CMC has been identified as an important infectious phenotype in patients suffering from inborn errors of immunity in particular those with (severe) T cell deficiencies, or altering the interleukin (IL)-17 pathway [2, 3]. For about half of CMC cases, signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations were found as the disease-causing etiology, and it has been suggested that the identification of a STAT1 variant in the setting of CMC should be followed by a thorough functional variant work-up [2, 4]. Patients with STAT1 GOF mutations suffer from a broad clinical phenotype including (myco-) bacterial, viral, and fungal, infections, autoimmunity, malignancies, and the development of aneurysms [4]. In contrast, patients with defects of the IL-17-response pathway such as autosomal dominant (AD) IL-17F or JNK1 deficiency, or autosomal recessive (AR) IL-17RA, IL-17RC, or ACT1 deficiencies are characterized by a narrow infectious spectrum mostly restricted to superficialC. albicans and Staphylococcus aureus diseases [2, 5-7].
The IL-17A- and IL-17F- (IL-17A/F)-mediated response is critical for the host defense against fungal pathogens affecting epithelium and mucosa [6, 8]. IL-17A/F-signaling requires the binding to a heterodimeric receptor(R) (IL-17RA/IL-17RC) and subsequent recruitment of the ubiquitin ligase adaptor protein ACT1, encoded by TRAF3IP2 , ubiquitously expressed in human tissues. ACT1 further recruits tumor necrosis factor receptor-associated factor 6 (TRAF6) to trigger downstream activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways (Figure 1). This results in the upregulation of pro-inflammatory cytokines and chemokines with critical roles in protective mucosal immunity [2, 9-11] .
Mutations of ACT1 were first reported in two siblings harboring a bi-allelic missense mutation (c.1607C>T, p.T536I) in the SEFIR (similar expression to fibroblast growth factor genes/IL-17) domain [12]. Both patients had early onset CMC and seborrheic dermatitis, and one patient had in addition bilateral persistent blepharitis due to S. aureus . The mutation impaired the homotypic interaction of ACT1 with IL-17RA and IL-17RC, abrogating IL17A/F-dependent signaling in fibroblasts, explaining the CMC phenotype. It also impaired ACT1 interaction with IL-17RB, abolishing IL-17E-dependent signaling in leukocytes, through IL-17RA/IL-17RB. In contrast, patients displayed enhanced proportions of Th17 cells, as measured ex vivo upon PMA/ionomycin stimulation [12]. More recently, eight additional patients with mutations of TRAF3IP2 have been described [13-16]. We present a 10-year-old girl with CMC due to AR ACT1 deficiency and review important clinical and laboratory characteristics of the so far published cases.
Methods