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