Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis

Abstract

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

Of Mycelium and Men: Inherent Human Susceptibility to Fungal Diseases

“…In addition to the preceding disorders that decrease IL-17 (and selectively IL-22) production, the distinctive feature of CMC and the principal of physiologic homogeneity led to the discovery of IEI that cause impaired responses to IL-17 due to either autosomal dominant (AD) mutations in the IL-17F cytokine [ 54 ], AR mutations in the IL-17 receptor subunits (IL17RA or IL17RC) [ 54 , 55 , 56 , 57 , 58 ], AR mutations in the adaptor molecule required for IL-17 receptor signaling (ACT1) [ 59 , 60 , 61 , 62 , 63 ], or AD mutations in the kinase essential for its signaling (JNK1) [ 64 ]. To date, no mutations compromising IL-22 signaling have been identified.…”

Diagnostic challenge in a series of eleven patients with hyper IgE syndromes

“…Since ten genes are now recognized to be responsible for HIES ( 10 ), a customized gene panel could help establish a HIES diagnosis and determine the specific etiology. This panel should include the ten HIES genes, DOCK8 gene, TYK2 gene, genes that could be responsible for atypical clinical presentations ( 36 ), and genes associated with moderate to severe refractory eczema and elevated Immunoglobulin E ( 14 , 37 ).…”

Isolated chronic mucocutaneous candidiasis due to a novel duplication variant of IL17RC

“…Among IEI causing isolated CMC, AR IL-17RA de ciency has been reported thus far in 28 cases from 16 kindreds, but AR IL-17RC de ciency has been reported in only four cases, including the current case (Case summary: Tables S3, S4) (27,29,30,(43)(44)(45). We therefore focused on causes of the difference in the frequency of AR IL-17RC de ciency and AR IL-17RA de ciency.…”