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.
Highlights
Hyper-IgE syndromes (HIES) and chronic mucocutaneous candidiasis (CMC) constitute rare primary immunodeficiency syndromes with overlapping phenotypes
The cohort comprises an initial group of 90 patients, in whom conventional diagnostics including Sanger sequencing of the suspected underlying target gene (STAT3, DOCK8, PGM3, STAT1) had not led to a definite molecular diagnosis
We analyzed a cohort of 275 patients by targeted panel sequencing, out of whom 211 had been clinically diagnosed with HIES by their referring physicians and 64 with CMC
Summary
Hyper-IgE syndromes (HIES) and chronic mucocutaneous candidiasis (CMC) constitute rare primary immunodeficiency syndromes with overlapping phenotypes. The most common underlying genetic defects are loss of function mutations of the transcription factor STAT3 [4, 5], which, in addition to the triad already mentioned, are associated with dental, skeletal, and connective tissue abnormalities [4, 5]. Mutations in CARD11, ERBB2IP, IL6R, IL6ST, PGM3, TGFBR1/2, and ZNF431 have been recognized as further genetic causes of HIES-like phenotypes [8,9,10,11]. The hyper-IgE phenotype overlaps with the one of chronic mucocutaneous candidiasis (CMC) in that patients may show increased susceptibility to fungal infections. Depending on the underlying molecular defect, additional clinical manifestations may include autoimmunity, endocrinopathy, increased susceptibility to bacterial infections, and malignancies. Laboratory findings may include elevated IgE and eosinophilia, adding to a common hyper-IgE phenotype
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