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

Frede, Natalie; Rojas-Restrepo, Jessica; Caballero Garcia de Oteyza, Andrés; Buchta, Mary; Hübscher, Katrin; Gámez-Díaz, Laura; Proietti, Michele; Saghafi, Shiva; Chavoshzadeh, Zahra; Soler-Palacin, Pere; Galal, Nermeen; Adeli, Mehdi; Aldave-Becerra, Juan Carlos; Al-Ddafari, Moudjahed Saleh; Ardenyz, Ömür; Atkinson, T Prescott; Kut, Fulya Bektas; Çelmeli, Fatih; Rees, Helen; Kilic, Sara S

doi:10.1007/s10875-021-01086-4

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

Journal

Journal of clinical immunology

Date Issued

2021-08-14

Author(s)

Frede, Natalie

Rojas-Restrepo, Jessica

Caballero Garcia de Oteyza, Andrés

Buchta, Mary

Hübscher, Katrin

Gámez-Díaz, Laura

Proietti, Michele

Saghafi, Shiva

Chavoshzadeh, Zahra

Soler-Palacin, Pere

Galal, Nermeen

Adeli, Mehdi

Aldave-Becerra, Juan Carlos

Al-Ddafari, Moudjahed Saleh

Ardenyz, Ömür

Atkinson, T Prescott

Kut, Fulya Bektas

Çelmeli, Fatih

Rees, Helen

Kilic, Sara S

Klein, Christoph

Kobbe, Robin

Korganow, Anne-Sophie

Lilic, Desa

Lunt, Peter

Makwana, Niten

Metin, Ayse

Özgür, Tuba Turul

Karakas, Ayse Akman

Seneviratne, Suranjith

Sherkat, Roya

Sousa, Ana Berta

Unal, Ekrem

Patiroglu, Turkan

Wahn, Volker

von Bernuth, Horst

Whiteford, Margo

Doffinger, Rainer

Jouhadi, Zineb

Grimbacher, Bodo

DOI

10.1007/s10875-021-01086-4

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.

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