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Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1

Katarina Trebuak Podkrajek¹, Tatjana Milenkovi², Roelof J Odink³, Hedi L Claasen-van der Grinten⁴, Nina Bratani⁵, Tinka Hovnik¹ and Tadej Battelino^1,5

¹ Centre for Medical Genetics, University Medical Centre, University Children's Hospital, Vrazov trg 1, SI-1000 Ljubljana, Slovenia² Mother and Child Health Care Institute of Serbia, Belgrade, Serbia³ Department of Pediatrics, Catharina Ziekenhuis, Eindhoven, The Netherlands⁴ Department of Metabolic and Endocrine Disease, University Medical Center St Radboud, Nijmegen, The Netherlands⁵ Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Centre, University Children's Hospital, Ljubljana, Slovenia

(Correspondence should be addressed to K T Podkrajek; Email: katarina.trebusak{at}kclj.si)

Objective: Autoimmune polyglandular syndrome type 1 (APS-1) is characterised by multiple autoimmune diseases. Detection of autoimmune regulator (AIRE) gene mutations facilitates timely and precise diagnosis.

Design: AIRE mutation detection was performed in a cohort of 11 patients. Two did not meet clinical APS-1 criteria and several started with atypical presentation.

Methods: Sequencing and TaqMan genotyping were used to identify AIRE mutations. Complete AIRE deletion was confirmed and framed by real-time PCR, long-range amplification and analysis of the microsatellite markers.

Results: Seven different mutations were detected, three were novel: c.892G>A in exon 8, silent mutation c.462A>T in exon 3 most likely affecting splicing, and a complete deletion of a single AIRE allele ((?_68)_(1567-14_?)del). Novel (chronic otitis) and rare (systemic juvenile rheumatoid arthritis, autoimmune bronchiolitis, epilepsy) clinical presentations were observed.

Conclusions: AIRE mutation detection was valuable in the diagnostics of APS-1 in patients with atypical presentation. Chronic otitis media possibly broadened the cluster of APS-1 manifestations.