ESPE Abstracts

Introduction: Autoimmune Polyglandular Syndrome Type I (APS1) is a rare condition caused by mutations in the AIRE gene (autoimmune regulator). The diagnosis is challenging and delayed due to its non-specific clinical manifestations such as candidiasis, hypoparathyroidism and hypoadrenalism. More than a hundred mutations of this gene have been described and hereby we present a girl who was found to have a novel mutation of AIRE gene with pathologic significance.

Case Presentation: A 5-year-old girl who had a history of consanguinity but no family history of diseases, presented to the emergency room with a tonic-clonic seizure. She was admitted the hospital where she was found to have an electrolytic imbalance. At this moment it was also noted that since she was 2 years old, she had several consults due to mucocutaneous candidiasis that didn’t improve with antifungal treatment, as well as frequent diarrhea episodes and dental problems. She was found to have a total calcium of 6.9 mg/dl (normal range: 8.8-10.8 mg/dl) and an ionic calcium of 3 mg/dl (normal range: 4.6-5.08 mg/dl). Her phosphorus was elevated at 11.4 mg/dl (normal range: 3.2- 5.8 mg/dl) and her PTH was extremely low at < 1.20 pg/ml (normal range: 1-13 pg/ml). Given the presence of chronic mucocutaneous candidiasis (CMC) and hypoparathyroidism, an extensive endocrine workup was performed. It revealed no other autoimmune endocrine diseases, but the presence of anti-insulin, anti-thyroglobulin and anti-microsomal antibodies was confirmed. Candida infection was confirmed by culture. A genetic testing of AIRE gene was required. A Next Generation Sequencing analysis was performed by using Clinical Exome Solution v2 and Sophia DDM^TM Platform (Sophia Genetics SA, Saint Sulpice, Switzerland) in a Miseq NGS device (Illumina Inc, San Diego, CA, USA). A gross homozygous deletion of the genomic region encompassing exons 1-3 of the AIRE gene, which includes the initiator codon, was detected. This alteration abrogates the first 463 nucleotides of AIRE gene coding sequence, resulting in the loss of a CARD domain, a HSR domain and NLS domain which is expecting to result in an altered or absent protein product. It was defined as pathogenic variant based on PVS1, PM2 and PP4 ACMG criteria.

Conclusions: In our patient two out of three diagnostic criteria (CMC and hypoparathyroidism) and other classic symptoms of APS1 were present, revealing a novel pathogenic variant in the AIRE gene.