SUN-040 Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) Syndrome: Prospective Screening of Asplenism and Pneumonitis in a Cohort of 25 Patients

Abstract

Background: APECED syndrome is a rare monogenic disease caused by homozygous mutation of AIRE gene. It classically presents with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency with an early onset in childhood. Non-endocrine manifestations as ectodermic dystrophy, asplenism and pneumonitis are also observed but their incidence remains unknown and their mechanisms not well understood. APECED has been poorly reported in France although it is widely described in several European countries. The aim of this study was to report on rare manifestations of APECED syndrome in a French cohort. Patients and methods: We performed a multicentric prospective observational study in France in order to collect clinical, biological, immunological and genetic data, after written informed consent in the frame of a PHRC (Hospital Project of Clinical Research #1927). Bronchiolitis, splenic atrophy and ocular manifestations were systematically investigated. Results We enrolled 25 patients between 2009 and 2016. Clinically, the median age at diagnosis was 12 while the median age of the first manifestation was 6, so there was diagnostic delay. The median number of manifestations was seven. 76 % of patients presented with the classical triad. Reduction of lung function was observed in 62% of patients, asplenism in 26%, and ocular manifestation in 33%. Genetically, eleven mutations of the AIRE gene were identified, two of which never previously reported: an intronic variation c.653-70G>A (intron 5) in a patient with hypoparathyroidism as unique manifestation , and c.1066del (p.Arg356GlyfsX22) (exon 9) in a patient from Guadeloupe with composite heterozygous mutations (c.967_979del13; exon 8). The most common AIRE mutation was the mutation R257X. Median age was 26 and sex ratio was 1.1. Biologically, 100% of tested sera were positive for anti-IFNα-antibodies, 15/18 for anti-IL-22, and 13/18 for anti-IL-17F antibodies. Conclusion: This series shows a high genotypic and phenotypic variability of APECED in France, that could be explained by different ethnic origins. The systematic screening for non-classic manifestations shows a more frequent occurrence than in other series. Systematic screening of asplenism and bronchiolitis could be a useful strategy to make an earlier diagnosis, to prevent infections by vaccination and to treat earlier pulmonary involvement. Lastly, antibodies against Th17 cytokines appear as good soluble markers for diagnosis of non-classical presentation of the syndrome.