ECE2019 Oral Communications Endocrine Connections 1 (5 abstracts)
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome: French prospective study in a cohort of 25 patients
Linda Humbert 1 , Sylvain Dubucquoi 1 , Helen Kemp 2 , Pascale Saugier Veber 3 , Nicole Fabien 4 , Isabelle Raymond Top 1 , Catherine Cardot Bauters 1 , Maryse Cartigny 1 , Brigitte Delemer 5 , Christine Docao 1 , Alfred Penfornis 6 , Laurence Guignat 7 , Veronique Kerlan 8 , Hervé Lefevbre 9 , Olivier Chabre 10 , Laura Vanhove 11 , Boualem Sendid 1 , Jean-Claude Carel 12 , Perre-François Souchon 5 , Jacques Weil 13 , Marie-Christine Vantyghem 1 , Jean-Louis Wemeau 1 & Emmanuelle Proust-Lemoine 14
1CHRU Lille, Lille, France; 2University of Sheffield, Sheffield S10 2RX, UK; 3Laboratoire de génétique moléculaire, CH Rouen, Rouen, France; 4Service d’Immunologie CHU de Lyon HCL - GH Sud, Lille, France; 5CHU Reims, Reims, France; 6CHU Besancon, Besancon, France; 7CHU Cochin, Paris, France; 8CHU Brest, Brest, France; 9CHU Rouens, Lille, France; 10CHU Grnoble, Grenoble, France; 11CH Bethune, bethune, France; 12CHU Hôpital Robert Debre, Paris, France; 13CHRU, Lille, France; 14CHRU Lillele, Lille, France.
Background: APECED syndrome is a rare monogenic disease caused by homozygous mutation of AIRE gene. It classically presents with chronic mucocutaneous candidiasis (CMC), hypoparathyroidism (HP), and adrenal insufficiency (AI) 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 and to determine the mutational spectrum of the AIRE gene at the national level.
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). Rare manifestations were systematically investigated in addition to the search of antibodies, analysis of AIRE gene, lymphocyte immunophenotyping and HLA genotyping. This evaluation was carried out 3 times in two years.
Results: We enrolled 25 patients (23 families) between 2009 and 2016. 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 Finnish mutation R257X. The median number of manifestations was 7. 76% of patients presented the Whitaker triad. The most common disorders were CMC, AI and HP but pulmonary involvement (62%), ectodermal dystrophy (80%) with ocular involvement (33%), malabsorption (32%) and asplenism (26%) were common. There was an NK lymphopenia with a significant increase in T4 and T8 lymphocytes with age-dependent alteration of B lymphocyte homeostasis (inversion of the naive LB/LB memory ratio) (P<0.001). 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: The French population of APECED patients shows a great genotypic and phenotypic variability. We confirm an alteration of B age-dependent lymphocyte homeostasis. Systematic screening of rare manifestations as asplenism and bronchiolitis could be a useful strategy to make an earlier diagnosis, to prevent infections by vaccination and to treat earlier pulmonary involvement. Antibodies against Th17 cytokines appear as good soluble markers for diagnosis of non-classical presentation of the syndrome.
Volume 63
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Endocrine Abstracts
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