The Journal of clinical endocrinology and metabolism · 2025
Lessons From Prospective Longitudinal Follow-up of a French APECED Cohort.
СтатьяНаблюдательное исследованиеМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Humbert Linda, Proust-Lemoine Emmanuelle, Dubucquoi Sylvain, Kemp Elisabeth Helen, Saugier-Veber Pascale, Fabien Nicole, Raymond-Top Isabelle, Cardot-Bauters Catherine, Carel Jean-Claude, Cartigny Maryse, Chabre Olivier, Chanson Philippe, Delemer Brigitte, Do Cao Christine, Guignat Laurence, Kahn Jean Emmanuel, Kerlan Veronique, Lefebvre Herve, Linglart Agnès, Mallone Roberto, Reynaud Rachel, Sendid Boualem, Souchon Pierre-François, Touraine Philippe, Wémeau Jean-Louis, Vantyghem Marie-Christine
Аннотация
BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort.
PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683).
RESULTS: Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC.
CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.
PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683).
RESULTS: Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC.
CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.