Long-term follow-up of autoimmune polyendocrine syndrome type-1 in Norway

Isil Kucuka; Anette S B Wolff; Lars Breivik; Thea Sjøgren; Eirik Bratland; Marianne Grytaas; Kari Lima; Anders Jørgensen; Ingrid Nermoen; Åsne Bakke; Hallvard Singsås; Margrethe Svendsen; Trine E Finnes; Bjørn Gunnar Nedrebø; Thor Haug; Guri Grimnes; Marthe Landsverk Rensvik; Cecilie G Gjerde; Mihaela C Marthinussen; Marianne Øksnes; Bergithe E Oftedal; Eystein S Husebye

doi:10.1210/clinem/dgag060

Long-term follow-up of autoimmune polyendocrine syndrome type-1 in Norway

J Clin Endocrinol Metab. 2026 Feb 12:dgag060. doi: 10.1210/clinem/dgag060. Online ahead of print.

Authors

Isil Kucuka¹, Anette S B Wolff^{2

3}, Lars Breivik^{1

2}, Thea Sjøgren², Eirik Bratland^{1

4}, Marianne Grytaas², Kari Lima⁵, Anders Jørgensen^{6

7}, Ingrid Nermoen^{5

8}, Åsne Bakke⁹, Hallvard Singsås¹⁰, Margrethe Svendsen¹¹, Trine E Finnes^{6

12}, Bjørn Gunnar Nedrebø^{1

13}, Thor Haug¹⁴, Guri Grimnes^{15

16}, Marthe Landsverk Rensvik¹⁷, Cecilie G Gjerde¹⁸, Mihaela C Marthinussen^{18

19}, Marianne Øksnes^{1

2}, Bergithe E Oftedal^{1

2}, Eystein S Husebye^{1

2}

Affiliations

¹ Department of Clinical Science, University of Bergen, Bergen, Norway.
² Department of Medicine, Haukeland University Hospital, Bergen, Norway.
³ Department of Biomedicine, University of Bergen, Bergen, Norway.
⁴ Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
⁵ Department of Endocrinology, Akershus University Hospital, Lørenskog, Norway.
⁶ Department of Endocrinology, Oslo University Hospital, Oslo, Norway.
⁷ Faculty of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ Department of Endocrinology, Stavanger University Hospital, Stavanger, Norway.
¹⁰ Department of Endocrinology, St. Olavs Hospital, 7006 Trondheim, Norway.
¹¹ Department of Medicine, Østfold Hospital, 1714 Grålum, Norway.
¹² Department of Endocrinology, Innlandet Hospital Trust, N-2318, Hamar, Norway.
¹³ Department of Medicine, Haugesund Hospital, Haugesund, Norway.
¹⁴ Department of Endocrinology, Molde Hospital, Molde, Norway.
¹⁵ Division of Medicine, University Hospital of North Norway, Tromsø, Norway.
¹⁶ Tromsø Endocrine Research Group, Institute of Clinical Medicine, The Arctic University of Norway, Tromsø, Norway.
¹⁷ Department of Medicine, Ålesund Hospital, 6017 Ålesund, Norway.
¹⁸ Department of Clinical Dentistry, Faculty of Medicine, University of Bergen, Bergen, Norway.
¹⁹ Oral Health Centre of Expertise in Western Norway/Vestland, Bergen, Norway.

PMID: 41678364
DOI: 10.1210/clinem/dgag060

Abstract

Context: Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare, yet severe multiorgan autoimmune disease caused by mutations in the Autoimmune Regulator (AIRE) gene. Classical APS-1 arises from biallelic recessive AIRE mutations, whereas dominant negative mutations cause a milder, non-classical phenotype with variable clinical presentation. Due to its rarity, long-term, population-based data are limited, underscoring the need for extended follow-up to guide lifelong care and research.

Objective: To characterize the clinical profiles of APS-1 and explore associations between disease manifestations, autoantibody profiles, and AIRE mutations over an extended follow-up (1996-2025).

Patients: All known Norwegian patients with APS-1.

Methods: We analysed longitudinal clinical and laboratory data of 71 APS-1 patients (49 classical, 22 non-classical) from the Norwegian Registry of Organ-specific Autoimmune Diseases. Data included clinical progression, autoantibody and cytokine profiles, and AIRE genotypes. Additionally, we compared age at diagnosis of primary adrenal insufficiency (PAI) in patients with and without (n=999) APS-1.

Results: In classical APS-1, the most frequent clinical manifestations were chronic mucocutaneous candidiasis, enamel hypoplasia, and PAI, while for non-classical APS-1 vitiligo, hypothyroidism, and PAI were most common. A broad pro-inflammatory cytokine signature was observed in classical APS-1, along with increased levels of the soluble form of the IFN-α/β receptor.

Conclusion: APS-1 should be considered in patients diagnosed with PAI before age 20, and AIRE sequencing is recommended for diagnostic confirmation. The presence of IFN-ω autoantibodies, a pro-inflammatory cytokine profile, and increased soluble IFN receptor levels further support the role of dysregulated interferon responses in APS-1 pathogenesis.

Keywords: AIRE mutations; autoimmune polyendocrine syndrome type 1; cytokine autoantibodies; interferon autoantibodies; monogenic diseases.