Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
Elise M.N. Ferre, et al.
Elise M.N. Ferre, et al.
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Research Article

Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous AIRE mutations. It classically presents with chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues; hypoparathyroidism and adrenal insufficiency are most common. Developing any two of these classic triad manifestations establishes the diagnosis. Although widely recognized in Europe, where nonendocrine autoimmune manifestations are uncommon, APECED is less defined in patients from the Western Hemisphere. We enrolled 35 consecutive American APECED patients (33 from the US) in a prospective observational natural history study and systematically examined their genetic, clinical, autoantibody, and immunological characteristics. Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13. All but one patient had anti–IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations. Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren’s-like syndrome, uncommon entities in European APECED cohorts, affected 40%–80% of American cases. Development of a classic diagnostic dyad was delayed at mean 7.38 years. Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad. Only 20% of patients had their first two manifestations among the classic triad. Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations. Patients exhibited expanded peripheral CD4+ T cells and CD21loCD38lo B lymphocytes. In summary, American APECED patients develop a diverse syndrome, with dramatic enrichment in organ-specific nonendocrine manifestations starting early in life, compared with European patients. Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications.

Authors

Elise M.N. Ferre, Stacey R. Rose, Sergio D. Rosenzweig, Peter D. Burbelo, Kimberly R. Romito, Julie E. Niemela, Lindsey B. Rosen, Timothy J. Break, Wenjuan Gu, Sally Hunsberger, Sarah K. Browne, Amy P. Hsu, Shakuntala Rampertaap, Muthulekha Swamydas, Amanda L. Collar, Heidi H. Kong, Chyi-Chia Richard Lee, David Chascsa, Thomas Simcox, Angela Pham, Anamaria Bondici, Mukil Natarajan, Joseph Monsale, David E. Kleiner, Martha Quezado, Ilias Alevizos, Niki M. Moutsopoulos, Lynne Yockey, Cathleen Frein, Ariane Soldatos, Katherine R. Calvo, Jennifer Adjemian, Morgan N. Similuk, David M. Lang, Kelly D. Stone, Gulbu Uzel, Jeffrey B. Kopp, Rachel J. Bishop, Steven M. Holland, Kenneth N. Olivier, Thomas A. Fleisher, Theo Heller, Karen K. Winer, Michail S. Lionakis

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Figure 2

Early manifestations and redefined diagnostic criteria in American autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

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Early manifestations and redefined diagnostic criteria in American autoi...
(A and B) Prevalence by age of the classic triad manifestations (A) and the adjunct triad of urticarial eruption, intestinal dysfunction, and enamel hypoplasia (B) within the first 7 years of life, before the mean age at which a diagnostic dyad was reached in the 35 American APECED patients. (C) Mean age at diagnosis of all clinical manifestations among the APECED patients who developed the corresponding disease components. Black bars denote the clinical manifestations with a mean age of diagnosis within the first 7 years of life, before the mean age at which a classic diagnostic dyad is reached. (D) Age of reaching diagnosis based on development of any 2 classic triad manifestations (current diagnostic criteria) versus reaching the diagnosis based on development of any 2 manifestations within the combined classic triad and adjunct triad of urticarial eruption, intestinal dysfunction, and enamel hypoplasia (expanded diagnostic criteria). (E) Redefined expanded diagnostic criteria and diagnostic algorithm aimed at promoting earlier diagnosis of American APECED patients. (F) Distribution of the initial manifestation in the 35 American APECED patients. Gray bars denote manifestations within the current classic diagnostic triad.