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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 CD21^loCD38^lo 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.

SUBMITTER: Ferre EM

PROVIDER: S-EPMC5004733 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Ferre Elise M N EM Rose Stacey R SR Rosenzweig Sergio D SD Burbelo Peter D PD Romito Kimberly R KR Niemela Julie E JE Rosen Lindsey B LB Break Timothy J TJ Gu Wenjuan W Hunsberger Sally S Browne Sarah K SK Hsu Amy P AP Rampertaap Shakuntala S Swamydas Muthulekha M Collar Amanda L AL Kong Heidi H HH Lee Chyi-Chia Richard CR Chascsa David D Simcox Thomas T Pham Angela A Bondici Anamaria A Natarajan Mukil M Monsale Joseph J Kleiner David E DE Quezado Martha M Alevizos Ilias I Moutsopoulos Niki M NM Yockey Lynne L Frein Cathleen C Soldatos Ariane A Calvo Katherine R KR Adjemian Jennifer J Similuk Morgan N MN Lang David M DM Stone Kelly D KD Uzel Gulbu G Kopp Jeffrey B JB Bishop Rachel J RJ Holland Steven M SM Olivier Kenneth N KN Fleisher Thomas A TA Heller Theo T Winer Karen K KK Lionakis Michail S MS

JCI insight 20160801 13

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by homozygous <i>AIRE</i> 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 autoi ...[more]

PMID: 27588307

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Project description:BackgroundThe rare monogenic syndrome Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) leads to multisystemic autoimmunity with possible lung involvement. Autoimmune pneumonitis is a rare manifestation, with bronchiectasis being the most frequent radiologic pattern, and may lead to fatal outcome. The Sardinian population in Italy has a high incidence of APECED, although no case of lung manifestation has been reported yet in this cohort. This is the case of a Sardinian APECED patient referred to a bronchiectasis clinic. Our aim is to raise awareness and screen these patients earlier for pulmonary involvement and to initiate multidisciplinary treatment for better outcome.Case presentationA 49-year-old female native of Sardinia from consanguineous parents was diagnosed with APECED in childhood and was referred to our bronchiectasis clinic in March 2023. In addition to typical APECED features, she reported recurrent respiratory infections since childhood, chronic purulent sputum and a hospitalization for pneumonia. She came to our attention with a recent isolation of P. aeruginosa on sputum culture and diffuse cylindrical and varicoid bronchiectasis on her first CT scan. She underwent aetiologic screening for bronchiectasis with no evidence of another cause of disease. Lung treatment was optimized according to bronchiectasis guidelines, and during follow-up the patient developed methicillin-resistant Staphylococcus aureus (MRSA) infection and M. intracellulare pulmonary disease. The patient was offered P. aeruginosa eradication treatment with intravenous antibiotics and initiation of antimycobacterial therapy.ConclusionThis is the first documented lung involvement case of APECED in a Sardinian patient, and the first patient reported to enter a bronchiectasis program. The patient was prescribed lung imaging late in time when bronchiectasis complications were already present. Our case report highlights the need for early pulmonary screening and multidisciplinary management in patients with APECED.

Dataset Information

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

Publications

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

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