title: 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 homozygousAIREmutations. 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 commonAIREmutation was c.967_979del13. All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelicAIREmutations. 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 CD21loCD38loB 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: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Elise M N
authors: EM
authors: Ferre
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Stacey R
authors: SR
authors: Rose
authors: Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Sergio D
authors: SD
authors: Rosenzweig
authors: Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA.
authors: Peter D
authors: PD
authors: Burbelo
authors: Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Kimberly R
authors: KR
authors: Romito
authors: Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Julie E
authors: JE
authors: Niemela
authors: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Lindsey B
authors: LB
authors: Rosen
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Timothy J
authors: TJ
authors: Break
authors: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., National Cancer Institute (NCI) Campus at Frederick, Frederick, Maryland, USA.
authors: Wenjuan
authors: W
authors: Gu
authors: Biostatistics Research Branch, Division of Clinical Research, NIAID, NIH, Bethesda, Maryland, USA.
authors: Sally
authors: S
authors: Hunsberger
authors: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Sarah K
authors: SK
authors: Browne
authors: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Amy P
authors: AP
authors: Hsu
authors: Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Shakuntala
authors: S
authors: Rampertaap
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Muthulekha
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authors: Swamydas
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Amanda L
authors: AL
authors: Collar
authors: Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
authors: Heidi H
authors: HH
authors: Kong
authors: Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
authors: Chyi-Chia Richard
authors: CR
authors: Lee
authors: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
authors: David
authors: D
authors: Chascsa
authors: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
authors: Thomas
authors: T
authors: Simcox
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Angela
authors: A
authors: Pham
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Anamaria
authors: A
authors: Bondici
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Mukil
authors: M
authors: Natarajan
authors: Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Joseph
authors: J
authors: Monsale
authors: Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
authors: David E
authors: DE
authors: Kleiner
authors: Dermatology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
authors: Martha
authors: M
authors: Quezado
authors: Sjögren's Syndrome and Salivary Gland Dysfunction Unit, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA.
authors: Ilias
authors: I
authors: Alevizos
authors: Oral Immunity and Inflammation Unit, National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland, USA.
authors: Niki M
authors: NM
authors: Moutsopoulos
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA; Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Lynne
authors: L
authors: Yockey
authors: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., National Cancer Institute (NCI) Campus at Frederick, Frederick, Maryland, USA.
authors: Cathleen
authors: C
authors: Frein
authors: Undiagnosed Diseases Program, Common Fund, NIH Office of the Director and National Human Genome Research Institute, Bethesda, Maryland, USA.
authors: Ariane
authors: A
authors: Soldatos
authors: Hematology Section, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Katherine R
authors: KR
authors: Calvo
authors: Epidemiology Unit, Laboratory of Clinical Infectious Diseases, NIH, Bethesda, Maryland, USA.
authors: Jennifer
authors: J
authors: Adjemian
authors: Laboratory of Immunology, NIAID, NIH, Bethesda, Maryland, USA.
authors: Morgan N
authors: MN
authors: Similuk
authors: Pediatric Consult Service, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: David M
authors: DM
authors: Lang
authors: Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Kelly D
authors: KD
authors: Stone
authors: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Gulbu
authors: G
authors: Uzel
authors: Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
authors: Jeffrey B
authors: JB
authors: Kopp
authors: Consult Services Section, National Eye Institute, NIH, Bethesda, Maryland, USA.
authors: Rachel J
authors: RJ
authors: Bishop
authors: Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, Maryland, USA.
authors: Steven M
authors: SM
authors: Holland
authors: Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA.
authors: Kenneth N
authors: KN
authors: Olivier
authors: Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, USA.
authors: Thomas A
authors: TA
authors: Fleisher
authors: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA.
authors: Theo
authors: T
authors: Heller
authors: Pediatric Growth and Nutrition Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors: Karen K
authors: KK
authors: Winer
authors: Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
authors: Michail S
authors: MS
authors: Lionakis