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.

Dental Findings in Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism: A Systematic Review

“…Table 2 illustrates study characteristics for Ns-HypoPT studies (Humphreys, 1939; Hansted and Holst, 1952; Hinrichs, 1956; Thew and Goulston, 1962; Pisanty, 1966; Sjöberg, 1966; Greenberg et al, 1969; Hermans et al, 1969; Moshkowitz et al, 1969; Riley, 1969; Nally, 1970; Frensilli et al, 1971; Lovestedt, 1971; Assif, 1977; Pisanty and Garfunkel, 1977; Myllärniemi and Perheentupa, 1978; Lindeberg, 1979; Goepferd and Flaitz, 1981; Illum et al, 1981; Jensen et al, 1981; Nikiforuk and Fraser, 1981; Børglum Jensen et al, 1983; Harrell, 1983; Ingemarsson, 1984; Lyles et al, 1985; de Carvalho et al, 1986; Porter and Scully, 1986; Ahonen et al, 1990; Porter et al, 1992, 1995; Walls and Soames, 1993; Hershkovitz et al, 1995; Lukinmaa et al, 1996; Firth et al, 1997; Jaquez et al, 1997; Perniola et al, 1998; Fukui et al, 2000; Winer and Merke, 2000; Klingberg et al, 2002, 2005, 2007; Al-Malik, 2004; López-Jornet et al, 2005; Oberoi and Vargervik, 2005; Yang et al, 2005; da Silva Dalben et al, 2008; McGovern et al, 2008; Kelly et al, 2009; Pavlic and Waltimo-Siren, 2009; Toka et al, 2010; Wasersprung et al, 2010; Heliövaara et al, 2011; Kollios et al, 2011; Oberoi et al, 2011; Nordgarden et al, 2012; Ponranjini et al, 2012; El Batawi, 2013; Kamarthi et al, 2013; Nortjé, 2013; Ali et al, 2014; Srirangarajan et al, 2014; Laccetta et al, 2015; Matthews-Brzozowska et al, 2015; Bruserud et al, 2016; Ferre et al, 2016; Bjanid et al, 2017; Lewyllie et al, 2017; Mohsenipour et al, 2017) with subgroups A–E corresponding to the classifi...…”

Autoimmune Polyendocrine Syndromes

“…8,18 Another common mutation is the so-called 13 base pair deletion (p.C322del13) in the histone protein reading region called plant homeodomain 1 (PHD1), prevalent in persons in Norway, the British Isles, France, and North-America. 6,7,19 Additionally, patients with unique dominant negative mutations in AIRE with autosomal dominant inheritance have recently been identified. These dominant negative mutations are associated with milder disease, often with accompanying pernicious anemia, vitiligo, autoimmune thyroid disease, and type 1 diabetes, 20–22 and can be confused with the much more common condition, APS-2, which has a complex inheritance.…”

“…38 In such patients, the presence of minor components can be very helpful diagnostic hints. Some minor components of APS-1 develop early in life (keratitis, periodic fever with rash, autoimmune hepatitis), 7 while others occur later (primary ovarian insufficiency under 30 years of age, enamel hypoplasia). 6 Since over 95% of patients with APS-1 have autoantibodies to type 1 interferons, 6,8 broad testing for such antibodies in suspected cases may be useful.…”

Oral microbiota in autoimmune polyendocrine syndrome type 1

“…The oral, gut, and skin microbiotas could play a key role in the pathogenesis of systemic and organ-specific autoimmune diseases [14]. Most APS-1 patients develop disease components affecting the oral cavity; enamel hypoplasia and CMC are both common manifestations [9,15]. Also a Sjögren’s-like syndrome without extractable nuclear antigen autoantibodies has recently been described [15,16].…”

“…Most APS-1 patients develop disease components affecting the oral cavity; enamel hypoplasia and CMC are both common manifestations [9,15]. Also a Sjögren’s-like syndrome without extractable nuclear antigen autoantibodies has recently been described [15,16]. These oral manifestations probably interfere with the homeostasis of the oral microbiota.…”