Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy: Insights into Genotype-Phenotype Correlation

Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named autoimmune regulator gene (AIRE) which results in a failure of T cell tolerance within the thymus. Chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease are the hallmarks of the syndrome. APECED is also characterized by several autoimmune endocrine and nonendocrine manifestations, and the phenotype is often complex. Moreover, even though APECED is a monogenic disease, its clinical picture is generally dominated by a wide heterogeneity both in the severity and in the number of components even among siblings with the same AIRE genotype. The variability of its clinical expression implies that diagnosis can be challenging, and a considerable delay often occurs between the appearance of symptoms and the diagnosis. Since a prompt diagnosis is essential to prevent severe complications, clinicians should be aware of all symptoms and signs of suspicion. The aim of this paper is to give an overview on the clinical presentation and diagnostic criteria of APECED and to focus on current knowledge on genotype-phenotype correlation.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: Report of Seven Additional Sicilian Patients and Overview of the Overall Series from Sicily

“…Nevertheless, considering all 15 Sicilian patients described so far by our study group, this mutation remains the most frequent, followed by R257X, which is one of the most common mutations worldwide and has been detected in 66% of all mutant alleles in northeastern Italy [9]. By contrast, R257X is very infrequent in patients from southern Italian regions such as Sardinia [6], Apulia [4], Campania [20] and Calabria [21]. …”

“…Other mutations that were found in the overall Sicilian study population were A21V (13%) and W78R (7%), which are typical of two southern Italy regions, Campania [20] and Apulia [14], respectively. Interestingly, the only patient of the entire series with two parents originating from different regions (mother from Sicily and father from Sardinia) exhibited, in compound heterozygosis, mutation R139X, which is typical of Sardinian patients [6].…”

Oral manifestations of systemic disease

“…Patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) not only have chronic candidal infection but may have diabetes mellitus (which presumably will increase the risk or severity of periodontitis), enamel hypocalcification (secondary to hypoparathyroidism) and hypermelanotic pigmentation of the oral mucosa (secondary to autoimmune-driven destruction of the adrenal cortex). [44][45][46][47] Late-onset chronic mucocutaneous candidiasis (Good's syndrome) is accompanied by thymoma, myasthenia gravis and bone marrow abnormalities and thus affected individuals may have abnormal movement of the eyes, mouth and/or face. 48 Chronic mucocutaneous candidiasis may be considered to be a rare risk factor for OSCC.…”

The Spectrum of Autoimmune Enteropathy

“…The wide spectrum of the clinical manifestations is attributed to a variable pattern of destructive autoimmune reaction mediated by specific antibodies that can attack any tissue or organ [99,100]. TPH is an enzyme involved in the synthesis of neurotransmitters in the nervous system and in the gastrointestinal endocrine cells.…”

“…The presence of autoantibodies against this enzyme is associated with AIE in APECED [101][102][103][104]. The gastrointestinal involvement also includes diarrhea, constipation, autoimmune hepatitis, chronic atrophic gastritis or autoimmune gastritis with pernicious anaemia [105]. Exocrine pancreatic failure results in malabsorption and steatorrhoea in a small subgroup of patients [98].…”