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

Abstract

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive inherited disease caused by the mutation of the AIRE gene on chromosome 21. To date, 8 Sicilian patients have been described and the R203X AIRE mutation was found to be the most common in this region. Aims: (1) To describe 7 additional Sicilian APECED patients and to review all 15 Sicilian APECED patients who have been investigated by our group in the last years, and (2) to report a novel AIRE gene mutation. Results: Among the 3 cardinal features of APECED, hypoparathyroidism has been already detected in all 15 patients, whereas Addison's disease and chronic mucocutaneous candidiasis have so far been found in 10/15 and 12/15 cases, respectively. In 2 consanguineous cases, AIRE gene analysis revealed a novel mutation, named IVS13+2T, in homozygosis. R203X was the most common mutation in this region (30% of alleles and 46.6% of patients), followed by R257X (20% of alleles and 40% of patients). Conclusions: Sicilian APECED patients are confirmed to have some peculiar characteristics from a clinical and genetic point of view. No correlations between genotype and phenotype were identified.

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

“…Indeed, highlighting the vast phenotypic diversity of the disease, greater than 30 distinct manifestations can be seen, with more than 25 of those involving non‐endocrine organs (Lionakis, unpublished data) . Specifically, beyond the classical triad components of APECED, patients may also exhibit varying frequencies of urticarial eruption, enamel hypoplasia, intestinal malabsorption, autoimmune hepatitis, autoimmune pneumonitis, autoimmune gastritis, Sjogren's‐like syndrome, B12 deficiency, vitiligo, keratoconjuctivits, alopecia, type‐1 diabetes, tubulointerstitial nephritis and asplenia, among others (Table , Figure ) . Of interest, some of the above clinical manifestations, particularly those that target the skin, the lungs, the salivary glands, the stomach, the intestine, and the liver appear to be significantly enriched among American APECED patients compared to their frequency reported in European patient cohorts.…”

“… Shown are approximate percentages of corresponding APECED manifestations pooled from various published studies comparing data from the American or other international cohorts …”

“…8,9 Specifically, beyond the classical triad components of APECED, patients may also exhibit varying frequencies of urticarial eruption, enamel hypoplasia, intestinal malabsorption, autoimmune hepatitis, autoimmune pneumonitis, autoimmune gastritis, Sjogren's-like syndrome, B12 deficiency, vitiligo, keratoconjuctivits, alopecia, type-1 diabetes, tubulointerstitial nephritis and asplenia, among others (Table 1, Figure 1). [7][8][9][18][19][20][25][26][27][28][29][30] Of interest, some of the above clinical manifestations, particularly those that target the skin, the lungs, the salivary glands, the stomach, the intestine, and the liver appear to be significantly enriched among American APECED patients compared to their frequency reported in European patient cohorts. Whether this phenotypic discrepancy is explained by genetic, environmental, microbiome, and/or other differences among the various patient cohorts or it is the result of the deeper systematic phenotyping that was recently performed in American APECED patients remains to be elucidated by future studies.…”

APECED in Turkey: A case report and insights on genetic and phenotypic variability

“…In Finnish, Sardinian and Iranian Jew populations APECED develops at the highest described prevalences between 1:9000-1:25,000 [9] with homozygous AIRE mutations c.769C > T, c.415C > T and c.254A > G having a founder effect respectively [8][9][10][11]. The syndrome is detected at lower incidences and with greater genetic variability [7,9,[12][13][14][15][16][17][18][19][20][21][22][23] in many European countries. American APECED patients showed a diverse clinical picture, with dramatic enrichment of organspecific non-endocrine manifestations starting early in life, compared to European cohorts [9].…”

Novel insight into Chronic Inflammatory Demyelinating Polineuropathy in APECED syndrome: molecular mechanisms and clinical implications in children

“…No serum autoantibodies against either myelin-associated glycoprotein or peripheral nerve myelin proteins (GM1 gangliosides and onco-neural antigens-HU), CV2, amphyphysin) [6]. By radioligand binding assay, however, both of these patients demonstrated autoantibodies against P0, suggesting that P0 is an important antigen in both mice and humans deficient in Aire [13].…”