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Aim: Autoimmune polyendocrinopathy syndrome type 3 (APS3) is defined as the presence of autoimmune thyroid disease along with another autoimmune disorder other than Addison’s disease. If an autoimmune gastrointestinal disease is a component of the syndrome, it is defined as APS3b. In this study, we aimed to determine the frequency of APS3b in patients diagnosed with type 1 diabetes (T1D) in childhood. Material and Methods: A patient group of 446 children (232 males) with T1D whose follow-ups were conducted between 01.06.2013 and 31.08.2019 was included in the study. Hashimoto’s thyroiditis (HT) was defined with positive anti-TPO and/or anti-Tg test results whereas autoimmune enteropathy was defined with histologic findings which consisted with celiac disease (CD) in small bowel biopsy following a positive anti tissue transglutaminase IgA. Results: In total, 61 (13.7%) patients had HT and 34 (7.6%) patients had CD. While 87 (19.5%) of the patients had HT or CD, the occurrence of both HT and CD (APS3b) in the same patient was observed in only 4 patients (3 females) (0.9%). Patients with APS3b had low median age of diagnosis compared with patients with HT or CD alone, and patients with none of these two diseases, but the difference is not statistically significant (p=0.087). Conclusion: While HT or CD has been detected in approximately one-fifth of children with T1D, APS3b is rarely observed in this patient group.

Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent fungal infections of the skin, mucosa and nails and is commonly associated with primary immune-deficiency states, autoimmune polyendocrinopathy syndrome and Hyper-IgE syndrome1 . STAT mutations are the commonest mutations associated with CMC2 . We present a young boy who was diagnosed CMC and pancytopenia.

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder. APS-1 diagnosed when patient have at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. Chronic mucocutaneous candidiasis (CMC), a condition of recurrent candidiasis infections that may involve the skin, nails, oral, anal and genital mucosa, is a hallmark of APS-1. We report a7 years old boy with history of fungal infections since early childhood affecting nails and skin. Also he has alopecia . recurrent abdominal pain,lethargy and vomiting. At diagnosis his skin was hyper pigmented at gums and palms and nail dystrophy. His laboratory shows high ACTH 1251 pmol/l and low aldosterone 57 pg/ml. he has positive candida culture in the nail. We send genetic study Whole Exome Sequencing and came to be positive for A homozygous pathogenic variant in the AIRE gene. c.205_208dup p.(Asp70Alafs*148). The child was treated with hydrocortisone and fludrocortisone. We report a rare case of a homozygous pathogenic variant in the AIRE gene that illustrate the typical presentation of APS type 1

We present a 42-year-old woman with pre-existing autoimmune polyendocrinopathy syndrome (APS) Type 2 and chronic kidney disease due to Type 1 diabetic nephropathy, who developed a rapid deterioration in renal function due to perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-associated vasculitis. Although possibly a chance occurrence, ANCA have been detected more frequently in patients with a history of certain autoimmune diseases. Such an association may simply reflect an underlying tendency to immune system dysfunction in these patients and the finding of positive ANCA serology does not reliably herald the development of ANCA-associated vasculitis. However, our case illustrates that positive ANCA serology in such circumstances is not always a benign phenomenon and should still be interpreted within the clinical context. Moreover, clinicians managing patients with pre-existing autoimmune disease should maintain a low threshold for appropriate assessment should such patients develop evidence suggestive of vasculitis.

Summary Context Genome-wide association studies have discovered various susceptibility alleles that are shared among different autoimmune conditions, implicating several biochemical pathways in the pathogenesis of autoimmunity. A nonsynonymous polymorphism in exon 7 of the gene encoding the lymphocyte cell-surface CD226 (DNAM1) receptor, Gly307Ser (rs763361), has recently been identified as conferring risk to many autoimmune disorders. We performed a case–control study to determine if the CD226 307Ser variant is also associated with autoimmune Addison’s disease (AAD). Patient and design We genotyped rs763361 in a UK cohort of 326 AAD subjects [183 with associated autoimmune conditions – autoimmune polyendocrinopathy syndrome type-2 (APS2)] and 311 healthy controls, using a Taqman genotyping assay. Results The susceptibility ‘T’ allele at rs763361 was found in 50·5% of patients with AAD compared to 46·5% of controls (P-value 0·16, OR 1·17; 95% CI 0·94–1·46). However, comparing the APS2 subgroup to healthy controls, the T allele was found in 53·8%vs 46·5% in controls (OR 1·34; CI 1·04–1·74, P-value 0·03). In contrast, the T allele frequency was 46·2% in isolated Addison’s disease (P-value 0·94 vs healthy controls). Conclusion It seems likely that the 307Ser variant of the CD226 receptor is associated with APS2 because of its underlying association with type 1 diabetes and autoimmune thyroid disease. The strength of association in patients with isolated AAD appears to be weak or nonexistent compared to that in APS2.

The various clinical manifestations of chronic mucocutaneous candidiasis (CMC) often result from acquired T-cell immunodeficiencies. More rarely, CMC results from inborn errors of immunity, the recent dissection of which has shed light on the molecular mechanisms of mucocutaneous immunity to Candida albicans. CMC may accompany various other infectious diseases in patients with almost any broad and profound T-cell primary immunodeficiency. By contrast, CMC is one of the few key infections in patients with autosomal dominant hyper IgE syndrome (mutations in STAT3), and in rare patients with autosomal recessive predisposition to mucocutaneous and invasive fungal infections (mutation in CARD9). In patients with mutations in STAT3 and CARD9 the development of IL-17-producing T cells is impaired. Moreover, CMC is the principal, if not only infection in patients with autosomal recessive autoimmune polyendocrinopathy syndrome-I (mutations in AIRE). Patients with this condition have high titers of neutralizing autoantibodies (auto-Abs) against the IL-17 cytokines IL-17A, IL-17F, and IL-22. Collectively, these data suggest that human IL-17A, IL-17F, and IL-22 are essential for mucocutaneous immunity to Candida albicans. They also suggest that the distinct syndrome of isolated CMC, without autoimmunity or other infections, may be caused by inborn errors of IL-17 immunity.

The autoimmune polyendocrinopathy syndromes are variable in presentation and can be challenging to diagnose and manage. Diagnosis of the type 1 autoimmune polyendocrinopathy syndrome can be difficult at an early age when often only one manifestation is present, and it may take years for others to appear. Increased awareness of polyendocrinopathy syndromes, combined with analysis of specific autoantibodies and molecular genetics, should help earlier diagnosis of these conditions and prevent serious complications. Further definition of susceptibility genes and autoantigens, as well as a better understanding of the pathogenesis, is required to improve the diagnosis and management of these patients.

Adrenal insufficiency is a rare, but potentially fatal medical condition. In children, the cause is most commonly congenital and in recent years a growing number of causative gene mutations have been identified resulting in a myriad of syndromes that share adrenal insufficiency as one of the main characteristics. The evolution of adrenal insufficiency is dependent on the variant and the particular gene affected, meaning that rapid and accurate diagnosis is imperative for effective treatment of the patient. Common practice is for candidate genes to be sequenced individually, which is a time-consuming process and complicated by overlapping clinical phenotypes. However, with the availability, and increasing cost effectiveness of whole-exome sequencing, there is the potential for this to become a powerful diagnostic tool. Here, we report the results of whole-exome sequencing of 43 patients referred to us with a diagnosis of familial glucocorticoid deficiency (FGD) who were mutation negative for MC2R, MRAP, and STAR the most commonly mutated genes in FGD. WES provided a rapid genetic diagnosis in 17/43 sequenced patients, for the remaining 60% the gene defect may be within intronic/regulatory regions not covered by WES or may be in gene(s) representing novel etiologies. The diagnosis of isolated or familial glucocorticoid deficiency was only confirmed in 3 of the 17 patients, other genetic diagnoses were adrenal hypo- and hyperplasia, Triple A, and autoimmune polyendocrinopathy syndrome type I, emphasizing both the difficulty of phenotypically distinguishing between disorders of PAI and the utility of WES as a tool to achieve this.

We investigated the presence of autoantibodies (aAbs) directed against the parathyroid gland in 17 patients with spontaneous isolated acquired hypoparathyroidism. Fourteen patients with acquired hypoparathyroidism (AH) associated with type I or II autoimmune polyendocrinopathy syndrome were also tested in comparison with a control group of 68 subjects without AH, including patients with other autoimmune diseases and healthy blood donors. aAbs against parathyroid tissue were screened using an indirect immunofluorescence technique on primate parathyroid tissue and human parathyroid adenoma. aAbs against the calcium-sensing receptor (CaSR) were analyzed using an immunoblotting assay with the recombinant extracellular domain of the human CaSR as antigen. Seven of the 31 patients with AH were positive for CaSR aAbs. Five of the positive sera were obtained from the group with isolated AH. The two other positive sera were from patients with autoimmune polyendocrinopathy syndrome. The sensitivity of the immunoblotting technique was higher than that of both the radioimmunological test using the extracellular domain of the CaSR and the indirect immunofluorescence technique. There were no positive sera in the control group. In conclusion, using an immunoblotting assay, we demonstrate the presence of CaSR aAbs in about one third of the patients with isolated AH, pointing out the value of detecting such aAbs to assess the autoimmune origin of the disease.

Hypothyroidism is a common condition. Rarely, it may occur in combination with autoimmune failure of other endocrine glands (autoimmune polyendocrinopathy syndrome type 2, previously known as Schmidt's syndrome). In such cases, restoring normal thyroid function may precipitate adrenal failure. Clinicians should have a high index of suspicion for this condition in patients with Addison's disease, those with a family history of autoimmune endocrine gland failure, patients with one autoimmune endocrine disease who develop nonspecific or serious illness, and patients with type 1 diabetes mellitus whose insulin requirements drop without obvious explanation.

Autoimmune polyendocrinopathy syndrome type 1 is a recessive Mendelian disorder resulting from mutations in a novel gene, AIRE, and is characterized by a spectrum of organ-specific autoimmune diseases. It is not known what tolerance mechanisms are defective as a result of AIRE mutation. By tracing the fate of autoreactive CD4+ T cells with high affinity for a pancreatic antigen in transgenic mice with an Aire mutation, we show here that Aire deficiency causes almost complete failure to delete the organ-specific cells in the thymus. These results indicate that autoimmune polyendocrinopathy syndrome 1 is caused by failure of a specialized mechanism for deleting forbidden T cell clones, establishing a central role for this tolerance mechanism.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the only described systemic autoimmune disease with established monogenic background, and the first autoimmune disorder localized outside the major histocompatibility complex (MHC) region. The primary biochemical defect in APECED is unknown. We have isolated a novel gene, AIRE, encoding for a putative nuclear protein featuring two PHD-type zinc-finger motifs, suggesting its involvement in transcriptional regulation. Five mutations in AIRE are reported in individuals with this disorder. This is the first report of a single-gene defect causing a systemic human autoimmune disease, providing a tool for exploring the molecular basis of autoimmunity.

Idiopathic hypoparathyroidism (IH) is often an isolated disorder in adults, but in children it is usually a component of the autoimmune polyendocrinopathy syndrome. The authors describe a patient diagnosed with isolated IH at age 57 and celiac disease at age 64. Testing of patients’ serum show antibodies of the immunoglobulin A isotype against endomysium, reticulin, and gliadin antigens, as well as immunoglobulin G against gliadin. The circulating immunoglobulins reacted with bovine parathyroid tissue, specifically smooth muscle of the blood vessels and glandular cells, as detected by indirect immunoflourescence. Testing of celiac disease positive sera showed similar parathyroid reactivity. When the patient was placed on a gluten-free diet, endomysial, reticulin, and gliadin antibodies decreased to undetectable levels, which was parallel with disappearance of the parathyroid immunoreactivity. The gluten-free diet also produced severe hypercalcemia that responded to calcitriol withdrawal, and ultimately required a reduction by half of the original calcitriol dose. It is possible that in this case the same antibody or antibodies may have caused both hypoparathyroidism and celiac disease. We conclude that, as in the case of childhood-onset IH variants, patients with late-onset isolated IH should be monitored for additional endocrine and extraendocrine autoimmune disorders.

Autoimmune polyendocrinopathy syndrome type 1 (APS1) is characterized by the presence of at least two out of three clinical features, which include Addison's disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. This disorder is caused by mutations in the AIRE (autoimmune regulator) gene. While several AIRE mutations have been described in APS1 patients of various ethnic origins, the genetic cause of APS1 in Arab patients requires further investigation. This study describes seven Arab families, in which 18 patients had APS1. In addition to the cardinal features of APS1, some patients exhibited alopecia, diabetes mellitus, nephrocalcinosis and other phenotypes associated with APS1. DNA sequencing of the AIRE gene of patients from this study identified four novel and one recurrent mutation. These mutations likely result in loss of AIRE function in the patients. In addition, it was noted that the non-pathogenic c.834C> G mutation (rs1800520, encoding for p.Ser278Arg) occurs with high incidence in the AIRE gene of Arab individuals. Furthermore, this investigation demonstrates inflammation of the hair follicles in APS1 patients with alopecia universalis. We conclude that Arab APS1 patients carry novel and recurrent mutations in the AIRE gene.

Since publication of the first edition of this book in 2003, two major new insights into the pathogenesis of thymoma-associated (paraneoplastic) autoimmunities, including myasthenia gravis (MG), have been achieved. First, it has become clear by the analysis of functional single nucleotide polymorphisms that tumor-independent, non-MHC genetic factors contribute to the pathogenesis of paraneoplastic MG at least in a subgroup of patients. Second, thymoma has been identified as a human model of ‘‘localized’’, i.e., tumor-restricted loss of AIRE (‘‘autoimmune regulator’’) expression. AIRE is a transcriptional regulator that controls immunologic tolerance by the pivotal regulation of ‘‘promiscuous’’ expression of tissue-specific self-antigens in the thymic medulla. The finding of AIRE deficiency in thymoma relates to earlier observations (1) that autoantibodies against type I interferons are a conceptionally and diagnostically important hallmark of both thymoma and a germ line-encoded AIRE deficiency syndrome termed autoimmune polyendocrinopathy syndrome type I (APS I). Of note, anti-IFN autoantibodies and APS I symptoms do not occur in AIRE knockout animals. Therefore, the new findings in thymoma patients have implications beyond paraneoplastic MG and underline the importance ofMG(+) compared toMG( ) thymomas as amodel system allowing for the analysis of humanspecific mechanisms leading to autoimmunity. MG is a heterogeneous autoimmune disease mediated by autoantibodies that interfere with the function of the neuromuscular junction. Taking the presence or absence of antibodies against the acetylcholine receptor (AChR) as a criterion, MG has been subdivided into seropositive and seronegative types. In seropositive MG, the pathogenic, high-affinity autoantibodies are directed against the nicotinic acetylcholine receptor (AChR) (2, 3), while so-called seronegative MG (SNMG) is now known to be heterogeneous with respect to autoantibody features: depending on ethnic and geographic backgrounds (4, 5, 6, 7), a quite variable percentage of SNMG cases result from autoantibodies (commonly IgG4) to muscle-specific tyrosine kinases (MuSK) at the neuromuscular endplate (8). Furthermore, a third ‘‘doublenegative’’ subgroup showing neither anti-AChR nor anti-MuSK autoantibodies exists (9). Whether these patients have autoantibodies against other autoantigen targets or whether their anti-AChR or anti-MuSK autoantibodies cannot be detected by current laboratory tests is the subject of ongoing research. In 80 90% of cases, MG is associated with pathologic changes of the thymus. In about 10% of anti-AChR-seropositive cases, MG is a paraneoplastic phenomenon caused by a subgroup of epithelial neoplasms of the thymus called thymomas. There are significant associations between

Context: In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations. Objectives: Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation. Design: The study was designed to detect autoantibodies against interferon-α2 and interferon-ω in antiviral neutralization assays. Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity. Outcome: The diagnostic value of anti-interferon autoantibodies was assessed. Results: We found antibodies against interferon-α2 and/or interferon-ω in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-ω, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n = 174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution. Conclusions: Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.

Three patients with graft-versus-host-like enterocolonopathy are reported. Their history was remarkable for thymoma and other autoimmune manifestations such as thrombocytopenia, red cell aplasia, interface dermatitis, Sjogren sialadenits, vanishing bile ducts and rheumatoid arthritis. In all patients, microsatellite analysis showed the autologous nature of the lymphocytes in the affected organs ruling out GVHD. In search for mechanisms that could mediate loss of tolerance to self-antigens we found in a panel of thymomas, including those of the three patients, a complete lack of autoimmune regulator (AIRE) and minimal expression of the transcription factor FOXP3 in the intra-tumoral T cells. AIRE is a recently discovered transcription factor which plays a key role in the maintenance of central tolerance and is mutated in the autosomal recessive autoimmune polyendocrinopathy syndrome APS-1. Our observations indicate that thymoma-related autoimmunity can potentially be elicited by an incomplete deletion of 'self'-specific T cells in concert with an insufficient formation of natural Tregs.

Autoimmune Polyendocrinopathy Syndrome Type I (APS1) is a severe human multiorgan autoimmune disorder, caused by mutations in the gene AIRE. Following this determination, a mouse model for the disease was rationally designed by knocking out the murine homologue, Aire. The Aire knockout mouse has demonstrated that Aire initiates immune tolerance via promiscuous transcription of organ-specific genes in the thymus. Recent studies using the Aire knockout mouse have demonstrated gene-dose dependency and disease modifier loci, returning the onus of exploration to human genetics. © 2006 Elsevier Ltd. All rights reserved. ispartof: Drug Discovery Today. Disease Models vol:3 issue:1 pages:33-40 status: published

Sri Lanka Journal of Child Health , 2014; 43 (4): 239-241 (Keywords: Autoimmune polyendocrinopathy syndrome type 2; APS type 2; Schmidt syndrome; child) DOI: http://dx.doi.org/10.4038/sljch.v43i4.7772

Purpose To report the ocular complications in a series of patients with autoimmune polyendocrinopathy syndrome, type 1 (APS1). Methods A retrospective study of 17 patients with APS1 syndrome treated at the department of ophthalmology, Our Lady's Hospital for Sick Children in Crumlin, Dublin, Ireland. All patients had clinical manifestations of the disease in keeping with the diagnostic criteria of APS1. Each patient had a comprehensive ophthalmic history taken and examination, including ocular symptoms, best-corrected visual acuity, slit-lamp biomicroscopy, tear film evaluation, and dilated ophthalmoscopic examination. Results Six of 17 patients (35%) had corneal changes. Two patients (12%) had severe keratoconjunctivitis requiring hospitalization and intensive topical steroids and lubricants. The inflammation resulted in visual acuity reduction in one patient secondary to central corneal scarring. Other ocular findings included reduced tear production, as tested with Schirmers tear strips (63%), lens opacities (18%), hypotrichosis (12%), hypertrichosis (5.9%), anisometropic amblyopia (5.9%), and myopia (5.9%). Conclusions The most common and clinically important ocular manifestation of APS1 was keratoconjunctivitis associated with dry eye. This can result in progressive corneal scarring and vision loss.

It is thought that the majority of autoimmune endocrinopathies, including Graves' disease, autoimmune hypothyroidism, type 1 diabetes mellitus and autoimmune Addison's disease (sporadic and as well as autoimmune polyendocrinopathy syndrome type 2) are inherited as complex genetic traits. Multiple genetic and environmental factors interact with each other to confer susceptibility to these disorders. In recent years there have been considerable efforts towards defining susceptibility genes for complex traits. These investigations have shown, with increasing evidence, that the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene is an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. Here we review the genetic and functional analyses of the CTLA-4 locus in autoimmune endocrinopathies, and discuss the recent efforts in fine-mapping this locus.

This chapter highlights the autoimmune aspects of hypoparathyroidism. Hypoparathyroidism occurs as a component of an autosomal recessive disorder that features hypofunction of one or more endocrine glands as well as a variety of additional problems because of autoimmune disease. Initially termed polyglandular autoimmune syndrome, type 1 or autoimmune polyendocrinopathy is often designated as autoimmune polyendocrinopathy syndrome, type 1 (APS1). It is an autosomal recessive disease characterized by: (1) autoimmune polyendocrine deficiencies, (2) chronic mucocutaneous candidiasis, and (3) ectodermal dystrophies. In addition, there can be pernicious anemia, hepatitis, intestinal malabsorption, splenic atrophy, or gallstones, and a large proportion of patients develop squamous-cell carcinoma of the oral mucosa. The major features of APS1: (1) hypoparathyroidism, (2) adrenal insufficiency, and (3) chronic mucocutaneous candidiasis. The pathogenesis of APS1—that is, the autoimmune destruction of endocrine tissues, is understood at a molecular level and the defective gene has been identified. Although immune dysfunction also occurs in the DiGeorge anomaly, dysembryogenesis rather than autoimmunity causes the associated hypoparathyroidism. However, there are other less well-characterized syndromes with hypoparathyroidism in which autoimmunity may be a pathogenetic factor.

Autoimmune diseases of the ovary and the stomach are major components of the murine autoimmune polyendocrinopathy syndrome that occurs following experimental perturbation of the normal immune system. Several methods of perturbation can lead to autoimmune disease, and the disease occurs in multiple organs in association with autoantibodies to tissue-specific antigen of the respective organs. The autoimmune diseases develop in a variety of laboratory mouse strains that are not prone to spontaneous autoimmune diseases. This unit describes the induction of autoimmune disease of the ovary and the stomach in mice by thymectomy at the age of day 3 (day-3 thymectomy) and methods for evaluating disease histologically and serologically.

A 27-year-old male was admitted with diabetic ketoacidosis and altered sensorium with slurring of speech and ataxia. He was managed with intravenous insulin and fluids and later shifted to basal bolus insulin regimen and during further evaluation was diagnosed to be suffering from primary hypothyroidism and adrenal insufficiency. He was started on thyroxin replacement and steroids only during stress. After three months of follow up he was clinically euthyroid. His glycemic control was adequate on oral anti-hyperglycemic drugs and adrenal insufficiency recovered. However, his thyrotropin levels were persistently elevated on adequate replacement doses of thyroxin. His repeat TSH was estimated after precipitating serum with polyethylene glycol which revealed normal TSH. Here we report reversible adrenal insufficiency with hypothyroidism with falsely raised TSH because of presence of heterophile antibodies in a case of poly glandular endocrinopathy syndrome.

We describe two cases of autoimmune polyendocrinopathy syndrome as a cause of primary ovarian failure. Antibodies against various endocrine organs cause pluriglandular insufficiency, in most cases hypoparathyroidism. Addison's disease, and primary ovarian insufficiency. In these patients, careful examination of all endocrine organs is necessary in order to provide an adequate hormone replacement.

Autoimmune polyendocrinopathy-candidiasis-ectodermal-distrophy (APECED) is a rare autosomal recessive disease, which is mainly characterized by the association of many autoimmune diseases, with a classic triad including chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure. Its clinical spectrum has significantly enlarged in the last years and other non-classic components have been recently described. Aim of this review was to alert pediatricians to these novel clinical aspects of this syndrome, that have been recently included among the autoimmune APECED manifestations: a) chronic lung disease, that may evolve to cor pulmonale and terminal respiratory failure; b) chronic inflammatory demyelinating polineuropathy, with progressive muscular weakness of both arms and legs and sensory loss; c) gastrointestinal dysfunction, with recurrent diarrhea, malabsorption and steatorrhea or chronic constipation. For each of these novel components of APECED, specific autoantibodies against either lung autoantigens or peripheral nerves or tryptophan hydroxylase have been just recently identified.