Autoimmune polyglandular syndrome type I is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis.
Malabsorption and diarrhea can be very striking and even dominate the clinical picture (Prader, 1972).
Neufeld et al. (1980) recognized 3 types of the polyglandular autoimmune syndrome. Neufeld et al. (1981) collated information on 295 patients ... Malabsorption and diarrhea can be very striking and even dominate the clinical picture (Prader, 1972). Neufeld et al. (1980) recognized 3 types of the polyglandular autoimmune syndrome. Neufeld et al. (1981) collated information on 295 patients with autoimmune Addison disease as part of a polyglandular autoimmune syndrome. The information was supplied to them by members of the Lawson Wilkins Pediatric Endocrine Society and obtained from the literature. PGA I is represented by patients who have at least 2 of the triad of Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Associated immune disorders may be present. The Addison disease of PGA I has its predominant age of onset in childhood or early adulthood. It is also frequently associated with chronic active hepatitis, malabsorption, juvenile-onset pernicious anemia, alopecia, and primary hypogonadism. Insulin-dependent diabetes mellitus (IDDM; see 222100) and/or autoimmune thyroid disease are infrequent. PGA II (Schmidt syndrome; 269200) is represented by patients who have Addison disease with autoimmune thyroid disease and/or insulin-dependent diabetes mellitus, but do not have hypoparathyroidism or candidiasis, although other autoimmune disorders may be present. Although not confined to one age group or sex, PGA II is predominantly a disease of middle-aged females. The autoimmune disorders that occur with PGA I (e.g., chronic active hepatitis) are rare in PGA II, except for a low frequency of gonadal failure. Addison disease probably has a different genetic basis in PGA I than in PGA II. PGA III is represented by patients who have autoimmune thyroid disease and one or more other autoimmune disorders but do not have Addison disease. In autoimmune adrenal insufficiency, isolated hypoaldosteronism may occur as a transient state on the way to Addison disease (Saenger, 1984). In a patient reported by Saenger et al. (1982) and in one reported by Marieb et al. (1974), impairment of fasciculata function or Addison disease developed over a period of several years after initial presentation with isolated hypoaldosteronism due to an early selective damage to the zona glomerulosa. At an early stage, primary hypoaldosteronism (203400, 610600) might be incorrectly diagnosed. Selective testing for antibodies against the 3 layers of the adrenal cortex is possible (Saenger, 1984). McKusick (1985) observed achalasia in this syndrome. The association is observed also in the syndrome of alacrimia, achalasia, and addisonianism (231550). Hendrix (1985) pointed out that although achalasia predisposes to esophageal candidiasis through lack of the normal cleansing effect of peristalsis, it is doubtful that invasive candidiasis can produce true achalasia, nor in ordinary achalasia is there evidence, it seems, of an autoimmune basis. Association of achalasia with autoimmune thyroiditis has not been observed, for example. Ahonen et al. (1990) reported data from a 10-month to 31-year follow-up of 68 patients from 54 families, aged 10 months to 53 years at the time of report. The largest previous reported series, aside from earlier studies in Finnish patients, involved 9 patients. Ahonen et al. (1990) emphasized the broad clinical spectrum. Hypoplasia of the dental enamel and keratopathy were frequent and were not attributable to hypoparathyroidism. Some of the manifestations of the disorder did not appear until the fifth decade. Thus, all patients need lifelong follow-up for the detection of new components of the disease. Candidiasis was the initial manifestation in 60% of the patients and was present in all patients at some time. Hypoparathyroidism was present in 79%, adrenocortical failure in 72%, and gonadal failure in 60% of female patients over 13 years of age, and in 14% of male patients over 16 years of age. Half of the patients had multiple endocrine deficiencies. Two affected women had given birth, and 3 men reported having fathered healthy children. No genetic data were presented. Betterle et al. (1998) reviewed the clinical findings of APECED. They found that the spectrum of associated minor clinical diseases includes other autoimmune endocrinopathies (hypergonadotropic hypogonadism, insulin-dependent diabetes mellitus, autoimmune thyroid diseases, and pituitary defects), autoimmune or immuno-mediated gastrointestinal diseases (chronic atrophic gastritis, pernicious anemia, and malabsorption), chronic active hepatitis, autoimmune skin diseases (vitiligo and alopecia), ectodermal dystrophy, keratoconjunctivitis, immunologic defects (cellular and humoral), asplenia, and cholelithiasis. The first manifestations usually occur in childhood with the 3 main diseases developing in the first 20 years of life, and other accompanying diseases continue to appear until at least the fifth decade. In a majority of cases, candidiasis is the first clinical manifestation to appear, usually before the age of 5 years, followed by hypoparathyroidism (usually before the age of 10 years), and later by Addison disease (usually before the age of 15 years). Overall, the 3 main components of APECED occur in chronologic order, but they are present together in only about one-third to one-half of the cases. Generally, the earlier the first components appear, the more likely it is that multiple components will develop; conversely, patients who have late manifestations of the disease are likely to have fewer components. Among 79 patients with central diabetes insipidus, Maghnie et al. (2000) identified 1 patient with autoimmune polyendocrinopathy. The patient was almost 25 years old at the time of presentation. Faiyaz-Ul-Haque et al. (2009) studied 18 patients with APS1 from 7 consanguineous Arab families and noted that although the patients displayed characteristic features of APS1, there was unusually early expression of hypoparathyroidism and mucocutaneous candidiasis, with onset during the neonatal period in 3 of 14 and 7 of 14 patients, respectively. Seven APS1 patients from 4 of the families had alopecia universalis, and scalp biopsies from 2 unrelated patients showed peribulbar lymphocytic inflammation of hair follicles associated with reduced follicle density, decreased presence of the anagen phase, increased presence of the catagen/telogen phase, and predominance of vellus hair. Zaidi et al. (2009) reported 9 Indian patients with APS1 from 8 families, 3 of whom had unusual manifestations, including presentation with type 1 diabetes, chronic sinusitis and otitis media, and facial dysmorphism. Two patients died of septicemia. - Polyglandular Deficiency Syndrome, Persian-Jewish Type Shapiro et al. (1987) detected a seemingly new variant of the polyglandular deficiency syndrome in 5 Persian Jews. All 5 had primary hypoparathyroidism and hypogonadism, 2 had adrenal insufficiency, 1 had insulin-dependent diabetes mellitus, and 1 had latent hypothyroidism. The last patient also had antithyroid and antinuclear antibodies. Two of the 5 patients were cousins, and 2 had first-cousin parents. Isolated primary hypoparathyroidism was found in the 16-year-old sister of 1 of the 5. One of the patients had alopecia totalis. Primary sertoli cell insufficiency was detected by laboratory evaluation. Pernicious anemia was documented in 1 patient. One patient had mild hypogammaglobulinemia and a low T4/T8 cell ratio. A high frequency of hypogonadism was considered a distinctive feature in this group of patients. Hypoparathyroidism was the most common initial presenting disorder, occurring before the age of 10 in 4 of the 5 subjects. Although the accepted criterion for diagnosis of type I polyglandular autoimmune syndrome is the presence of at least 2 of the 3 components (hypoparathyroidism, candidiasis, and adrenal insufficiency), hypoparathyroidism may be the only manifestation. Zlotogora and Shapiro (1992) reported on 19 families of patients with hypoparathyroidism from the Iranian Jewish community in which 23 persons (11 males and 12 females) were affected with what these workers considered to be PGA I. All but 1 had hypoparathyroidism (96%), and most were diagnosed by the age of 20 years (91%). Adrenal insufficiency was diagnosed in 5 of the patients; in all cases but 1, it appeared after hypoparathyroidism. Mild oral candidiasis was present in 4 patients, and 6 of the patients (3 males and 3 females) had hypogonadism. Other features of the syndrome found in some patients were pernicious anemia, hypothyroidism, and alopecia. The inheritance was clearly autosomal recessive. The prevalence among Iranian Jews was estimated to be between 1:6,500 and 1:9,000. This is comparable to the high incidence among Finns. Compared with the Finns, the disorder showed relative rarity of candidiasis and absence of keratopathy among the Iranian Jews. To investigate the question of locus heterogeneity in this disorder. Bjorses et al. (1996) performed linkage and haplotype analyses on APECED families from these 2 isolated populations and in other population groups. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant lod scores for all these markers (maximum lod = 10.23). The haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggested the existence of 1 major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence of locus heterogeneity. The haplotype analyses suggested to Bjorses et al. (1996) that in different populations APECED is due to a number of different mutations in a gene on chromosome 21. Thus, linkage studies demonstrated that the condition previously called polyglandular deficiency syndrome, Persian-Jewish type, is the same as APECED. Eisenbarth and Gottlieb (2004) compared the features of 3 autoimmune polyendocrine syndromes: autoimmune polyendocrine syndrome type I, autoimmune polyendocrine syndrome type II, and X-linked polyendocrinopathy with immune dysfunction and diarrhea (304790).
Nagamine et al. (1997) found 2 mutations in the AIRE gene in Swiss and Finnish APECED patients: (R257X; 607358.0001), found in 10 of 12 alleles in the Finnish patients, and (K83E; 607358.0002). The Finnish-German APECED Consortium (1997) identified ... Nagamine et al. (1997) found 2 mutations in the AIRE gene in Swiss and Finnish APECED patients: (R257X; 607358.0001), found in 10 of 12 alleles in the Finnish patients, and (K83E; 607358.0002). The Finnish-German APECED Consortium (1997) identified 5 AIRE mutations, 4 in addition to the common Finnish mutation. Using SSCP analysis and direct DNA sequencing, Pearce et al. (1998) identified a 13-bp deletion (607358.0003) in the AIRE gene in 17 of 24 mutant alleles in 12 British families with APS I. This mutation was found to occur de novo in 1 affected subject. A common haplotype spanning the AIRE locus was found in chromosomes that carried the deletion mutation, suggesting a founder effect in this population. One of 576 normal subjects was also a heterozygous carrier of the deletion mutation. Six other point mutations were found, including two 1-bp deletions, 3 missense mutations, and a nonsense mutation. Scott et al. (1998) likewise found common mutations in patients of various ethnic origins with APS I. To understand the complexity of the APECED phenotype, Halonen et al. (2002) studied the AIRE and HLA class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, arg257 to ter (607358.0001), than in those with other mutations. Addison disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04/DQB1*0302 (P less than 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15/DQB1*0602 (P = 0.036). The authors concluded that AIRE mutation has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant. Harris et al. (2003) reported the association of a theretofore undescribed reversible metaphyseal dysplasia with autoimmune APECED in 2 patients, 1 homozygous and the other heterozygous for a 13-bp deletion in exon 8 of the AIRE gene (607358.0003). One patient also had a novel deletion in exon 6, resulting in a frameshift mutation and introduction of a stop codon in exon 10 (607358.0009). Their APECED phenotypes differed, but both patients developed progressive skeletal deformities and growth failure from early childhood. Radiologic examination suggested a generalized abnormality of endochondral ossification, with irregular, flared, radioopaque regions in the metaphyses, subjacent to the growth plates. Histopathology in patient 1 showed islands of calcified cartilage within bone, consistent with impaired coupling of cartilage resorption with vascular invasion and ossification. Despite discordance for puberty, both patients experienced radiologic resolution of their bone disease in their mid-teens, with improvement in histopathology in patient 1. Among 14 unrelated Polish patients with APECED, Stolarski et al. (2006) identified 6 different mutations in the AIRE gene, including 3 novel mutations (see, e.g., 607358.0008). R257X was the most common mutation, accounting for 71% of mutant alleles. The authors stated that 57 pathogenic mutations in the AIRE gene had been described. Eggermann et al. (2007) followed a patient previously diagnosed by Brodehl et al. (1967) with idiopathic hypoparathyroidism and isolated hypercystinuria (see 220100) discovered during an episode of candidiasis at 2 years of age, who subsequently developed Addison disease at 26 years of age, leading to the diagnosis of APS1. Two older sibs had died from hypocalcemic tetany. Direct sequencing of the AIRE gene revealed compound heterozygosity for the common R257X (607358.0001) and 964del13 (607358.0003) mutations; the patient was also found to carry a mutation in the SLC7A9 gene (604144.0014) believed to be responsible for the cystinuria phenotype. Faiyaz-Ul-Haque et al. (2009) reported 18 patients with APS1 from 7 consanguineous Arab families. One recurrent (607358.0010) and 4 novel mutations in the AIRE gene were identified in 6 of the families; in 1 family no mutation was present in the coding region or exon/intron boundaries of the AIRE gene. In 9 Indian patients with APS1 from 8 families, Zaidi et al. (2009) identified homozygosity for 3 mutations previously reported in Caucasian individuals (607358.0001, 607358.0003, 607358.0004) and 2 novel mutations, 1 of which appeared to be an ancestral mutation (607358.0011), in the AIRE gene. - Autoimmune Polyendocrinopathy Syndrome, Type I, Autosomal Dominant Cetani et al. (2001) identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism. Serologic and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classic autoimmune polyendocrinopathy. Direct sequencing of the entire coding region of the AIRE gene revealed the presence in the proband of a novel missense mutation in exon 6, gly228 to trp, in heterozygous state (G228W; 607358.0007). In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in this family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the APECED phenotype to the offspring in each generation in the absence of consanguinity. The G228W mutation closely cosegregated with hypothyroid autoimmune thyroiditis in this family, whereas a low penetrance of the full autoimmune polyendocrinopathy phenotype was observed. Ilmarinen et al. (2005) analyzed the effect of AIRE proteins with mutations in the SAND domain on wildtype AIRE in a simulated heterozygous situation in vitro. Only the G228W mutant changed the subcellular localization and severely disrupted the transactivating capacity of wildtype AIRE. Ilmarinen et al. (2005) concluded that the G228W protein acts with a dominant-negative effect by binding to wildtype AIRE, preventing the protein from forming the complexes needed for transactivation.
Perheentupa (1980) stated that 40 cases of APECED in 28 families had been identified in Finland as compared to less than 100 cases elsewhere in the world. Ahonen (1985) also demonstrated that APECED is part of the 'Finnish ... Perheentupa (1980) stated that 40 cases of APECED in 28 families had been identified in Finland as compared to less than 100 cases elsewhere in the world. Ahonen (1985) also demonstrated that APECED is part of the 'Finnish heritage of disease.' The disorder is unusually frequent in some Finnish subpopulations. Bjorses et al. (2000) stated that APECED is enriched in 3 genetically isolated populations: the Finnish, Iranian Jews, and Sardinians. Falorni et al. (2004) studied 222 Italian patients with primary adrenal insufficiency (PAI) and found APS1 in 11. The prevalence of APECED is increased in Finland and Sardinia, where it occurs in 1 in 25,000 (Ahonen et al., 1990) and 1 in 14,000 (Rosatelli et al., 1998) individuals, respectively. Estimates in other populations include 1 in 80,000 in Norway (Myhre et al., 2001), 1 in 43,000 in Slovenia (Podkrajsek et al., 2005), and 1 in 129,000 in Poland (Stolarski et al., 2006). Wolff et al. (2007) estimated the prevalence of APS1 in Norway to be 1 in 90,000.