Autoimmune Polyendocrine Syndrome, Type I, With Or Without Reversible Metaphyseal Dysplasia

A number sign (#) is used with this entry because autoimmune polyendocrinopathy syndrome type I is caused by homozygous, compound heterozygous, or heterozygous mutation in the autoimmune regulator gene (AIRE; 607358) on chromosome 21q22.

Description

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 (Neufeld et al., 1981).

Clinical Features

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 achalasia-addisonianism-alcrima syndrome (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.

Bourgault et al. (2015) reported the ocular features and characterized the retinal phenotype in a retrospective study of 5 patients with molecularly confirmed APS1. Age at presentation ranged from 19 months to 44 years, and follow-up ranged from 4 to 13 years (average, 8 years). All but 1 patient, aged 11 years, had decreased vision on presentation, and acuity did not correlate with age. The youngest patient at presentation had no light perception acuity. All cases had peripheral pigmentary retinal changes ranging from isolated patchy atrophy of the retinal pigment epithelium to a retinitis pigmentosa-like fundus with bone spicules, waxy pallor of the optic disc, and attenuated vasculature. Macular atrophy was noted in 4 patients. The most common feature on spectral-domain optical coherence tomography, which was found in 3 patients, was a disruption of the external limiting membrane and the inner segment ellipsoid band. The 4 patients who were tested for antiretinal antibodies were found to be positive by immunohistochemistry and/or Western blot analysis. Visual fields were constricted in all 3 patients tested. The rod ERG was abnormal in all of the patients, but the relative involvement of rods and cones differed. Bourgault et al. (2015) concluded that photoreceptor degeneration is part of the APS1 phenotype and that the presence of antiretinal antibodies strongly supports an etiology similar to that of nonparaneoplastic autoimmune retinopathy.

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).

Inheritance

Fox et al. (1970) made a brief note of a sibship, offspring of first-cousin parents, containing 2 female sibs with idiopathic Addison disease. One also had primary hypoparathyroidism and one had oral candidiasis. Ahonen (1985) provided a genetic analysis of 58 patients in 42 families and corroborated autosomal recessive inheritance.

Cetani et al. (2001) identified an Italian family with autoimmune polyendocrinopathy syndrome and a pattern of inheritance suggestive of a dominant mechanism (see MOLECULAR GENETICS).

Mapping

Taking advantage of the high frequency of APECED in Finland, Aaltonen et al. (1994) did linkage studies and mapped the locus to 21q22.3 with DNA markers. Studies of linkage disequilibrium increased the informativeness of the analyses and helped to locate the gene to a 500-kb segment. This was perhaps the first gene involving an autoimmune disorder that had been located outside the major histocompatibility complex (MHC) region on chromosome 6.

Pathogenesis

Autoantibodies

Blizzard and Kyle (1963) offered the first substantial evidence for the autoimmune concept. They found antiadrenal antibodies in 36 of 71 patients with Addison disease and antithyroid antibodies in 22. Hung et al. (1963) found circulating adrenal antibodies in 2 sibs with Addison disease. A third sib had died from Addison disease. One of the affected sibs also had hypoparathyroidism, pernicious anemia, and superficial moniliasis. The authors suggested the disorder may not be inherited as a simple mendelian recessive but may be autoimmune in nature.

In studies performed in Finland and Estonia, Krohn et al. (1992) screened serum samples from patients with Addison disease as part of the type I polyendocrine autoimmunity syndrome. In 3 patients they demonstrated precipitating antibodies against adrenal proteins. They cloned these proteins and found that one of them was 17-alpha-hydroxylase, the steroid hormone that is deficient or defective in one form of congenital adrenal hypoplasia (202110). Patients with idiopathic Addison disease likewise showed antibodies to this protein.

Husebye et al. (1997) investigated the presence of autoantibodies against the enzyme aromatic L-amino acid decarboxylase (AADC) of pancreatic beta-cells in a cohort of PGA I and isolated IDDM patients. They found AADC autoantibodies in 35 of 69 (51%) PGA I patients but in none of 138 isolated IDDM patients or 91 controls. Among PGA I patients, anti-AADC antibodies were found more often in those with hepatitis (11 of 12, 92%) than in those without hepatitis (24 of 57, 42%) (P = 0.003). Similarly, 12 of 15 (80%) patients with vitiligo had antibodies, compared with 23 of 54 (43%) without vitiligo (P = 0.021). Of the 9 PGA I patients with IDDM, 5 had antibodies against both AADC and glutamate decarboxylase, 2 against AADC only, and 2 against glutamate decarboxylase only. Thus, an autoimmune reactivity against AADC may be involved in the pathogenesis of autoimmune chronic active hepatitis and vitiligo in PGA I patients, but the role of AADC in the development of IDDM in these patients remains to be determined.

Clemente et al. (1997) studied autoantibodies for proteins of the adrenal cortex and the liver in 88 subjects of Sardinian descent, including 6 with autoimmune polyglandular syndrome type I, 22 relatives of APS I patients, 40 controls with other autoimmune diseases, and 20 healthy controls. Indirect immunofluorescence of tissue sections of the adrenal cortex revealed a cytoplasmic staining pattern in 4 of 6 patients with APS I. The autoantigens were identified as P450 scc (CYP11A; see 118485) and P450 c17 (CYP17A1; 609300). One of 6 APS I patients suffered from chronic hepatitis. In this patient, immunofluorescence revealed a centrolobular liver and a proximal renal tubule staining pattern. The autoantigen was identified as cytochrome P450 1A2 (124060). Since P450 1A2 usually is not detected by sera of patients with isolated autoimmune liver disease, Clemente et al. (1997) suggested that P450 1A2 might be a hepatic marker autoantigen for patients with APS I.

Using the immunoblotting of E. coli-expressed antigens to analyze humoral immunity to steroidogenic P450 cytochromes in 18 Eastern and Central European APECED patients, Cihakova et al. (2001) showed that 67%, 44%, and 61% had autoantibodies to P450 c17, P450 c21 (613815), and P450 scc, respectively.

Hedstrand et al. (2000) related a new autoantigen to APS I; they identified autoantibodies against tyrosine hydroxylase (TH; 191290) in sera from patients with alopecia areata (104000) through immunoscreening of a scalp cDNA library. Immunoreactivity against in vitro-expressed TH was found in 41 (44%) of 94 APS I patients studied, and this reactivity correlated with the presence of alopecia areata.

Another autoantigen in APSI, tryptophan hydroxylase (TPH; 191060), is associated with intestinal dysfunction. TPH and TH, together with phenylalanine hydroxylase (PAH; 612349), constitute the group of biopterin-dependent hydroxylases, which all are involved in the biosynthesis of neurotransmitters. Using a clone encoding PAH for in vitro transcription/translation, followed by immunoprecipitation with sera from 94 APS I patients and 70 healthy controls, Ekwall et al. (2000) investigated whether PAH is an autoantigen in APS I and whether crossreactivity exists between antibodies to these 3 highly homologous enzymes. Of the APS I patients, 25% had PAH antibodies, and no reactivity was detected in the controls. No association with the main clinical components of APS I was found with PAH antibodies. Altogether, 59 sera from the 94 APS I patients reacted with at least 1 of TPH, TH, or PAH, whereas 35 showed no reactivity. Nineteen of the sera contained antibodies towards all enzymes, 12 to TPH only, and 12 to TH only. No sera showed antibodies that reacted to only PAH. An immunocompetition assay demonstrated that the reactivity against PAH represents a crossreactivity with TPH, whereas antibodies against TPH and TH are directed towards epitopes unique for the 2 enzymes.

Individuals with APECED are at high risk of developing IDDM, but the positive predictive value of GAD65 (138275) or islet cell antibodies for IDDM is only 27%. Autoantibodies against the IA2 tyrosine phosphatase-like protein (601773) or insulin (176730) have been suggested to be better markers for active beta cell destruction. Gylling et al. (2000) studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed IDDM. Four (36%) of the 11 patients for whom prediabetic samples were available had antibodies against IA2, and 4 (36%) had antibodies against insulin. None of the 48 nondiabetics had antibodies against insulin, and only 2 (4%) had antibodies against IA2. Both had the antibodies for years without diabetes. Thus, antibodies against IA2 or insulin have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for IDDM in patients with APECED. None of the 11 patients with IDDM, but 15 of the 56 (27%) nondiabetic patients and 24 of 93 (26%) of the control subjects had the DQB1*0602 allele (see 604305), which is considered protective for IDDM. Gylling et al. (2000) noted that theretofore no positive or negative associations had been reported for any disease components of APECED with human leukocyte II antigens.

Soderbergh et al. (2004) used multiple logistic regression analysis on a cohort of 90 APS I patients from Finland, Norway, and Sweden to clarify the significance of each of 10 different autoantibodies as markers for the various disease manifestations of APS I. Reactivities against 21-hydroxylase (P450 c21) and side chain cleavage enzyme (P450 scc) were associated with Addison disease with odds ratios of 7.8 and 6.8, respectively. Hypogonadism was exclusively associated with autoantibodies against P450 scc with an odds ratio of 12.5. Autoantibodies against tyrosine phosphatase-like protein IA-2 were associated with IDDM with an odds ratio of 14.9, but with low sensitivity. Reactivities against TPH and, surprisingly, GAD65 were associated with intestinal dysfunction, with odds ratios of 3.9 and 6.7, respectively. TPH reactivity was the best predictor for autoimmune hepatitis, with an odds ratio of 27.0. The authors concluded that analysis of autoantibodies in APS I patients is a useful tool for establishing autoimmune manifestations of the disease as well as providing diagnosis in patients with suspected disease.

Gylling et al. (2003) sought to identify the determinants and mechanism of hypoparathyroidism in APECED, the most common endocrine component of the disorder. For the determinants, they evaluated gender and HLA class II (see 142857). For the mechanism, they searched for parathyroid autoantibodies, including antibodies against CASR (601199) and PTH (168450). Also, they studied whether AIRE (607358) is expressed in the human parathyroid because its absence could be a pathogenetic factor. Gylling et al. (2003) found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped hypoparathyroidism, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs 7% of females. In contrast, they found no linkage to the HLA class II.

Alimohammadi et al. (2008) studied the specific autoimmunity responsible for hypoparathyroidism, a hallmark of APS1 and its most common autoimmune endocrinopathy. They found that autoantibodies specific for NACHT leucine-rich repeat protein-5 (NALP5; 609658) were demonstrable in 49% of patients who had APS1 and hypoparathyroidism but were absent in all patients with APS1 without hypoparathyroidism, as well as in all patients with other autoimmune endocrine disorders and in all healthy controls. NALP5 was predominantly expressed in the cytoplasm of parathyroid chief cells. Thus NALP5 appears to be a tissue-specific autoantibody involved in hypoparathyroidism in patients with APS1. Autoantibodies against NALP5 may be diagnostic for this prominent component of APS1.

Using multiplex particle-based flow cytometry and ELISA analysis, Puel et al. (2010) screened 33 APS1 patients, 37 healthy controls, and 103 patients with other autoimmune conditions and detected high-titers of neutralizing IgG autoantibodies against IL17A (603149), IL17F (606496) and/or IL22 (605330), but not against other cytokines, except for interferon-alpha (IFNA1; 147660), in APS1 patients only. Twenty-two APS1 patients had a reaction against all 3 cytokines, 6 had reaction against 2 cytokines, and 5 had reaction against 1 cytokine. Chronic mucocutaneous candidiasis (CMC) was observed in 29 of the 33 APS1 patients. Puel et al. (2010) proposed that anti-IL17 autoantibodies may contribute to the development of CMC in APS1 patients.

Loss of CD8-Positive T-Cell Homeostasis

Although murine studies have linked Aire to thymocyte selection and peripheral deletional tolerance, the pathogenesis of human APECED is unclear. Laakso et al. (2011) demonstrated increased CD8 (see 186910)-positive/CD45RO (see 151460)-negative T cells (i.e., CD8RA, or naive, T cells) that also expressed the proliferation marker Ki67 (MKI67; 176741) in APECED patients with loss-of-function mutations in AIRE. ELISA indicated increased plasma IL7 (146660), while FACS analysis showed reduced IL7R (146661) on CD8-positive cells and, to a lesser extent, CD4 (186940)-positive T cells. Patients also had reduced CD5 (153340), CD62L (SELL; 153240), and CCR7 (600242) expression, but somewhat increased perforin (PRF1; 170280) expression, on CD8RA cells. Likewise, there was reduced expression of CD31 (PECAM1; 173445), a marker for recent thymic emigrants. Laakso et al. (2011) proposed that loss of CD8-positive T-cell homeostasis is likely to play a significant role in the pathogenesis of APECED.

Molecular Genetics

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.

Population Genetics

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.

History

An infectious etiology was suggested by Kunin et al. (1963) who pointed out that hepatitis had occurred in a number of these cases before the development of endocrinopathy.

Heterogeneity in Addison disease and hypoparathyroidism was suggested by the analysis of Spinner et al. (1968).

Maclaren and Riley (1986) found that autoimmune Addison disease was strongly associated with HLA-DR3 and HLA-DR4; relative risks were 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/DR4, respectively. This is similar to the findings for insulin-dependent diabetes. Patients with type I autoimmune polyglandular syndrome did not show the association.