Mutations In AIRE Gene Research Articles

FRI054 Partial Lipodystrophy As A Manifestation Of Autoimmune Polyglandular Syndrome 1

Abstract Disclosure: S. Agarwal: None. C. Xing: None. M.S. Anderson: Stock Owner; Self; Medtronic Diabetes, Merck. A. Garg: None. Background: Autoimmune polyglandular syndrome 1 (APS1) is a rare autosomal recessive disorder due to mutations in AIRE gene that manifests mainly with chronic mucocutaneous candidiasis, primary hypoparathyroidism and adrenal insufficiency. We report an extremely rare APS1 patient who developed partial lipodystrophy during adulthood. Clinical Case: This 39-year-old white female developed frequent diaper rashes, oral thrush and tetany at the age of one year due to candidiasis and hypoparathyroidism. At 6 years, she developed hypothyroidism. At 11 years, she developed fatigue, excessive thirst, and anorexia due to primary adrenal insufficiency. At 13 years of age, she had thelarche and adrenarche but never attained menarche. At 14 years, she underwent a sibling matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At 35 years, her serum triglycerides level was 904 mg/dL and loss of subcutaneous fat from the upper and lower extremities and hips was noted but she had increased subcutaneous fat on the chest and abdomen as well as buffalo hump. Thigh skinfold thickness was 8 mm (<10th percentile of normal). A whole-body dual-energy X-ray absorptiometry revealed a total body fat of 38% with lower extremity fat of 25%-27% (<1st percentile of normal). Whole exome sequencing on DNA extracted from saliva revealed two pathogenic variants in AIRE gene; c.83T>C; p.Leu28Pro and c.769C>T; p.Arg257* confirming the diagnosis of APS1. No other pathogenic variants were noted in the known lipodystrophy genes. Serum was negative for anti-perilipin 1 autoantibody. Discussion: Biallelic mutations in the AIRE hinder the process of selective apoptosis of T-cells in the thymic medulla that have a strong affinity to self-antigens leading to autoimmunity manifesting as APS1. Previously, a 5-year-old boy with APS1 was reported to develop generalized lipodystrophy and his serum was positive for anti-perilipin 1 autoantibody. Recently, serum anti-perilipin-1 autoantibodies have also been reported in the Aire gene knock out mice. In contrast, our patient has partial lipodystrophy and was negative for anti-perilipin 1 autoantibody. This suggests that patients with APS1 may harbor many different autoantibodies against adipocyte expressed proteins and develop different patterns of autoimmune lipodystrophies. Presentation: Friday, June 16, 2023

Analysis of a series of Italian APECED patients with autoimmune hepatitis and gastro-enteropathies.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNωAbs or AIRE mutations (Ferre-Lionakis criteria). We analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms. Based on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic l-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome. Although Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED.

RARE MUTATION IN AIRE GENE IDENTIFIED IN PATIENT WITH VERY EARLY ONSET IBD

<h3>Introduction</h3> The etiology of very early-onset inflammatory bowel disease (VEO IBD) is thought to have a greater likelihood of being due to a monogenic inborn error of immunity than later-onset IBD. <h3>Case Description</h3> We present the case of a 6-year-old female with VEO IBD who was found to have a variant of unknown significance (VUS) in the AIRE gene. She was diagnosed with VEO IBD at 2 years old after she was found to have failure to thrive, diarrhea, and blood in stool. She was initially treated with mesalamine, azathioprine, and steroids, but never went into remission. She does not have history of recurrent infections or other symptoms of autoimmune disease. There is no significant known family history of autoimmune disease. Labs were notable for normal antibody responses to Hep A, Hep B, and VZV vaccines, but low S. pneumoniae titers despite vaccination with Prevnar. She had normal T and B-cell counts, including T-cell subsets, and a normal oxidative burst test. Invitae PID panel was notable for a rare heterozygous VUS in AIRE gene. Given mutations in AIRE gene are associated with the autoimmune disease APECED, plan was made to test family for VUS in AIRE and evaluate for immunologic defects seen in AIRE, such as low Tregs and IL-17, as well as elevated ANA and autoantibodies to GAD65 and thyroid. <h3>Discussion</h3> While various organs are affected in APECED, the intestinal tract is not usually affected. Nonetheless, given early onset of IBD, strong suspicion remains for monogenic disorder, either in AIRE or other genes.

Familial Isolated Hypoparathyroidism caused by AIRE gene mutation

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Autoimmune polyendocrinopathy syndrome type 1: new conceptions on pathogenesis and extended clinical symptoms

The objective was to present the caseof autoimmune polyendocrinopathy syndrome type 1 (APS1) and new clinical aspects and current knowledge of its pathogenesis.Materials and methods. This article includes clinical data, laboratory parameters, treatment and follow­updata of the patient with APS1. Also, a review of the latest data in world literature was made.Results and discussion. The described patient has two main criteria for APS1: hypoparathyroidism and chronic mucosal candidiasis, as well as some additional ones such as: autoimmune thyroiditis with hypothyroidism, type 1 diabetes, malabsorption syndrome. Periodic seizures and gait abnormality may be due to a chronic inflammatory demyelinating polyneuropathy. The diagnosis of APS1 is to detect the genetic anomaly underlying the syndrome: mutations in the AIRE gene and identification of organspecific antibodies. International studies have shown that 100 % of patients with APS1have autoantibodies that interact with interferon omega, so tests for such autoantibodies can help to get quick diagnosis. The treatment consists of correction of endocrine insufficiency with hormone replacement therapy, and specific treatment of other diseases common to APS1.Conclusions. APS1 is extremely diverse in its symptoms and the progression of the disease causes the expanding of clinical spectrum of its components. Therefore this syndrome must be diagnosed in the early stages, taking into account high morbidity and mortality. The main purpose of treatment is to preserve the patient’s life and maintain its quality good. Awareness of this rare autoimmune polyendocrine disorder can help a doctor to recognize it and treat timely, preventing potential death­related illnesses.

Clinical and immunological characteristics of diabetes mellitus in patients with autoimmune polyglandular syndrome type 1 in Russia

Background. Autoimmune polyglandular syndrome type 1 (APS type 1) is a rare inherited autoimmune disease caused by mutations in AIRE gene (autoimmune regulator) and characterized by list of components. Diabetes mellitus (DM) can be one of components of this disease.&#x0D; Aims. To show frequency of DM in patients with APS type 1 in Russia, to describe clinical and immunological aspects of DM in patients with APS type 1&#x0D; Materials and methods. 113 patients have been enrolled in the study, 16 of them had DM (15/16) or impaired glucose tolerance (1/16). Antibodies against glutamate decarboxylase, tyrosine phosphatase, zinc transporter-8, insulin and -cells of pancreas were investigated in 30 patients with APS type 1 without DM and in 11 patients with APS type 1 and DM. ELISA test was used for detection autoantibodies.&#x0D; Results. Frequency of DM in patients with APS type 1 in Russia is 14.1% (16/113). Some patients had slow-progressive DM 19%(3/16). Antibodies against insulin and -cells were not specific and also were not sensitive markers for DM in APS type 1. Antibodies against tyrosine phosphatase and zinc transporter-8 test showed high specificity (100% и 97%), but low sensitivity (42% и 33,3%). Antibodies against glutamate decarboxylase were less specific (70%) and had very low sensitivity (58,3%).&#x0D; Conclusions. Frequency of DM in patients with APS type 1 in Russia is high to compare to other countries. 20% of Russian patients had slow-progressive course of DM. Antibodies against tyrosine phosphatase and zinc transporter-8 were the most specific for DM in patients with APS type 1, but sensitivity of these antibodies was low.

Transglutaminase 4 as a prostate autoantigen in male subfertility

Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.

The new immunological methods for diagnostics of type 1 autoimmune polyendocrine syndrome

Type 1 autoimmune polyglandular syndrome (type 1APS) is a rare genetic disease resulting from mutations in the AIRE gene. Diagnostics of this pathology is based not only on the results of genetic studies but also on the measurement of the level of antibodies against type 1 interferons, such as interferon-ω and interferon-α2. The present review of the literature is focused on type 1 interferons, anti-interferon antibodies, and pathophysiological characteristics of the processes induced by these antibodies.

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

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.

OP0138 B cell subsets phenotype in autoimmunity with immunodeficiency: Analysis of a large cohort of patients with apeced syndrome

BackgroundAutoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare autosomal recessive syndrome due to mutations in AIRE gene, characterized by autoimmune endocrinopathies and mucocutaneous candidiasis. It is accompanied by generation...

Divergent Effects of T Cell Costimulation and Inflammatory Cytokine Production on Autoimmune Peripheral Neuropathy Provoked by Aire Deficiency

Chronic inflammatory demyelinating polyneuropathy results from autoimmune destruction of the peripheral nervous system and is a component of the multiorgan autoimmunity syndrome that results from Aire gene mutations in humans. In parallel, peripheral nervous system autoimmunity resembling chronic inflammatory demyelinating polyneuropathy develops spontaneously in NOD mice with a partial loss of Aire function (NOD.Aire(GW/+) mice) and is a T cell-mediated disease. In this study, we analyze how key aspects of T cell activation and function modulate disease development in Aire-deficient mice. We show that genetic ablation of the Th1 cytokine IFN-γ completely prevents clinical and electrophysiological evidence of neuropathy in NOD.Aire(GW/+) mice. IFN-γ deficiency is associated with absence of immune infiltration and decreased expression of the T cell chemoattractant IP-10 in sciatic nerves. Thus, IFN-γ is absolutely required for the development of autoimmune peripheral neuropathy in NOD.Aire(GW/+) mice. Because IFN-γ secretion is enhanced by B7-CD28 costimulation of T cells, we sought to determine the effects of these costimulatory molecules on neuropathy development. Surprisingly, B7-2 deficiency accelerated neuropathy development in NOD.Aire(GW/+) mice, and Ab blockade of both B7-1 and B7-2 resulted in fulminant, early-onset neuropathy. Thus, in contrast to IFN-γ, B7-2 alone and B7-1/B7-2 in combination function to ameliorate neuropathy development in NOD.Aire(GW/+) mice. Together, these findings reveal distinct and opposing effects of the T cell costimulatory pathway and IFN-γ production on the pathogenesis of autoimmune peripheral neuropathy.

Polyglandular Autoimmune Syndromes

Polyglandular Autoimmune Syndromes (PAS) form different clusters of autoimmune disorders characterized by the coexistence of at least two glandular autoimmune mediated diseases [1]. They are generally classified into three types: a very rare juvenile type 1(PAS I) and a relatively common adult type with (PAS II) or without adrenal failure (PAS III) [2, 3]. PAS I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is associated with candidiasis, hypoparathyroidism, and adrenal failure. PAS II is associated with adrenal failure, thyroid diseases and type 1 diabetes mellitus. In this review we will shed light on both types of PAS including their clinical picture and ways of management. Keywords: Addison’s disease, AIRE gene mutation, candidiasis, chronic hypoparathyroidism, Hashimoto's thyroiditis, hyperthyroidism, polyglandular autoimmune syndromes, type I diabetes mellitus

Polyendocrinopathies auto-immunes de type 1 : caractéristiques cliniques et évolutives sur la base d’une enquête interrégionale et nationale

Nineteen patients with autoimmune polyendocrine syndrome type 1 were identified in a longitudinal study conducted in northern France (Nord-Picardie-Normandie region, 9 million inhabitants), giving a prevalence of 1/500 000 inhabitants. This survey confirmed the usual onset in childhood, and the high frequency of candidiasis, adrenal insufficiency, alopecia and hypoparathyroidism. Broad phenotypic variability was observed, even within a given family. The AIRE gene mutations identified in these patients were closer to those observed in the United Kingdom than in Finland. Preliminary results of an ongoing nationwide survey suggest that the prevalence tends to be higher in the north.

Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation.

Autoimmune polyendocrinopathycandidiasis-ectodermal-dystrophy (APECED), also known as autoimmune polyendocrine syndrome type 1 (APS-1) (OMIM 240300), is a very rare disease. Accepted criteria for diagnosis require the presence of at least 2 of 3 major clinical features: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), and Addison's disease (AD). We analyzed AIRE gene mutations and genotype-phenotype correlation in APECED patients originating from Sicily and in their relatives. In 4 patients, clinical evaluations, genetic analysis of AIRE, and APECED-related autoantibodies were performed. Two patients carried the mutation R203X in homozygosis on exon 5. One had the mutation R203X combined with R139X. The fourth had the R203X mutation in heterozygosis with R257X. Expression of the disease showed wide variability of clinical manifestations. Analysis of relatives allowed the identification of 10 heterozygotes for AIRE gene mutations. None of these subjects presented major findings of APECED. Three of the 4 patients were positive for autoantibodies to interferon-ω. In Sicily, R203X is confirmed to be the typical recessive and prevalent AIRE gene mutation on exon 5. Genotype-phenotype correlation failed to reveal a relationship between detected mutations and clinical expression. Mutations in heterozygosity in AIRE gene are not associated with major findings of APECED.

Asian network for molecular diagnosis of primary immunodeficiencies

Primary immunodeficiency disorders (PIDs) are inborn errors of the immune system. There are over 150 types of PIDs and because of their rarity, multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights about the phenotypic and genetic diversities of PIDs. Since 2001, our unit established collaboration with 30 pediatric centers in China and Southeast Asia to provide e-consultation and free molecular diagnosis for PIDs. It is imperative to organize the data systematically to yield information on epidemiology of PIDs in the region. By Aug 2010, we have performed genetic tests for 392 patients referred to us and 243 patients (62%) have their genetic mutations identified. 107 patients (27%) were from Hong Kong, 222 (57%) were from mainland China while the rest were from Taiwan, Singapore, Malaysia, Thailand, the Philippines and Australia. In addition, 200 carriers were identified from 331 potential carriers in these 49 families. X-linked agammaglobulinemia (n=90), Wiskott-Aldrich syndrome (n=49), X-linked chronic granulomatous disease (CGD, n=28), X-linked hyperIgM (n=17) and X-linked severe combined immunodeficiency (SCID, n=19) constituted majority of cases. We also identified mutations of rare PIDs, such as autosomal-recessive SCID (IL7R, JAK3, RAG2 and DCLRE1C), autosomal-recessive CGD (NCF1, CYBA), defects of IL12/IFN-gamma axis in patients susceptible to mycobacterial infections, FOXP3 mutation in immunodysregulation- polyendocrinopathy-X-linked (IPEX) syndrome, SH2D1A mutations in X-linked lymphoproliferative syndrome, TACI in common variable immunodeficiency, ITGB2 mutations in leucocyte adhesion deficiency, and AIRE gene mutation in autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED). However, mutations could not be identified in about 40% of patients despite distinct clinical and immunological phenotypes. This is the group of patients that would probably yield novel genes responsible for PIDs with appropriate strategic analysis, combining both functional and genomic analysis. Establishment of PID data and referral network is an initial step to multi-center collaboration. This constitutes the foundation for PID research and documentation of prevalence, disease burden and outcome of patients with PIDs in Asia, as well as identifying new genes critical for immunohomeostasis.

Pattern recognition receptor expression is not impaired in patients with chronic mucocutanous candidiasis with or without autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1-10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.

Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes

AbstractNeutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-α cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-ω but not IFN-α showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.

AIRE and immunological tolerance: insights from the study of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy

To review the clinical and molecular features of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy and discuss recent advances in the function of the AIRE protein. We will summarize how AIRE contributes to immunological tolerance, and thus to the prevention of autoimmunity. The organization of a well-structured thymic microenvironment and the interaction between nascent thymocytes and thymic epithelial cells have been shown to be essential for AIRE expression. AIRE is involved in the expression of ectopic proteins by medullary thymic epithelial cells. This allows the establishment of central tolerance and contributes to the prevention of organ-specific autoimmunity, as shown by findings in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (a disease caused by AIRE gene mutations) and in aire (-/-) mice. Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy represents a unique model to investigate the cellular and molecular mechanisms that govern central tolerance and help prevent autoimmunity. Recent findings indicate that the compartmentalization of AIRE and interaction with other proteins are involved in this mechanism. The disturbance of AIRE expression may also be responsible for autoimmune manifestations in disorders with disrupted thymic structure other than autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy alone.

Autoimmune hypogonadism as part of an autoimmune polyglandular syndrome.

The most compelling case for autoimmune mediated hypogonadism occurs when ovarian failure is part of an autoimmune polyglandular syndrome (APS). In patients with the rare, recessively inherited type 1 APS (APS-1), characterized by the triad of chronic mucocutaneous moniliasis, hypoparathyroidism, and Addison's disease, primary amenorrhea (elevated pituitary gonadotropins) or oligomenorrhea and infertility are constant features. Ovarian failure is associated with autoantibodies to steroid hormone secreting cells in the adrenal cortex, Leydig cells of the testes, granulosa/thecal cells of the Graffian follicles, corpus luteum, and the syncytiotrophoblast of the placenta. These autoantibodies react with 3 P450 enzymes involved with steroidogenesis, namely, 21-hydroxylase (adrenal specific), 17 alpha-hydroxylase, and the side chain cleavage enzyme. Recently the 14 exon, APS-1 (autoimmune regulator or AIRE) gene has been cloned (chr. 21p22.3), and multiple mutants discovered. Parents who are obligatory heterozygotes for a single mutant gene lack clinical features of APS-1. They also do not develop APS-1 autoantibodies. Thus, hypogonadal patients without features of APS-1 are unlikely to have AIRE gene mutations. In the more common APS-2/3, characterized by combinations of autoimmune thyroid disease, immune mediated type 1 diabetes, vitiligo, pernicious anemia, and Addison's disease (type 2, not type 3), ovarian disease may be seen. In primary hypogonadism outside of the context of an APS, these autoantibodies are rare.