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| Familial hypoparathyroidism v3.4 | AIRE | Ida Ertmanska Publications for gene: AIRE were set to 19393987; 27253668; 31905445; 35521792; 37993717; 37235056 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska edited their review of gene: AIRE: Changed publications to: 11600535, 19393987, 27253668, 29129473, 31905445, 35521792, 37993717, 37235056 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 35521792 Cranston et al., 2022 Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases: Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism. Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and hypoparathyroidism at age 5, and CMC at age 11. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 35521792 Cranston et al., 2022 Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases: Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism. Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be changed to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are numerous individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, with hypoparathyroidism being the most common symptom - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 35521792 Cranston et al., 2022 Biallelic AIRE variants identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. Hypoparathyroidism was present in 87% of 40 mutation-positive individuals - most common symptom in this cohort. Selected cases: Proband 3: age 14, homozygous for c.44G>A, p.(Arg15His) in AIRE; presented with hypoparathyroidism, candidiasis, adrenal insufficiency, hypothyroidism. Proband 5: age of onset 9yo; compound het: c.242T>C, p.(Leu81Pro); 1265delC, p.(Pro422fs); symptoms: hypoparathyroidism, adrenal insufficiency, type 1 diabetes. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism, until more evidence emerges. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There are 2 unrelated families reported in literature with heterozygous AIRE variants and hypoparathyroidism;the variant did not segregate with disease in the family reported in PMID:37235056. There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no hypoparathyroidism. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Familial hypoparathyroidism v3.3 | AIRE |
Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Familial hypoparathyroidism v3.3 | AIRE |
Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska changed review comment from: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with APS-1, they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism.; to: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with Autoimmune polyendocrinopathy syndrome, type I (APS-1), they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.3 | AIRE | Ida Ertmanska Publications for gene: AIRE were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.2 | AIRE | Ida Ertmanska Tag Q4_25_MOI tag was added to gene: AIRE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.2 | AIRE |
Ida Ertmanska changed review comment from: PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. Of 25 patients examined by a dentist, 18 presented with enamel hypoplasia (72%), onset mostly in adolescence. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. Functional evidence: PMID: 37993717 Gruper et al., 2023 Enamel defects similar to APS1 presentation develop in 20-50% of children with coeliac disease. Study shows that both APS1 and coeliac disease patients develop autoantibodies (mostly IgA isotype) against ameloblast specific proteins, leading to defects in enamel formation. AIRE-deficient (-/-) mice have defective enamel formation; the KO mice showed autoreactivity to ameloblast antigens (slot-blot immunoassay). AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Family IV - Greek - individual II-1 presented with hypoparathyroidism, Positive AAbs against IFN-ω; heterozygous for c.916G>A, p.G306R. Mother and uncle carried the same variant in AIRE, but were unaffected. The other 10 probands reported did not present with hypoparathyroidism. PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. Panoramic tomogram at age 11 showed markedly thin and uneven enamel; premolars erupted with discoloured and hypoplastic enamel; she needed prosthetic crowns for her premolars before age 15; moderate to severe tooth sensitivity. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. 38/52 patients presented with hypoparathyroidism (73%), and it was the initial presenting symptom in 17 patients in the cohort. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. In this cohort, 7% of mutation positive individuals, and 3% of mutation negative probands, presented with enamel hypoplasia. Ethnic background not disclosed. AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Familial hypoparathyroidism v3.2 | AIRE | Ida Ertmanska commented on gene: AIRE: Comment on mode of inheritance: While monoallelic variants in AIRE have been associated with APS-1, they result in an incompletely penetrant, milder phenotype. There is one individual reported in literature with a heterozygous AIRE variant and hypoparathyroidism, but the variant did not segregate with disease in the family (PMID: 37235056). There are at least 4 unrelated individuals reported with biallelic variants in AIRE with Autoimmune polyendocrinopathy syndrome type 1, including hypoparathyroidism - heterozygous family members reported as unaffected (PMIDs: 19393987; 27253668; 35521792). Based on the available evidence, the MOI should be set to BIALLELIC, autosomal or pseudoautosomal for Familial hypoparathyroidism. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.2 | AIRE | Ida Ertmanska reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: 19393987, 27253668, 31905445, 35521792, 37993717, 37235056; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300, autoimmune polyendocrine syndrome type 1, MONDO:0009411; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v3.2 | AIRE | Ida Ertmanska Phenotypes for gene: AIRE were changed from Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia 240300 to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Familial hypoparathyroidism v1.10 | AIRE | Ivone Leong commented on gene: AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||