Familial hypoparathyroidism

Gene: AIRE

Green List (high evidence)

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.

Created: 5 Nov 2025, 1:16 p.m. | Last Modified: 5 Nov 2025, 2:18 p.m.

Panel Version: 3.3

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).

Created: 5 Nov 2025, 1:09 p.m. | Last Modified: 5 Nov 2025, 2:19 p.m.

Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, OMIM:240300; autoimmune polyendocrine syndrome type 1, MONDO:0009411

Publications

• 11600535
• 19393987
• 27253668
• 29129473
• 31905445
• 35521792
• 37993717
• 37235056

As discussed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group agreed that there is enough evidence to rate this gene green.

Created: 5 Feb 2019, 2:36 p.m.

Green List (high evidence)

generally reported as syndromic, but from own NHS cohort we have a couple of cases where hypoparathyroidism was the first presenting feature.
a couple of rare reports of autosomal dominant inheritance

Created: 20 Jul 2016, 7:04 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
ACEPED; APS1

Variants in this GENE are reported as part of current diagnostic practice

Comment when marking as ready: Associated with phenotype (240300) in OMIM and G2P which includes hypoparathyroidism. Found in 2/4 sources. Reviewer recommends Green. Current diagnostic test.

Created: 6 Jun 2016, 7:57 a.m.