Autoimmune polyendocrine syndrome type 1

Autoimmune polyendocrine (polyglandular) syndrome type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autosomal recessive condition caused by pathogenic variants in the AIRE gene, which has a critical role in the development of immune tolerance. APECED is clinically defined by the classic triad of chronic mucosal candidiasis, hypoparathyroidism and adrenal insufficiency. Patients typically present after one year of age with multiple autoimmune conditions, including type 1 diabetes mellitus, autoimmune thyroiditis and pancreatic insufficiency.

Classically, children with APECED present with:

• chronic mucocutaneous candidiasis, which typically presents at around 18 months to three years of age with oral cavity redness and/or ulceration;
• hypoparathyroidism, which typically presents between two and eight years of age with muscle cramps and seizures secondary to hypocalcaemia; and
• Addison disease or autoimmune adrenal failure, which typically presents between five and 15 years of age with abdominal pain, fatigue, hyperpigmentation and weight loss.

Other autoimmune conditions may also present variably throughout childhood and into adulthood. These include:

• autoimmune hepatitis;
• malabsorption caused by autoimmune exocrine pancreatic insufficiency;
• vitiligo;
• alopecia;
• premature gonadal failure;
• hypothyroidism;
• type 1 diabetes mellitus;
• autoimmune gastritis/pernicious anaemia;
• Sjogren syndrome; and
• enamel hypoplasia.

APECED is caused by biallelic loss-of-function genetic variants in the autoimmune regulator AIRE gene. Loss of function of AIRE, which encodes a key transcription factor in organ-related immune tolerance, leads to the production of peripheral self-reactive lymphocytes, which in turn cause tissue-specific damage.

The condition is rare, but founder variants have been described in Finnish, Sicilian, Persian Jew and Sardinian populations. In total, over 100 different pathogenic variants have been described throughout the AIRE gene. Phenotypic variation can exist within families with the same AIRE genotype. Despite this, it has been observed that candidiasis and primary adrenal insufficiency are infrequent in Persian Jews with the p.Y85C founder pathogenic variant.

While the early-onset classical triad of APECED is caused by biallelic loss-of-function variants, heterozygous dominant-negative missense genetic variants in the PHD1 domain of AIRE have been associated with milder autoimmune features, which may present later in life or not at all (this is incomplete penetrance).

APECED is caused by variants in the autoimmune regulator AIRE gene, a key transcription factor in organ-related immune tolerance. It can be inherited in an autosomal recessive or dominant pattern.

Autosomal recessive inheritance

• Caused by biallelic loss-of-function variants in the AIRE gene.
• More than 100 different pathogenic variants have been described throughout the gene.
• Founder variants are described in Finnish, Sicilian, Persian Jew and Sardinian populations.
• The majority of patients have one of the two most common variants, which are arginine substitution at position 257 and 13 base pair deletion in exon 8.
• Significant phenotypic variation can exist within families.
• Persian Jews with the p.Y85C founder pathogenic variant are less frequently described with candidiasis and primary adrenal insufficiency.

Autosomal dominant inheritance

• Caused by heterozygous dominant-negative variants – typically, missense variants in the PHD1 domain of AIRE.
• Associated with milder autoimmune features, which may present later in life.
• May demonstrate incomplete penetrance.

Genomic testing should be considered in patients with early-onset organ-related autoimmunity, particularly if one of the classical triad of hypoparathyroidism, Addison disease or chronic mucocutaneous candidiasis presents within the first five years of life. A lower threshold for genomic testing is appropriate in patients from certain populations, such as the Persian Jewish population, in which there is reduced incidence of candidiasis and/or adrenal insufficiency. For more information about testing, see ‘Child with suspected autoimmune polyendocrine syndrome‘.

Functional confirmation of a genomic diagnosis includes identification of:

• adrenal cortex autoantibodies;
• type 1 interferon autoantibodies, particularly autoantibodies to interferon-omega;
• fungal culture of Candida sp on mucosal surfaces;
• other tissue antigen-specific autoantibodies, such as anti-ovarian or liver autoantibodies, although these have less sensitivity and specificity for both APECED and specific organ-related autoimmunity; and/or
• the presence of anti-islet antigen-2 (IA2) autoantibodies, which may precede diagnosis of type 1 diabetes mellitus.

APECED may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to clinical genetics or relevant local paediatric services. Please refer to the local pathway for your region for this condition.

APECED is caused by pathogenic variants in the AIRE gene. The majority of cases are inherited in an autosomal recessive pattern, though autosomal dominant inheritance with incomplete penetrance has been described.

Pathogenic founder variants are recognised in Finnish, Norwegian, Sicilian, Sardinian and Persian Jewish populations, in which prevalence can be as high as 1 in 9,000 individuals.

For autosomal recessive conditions, both parents are typically carriers (though de novo variants do occur). If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
  • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
  • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant. The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%). Incomplete penetrance can occur.

Reproductive options are available for those at risk of having an affected child and genetic counselling is recommended, prior to conception if possible. Options include testing in early pregnancy and preimplantation genomic testing.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

The management for APECED can be challenging and should be undertaken by a multidisciplinary team, including tertiary paediatric immunology and/or a tertiary paediatric endocrinology services. The chronicity and severity of symptoms can be physically and psychologically debilitating, and mental health problems are widely reported.

In the first instance, patients should be screened for hypocalcaemia, which occurs secondary to hypoparathyroidism and includes performing an electrocardiogram (ECG). Calcium and activated vitamin D supplementation may be required. Patients may also have early symptoms of chronic mucosal candidiasis, and treatment is indicated with nystatin or other oral antifungals. Complications of chronic candidiasis, such as oesophageal stricture and anti-fungal resistance, should also be routinely screened for, as well as adrenal insufficiency, for which patients should be started on cortisol and mineralocorticoid replacement therapy if required. Parents of affected children should be made aware of the risk of adrenal crisis, particularly if there is intercurrent infection or a surgical procedure.

There is no recommended definitive treatment, but immunomodulatory medication has been used in some cases to slow progression of multi-organ autoimmunity.

APECED may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Further information about management can be found through the resources section below.

For clinicians

• NICE: Nystatin

References:

• Bruserud Ø, Oftedal BE Wolff AB and others. ‘AIRE-mutations and autoimmune disease’. Current Opinion in Immunology 2016: volume 43, pages 8–15. DOI: 10.1016/j.coi.2016.07.003
• Ferré EMN, Schmitt MM and Lionakis MS. ‘Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy‘. Frontiers in Pediatrics 2021: volume 9. DOI: 10.3389/fped.2021.723532
• Oftedal BE, Hellesen A, Erichsen MM and others. ‘Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases‘. Immunity 2015: volume 42, issue 6, pages 1,185–1,196. DOI: 10.1016/j.immuni.2015.04.021

For patients

• Autoimmune Association: What is Polyglandular Syndromes Types I, III, III
• Immune Deficiency Foundation
• Immunodeficiency UK