SUMMARY
1. Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy (APECED) is an autosomal recessive disorder of immune dysregulation. It is also known as Autoimmune Polyendocrine syndrome Type I (APS-I).
2. APECED is characterized by chronic mucocutaneous candidiasis (CMC) and polyendocrinopathy (adrenal insufficiency and hypoparathyroidism). Patients do not appear to have increased susceptibility to other types of infections.
3. Additional endocrinopathies can include gonadal failure, thyroid disease and IDDM. Non-endocrine manifestations include enamel hypoplasia, nail dystrophy, alopecia, malabsorption, and vitiligo.
4. APECED is caused by mutations in the gene for AIRE. AIRE is prominently expressed in medullary thymic epithelial cells. In the thymus, AIRE induces ectopic expression of self-antigens that are otherwise restricted to peripheral tissues. This allows for negative selection of self-reactive T cells and induction of central tolerance. Lack of AIRE expression allows for autoreactive T cells to escape thymic negative selection these cells cause multi-organ autoimmunity in the periphery.
5. The diagnosis of APECED is typically made on clinical grounds based on the triad of candidiasis, hypoparathyroidism and adrenal failure. Typically, candidiasis appears in early childhood followed by hypoparathyroidism and adrenal insufficiency later in life.
6. There are no specific serologic tests available for the diagnosis of APECED. Standard humoral and cell-mediated immune testing is normal in patients. A definitive diagnosis relies on mutation analysis of the AIRE gene.
7. Patients typically require systemic antifungal therapy for CMC, cortisol replacement for adrenal insufficiency and calcium/vitamin D supplementation for hypoparathyroidism. Routine surveillance for known disease manifestations is critical.
8. HSCT is not indicated as replacement of bone marrow derived cells cannot correct the underlying defect in central tolerance.
OVERVIEW
Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy (APECED) is an autosomal recessive disorder of immune dysregulation. It is also known as Autoimmune Polyendocrine syndrome Type I (APS-I).
APECED is characterized by chronic mucocutaneous candidiasis (CMC) and polyendocrinopathy. Patients do not appear to have increased susceptibility to other types of infections.
Below is a list of clinical features in APECED and their frequency (%):
Endocrine Features:
•Hypoparathyroidism (79%)
•Addison disease (72%)
•Ovarian failure (60%)
•Pernicious anemia (13%)
•Type I diabetes (12%)
•Hypothyroidism (4%)
Non-endocrine Features:
•Mucocutaneous candidiasis (100%)
•Enamel Hypoplasia (77%)
•Nail dystrophy (52%)
•Keratopathy (35%)
•Malabsorption (18%)
•Vitiligo (13%)
•Autoimmune Hepatitis (12%)
APECED is caused by mutations in the AIRE gene. AIRE is prominently expressed in medullary thymic epithelial cells. In the thymus, AIRE induces ectopic expression of self-antigens that are otherwise restricted to peripheral tissues. This allows for negative selection of self-reactive T cells and induction of central tolerance. Lack of AIRE expressions allows for autoreactive T cells to escape thymic deletion these cells cause multiorgan autoimmunity in the periphery.
EVALUATION
Patients with CMC, adrenal insufficiency, and hypoparathyroidism should be evaluated for APECED. CMC typically manifests at a young age while endocrinopathies appear later in life.
Step 1: Immune Evaluation
-Flow cytometry for B cell, T cell, and NK cell enumeration
-T cell proliferation to mitogens
-T cell proliferation to antigens (candida and tetanus)
- HIV Test
-T cell numbers should be quantified by flow cytometry to screen for other T cell or combined defects that could cause mucocutaneou candidiasis.
-Similarly, T cell proliferation to mitogens and specific antigens (candida and tetanus) should be tested. Mitogen proliferation is normal in APECED. Some patients with CMC have decreased T cell proliferation to candida.
-HIV testing should be performed as CMC can be a presenting feature of this infection.
Step 2: Screening for Endocrinopathies
-A.M. cortisol Level (ACTH level if cortisol is low)
-Calcium and PTH Level
-Fasting Glucose Level
-TSH, Free T4
-Low a.m. cortisol levels coupled with elevated ACTH levels is support a diagnosis of primary adrenal insufficiency. An ACTH stimulation test should be performed if these initial tests are abnormal.
-Calcium and parathyroid hormone levels can be measured to screen for hypoparathyroidism.
-Fasting glucose levels can be measured to screen for Type 1 Diabetes.
-TSH and Free T4 can be evaluated to screen for thyroid disease.
Step 3: Gene Sequencing
-AIRE Gene Sequencing
-AIRE gene sequencing is commercially available through Gene Dx.
MANAGEMENT
Treatment of patients requires the control of CMC and management of endocrine complications. Patients typically require systemic antifungal therapy for CMC, cortisol replacement for adrenal insufficiency and calcium/vitamin D supplementation for hypoparathyroidism. Routine surveillance for known endocrine and non-endocrine disease manifestations is critical. HSCT is not indicated as replacement of hematopoietic stem cells cannot correct the underlying defect in central tolerance.
RESOURCES
Diagnostic Resources
AIRE gene sequencing
- Available through Gene Dx
Literature Resources
1. Owen 2009
Diagnosis & Management of Polyendocrinopathy Syndromes
Features of 91 APECED Patients