APECED Syndrome

At a glance

APECED is an acronym that stands for Autoimmune PolyEndocrinopathy, Candidiasis, Ectodermal Dystrophy Syndrome. This autoimmune disorder consists of potentially multiple endocrinopathies associated with various other signs, including hepatitis and eye abnormalities.

Synonyms

Whitaker Syndrome; Autoimmune Polyendocrinopathy Syndrome Type I; Polyglandular Autoimmune Syndrome Type I; Hypoadrenocorticism Hypoparathyroidism Moniliasis.

Incidence

APECED is an overall rare disease, but occurs more commonly in Iranian Jews with an estimated prevalence of 1:9,000, in Finns with 1:25,000 and in Sardinians (Italy) with 1:14,500. Depending on the source, females are affected up to twice as often as males.

Genetic inheritance

It is caused by mutations in the Autoimmune regulator (AIRE) gene, which has been mapped to chromosome 21q22.3.

Pathophysiology

APECED is a prototype monogenic autoimmune disorder. Mutations in the single AIRE gene result in failure of T-cell tolerance. Central immunotolerance develops in the thymus and describes the mechanism that allows potentially autoreactive T-cells to be eliminated or inactivated. The expression of tissue-specific antigens by medullary thymic epithelial cells is a key process in central tolerance and is driven by the AIRE gene protein. AIRE mutations are responsible for the failure of this process and cause the systemic autoimmune reactions in APECED. However, the great clinical variability in symptoms and severity of APECED suggests that, independent of the AIRE genotype, most likely other factors (eg, environmental) also play a role in the disease process.

Diagnosis

Based on the presence of two of the three major clinical symptoms: (1) hypoparathyroidism (present in almost 80% of patients), (2) adrenocortical failure (in about 70%), and/or (3) chronic mucocutaneous candidiasis. It typically affects children and adults younger than 35 years and can be lethal in infancy or childhood.

Clinical aspects

Age at onset of the disease is typically childhood or early adulthood. Mucocutaneous candidiasis is most often the first symptom (in 60%) and usually appears between 3 and 5 years of age, but neonatal disease onset with hypoparathyroidism and mucocutaneous candidiasis has been described. Over the following 5 years, hypoparathyroidism is very likely to develop, whereas adrenal insufficiency often takes another 5 years to become clinically manifest. This is the most common order and time frame; however, wide variations are possible, and the different organ manifestations of this disease can occur independently of each other and only about 30 to 50% of the patients have all three disorders simultaneously. More than three-quarters of APECED patients develop chronic hypoparathyroidism that can lead to tetany with carpopedal spasms (Trousseau sign), Chvostek sign, acral paresthesias, laryngospasm, mild encephalopathy, seizures, cataracts, and papilledema. The patient may have ventricular arrhythmias and the ECG may show QT-interval prolongation. ...