APECED is a rare genetic disorder characterized by problems with the immune system that affect many of the body’s organs. APECED stands for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. People with APECED typically have chronic Candida yeast infections and various autoimmune problems. Breaking down the name, APECED, helps explain the syndrome.

Autoimmune refers to a process during which a person’s immune system mistakenly attacks healthy cells, organs, or tissues. People with APECED often experience autoimmune problems with organs of the endocrine system, which secrete hormones into the blood to help regulate body functions. They also have autoimmunity against non-endocrine organs, including the liver, lungs, and intestines. For example, people with APECED may experience autoimmune hepatitis (the body mistakenly attacks the liver), autoimmune pneumonitis (the body mistakenly attacks the lungs), and autoimmune enteropathy (the body mistakenly attacks the intestines), as well as other autoimmune disorders.

Polyendocrinopathy refers to problems with multiple endocrine glands. In people with APECED, endocrinopathy is caused by autoimmunity. For example, autoimmune problems in the parathyroid and adrenal glands of APECED patients commonly cause hypocalcemia (low calcium levels), hypoglycemia (low blood sugar), and hypotension (low blood pressure). Other autoimmune-mediated endocrine problems include ovarian or testicular failure, type 1 diabetes, thyroid disease, and pituitary failure.

Candidiasis is an infection caused by the yeast Candida. Candida infections of the skin and mucosal surfaces such as the mouth, esophagus, and vagina are common in people with APECED. However, people with APECED generally are not susceptible to developing systemic Candida infections, which involve the blood and deep-seated organs.

Ectodermal refers to the ectoderm, the most exterior of the three primary layers in an early embryo. The ectoderm gives rise to many important tissues and structures, including the skin, sweat glands, hair, nails, and teeth.

Dystrophy is a state of weakness, degeneration, or abnormal development (in this case, of the ectoderm). People with APECED may have problems with their nails, hair, and the enamel on their teeth. For example, they may experience nail dystrophy, alopecia, or enamel hypoplasia with or without evidence of an accompanying Candida infection.

Diagnosis of APECED, which also is called autoimmune polyendocrinopathy syndrome type 1 (APS-1) or polyglandular autoimmune (PGA) syndrome type 1, is based on clinical symptoms, laboratory findings, and genetic testing. Most people with APECED begin having symptoms in early childhood, although the time between onset of symptoms and APECED diagnosis can be frustratingly long for many families.

APECED syndrome is caused by mutations in the gene AIRE. AIRE provides instructions for making a protein called the autoimmune regulator (AIRE), which helps control when other genes get “turned on,” or expressed. The AIRE protein is expressed in the thymus, a key immune organ located behind the breastbone. As its name suggests, AIRE plays an important role in regulating certain aspects of the immune system. In particular, AIRE helps teach immune cells how to distinguish the body’s own healthy cells and tissues.

Mutations in the AIRE gene reduce or eliminate the function of the AIRE protein, making it more likely that the immune system will attack the body’s own healthy tissues. This autoimmunity underlies many APECED symptoms.

Mutations of many types and in many locations along the length of the AIRE gene have been reported. Interestingly, different mutations have been found to be somewhat specific to certain populations. For example, the nonsense mutation R257X is common among Finnish APECED patients; the deletion mutation 1094-1106del13 is common among British, Irish, Norwegian, and North American APECED patients; and the missense mutation Y85C frequently appears among Iranian Jews with APECED. However, potential correlations between a specific AIRE mutation and a patient’s clinical status remain unclear.

Normal Function

The AIRE gene provides instructions for making a protein called the autoimmune regulator. This protein is active primarily in the thymus, which is an organ located behind the breastbone that plays an important role in immune system function. The thymus prepares immune cells called T cells for their role in fighting infection; this process is called thymic education.

For a person to remain healthy, immune system cells such as T cells must be able to identify and destroy potentially harmful invaders (such as bacteria, fungi, and viruses) while sparing the body's normal tissues. The autoimmune regulator protein plays an important role in this process by helping T cells distinguish the body's own proteins from those of foreign invaders. When this system malfunctions, the immune system's ability to distinguish between the body's proteins and foreign invaders is impaired, and it may attack the body's own tissues and organs. This abnormal reaction is called autoimmunity. In the thymus, the autoimmune regulator protein destroys T cells that otherwise would cause autoimmune damage.

Health Conditions Related to Genetic Changes

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

More than 90 mutations in the AIRE gene have been identified in people with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). APECED is an inherited condition that affects many of the body's organs. A major feature of this disorder is chronic mucocutaneous candidiasis (CMC), which is a tendency to develop infections of the skin, the nails, and the moist lining of body cavities (mucous membranes) caused by a type of fungus called Candida. Other common signs and symptoms of APECED involve dysfunction of the body's network of hormone-producing glands (the endocrine system), as well as other organs and tissues.

The AIRE gene mutations that cause APECED lead to the production of an abnormally short, nonfunctional version of the autoimmune regulator protein or change single protein building blocks (amino acids) in critical regions of the protein. These mutations reduce or eliminate the function of the autoimmune regulator protein. Without enough of this protein function, the immune system's ability to distinguish between the body's proteins and foreign invaders is impaired, and immune cells may attack the body's own organs, resulting in autoimmunity. This abnormal reaction leads to inflammation and can damage otherwise healthy cells and tissues. Autoimmune damage to the adrenal glands, parathyroid glands, and other organs underlies many of the major features of APECED.

Studies suggest that AIRE gene mutations also result in immune substances (antibodies) mistakenly attacking proteins involved in an immune process called the IL-17 pathway, which is important in the body's defense against Candida. This pathway, which depends on specialized proteins called IL-17 cytokines for signaling, creates inflammation, sending additional cytokines and white blood cells to fight foreign invaders and promote tissue repair. In addition, the IL-17 pathway promotes the production of certain antimicrobial protein segments (peptides) that control growth of Candida on the surface of mucous membranes. By damaging IL-17 cytokines, AIRE gene mutations are thought to impair the IL-17 pathway's function, resulting in CMC in people with APECED.

Alopecia areata

MedlinePlus Genetics provides information about Alopecia areata

Other Names for This Gene

• AIRE1
• AIRE_HUMAN
• APECED
• APS1
• APSI
• Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy protein
• PGA1

Genomic Location

APECED is inherited in an autosomal recessive manner. In autosomal recessive inheritance, an affected person has a mutation on each of their two copies of the AIRE gene—one inherited from the mother and one from the father. Typically, both parents of an affected person carry one abnormal AIRE gene and are unaffected by the disease. When both parents are carriers, each child has a 25 percent, or one in four, chance of being affected by the disease.

Sometimes the two copies of the AIRE gene that a child inherits have identical, or homozygous, mutations. Most North American APECED patients have different mutations on the two copies of AIRE, called compound heterozygous mutations. In either case, the patient is not able to produce functional AIRE protein.

Recent evidence suggests that in a minority of APECED patients, the disease is inherited in an autosomal dominant manner. In autosomal dominant inheritance, an affected person has a mutation on one of their two copies of the AIRE gene. The mutation is inherited from a parent who is also affected by the syndrome. The other parent does not carry a mutation in the AIRE gene and is healthy. In this situation, each child has a 50 percent, or one in two, chance of being affected by the disease. Such mutations have been reported in European APECED patients, but so far have not been observed in North American APECED patients.

About 15 to 20 percent of North American patients with APECED symptoms do not have detectable mutations in both copies of the AIRE gene, suggesting that other undiscovered genetic factors also are involved in the syndrome.

APECED is a disorder with striking variability, even within the same family. This implies that complex interactions among genetic, epigenetic (influences on gene expression not explained by the DNA sequence), and environmental factors contribute to the disease.

Chronic Mucocutaneous Candidiasis

Chronic mucocutaneous candidiasis—persistent Candida infection of the skin, nails, or mucosal membranes—is typically the first symptom to appear, usually in the form of oral candidiasis, commonly known as oral thrush. Thrush can range in severity from redness and soreness at the corners of the mouth to whole-mouth involvement, which can interfere with eating spicy or acidic foods. Chronic inflammation of the mouth and throat makes some APECED patients (5 to 10 percent) susceptible to oral squamous cell carcinoma, a type of cancer. Candidiasis can also affect the esophagus, intestines, or vagina.

Autoimmunity

Autoimmunity can affect virtually any tissue or organ. Doctors have identified autoantibodies—immune system proteins that recognize and counteract numerous tissues and organs in the body—in people with APECED. In addition, autoreactive T cells, which normally are removed in the thymus in the presence of functional AIRE, attack different organs in people with APECED. Most commonly, autoantibodies and autoreactive T cells attack the parathyroid glands, adrenal glands, thyroid gland, and ovaries or testes. This can result in hypoparathyroidism, adrenal insufficiency, hypothyroidism, and ovarian or testicular failure. Autoimmunity affecting the gastrointestinal tract, ectodermal structures (skin, teeth, nails, and parts of the eyes), spleen, blood, lungs, and other organs and tissues has also been reported in APECED patients.

Ectodermal Symptoms

APECED can affect structures of the ectoderm, resulting in a wide variety of symptoms. These include keratitis of the eye, rashes with fever, alopecia, vitiligo, nail dystrophy, tooth enamel hypoplasia, and calcification of the inner ear’s tympanic membrane. Some, but not all, of these symptoms may be caused by underlying autoimmune problems.

Doctors may diagnose APECED based on genetic testing and the presence of at least two of the three classic components of the syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. However, these criteria are imperfect. Some patients have other symptoms for decades before the classic APECED symptoms become apparent or their doctor performs a targeted evaluation for APECED. The rarity of APECED and the variation in disease symptoms and severity among people with the disease contribute to the likely underdiagnosis of this condition. As researchers work toward a better characterization of APECED, the diagnostic criteria likely will evolve.

Treatment is based on a person’s clinical condition and may include medications and other strategies to manage Candida, autoimmunity, and endocrine problems. Some treatments may be specific for APECED, while others are standard treatments for conditions experienced by APECED patients, such as hypoparathyroidism. Because APECED affects many of the body’s organs and tissues, optimal care requires a team of specialists working closely with the patient. The goal of treatment is to preserve the patient’s quality of life and recognize and address early signs of new disease symptoms, which may appear throughout life.

Living with APECED can be difficult not only for the person who has it but also for their family members. It is important for families to talk openly about APECED and about how the family is dealing with it so that misconceptions can be corrected and everyone can learn to cope to the best of their ability. Some people with APECED have to work hard to develop their self-confidence and sense of security. Everyone benefits from being reminded that they have many positive characteristics, but this is especially important when a person’s appearance attracts attention (for example, due to candidiasis, alopecia, or vitiligo) or affects their quality of life (for example, because of malabsorption).

Some children who have siblings with APECED feel anxious about their brother or sister being in pain or even dying from the disease. Some think that they may develop symptoms because they look or act like a sibling who has the disease or that the disease is contagious. Some children struggle with how much time their parents spend with their sick sibling. Many families benefit from meeting or talking to other families affected by the same rare disease. Patient organizations such as the Immune Deficiency Foundation (www.primaryimmune.org) or an APECED support group (www.apstype1.org) are great resources for providing useful information and connecting families. Counseling also can help families cope with the challenges of APECED.

At the same time, many families say that APECED has brought them closer together. Through their experiences with the disease and its treatment, family members learn about controllable and uncontrollable aspects of life. How a family responds to the stress of any illness is controllable and an important aspect of managing APECED. Children also learn who they can turn to for support and how to solve problems. Acknowledging both the challenges and opportunities presented by APECED helps everyone develop resilience.