Autoimmune Polyglandular Syndrome Type 1

NORD gratefully acknowledges Noel K. Maclaren, MD, Clinical Professor of Pediatrics, Weill College of Medicine of Cornell University, Director of BioSeek Endocrine Clinics, for assistance in the preparation of this report.

Synonyms of Autoimmune Polyglandular Syndrome Type 1

  • APS-1
  • APS type 1
  • autoimmune-polyendocrine-candidiasis-ectodermal dystrophy syndrome
  • autoimmune polyendocrinopathy type 1 (APECED)
  • polyglandular autoimmune (PGA) syndrome type 1

General Discussion
Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder of immune-cell dysfunction with multiple autoimmunities. It presents as a group of symptoms including potentially life-threatening endocrine gland and gastrointestinal dysfunctions. Autoimmune disorders occur when antibodies and immune cells are launched by the body against one or several antigens of its own tissues. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. HLA-DR/DQ genes also play a role in predisposing to which of the component autoimmune disease the patient actually develops.

APS-1 needs to be distinguished from the unrelated but more common APS-2 which is characterized by type-1 diabetes and autoimmune thyroid diseases.

Signs & Symptoms
While the symptoms of APS-1 are variable in each patient, they often will have components of at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency.

Chronic mucocutaneous candidiasis (CMC), a condition of recurrent candidiasis infections that may involve the skin, nails, oral, anal and genital mucosa, is a hallmark of APS-1. It is often the first manifestation of APS-1, typically appearing and recurring frequently within the first two years of life. The CMC of APS-1 generally presents in babies as thrush (oral candidiasis), diaper rash, and/or nail involvement. (For further information on CMC, please see ‘Related Disorders’ section of this report.)

The term ectodermal dystrophy refers to the particular abnormalities of the nails, dental enamel (enamel hypoplasia of permanent teeth), hair (alopecia), corneas (keratopathy) and skin (vitiligo–areas of depigmention of the skin) that may be seen in patients with APS-1. These findings are not all necessarily present in every patient with APS-1. However, alopecia and vitiligo are caused by specific autoimmunities, while nail deformities result from chronic candidiasis. The cause of dental enamel hypoplasia in APS-1 has not yet been determined.

Metaphyseal dysplasia, a bone disorder in which the ends (metaphyses) of the bones are abnormally broad, has also recently been described in the legs in people with APS-1.

Patients with APS-1 have a defect of the immune system involving a particular subset of T-cells called Treg (T-regulatory) cells. It is suggested that this Treg-cell defect leads to the wide spread loss of immune tolerance, causing the autoimmunities in the disease. However, a specific defect in immunity to candidiasis indicates the presence of an immune effector defect also. Possibly, the invariable presence of auto-antibodies to the interferon family of immunological molecules called cytokines may prove to be the underlying reason.

The first endocrine gland dysfunction to occur in APS-1 is usually hypoparathyroidism (under functioning of the parathyroid glands). More than 75% of patients develop hypoparathyroidism, usually before age 10-years. Dysfunction of the parathyroid glands leads to below-normal level of serum calcium together with elevated phosphorus levels. In turn, this can lead to a host of clinical findings, including muscle cramping and spasms, rigidity (tetany) and even seizures. (For further information on hypoparathyroidism, see Related Disorders Section of this report.)

Adrenocortical insufficiency (Addison’s disease) is typically the second endocrine disorder to appear in APS-1. Adrenocortical insufficiency is characterized by chronic and insufficient functioning of the cortex (outer layer) of the adrenal gland. This malfunction results in a deficiency of the glucocorticoid and salt retaining hormones cortisol and aldosterone respectively. Deficiencies of these hormones may lead to weakness, muscle cramps, faintness, diarrhea, nausea and vomiting, low blood pressure, dehydration, and salt craving. These side-effects can become pronounced and life-threatening if not correctly identified and treated. However, steroid replacement therapy can precipitate or worsen hypocalcemia when hypoparathyroidism has not been already identified. (For further information on adrenocortical insufficiency, see Related Disorders Section of this report.)

Patients with APS-1 can also develop many other autoimmune disorders, including autoimmune liver disease (chronic active hepatitis), ovarian failure (hypogonadism), early onset pernicious anemia from atrophic gastritis, and a variety of gastrointestinal problems resulting in chronic malabsorption and diarrhea. Insulin-dependent diabetes may also occur, albeit more often in Scandinavian patients than is seen in the US.

APS-1 is caused by mutations in the AIRE gene. To date, more than 60 mutations in the AIRE gene have been identified in people with APS-1.

The AIRE gene is responsible for the production of a protein called ‘autoimmune regulator’ which is highly expressed in the thymus gland, and generates thymus derived or T lymphocytes. If there is a deficiency of this protein, then those T-cells which have receptors capable of interacting with self-antigens can escape into the circulation (instead of being destroyed in the thymus and not released) and result in autoimmunities. For reasons that are still unclear, defects of the autoimmune regulator protein seem to mostly affect endocrine (hormone-producing) glands.

APS-1 is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Affected Populations
APS-I is a very rare disorder that tends to cluster in certain homogenous populations, including certain groups of Finns, Iranian Jews, and Sardinians. However, it can be found in numerous populations and among multiple ethnic groups. In the US, APS-1 probably affects as few as 1 in every 2-3 million newborns.

Related Disorders
The following disorders, which are components of APS-1, can also occur on their own, separate from the diagnosis of APS-1:

Chronic mucocutaneous candidiasis (CMC) refers to a condition of persistent or recurrent yeast infections of the skin, nails, and/or mucous membranes. The most prevalent of these organisms is Candida albicans. When significant CMC occurs, it is often a sign of an underlying T cell disorder, including APS-1. Fortunately the conazole class of drugs has made this disease more easily managed than in former years. Candida is yeast that is part of the normal flora of the gastrointestinal tract, skin, and mucous membranes. Healthy, intact skin and an intact immune system usually provide effective barriers to prevent candida invading these tissues.

People with CMC present with recurrent or persistent candidiasis infections of the oral cavity (thrush) and other mucous membranes, but often have more extensive involvement. The nails may be markedly thickened and discolored with significant swelling of the surrounding tissue. The scalp may be involved, leading to alopecia in areas of scarring. However, alopecia is more commonly an autoimmune disorder which can result in alopecia universalis where all bodily hair is lost. There may be clinically significant esophageal candidiasis also in APS-1. Oropharygeal cancers and cancers of the stomach and tongue occur at increased frequencies in APS-1. CMC is definitively diagnosed by the presence of Candida on fungal skin scrapings.

Hypoparathyroidism is a condition characterized by insufficient production of parathyroid hormones by the parathyroid glands, the small, oval glands located behind the thyroid gland in the neck. Parathyroid hormones (along with vitamin D) play a role in regulating levels of calcium in the blood. Due to a deficiency of parathyroid hormones, affected individuals exhibit abnormally low levels of calcium in the blood (hypocalcaemia) often accompanied by elevated phosphorus.

Symptoms and findings associated with hypoparathyroidism may include weakness, muscle cramps, excessive nervousness, headaches, and/or increased excitability (hyper excitability) of nerves. This can lead to uncontrollable twitching and cramping spasms of certain muscles such as those of the hands, feet, arms, and/or face (tetany).

Hypoparathyroidism in APS-1 has an autoimmune cause, but it can occur as a separate disorder associated with maldevelopment of the thymus, aortic arch and parathyroid glands (DiGeorge syndrome) or may also arise as a separate inherited disorder. While an antibody to antigens present on the surface of parathyroid cells (the calcium sensing receptor) had previously been reported in APS-1, more recently, researchers from University Hospital in Uppsala, Sweden have isolated another auto-antigen involved.

Chronic adrenocortical insufficiency (Addison’s disease) is a rare disorder characterized by chronic, usually progressive, inadequate production of the steroid hormones cortisol and aldosterone by the outer layer of cells of the adrenal glands (adrenal cortex). Classical Addison’s disease is a consequence of the loss of both of these hormones.

Cortisol affects carbohydrate metabolism, connective tissue development, arterial tone and the amount of water in the body. The level of cortisol rises in response to physical and emotional stresses. Aldosterone affects the sodium (retention) and potassium (excretion) equilibria in the body. When these hormone levels are subnormal, blood pressure and blood volume drop due to increased excretion of salt and thereby water. Dehydration can occur. Major symptoms of Addison’s disease include fatigue, weakness, gastrointestinal discomfort, salt craving and changes in skin color (hyperpigmentation). Electrolyte disturbances include elevations in serum potassium and low serum sodium levels. Adrenal autoimmunity is associated with auto antibodies against an adrenocortical enzyme named 21-hydroxylase.

An acute, life-threatening state of extreme insufficiency of adrenocortical hormones (Addisonian crisis) may occur in the form of a sudden loss of strength, dehydration, and faintness from hypotension. Females with APS-1 usually develop significant ovarian failures associated with autoantibodies against the side chain cleavage and 17 alpha hydroxylase enzymes of the ovaries. Hypogonadism is common and infertility is usually present.

Additional concerns with APS-1:

Autoimmunities can also involve the anterior pituitary gland (hypophysitis), the gastric mucosa (antibodies seen include parietal cell antibodies (antibodies against the hydrogen-potassium ATPase enzyme), and intrinsic factor binding proteins), celiac disease (antibodies against tissue transglutaminase enzyme of the intestinal mucosa), inflammatory bowel disease with an autoimmunity directed at the serotonin rich cells of the small intestine (antibodies against the tryptophan hydroxylase enzyme), and interferons as mentioned above. Many patients are born with hypoplastic spleens, leaving them subject to septicemia especially by strep pneumonia bacteria. It is advised that APS-1 patients be vaccinated against pneumococcus. The predisposition to GI cancers, especially involving the tongue and/or stomach, was also mentioned above.

APS-1 is diagnosed definitively through DNA analysis (via blood test) of mutations in the AIRE gene. The diagnosis should be strongly considered in people under 30 years of age who present with at least two of the three typical disease components (CMC, hypoparathyroidism, and/or Addison’s disease). Recently, typical AIRE mutations have been identified in patients who have only one of these three cardinal features, but have other less common APS-1 associated autoimmunities. Since virtually all APS-1 patients have interferon autoantibodies, such antibodies when more freely available will serve as a less expensive diagnostic test.

A clinical history and physical exam that suggests more than one endocrine disorder, with or without CMC, should prompt the physician to obtain serum endocrine autoantibody blood tests.

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