Autoimmune Polyglandular Syndrome Type 1
Autoimmune Polyglandular Syndrome Type 1
National Organization for Rare Disorders, Inc.
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Autoimmune polyglandular syndrome type 1 (APS1) is a rare and complex inherited disorder of immune-cell dysfunction with multiple autoimmunities. It presents as a constellation of symptoms including potentially life-threatening endocrine gland and gastro-intestinal dysfunctions.
A condition is said to be "autoimmune" when antibodies and immune cells are launched by the body against one or several antigens of its own tissues. Since most of the target antigens have now been discovered, the corresponding auto-antibodies can be measured in the blood as markers for the ongoing autoimmune disease to which they correspond.
APS1 is caused by mutations of both sets of the autoimmune regulator (AIRE) gene. (For further information about the AIRE gene, please go to the 'Causes' section of this report.) HLA-DR/DQ genes also play a role in predisposing to which of the component disease the patient actually develops.
While the symptoms of APS-1 are variable in each patient, they 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 APS1. It is often the first manifestation of APS1, typically appearing and recurring frequently within the first two years of life. The CMC of APS1 generally presents in babies as frequent thrush (oral candidiasis), diaper rash, and/or skin rashes. (For further information on CMC, please see ‘Related Disorders' section of this report.)
The ectoderm is the outermost layer of the three primary cell layers of a developing embryo. It gives rise to specific tissues, including the skin, teeth, nails, hair and mucous membranes. A ‘dystrophy' is a disorder of the structure of an organ or tissue of the body.
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 APS1. These findings are not all necessarily present in every patient with APS1, but can develop as a result of specific AIRE mutations. However, alopecia and vitiligo are caused by other specific autoimmunities, while nail deformities result from chronic candidiasis. The cause of dental enamel hypoplasia in APS1, however, has not yet been determined. Metaphyseal dysplasias of the lower limb bones have recently been also described.
Patients with APS1 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 present 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 APS1 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 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 eventually, 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 APS1. 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 a small-sized heart. These side-effects can become pronounced and life-threatening if not correctly identified and treated. (For further information on adrenocortical insufficiency, see Related Disorders Section of this report.)
Patients with APS1 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 gastro-intestinal 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.
APS1 is the result of autosomal recessive genetic transmission of mutations of a single gene. This gene is called the autoimmune regulator or AIRE gene. To date, more than 60 mutations in the AIRE gene have been identified in people with APS1.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but will not show symptoms. The risk for two carrier parents to both pass the defective gene and 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry many abnormal single copy genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
The AIRE gene leads to the production of a protein called ‘autoimmune regulator' which is highly expressed in the thymus gland, which is the random generator of 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 primarily affect endocrine (hormone-producing) glands.
APSI 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, APS1 probably affects as few as 1 in every 2-3 million newborns.
The following disorders, which are components of APS1, can also occur on their own, separate from the diagnosis of APS1:
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 APS1. Fortunately the conazole class of drugs has made this disease more easily managed than in former years. Candida is a 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. There may be esophageal candidiasis also. Oropharygeal cancers and cancers of the stomach and tongue occur at increased frequencies in APS1. 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).
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 APS1 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 be an inherited disorder. While an antibody to antigens present on the surface of parathyroid cells (the calcium sensing receptor) had previously been reported, more recently, researchers from University Hospital in Uppsala, Sweden have isolated another auto-antigen involved in the hypoparathyroidism of APS1.
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, and the amount of water in the body. Aldosterone affects the sodium and potassium equilibrium 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, 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, severe pain in the abdomen or lower back, and/or kidney failure.
Females with APS1 usually develop significant ovarian failures associated with autoantibodies against the side chain cleavage and 17 alpha hydroxylase enzymes of the ovaries. Infertility problems result.
Additional concerns with APS1:
Autoimmunities can also involve the anterior pituitary gland (hypophysitis), the gastric mucosa (antibodies seen includes parietal cell antibodies or antibodies against the hydrogen-potassium ATPase enzyme, and intrinsic factor binding proteins), celiac disease (antibodies against tissue transglutaminase enzyme of the intestinal mucosa), the serotonin rich cells of the small intestine (antibodies against the tryptophan hydroxylase enzyme), and interons as mentioned above. Many patients are born with hypoplastic spleens, leaving them subject to septicemia especially by strep pneumonia bacteria. The predisposition to GI cancers, especially involving the tongue and/or stomach, was also mentioned above.
APS1 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 APS1 associated autoimmunities. Since virtually all APS1 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.
Treatment of APS1 Syndrome is currently directed toward the specific diseases that are apparent in each patient. In general, replacement therapy of the endocrine hormones that may be lacking, and patient education about the signs and symptoms of these deficiencies, are integral to treatment success. The educational aspect is of extreme importance, as this allows the patient to self-monitor, hopefully avoiding a life-threatening situation.
Addison's disease is treated with drugs such as hydrocortisone and fludrocortisone to replace the cortisol and aldosterone that are deficient in such patients.
Hypoparathyroidism is treated with oral calcium supplements and activated forms (1, 25 dihydroxy) of vitamin D such as Calctriol or Rocaltrol.
For chronic mucocutaneous candidiasis, oral fluconazole (Diflucan) is prescribed.
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