June 26, 2018
Years published: 1991, 1999, 2007, 2008, 2012, 2015, 2018
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.
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.
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.
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.
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.
Treatment of APS-1 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. Recently, parathyroid hormone has become available as a treatment.
For chronic mucocutaneous candidiasis, oral fluconazole (Diflucan) is prescribed.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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