Practice Essentials
Type I polyglandular autoimmune syndrome (PGA-I) is a rare disorder with sporadic autosomal recessive inheritance. The three major components of PGA-I are as follows:
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Chronic mucocutaneous candidiasis
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Hypoparathyroidism
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Autoimmune adrenal insufficiency
Signs and symptoms
The presence of all 3 components is not required to make a diagnosis; at least 2 components have to be present in an individual. Additional manifestations, including, among others, type 1A diabetes (documented autoimmune etiology), primary hypogonadism, pernicious anemia, malabsorption, autoimmune hepatitis, ovarian failure, pure red cell aplasia, alopecia, and vitiligo, may be present as well.
The first manifestation usually occurs in childhood, and the complete evolution of the 3 main diseases takes place within the first 20 years of life. Accompanying diseases continue to appear at least until the fifth decade of life.
Candidiasis usually is the first clinical manifestation, most often presenting in people younger than 5 years. Hypoparathyroidism occurs next, usually in people younger than 10 years. Lastly, Addison disease occurs in people younger than 15 years.
See Presentation for more detail.
Diagnosis
Laboratory studies
In diagnosing PGA-I, clinical history and examination findings that suggest evidence of more than 1 endocrine deficiency should prompt the use of serum endocrine autoantibody screening tests. End-organ function tests are necessary to confirm the diagnosis.
Imaging studies
Perform a computed tomography (CT) scan of the adrenal glands to exclude hemorrhage and fungal infections as the cause of primary adrenal insufficiency. Other imaging studies depend on the syndrome components or other associated disorders present at the time of the evaluation.
See Workup for more detail.
Management
The treatment for PGA-I is targeted at whatever organ is affected. It is always best to identify and treat the respective autoimmunity before any significant morbidity can develop.
For the most part, replacement therapy and patient education about the chronic diseases are integral to treatment success.
See Treatment and Medication for more detail.
Background
Polyglandular autoimmune (PGA) syndromes (otherwise known as polyglandular failure syndromes) are constellations of multiple endocrine gland insufficiencies. Other descriptive terminologies, such as autoimmune polyendocrine syndrome (APS), also are used in the literature. In the classification of these syndromes, Roman numerals (eg, I and II) and Arabic numbers (eg, 1 and 2) have been variably used in the literature. For the purpose of consistency in this article, the term PGA and Roman numerals will be used.
Essentially, 2 types of PGA exist, type I and the more common type II, also known as Schmidt syndrome. A third type (type III), which occurs in adults, has been described. Type III does not involve the adrenal cortex, but it includes 2 of the following: thyroid deficiency, pernicious anemia, type 1A diabetes mellitus, vitiligo, and alopecia. Other disorders also have been described in association with the PGA syndromes; pulmonary hypertension in association with PGA syndrome type II (PGA-II) is one example. [1]
Historically, the interest in these syndromes began in the 19th century and essentially focused on the adrenal cortex. In 1849, Thomas Addison first described the clinical and pathologic features of adrenocortical failure in patients who also appeared to have coexisting pernicious anemia. Between 1849 and 1980, geneticists, immunologists, and endocrinologists generated a wealth of new information concerning the pathogenesis of the PGA syndromes and their component disorders.
In 1929, Thorpe and Handley recognized the association of mucocutaneous candidiasis with glandular failure, and case reports and case series have since appeared in the international literature. In 1981, Neufeld and colleagues distinguished 2 major PGA syndromes, and other authors subsequently began to add to our knowledge of these conditions. [2] In 2004, Eisenbarth and Gottlieb extended the discussion on the classification of these syndromes. [3] While they acknowledged the system that was adopted by the so-called splitters, dividing the syndromes into 4 subtypes (I, II, III, IV), Eisenbarth and Gottlieb recommended the system adapted by the "lumpers." The latter system "lumps" the syndromes into just 2 types, I and II. Finally, according to Eisenbarth and Gottlieb, the term polyendocrine is a misnomer, because these syndromes include a number of nonendocrine disorders.
PGA-I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or as Whitaker syndrome, is associated with candidiasis, hypoparathyroidism, and adrenal failure [4] (although PGA-I without mucocutaneous candidiasis has been reported in an adolescent). [5] A syndrome with these features was first described in 1946.
Pathophysiology
The evidence supporting the autoimmune etiology of polyglandular autoimmune (PGA) syndrome, type I, is based on the presence of chronic inflammatory infiltrates composed mainly of lymphocytes in the affected organs and on the presence of autoantibodies reacting to target tissue – specific antigens. The antibodies are believed to occur as a result of a breakdown in normal immunologic tolerogenesis or as a consequence of immunization with an environmental agent that has a similar antigenic molecular structure to a self-antigen.
The 3 main types of autoantibodies are directed to the surface receptor molecules, intracellular enzymes, and secreted proteins, such as hormones. Their pathogenic relevance is still unclear, and even measuring levels of these autoantibodies against endocrine glands or their components does not appear to be useful, because such antibodies may persist for years without the patient developing endocrine failure. Their primary function is to differentiate autoimmune causes and infectious/iatrogenic causes of endocrine insufficiency.
Another immunological feature is the presence of circulating neutralizing antibodies to cytokines in the peripheral blood of APECED patients. Neutralizing Abs to Th (T helper) cytokines are present in the peripheral blood of patients causing defective antifungal response, contributing to the development of mucocutaneous candidiasis. [6] Virtually all the of patients with PGA-1 have been found to express autoantibodies reacting with interferon-omega and the great majority express autoantibodies reacting with interferon alpha. [7]
With regard to genetic susceptibility, PGA-I is unique among autoimmune endocrine disorders, because it has no HLA antigen association. However, an increased frequency of HLA-A28 and HLA-A3 has been documented in PGA-I, more so than in normal controls. The genetic locus responsible for the disease has been localized to the short arm of chromosome 21 near markers D21s49 and D21s171 on band 21p22.3. A Finnish study concluded that the mutation R257X is responsible for 82% of cases. [8]
A monogenic mutation of AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs, is very strongly linked to PGA-I. [9] In autoimmune disorders such as Addison's disease, patients without the PGA-1 syndrome, do not show AIRE mutations suggesting that the gene alterations are not involved in these more common diseases, but unique to PGA-1.
Studies on young, thymectomized mice have contributed significantly to the understanding of the pathophysiology of PGA-I, as neatly illustrated by Eisenbarth and Gottlieb in a 2004 review article. [3]
Etiology
Genetic
HLA alleles are not seen in polyglandular autoimmune (PGA) syndrome, type I. The postulated genetic locus is described in Pathophysiology, with most notably being mutation of the AIRE gene.
Environmental
Precipitators of autoimmunity exist, but they continue to be elusive. Postulations include the association between congenital rubella infections and type 1 diabetes mellitus or hypoparathyroidism.
Epidemiology
United States statistics
In North America, polyglandular autoimmune (PGA) syndrome, type I, is extremely rare, and only scattered US case reports have been published. Most of the published literature has come from Europe, where the disease clusters in certain populations (see International Frequency, below). Frequency, therefore, is not well documented in the United States; the mixed ethnic makeup of the US population may explain the low rate of case clustering. The 2 largest case series from North America were published by Neufeld and colleagues in 1981 and by Heino and coauthors in 1999. [2, 10] In the latter report, 16 patients were described, including 13 white patients, 1 Hispanic individual, 1 Middle Eastern patient, and 1 Asian person.
International statistics
Polyglandular autoimmune (PGA) syndrome, type I, is a very rare disorder; it clusters in certain homogeneous ethnic populations due to consanguineous marriages and/or clustering of descendants of common family founders. These populations include special groups of Finns, Sardinians, and Iranian Jews. Less frequent clustering has been reported from northern Italy, northern Britain, Norway, and Germany. Scattered case reports from various countries around the world have been published. The highest number of patient groups has notably been reported in Finland, in successive case series over the last few decades. The prevalence of PGA-I in Finland has been estimated to be 1 case per 25,000. [8] Known frequencies in other ethnic groups include 1 case per 14,400 in Sardinians and 1 case per 9,000 in Iranian Jews. [11, 12] Approximately 400 cases have been reported worldwide. [13]
Race-, sex-, and age-related demographics
As discussed in Frequency, ethnic clustering of polyglandular autoimmune (PGA) syndrome, type I, has been observed in certain ethnic populations. Sporadic cases reported around the world have most likely been caused by various isolated mutations, many of which have been identified.
The female-to-male ratio for polyglandular autoimmune (PGA) syndrome, type I, ranges from 0.8:1 to 1.5:1, as reported in earlier case series. Figures from 2003 indicate that this ratio is between 0.8:1 and 2.4:1, indicating some tendency toward female preponderance. [14] A sporadic report from Italy, by Iannello and colleagues, showed a rather exclusive female preponderance in an X-linked inheritance fashion. [15] In reports from around the world, however, autosomal recessive inheritance has been found to be the genetic mode of transmission in most families.
Polyglandular autoimmune (PGA) syndrome, type I, usually occurs in children aged 3-5 years or in early adolescence, but it always occurs by the early part of the third decade of life. A general trend has been noted in the order of appearance of the 3 major systemic manifestations, eg, candidiasis, hypoparathyroidism, and Addison disease. However, that is not always the case, and decades may pass before the appearance of newer syndromic components. Therefore, lifelong follow-up is prudent for early detection of additional components. This cannot be overemphasized, because unrecognized hypoparathyroidism or adrenal insufficiency can be life-threatening.
Prognosis
The prognosis is variable, depending on how organs are affected and the severity of the disease.
Morbidity/mortality
The mortality and morbidity associated with polyglandular autoimmune (PGA) syndrome, type I, appear to be equivalent to the individual components of the syndrome. Certainly morbidity and mortality can be reduced with improved case findings in relatives of index cases. In individual cases, early detection of life-threatening complications, such as adrenal crisis, hypocalcemia, and sepsis, is prudent.
Complications
The following are complications of hypoparathyroidism:
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Laryngospasm
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Basal ganglial calcification
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Renal stones may arise from vitamin D use due to possible excessive urine Ca++ excretion. Urine calcium excretion may be monitored in these patients.
The following are complications of Addison disease:
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Arrhythmias secondary to electrolyte imbalance
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Loss of libido
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Psychotic illnesses
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Gastrointestinal complaints
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Complications from treatment, such as osteoporosis or gastrointestinal ulceration with concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs)
Other complications include the following:
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Neuropathies and anemia (pernicious anemia)
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Malabsorption (celiac disease)
Patient Education
Outpatient management should include patient education on the various components of polyglandular autoimmune (PGA) syndrome, type I, and the need to screen close relatives as appropriate. An important aspect of patient education is the provision of information about adrenal deficiency; subtle deficiency that goes unnoticed in normal, daily-life situations may become life-threatening in stressful situations.
