eMedicine Specialties > Endocrinology > Multiple Endocrine Disease and Miscellaneous Endocrine Disease

Polyglandular Autoimmune Syndrome, Type I

Author: Saleh A Aldasouqi, MD, FACP, FACE, Assistant Professor of Medicine, Associate Program Director, Department of Medicine, Division of Endocrinology, Michigan State University College of Human Medicine
Coauthor(s): Olakunle PA Akinsoto, MD, MB, BCh, Consulting Staff, Family Health Center, Jacksonville Medical Center; Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University
Contributor Information and Disclosures

Updated: Jan 7, 2009

Introduction

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 failure⁴ (although PGA-I without mucocutaneous candidiasis has been reported in an adolescent⁵ ). A syndrome with these features was first described in 1946. It is a rare disorder, with sporadic autosomal recessive inheritance.

Related eMedicine topics:
Polyglandular Autoimmune Syndrome, Type II
Polyglandular Autoimmune Syndrome, Type III

Pathophysiology

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.

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.⁶

A monogenic mutation of AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs, is believed to be the likely pathogenic paradigm for PGA-I.⁷

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

Frequency

United States

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.^2,8 In the latter report, 16 patients were described, including 13 white patients, 1 Hispanic individual, 1 Middle Eastern patient, and 1 Asian person.

International

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 25,000.⁶ Known frequencies in other ethnic groups include 1 case per 14,400 in Sardinians and 1 case per 9,000 in Iranian Jews.^9,10

Mortality/Morbidity

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.

Race

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.

Sex

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.¹¹ A sporadic report from Italy, by Iannello and colleagues, showed a rather exclusive female preponderance in an X-linked inheritance fashion.¹²  In reports from around the world, however, autosomal recessive inheritance has been found to be the genetic mode of transmission in most families.

Age

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.

Clinical

History

• Overview of clinical features
  • The 3 major components of polyglandular autoimmune (PGA) syndrome, type I, are (1) chronic mucocutaneous candidiasis, (2) hypoparathyroidism, and (3) autoimmune adrenal insufficiency.
  • 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), hypogonadism, pernicious anemia, malabsorption, 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.
  • Overall, the 3 components occur in fairly precise chronological order, and they are present in roughly 40% of cases. As mentioned earlier, however, careful follow-up is mandatory to watch for the more dreadful manifestations, eg, adrenal insufficiency, regardless of the reportedly expected pattern of appearance.
  • The probability that multiple components of the disease will occur depends on how early the symptoms appear.
  • In a case of PGA-I reported by Bhansali and colleagues, no candidiasis was noted in an East Indian boy aged 16 years.⁵
• Mucocutaneous candidiasis
  • This condition usually occurs earliest and is the most common of the 3 main diseases of PGA-I.
  • Assess any young person with moniliasis for a possible state of T-cell deficiency and PGA-I.
  • Between 50 and 100% of patients with PGA-I develop a recurrent monilial infection. Most of the lesions are limited to the skin (usually <5% of surface area), nails, and oral and anal mucosa.¹³ Esophageal involvement may be complicated by strictures and stenosis.
  • Even though the presence of candidiasis is consistent with a T-cell defect, no increased frequency of other opportunistic infections exists.
  • Because these patients have a normal B-cell response to candidal antigens, they are spared from developing disseminated candidiasis.
• Hypoparathyroidism⁴
  • This is the first endocrine disease to occur during the course of PGA-I, usually developing after candidiasis and before Addison disease.
  • Antiparathyroid antibodies have been reported in 10-40% of patients with hypoparathyroidism; however, whether these are being confused with mitochondrial autoantibodies is still under debate. The pathologic significance of these antibodies is not clear.
  • Other disease states presenting with neonatal hypocalcemia (DiGeorge syndrome or congenital absence or malformation of the parathyroid) must be differentiated from PGA-I. DiGeorge syndrome results from a congenital defective disorder of the branchial clefts. It manifests as hypoparathyroidism and cutaneous candidiasis; unlike PGA-I, DiGeorge syndrome does not involve the adrenal glands.
  • More than 75% of patients develop hypoparathyroidism, which usually presents in persons younger than 10 years.
  • Clinical features may include, among others, (1) tetanic clinical symptoms, such as carpopedal spasm and paresthesias of the lips, fingers, and feet; (2) seizures; (3) laryngospasm; (4) leg cramps; (5) diffuse mild encephalopathy; (6) cataracts; and (7) papilledema. Electrocardiography may show a prolonged QT interval.
• Adrenocortical failure (Addison disease)
  • Addison disease typically occurs in people aged 10-30 years (mean, 12-13 y); it usually is the third disease to appear in PGA-I.
  • Mineralocorticoid and glucocorticoid deficiencies usually arise simultaneously, but their onset can be dissociated by up to 3 years.
  • CYP21 appears to be the major autoantigen in isolated Addison disease and Addison disease associated with PGA-II. Autoantibodies to CYP17 and a side-chain cleavage enzyme (CYP11A1) have been associated with Addison disease in PGA-I.
  • Early symptoms include weakness, fatigue, and orthostatic hypotension.
  • Pigmentation usually is increased and may serve as a differentiating point from secondary hypoadrenalism (primary pituitary failure).
  • Anorexia, nausea, vomiting, diarrhea, and cold intolerance often occur.
  • Late symptoms include weight loss, dehydration, hypotension, and a small-sized heart.
• Less common clinical manifestations
  • Hypergonadotropic hypogonadism
  • Type 1 diabetes mellitus
  • Autoimmune thyroid disease (not including Graves disease)
  • Pernicious anemia
  • Chronic atrophic gastritis
  • Chronic active hepatitis
  • Enamel hypoplasia, which occasionally precedes the onset of hypoparathyroidism
  • Asplenia
  • Keratoconjunctivitis
  • Cholelithiasis
  • Malabsorption
  • Alopecia
  • Vitiligo
  • Interstitial nephritis

Related eMedicine topics:
Addison Disease [Dermatology]
Addison Disease [Endocrinology]
Adrenal Insufficiency
Adrenal Insufficiency and Adrenal Crisis
Candidiasis, Chronic Mucocutaneous
Hypoparathyroidism [Emergency Medicine]
Hypoparathyroidism [Endocrinology]
Hypoparathyroidism [Pediatrics: General Medicine]

Physical

Physical findings in polyglandular autoimmune (PGA) syndrome, type I, are dependent on the components of the syndrome that are clinically manifested at the time of examination.

Causes

• Genetic
  • HLA alleles are not seen in polyglandular autoimmune (PGA) syndrome, type I.
  • The postulated genetic locus is described in Pathophysiology.
• 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.

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