AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Background

Polyglandular autoimmune (PGA) syndromes (otherwise known as polyglandular failure syndromes) are constellations of multiple endocrine gland insufficiencies. Other descriptive terminologies are used in the literature; autoimmune polyendocrine syndrome (APS) is an example. Furthermore, in the classification of these syndromes, both 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 former terminology (PGA) and Roman numerals will be used.

Essentially, 2 types exist, type I and the more common type II, also known as Schmidt syndrome. A third type (type III) has been described, which occurs in adults. 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, newer disorders have been described recently in association with the PGA syndromes; pulmonary hypertension in association with PGA-II is one example.

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 1980, Neufeld et al distinguished 2 major PGA syndromes, and subsequently other authors began to add to our knowledge about this syndrome. In 2004, Eisenbarth and Gottlieb extended the discussion on the classification of these syndromes. While they acknowledged the system 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 since these syndromes include a number of nonendocrine disorders.

PGA syndrome type I (PGA-I), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or Whitaker syndrome, is associated with candidiasis, hypoparathyroidism, and adrenal failure. A syndrome with these features was first described in 1946. It is a rare disorder with sporadic autosomal recessive inheritance. More recently, PGA-I has been reported without mucocutaneous candidiasis in an adolescent.

Pathophysiology

The evidence supporting the autoimmune etiology of this disease is based on the presence of chronic inflammatory infiltrates mainly composed of lymphocytes in the affected organs and on the presence of autoantibodies reacting to target tissue-specific antigens. The antibodies are believed to arise from a breakdown in normal immunologic tolerogenesis or by 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 the secreted proteins, like 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.

More recently, 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. More recent studies on young thymectomized mice have contributed significantly to the understanding of the pathophysiology of this syndrome, as neatly illustrated by Eisenbarth and Gottlieb in a recent review article (2004).

Frequency

United States

In North America, PGA-I is extremely rare, and only scattered case reports have been published from the USA. Most of the published literature came from Europe where the disease clusters in certain populations (see International frequency below). Frequency, therefore, in the United States is not well documented; the mixed ethnic make up of the US population may explain the low rate of case clustering. The largest 2 case series from North America were published by Neufeld et al in 1981 and by Heino et al in 1999. In the latter report, 16 patients were described including 13 white, 1 Hispanic, 1 Arab, and 1 Asian.

International

PGA-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 have been published from various countries around the world. The highest number of patient groups has notably been reported in Finland in successive case series over the last few decades. The prevalence in Finland was estimated to be 1 case per 25,000. Known frequencies in other ethnic groups include: 1 case per 14,400 in Sardinians and 1 case per 9,000 in Iranian Jews.

Mortality/Morbidity

The mortality and morbidity of PGA-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 PGA-I syndrome has been observed in certain ethnic populations. Sporadic cases reported around the world are most likely caused by various isolated mutations, many of which have been identified.

Sex

The female-to-male ratio ranges from 0.8-1.5:1, as reported in earlier case series. Figures from 2003 indicate a ratio of 0.8:1 to 2.4:1 indicating some tendency toward female preponderance. A sporadic report by Iannello et al from Italy showed a rather exclusive female preponderance in an X-linked inheritance fashion. Otherwise, the autosomal recessive mode is the genetic mode of transmission in most families reported worldwide.

Age

PGA-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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

History

• Overview of clinical features
  
  
  • The 3 major components of PGA-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. Various other manifestations, including type 1A diabetes (documented autoimmune etiology), hypogonadism, pernicious anemia, malabsorption, alopecia, and vitiligo (and other recently recognized disorders), may be present as well.
  
  
  
  • In general, 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 recently reported case of PGA-I by Bhansali et al, no candidiasis was noted in an East Indian boy aged 16 years.  
     
• Mucocutaneous candidiasis
  
  
  • It 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. 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 normal B-cell response to candidal antigens, they are spared from developing disseminated candidiasis.
     
• Hypoparathyroidism
  
  
  • It is the first endocrine disease to occur during the course of PGA-I, usually occurring 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 pathological 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.
  
  
  
  • More than 75% of patients develop hypoparathyroidism, and it usually presents in people younger than 10 years.
  
  
  
  • To mention a few, clinical features may include (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. ECG may show a prolonged QT interval. It is the first endocrine disease to occur during the course of PGA-I, usually occurring after candidiasis and before Addison disease.
     
• Adrenocortical failure (Addison disease)
  
  
  • It typically occurs in people aged 10-30 years (mean, 12-13 y), and it usually is the third disease to appear in this syndrome.
  
  
  
  • Mineralocorticoid and glucocorticoid deficiencies usually arise simultaneously, but their onsets 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 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

Physical

Physical findings are dependent on the components of the syndrome clinically manifested at the time of examination.

Causes

• Genetic
  
  
  • HLA alleles are not seen in PGA-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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Other Problems to be Considered

Chromosomal disorder (45,O; trisomy 21)
Congenital rubella
Hemochromatosis
Kearns-Sayre syndrome - Possibly occurring with myopathic disease with hypoparathyroidism, primary hypogonadism, type 1 diabetes mellitus, and hypopituitarism, with or without cardiac conduction defects
Myotonic dystrophy - Hypogonadism and, occasionally, diabetes
Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS), usually occurring in Japanese patients
Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness [DIDMOAD])
Thymoma - Malignant more frequently than benign and associated with myasthenia gravis; as many as 50% of cases occur in people older than 40 years; possibly associated with Cushing, Graves, or Addison disease

Other conditions that may give rise to any of the components of the syndrome if solely present

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Lab Studies

A clinical history and examination that suggest evidence of more than 1 endocrine deficiency should prompt the use of the following tests:

• Serum endocrine autoantibody screen
• • This helps verify the autoimmune etiology of the disease and identify patients who may later develop multi-endocrine deficiency.
  
  
  
  • It is useful for screening family members who may develop autoimmune endocrine disease in the future.
  
  
  
  • The screening panel may include autoantibodies to 21-hydroxylase, 17-hydroxylase, thyroid peroxidase (TPO) and thyroid-stimulating immunoglobulins (TSI), glutamic acid decarboxylase and islet cell antibodies, and parietal cell enzyme (H⁺/K⁺-ATPase) antibodies.
  
  
  
  • Not all patients have positive antibodies; therefore, the absence of these antibodies does not exclude the disease.


• End-organ function tests are necessary to confirm the diagnosis.
  
  
  • Test testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in males.
  
  
  
  • In females who have regular menses, no laboratory assessment of the gonadotropin axis is necessary. If menses are irregular or absent, then obtain estradiol, FSH, LH, and prolactin levels.
  
  
  
  • TSH and, if necessary, free thyroxine (T4) and free triiodothyronine (T3): TSH may be elevated, and free T4 and T3 may be low.
  
  
  
  • Adrenocorticotropic hormone (ACTH) and Cortrosyn-stimulation test: ACTH may be elevated with an abnormal Cortrosyn test, which is a low cortisol level found 30 minutes after administering Cortrosyn.
  
  
  
  • Plasma renin activity: High renin activity may be noted.
  
  
  
  • Electrolytes; calcium, phosphorus, magnesium, and albumin; and fasting blood glucose: Hyponatremia, hyperkalemia, mild metabolic acidosis, and azotemia may occur with dehydration. The values for calcium, phosphorus, and magnesium vary, depending on the extravascular status of the patient and the severity and duration of illness. These also depend on the severity of hypoparathyroidism, which causes low calcium, an elevated phosphorus, and low magnesium.
  
  
  
  • Fungal skin scrapings: These may be positive for candidiasis.
  
  
  
  • Complete blood count with mean cell volume (MCV) and vitamin B-12 levels: These may show lymphocytosis, neutropenia, and anemia. If coexisting pernicious anemia exists, the MCV is elevated and the vitamin B-12 levels are low.
  
  
  
  • CD4 counts, and, possibly, HIV testing: Both of these are performed to exclude the differential diagnosis of HIV.
  
  
  
  • Some authorities recommended that some of these tests be performed on an annual basis because not all diseases manifest at the time of the initial diagnosis.
     
• Depending on the presentation, liver function tests along with antibodies to the liver, kidney, and spleen (autoimmune hepatitis) may be considered because of their occasional association with PGA-I.



• Malabsorption and atrophic gastritis occasionally are associated with PGA-I, and patients with suggestive clinical features may require endoscopic biopsies to prove the diagnosis.

Imaging Studies

• Perform 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 evaluation.

Other Tests

Other tests depend on the syndrome components or other associated disorders present at the time of evaluation.

Procedures

• Endoscopies with biopsies of the stomach and small bowel are used to rule out atrophic gastritis and celiac disease.



• Other procedures depend on the syndrome components or other associated disorders present at the time of evaluation.

Histologic Findings

Histology depends on the organ affected. There usually is chronic inflammatory cell infiltration of the affected organs. A few examples are as follows:

• Adrenal gland - May be anything ranging from cellular infiltration (lymphocytic and plasma cells) to extensive fibrosis of the adrenal cortex

• Gastric atrophy - Lymphocytic/plasma cell infiltration of the lamina propria, with a progression of parietal cells and eventual atrophy with only mucous glands

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Medical Care

Treatment is targeted to 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. The educational aspect is extremely important because it helps the patient with the early detection of any new autoimmune states and aids in the adequate treatment of this chronic syndrome.

• Mucocutaneous candidiasis
  
  
  • It is treated with oral fluconazole and ketoconazole.
  
  
  
  • Absorption of ketoconazole may be compromised if coexistent atrophic gastritis exists. Ketoconazole also may inhibit adrenal and gonadal synthesis, which could worsen the coexistent Addison disease and cause hepatitis.
  
  
  
  • Fluconazole is preferred because it does not inhibit steroidogenesis and has a less frequent occurrence of hepatitis. However, it is expensive.
     
• Hypoparathyroidism
  
  
  • It usually is gradual and permanent, and oral calcium and vitamin D usually are adequate therapy. Doses of vitamin D range from 50,000-100,000 U/d. Calcitriol (1,25-dihydroxy D) is a better choice physiologically, but it is more expensive. Other newer vitamin D synthetic analogues are also suitable for replacement, but cost is to be again considered.
  
  
  
  • In cases with coexisting malabsorption, tetany may occur and IV calcium gluconate and magnesium may be necessary.
  
  
  
  • The hypocalcemia seen in PGA-I also has been reported to be from pancreatic insufficiency, giardiasis (which occurs with increased frequency in PGA-I), and lymphangiectasia. Each of these requires specific therapy.
     
• Adrenal insufficiency (Addison disease)
  
  
  • The treatment of adrenal failure mainly depends on 2 things.
    
    
    • Whether the patient is in crises with hypotension and, as such, requires IV fluids and IV steroids influences treatment. Otherwise, whether chronic and otherwise stable oral steroids, eg, prednisone, can be used with or without fludrocortisone influences treatment.
    
    
    
    • Whether a confident diagnosis of adrenal failure can be made based on the information at hand when the patient is seen is another factor influencing treatment. This may determine what kind of IV steroid is used. If the diagnosis is not clear, then the physician may opt to use dexamethasone IV because it does not interfere with subsequent cortisol measurements required for the diagnosis of Addison disease. However, if sufficient clinical evidence exists in favor of Addison disease, then using hydrocortisone is better because of its additional mineralocorticoid benefit, as an aldosterone defect also is seen. Most of the time, a mineralocorticoid (eg, fludrocortisone) also is added to the regimen.
       
  • The glucocorticoid dose is changed according to the patient's symptoms. Monitor electrolytes and the activity levels of plasma renin to assess the efficacy of treatment with fludrocortisone.
  
  
  
  • In cases of intercurrent illness, increase the doses of hydrocortisone.
  
  
  
  • In the presence of coexisting diabetes occasionally seen with PGA-I, the daily dose usually should not exceed 30 mg/d, unless the need for a larger dosage is confirmed. This necessitates higher doses of insulin; on many occasions, this results in difficulty controlling glucose levels.
  
  
  
  • Other deficiencies seen in association with diabetes and pernicious anemia, eg, hypothyroidism, can be corrected by replacement therapy.
  
  
  
  • Adrenal gland transplants have been successful in experimental rodents and humans.
  
  
  
  • Vitamin and mineral replacement occasionally is needed to compliment hormonal replacement.

Surgical Care

No specific surgical interventions exist that are uniquely needed in the management of the PGA-I syndrome. However, complications from a component of the syndrome may require therapeutic procedures or surgical interventions, as appropriate. For example, a patient going into adrenal crisis culminating in septic/hypovolemic shock and requiring intubation and other critical care therapeutic interventions.

Consultations

• Endocrinology: Complex interactions exist that may affect the replacement of adrenal, thyroid, and parathyroid hormones; these are best handled by an endocrinologist.



• Infectious diseases - To help with recurrent candidiasis



• Gastroenterology - If bowel or hepatic involvement is noted



• Rheumatology - If necessary because of the autoimmune nature of the disease, especially when considering immunosuppressive therapy



• Other consultations may be needed according to the clinical situation.

Diet

• A high-salt diet is beneficial to patients with adrenal insufficiency.



• If coexisting diabetes is present, institute a diabetic diet.

Activity

As tolerated

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

The drugs listed here primarily are used for replacement of deficient hormones and electrolytes (except for ketoconazole). The medications detailed in the list below are the major, well-established medications available for each category. However, newer medications, especially in the antifungal category, have been introduced, and may be used by physicians qualified in using them, especially in critically ill patients in the ICU.

Drug Category: Corticosteroids

Used for adrenocortical insufficiency replacement. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Drug Category: Antifungals

These drugs treat mucocutaneous candidiasis. Mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Drug Category: Vitamins and mineral salts

Used as nutritional supplements.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Further Inpatient Care

If evidence of hypothyroidism is present, perform an adrenal evaluation before any thyroid replacement. If replacement of thyroid hormones is urgent, draw blood for later adrenal evaluation, and administer steroids before starting thyroid replacement dosing.

Further Outpatient Care

Apart from the usual medications, enforce the following measures:

• The patient's diet should be high in calcium, fresh fruits, and vegetables and low in simple carbohydrates.



• In addition to any other stress management techniques, encourage moderate exercise. This is mainly relevant for patients with adrenal insufficiency.



• Patients may need a dual-energy x-ray absorptiometry (DEXA) scan to assess any degree of osteoporosis due to long-term steroid use.



• Inform patients about the symptoms of an acute exacerbation, such as dizziness, lightheadedness, abdominal pain, and nausea and vomiting.



• In addition, make patients aware of the signs and symptoms of hypoparathyroidism, including muscle cramps or spasms.



• If evidence of hypothyroidism exists, perform an adrenal evaluation before any thyroid replacement. If replacement of thyroid hormones is urgent or emergent, draw blood for later adrenal evaluation, and administer steroids before starting thyroid replacement dosing.

In/Out Patient Meds

These medications depend on the components present in individual patients, ranging from hormone replacement to medications to manage fungal infections and other complications/deficiencies.

Deterrence/Prevention

• Strongly advise patients to wear medical alert bracelets indicating that they have adrenal insufficiency.
• Provide patients with increased steroid coverage before surgeries or periods of stress, for example, with febrile illnesses.

Complications

• Hypoparathyroidism
  • Cataracts

  • Laryngospasm

  • Basal ganglial calcification

  • Ventricular arrhythmias

  • Renal stones may arise from vitamin D use due to possible excessive urine Ca⁺⁺ excretion. Urine calcium excretion may be monitored in these patients.

• Addison disease
• • Arrhythmias secondary to electrolyte imbalance

  • Loss of libido

  • Psychotic illnesses

  • Hypoglycemic spells

  • Gastrointestinal complaints

  • Complications from treatment, such as osteoporosis or gastrointestinal ulceration with concurrent use of NSAIDs

• Other complications include the following:
• • Neuropathies and anemia (pernicious anemia)

  • Malabsorption (celiac disease)

Prognosis

The prognosis is variable, depending on how organs are affected and the severity of the disease.

Patient Education

• Outpatient management should include patient education on the various components of the syndrome and the need to screen close relatives as appropriate. An important aspect of patient education is education on adrenal deficiency, since subtle deficiency unnoticed in normal daily-life situations may become life-threatening in stressful situations.



• See Further Outpatient Care.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Medical/Legal Pitfalls

• Failure to refer the patient to a specialist (usually an endocrinologist)



• Failure to provide proper follow-up care
  
  
  • This chronic disease can have multiple pathologies.
  
  
  
  • It has an unpredictable outcome because each pathology can occur anytime during the course of the disease.
  
  
  
  • Failure to see these patients as frequently as possible can result in missing the onset of a potentially fatal pathology.
     
• Failure to provide appropriate genetic counseling

Special Concerns

When evidence of a second autoimmunity is present, consider that the patient may have PGA-I or PGA-II because of the different prognoses in the syndromes.

FURTHER READING

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

• Bjorses P, Halonen M, Palvimo JJ, et al: Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am J Hum Genet. Feb 2000;66(2): 378-92. [Medline].
• Soderbergh A, Myhre AG, Ekwall O, et al: Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab. Feb 2004;89(2): 557-62. [Medline].
• Toonkel R, Levine M, Gardner L. Erythropoietin-deficient anemia associated with autoimmune polyglandular syndrome type I. Am J Hematol. Feb 2004;75(2):84-8. [Medline].
• Högenauer C, Meyer RL, Netto GJ, Bell D, Little KH, Ferries L. Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I. N Engl J Med. Jan 25 2001;344(4):270-4. [Medline].
• An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. The Finnish-German APECED Consortium. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. Nat Genet. Dec 1997;17(4):399-403. [Medline].

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

• Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. Jun 28 1990;322(26):1829-36. [Medline].
• Beers MH, Berkow R. The Merck Manual of Diagnosis and Therapy. 1999:119-120.
• Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. Apr 1998;83(4):1049-55. [Medline].
• Bhansali A, Kotwal N, Suresh V, et al. Polyglandular autoimmune syndrome type 1 without chronic mucocutaneous candidiasis in a 16 year-old male. J Pediatr Endocrinol Metab. Jan 2003;16(1):103-5 (Abstract). [Medline].
• Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. Jul 2003;88(7):2983-92. [Medline].
• Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. May 13 2004;350(20):2068-79. [Medline].
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Article Last Updated: Sep 7, 2006