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Polyglandular Deficiency Syndromes

(Autoimmune Polyglandular Syndromes; Polyendocrine Deficiency Syndromes)

by Jennifer M. Barker, MD

Polyglandular deficiency syndromes (PDS) are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often autoimmune. Categorization depends on the combination of deficiencies, which fall within 1of 3 types. Diagnosis requires measurement of hormone levels and autoantibodies against affected endocrine glands. Treatment includes replacement of missing or deficient hormones and sometimes immunosuppressants.

Etiology

The etiology is most often autoimmune. Risk factors for development of autoimmunity include

  • Genetic factors

  • Environmental triggers

Genetic factors include the AIRE gene mutation, which is causative of type 1, and certain HLA subtypes, which are important in the development of types 2 and 3. Environmental triggers include viral infections, dietary factors, and other as yet unknown exposures.

Pathophysiology

The underlying autoimmune reaction involves autoantibodies against endocrine tissues, cell-mediated autoimmunity, or both and leads to inflammation, lymphocytic infiltration, and partial or complete gland destruction. More than one endocrine gland is involved, although clinical manifestations are not always simultaneous. The autoimmune reaction and associated immune system dysfunction can also damage nonendocrine tissues.

Classification

Three patterns of autoimmune failure have been described ( Characteristics of Types 1, 2, and 3 Polyglandular Deficiency Syndromes), which likely reflect different autoimmune abnormalities. Some experts combine type 2 and type 3 into a single group.

Type 1

Type 1 usually begins in childhood. It is defined by the presence of ≥ 2 of the following:

  • Chronic mucocutaneous candidiasis

  • Hypoparathyroidism

  • Adrenal insufficiency (Addison disease)

Candidiasis is usually the initial clinical manifestation, most often occurring in patients < 5 yr. Hypoparathyroidism occurs next, usually in patients < 10 yr. Lastly, adrenal insufficiency occurs in patients < 15 yr. Accompanying endocrine and nonendocrine disorders ( Characteristics of Types 1, 2, and 3 Polyglandular Deficiency Syndromes) continue to appear at least until patients are about age 40.


Type 2 (Schmidt syndrome)

Type 2 usually occurs in adults; peak incidence is age 30. It occurs 3 times more often in women. It typically manifests with the following:

  • Adrenal insufficiency

  • Hypothyroidism or hyperthyroidism

  • Type 1 diabetes (autoimmune etiology)


Type 3

Type 3 is characterized by

Type 3 does not involve the adrenal cortex.

Characteristics of Types 1, 2, and 3 Polyglandular Deficiency Syndromes

Characteristic

Type 1

Type 2

Type 3

Demographics

Age at onset

Childhood (3–5 yr)

Adulthood (peak 30 yr)

Adulthood (particularly middle-aged women)

Female:male

4:3

3:1

N/A

Genetics

HLA types

May influence the development of specific components of the disorder

Primarily, B8, DW3, DR3, DR4

Others in specific disorders

DR3, DR4

Inheritance

Autosomal recessive mutation of the AIRE gene

Polygenic

Polygenic

Glands affected

Common

Parathyroid

Adrenals

Gonads

Adrenals

Thyroid

Pancreas

Thyroid

Pancreas

Less common

Pancreas

Thyroid

Gonads

Variable

Clinical

Adrenal insufficiency (Addison disease)

73–100%

100%

Not seen

Alopecia

26–32%

Not seen

*

Celiac disease

Rare

Incidence uncertain

*

Chronic active hepatitis

20%

Not seen

N/A

Chronic mucocutaneous candidiasis

73–97%

Not seen

N/A

Diabetes mellitus (type 1)

2–30%

52%

*

Gonadal failure

In men, 15–25%

In women, 60%

3.5%

*

Hypoparathyroidism

76–99%

Not seen

Not seen

Malabsorption

22–24%

Not seen

N/A

Myasthenia gravis

Not seen

Incidence uncertain

*

Pernicious anemia

13–30%

< 1%

*

Sarcoidosis

Not seen

Not seen

*

Thyroid disorders

10–11%

69%

100%

Vitiligo

4–30%

5–50%

N/A

*Associated; incidence uncertain.

Usually chronic lymphocytic thyroiditis but also includes Graves disease.

N/A = data not available.

Data from Husebye ES, Perheentupa J, Rautemaa R, Kampe O: Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type 1. Journal of Internal Medicine 265: 519–529, 2009; Trence DL, Morley JE, Handwerger BS: Polyglandular autoimmune syndromes. American Journal of Medicine 77(1):107–116, 1984; Leshin M: Polyglandular autoimmune syndromes. American Journal of Medical Sciences 290(2):77–88, 1985; Dittmar M, Kahaly GJ: Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. Journal of Clinical Endocrinology and Metabolism 88:2983–2992, 2003; and Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. New England Journal of Medicine 350:2068–2079, 2004.


Symptoms and Signs

The clinical appearance of patients with PDS is the sum of the individual endocrine deficiencies and associated nonendocrine disorders; their symptoms and signs are discussed elsewhere in T he M anual . The deficiencies do not always appear at the same time and may require a period of years to manifest; in such cases they do not follow a particular sequence.

Diagnosis

  • Measurement of hormone levels

  • Sometimes autoantibody titers

Diagnosis is suggested clinically and confirmed by detecting deficient hormone levels. Other causes of multiple endocrine deficiencies include hypothalamic-pituitary dysfunction and coincidental endocrine dysfunction due to separate causes (eg, tuberculous hypoadrenalism and nonautoimmune hypothyroidism in the same patient). Detecting autoantibodies to each affected glandular tissue can help differentiate PDS from the other causes, and elevated levels of pituitary tropic hormones (eg, thyroid-stimulating hormone) suggest the hypothalamic-pituitary axis is intact (although some patients with type 2 PDS have hypothalamic-pituitary insufficiency).

Because decades may pass before the appearance of all manifestations, lifelong follow-up is prudent; unrecognized hypoparathyroidism or adrenal insufficiency can be life threatening.

Relatives should be made aware of the diagnosis and screened when appropriate. Trials following relatives of patients with type 1 diabetes for development of autoimmunity are currently enrolling.

Treatment

  • Hormone replacement

Treatment of the various individual glandular deficiencies is discussed elsewhere in T he M anual ; the treatment of multiple deficiencies can be more complex than treatment of an isolated endocrine deficiency. For example, treatment of hypothyroidism with thyroid hormone replacement can precipitate an adrenal crisis in patients with undiagnosed adrenal insufficiency.

Chronic mucocutaneous candidiasis usually requires lifelong antifungal therapy (eg, oral fluconazole or ketoconazole—see Treatment).

Clinical trials of interventions to slow the autoimmune process in type 1 diabetes have shown some promise in delaying the complete destruction of insulin -producing β-cells.

Key Points

  • Polyglandular deficiency syndromes (PDS) involve deficiencies in the function of several endocrine glands, which may occur simultaneously or sequentially.

  • Nonendocrine organs also may be affected.

  • Most cases are autoimmune; triggers are often unknown but may involve viruses or dietary substances.

  • PDS are distinguished by the glands affected.

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