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Polyglandular deficiency syndromes are characterized by sequential or simultaneous deficiencies in the function of several endocrine glands that have a common cause. Etiology is most often autoimmune. Symptoms depend on the combination of deficiencies, which fall within one of 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

Although individual endocrine glands can be damaged by numerous causes, including infection, infarction, and tumors, polyglandular deficiency syndromes (PDS) usually result from an autoimmune reaction, probably triggered by a virus or other environmental antigen.

Genetic factors increase susceptibility to these syndromes, as shown by the increased presence of certain HLA subtypes in affected people and the recognition of several inheritance patterns (see Table 1: Polyglandular Deficiency Syndromes: Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes).

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 (see Table 1: Polyglandular Deficiency Syndromes: Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes), which likely reflect different autoimmune abnormalities.

Type I: Type I usually begins in childhood. The 3 primary components are

• Chronic mucocutaneous candidiasis
• Hypoparathyroidism
• Adrenal insufficiency (Addison's 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 (see Table 1: Polyglandular Deficiency Syndromes: Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes) continue to appear at least until patients are about age 40.

Type II (Schmidt's syndrome): Type II usually occurs in adults; peak incidence is age 30. It occurs 3 times more often in women than in men. It typically manifests with

• Adrenal insufficiency
• Hypothyroidism or hyperthyroidism
• Type 1 diabetes (autoimmune etiology)

Type III: Type III is characterized by

• Glandular failure occurring in adults, particularly middle-aged women
• Hypothyroidism
• At least one of a variety of other disorders (see Table 1: Polyglandular Deficiency Syndromes: Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes)

Type III does not involve the adrenal cortex.

Table 1
Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes Characteristic Type I Type II Type III 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 A28, A3 Primarily, B8, DW3, DR3, DR4 Others in specific disorders DR3, DR4 Inheritance Autosomal recessive mutation of the AIRE gene Polygenic dominant Largely unknown but may be polygenic dominant Glands affected       Common Parathyroid Adrenals Gonads Adrenals Thyroid Pancreas Thyroid Pancreas Less common Pancreas Thyroid Gonads Variable Clinical       Adrenal insufficiency (Addison's disease) 73–100% 100% Not seen Alopecia 26–32% Not seen * Celiac disease Not seen Incidence uncertain * Chronic active hepatitis 11–13% Not seen N/A Chronic mucocutaneous candidiasis 73–78% Not seen N/A Diabetes mellitus (type 1) 2–4% 52% * Gonadal failure In men, 15% 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 13–15% < 1% * Sarcoidosis Not seen Not seen * Thyroid disorders† 10–11% 69% 100% Vitiligo 4% 5–50% N/A N/A = Data not available. * Associated; incidence uncertain. †Usually chronic lymphocytic thyroiditis but also includes Graves' disease. Data from 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 The Manual. 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 II 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; measurement of glutamic acid decarboxylase antibodies may be useful in determining risk.

Treatment

• Hormone replacement

Treatment of the various individual glandular deficiencies is discussed elsewhere in The Manual; the treatment of multiple deficiencies can be more complex than treatment of an isolated endocrine deficiency.

Chronic mucocutaneous candidiasis usually requires lifelong antifungal therapy (eg, oral fluconazole Some Trade Names
DIFLUCAN
Click for Drug Monograph
or ketoconazole Some Trade Names
NIZORAL
Click for Drug Monograph
—see Immunodeficiency Disorders: Chronic Mucocutaneous Candidiasis). If given early (within the first few weeks to months) in the course of endocrine failure, immunosuppressive doses of cyclosporine Some Trade Names
NEORAL
SANDIMMUNE
Click for Drug Monograph
may benefit some patients.

IPEX Syndrome

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) is a recessive syndrome involving aggressive autoimmunity.

This rare disorder results from mutation of the transcriptional activator, FoxP3, which causes regulatory T-cell dysfunction and a subsequent autoimmune disorder.

IPEX syndrome manifests as severe enlargement of the secondary lymphoid organs, type 1 diabetes mellitus, eczema, food allergies, and infections. Secondary enteropathy leads to persistent diarrhea.

Diagnosis is suggested by clinical features and confirmed by genetic analysis.

Untreated, IPEX syndrome is usually fatal in the first year of life. Immunosuppressants and bone marrow transplantation can prolong life but are rarely curative.

POEMS Syndrome

(Crow-Fukase Syndrome)

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) is a nonautoimmune polyglandular deficiency syndrome.

POEMS syndrome is probably caused by circulating immunoglobulins caused by a plasma cell dyscrasia (see also Plasma Cell Disorders). Circulating cytokines (IL-1-β, IL-6), vascular endothelial growth factor, and tumor necrosis factor-α are also increased.

Patients may have the following:

• Hepatomegaly
• Lymphadenopathy
• Hypogonadism
• Diabetes mellitus type 2
• Primary hypothyroidism
• Hyperparathyroidism
• Adrenal insufficiency
• Excess production of monoclonal IgA and IgG from plasmacytomas and skin abnormalities (eg, hyperpigmentation, dermal thickening, hirsutism, angiomas, hypertrichosis)

Like other syndromes of undefined pathophysiology, POEMS syndrome is diagnosed based on the constellation of symptoms and signs. Criteria include the presence of polyneuropathy and monoclonal paraproteinemia plus any 2 of the other manifestations of the disorder.

Treatment consists of chemotherapy and radiation therapy followed by autologous hematopoietic or stem cell transplantation. Five-year survival is about 60%.

Last full review/revision November 2009 by Syed H. Tariq, MD

Content last modified November 2009