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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. Symptoms depend 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
Although individual endocrine glands can be damaged by numerous causes, including infection, infarction, and tumors, these syndromes 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
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. It typically manifests with
More rare features may also be present (see Table 1: Polyglandular Deficiency Syndromes: Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes).
Type III
Type III is characterized by
Type III does not involve the adrenal cortex.
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Table 1
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| Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes |
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Characteristic
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Type I
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Type II
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Type III
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Demographics
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Age at onset
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Childhood (3–5 yr)
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Adulthood (peak 30 yr)
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Adulthood (particularly middle-aged women)
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Female:male
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4:3
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3:1
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N/A
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Genetics
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HLA types
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A28, A3
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Primarily, B8, DW3, DR3, DR4
Others in specific disorders
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DR3, DR4
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Inheritance
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Autosomal recessive mutation of the AIRE gene
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Polygenic dominant
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Largely unknown but may be polygenic dominant
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Glands affected
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Common
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Parathyroid
Adrenals
Gonads
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Adrenals
Thyroid
Pancreas
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Thyroid
Pancreas
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Less common
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Pancreas
Thyroid
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Gonads
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Variable
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Clinical
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Adrenal insufficiency (Addison's disease)
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73–100%
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100%
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Not seen
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Alopecia
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26–32%
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Not seen
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*
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Celiac disease
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Not seen
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Incidence uncertain
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*
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Chronic active hepatitis
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11–13%
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Not seen
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N/A
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Chronic mucocutaneous candidiasis
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73–78%
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Not seen
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N/A
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Diabetes mellitus (type 1)
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2–4%
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52%
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*
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Gonadal failure
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In men, 15%
In women, 60%
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3.5%
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*
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Hypoparathyroidism
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76–99%
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Not seen
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Not seen
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Malabsorption
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22–24%
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Not seen
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N/A
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Myasthenia gravis
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Not seen
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Incidence uncertain
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*
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Pernicious anemia
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13–15%
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< 1%
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*
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Sarcoidosis
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Not seen
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Not seen
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*
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Thyroid disorders†
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10–11%
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69%
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100%
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Vitiligo
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4%
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5–50%
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N/A
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*Associated; incidence uncertain.
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†Usually chronic lymphocytic thyroiditis but also includes Graves' disease.
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N/A = data not available.
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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.
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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
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
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 or ketoconazole—see Immunodeficiency Disorders: Treatment). If given early (within the first few weeks to months) in the course of endocrine failure, immunosuppressive doses of cyclosporine 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:
Other symptoms and signs may include edema, ascites, pleural effusion, papilledema, and fever.
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
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