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Polyglandular deficiency syndromes are characterized by concurrent subnormal function of several endocrine glands. 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.

Etiology and Pathophysiology

Endocrine deficiency can be caused by infections, infarctions, or tumors that produce partial or complete gland destruction. However, polyglandular endocrine deficiency is usually caused by an autoimmune reaction that produces inflammation, lymphocytic infiltration, and partial or complete gland destruction. Impairment of one gland by autoimmune disease is frequently followed by impairment of other glands, resulting in multiple endocrine failure. Three patterns of autoimmune failure have been described (see Table 1: Polyglandular Deficiency Syndromes: Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes).

Table 1
Characteristics of Types I, II, and III Polyglandular Deficiency Syndromes Characteristic Type I Type II Type III Age at onset Childhood (3–5 yr) Adult (peak 30 yr) Adult (before age 35) HLA types A28, A3 Primarily B8, DW3, DR3, DR4; others in specific diseases DR3, DR4 Female/male 1.4/1.0 1.8/1.0 N/A Clinical manifestations       Addison's disease 67% 100% Not seen Thyroid disease* 10–11% 69% 100% Pernicious anemia 13–15% < 1% † Diabetes mellitus ( insulin Some Trade Names HUMULIN NOVOLIN Click for Drug Monograph -dependent) 2–4% 52% † Gonadal failure 45% 3.5% † Hypoparathyroidism 82% Not seen Not seen Vitiligo 4% 5–50% N/A Chronic mucocutaneous candidiasis 73–78% Not seen N/A Chronic active hepatitis 11–13% Not seen N/A Alopecia 26–32% Not seen † Malabsorption 22–24% Not seen N/A Celiac disease and myasthenia gravis Not seen Incidence uncertain † Sarcoidosis Not seen Not seen † N/A = Data not available. *Usually chronic lymphocytic thyroiditis, but also includes Graves' disease. †Associated; incidence uncertain. Adapted from Trence DL, Morley JE, Handwerger BS: Polyglandular autoimmune syndromes. American Journal of Medicine 77(1):107–116, 1984; and from Leshin M: Polyglandular autoimmune syndromes. American Journal of Medical Sciences 290(2):77–88, 1985; used with permission.

Type I: Onset usually occurs in childhood (particularly between ages 3 and 5) or in adulthood before age 35. Hypoparathyroidism is the most frequent endocrine deficiency (79%), followed by adrenocortical failure (72%). Gonadal failure occurs after puberty in 60% of women and in about 15% of men. Chronic mucocutaneous candidiasis is common. Malabsorption associated with cholecystokinin deficiency can occur; causative factors include intestinal lymphangiectasia, IgA deficiency, hypoparathyroidism, and bacterial overgrowth. Although ²⁄₃ of patients have antibodies to pancreatic glutamic acid decarboxylase, type 1 diabetes mellitus occurs infrequently. Ectodermal diseases (eg, dental enamel hypoplasia, tympanic membrane sclerosis, tubulointerstitial disease, keratoconjunctivitis) also occur. Type I may be inherited, usually in an autosomal recessive pattern.

Type II (Schmidt's syndrome): Multiple glandular failure generally occurs in adults, with peak incidence at age 30. It occurs twice as often in women. It always involves the adrenal cortex and frequently the thyroid gland and the pancreatic islets, producing type 1 diabetes. Autoantibodies against the target glands are frequently present, especially against P-450 cytochrome adrenocortical enzymes. Both mineralocorticoid and glucocorticoid deficiency can occur. Glandular destruction results mostly from cell-mediated autoimmunity, either from depressed suppressor T-cell function or some other type of T-cell–mediated injury. Reduced systemic T-cell–mediated immunity is common, manifested by a poor response on skin testing to standard antigens. Reactivity is also reduced in about 30% of 1st-degree relatives with normal endocrine function.

Some patients have thyroid-stimulating antibodies and initially present with symptoms and signs of hyperthyroidism.

Theoretically, specific HLA types may have increased susceptibility to certain viruses that might induce the destructive reaction. Inheritance usually follows an autosomal dominant pattern with variable expressivity.

Type III: Type III is characterized by glandular failure in adults, particularly middle-aged women. It does not involve the adrenal cortex but includes at least 2 of the following: thyroid deficiency, type 1 diabetes, pernicious anemia, vitiligo, and alopecia. Inheritance may follow an autosomal dominant pattern with incomplete penetrance.

Symptoms, Signs, and Diagnosis

The clinical appearance of patients with polyglandular deficiency syndromes is the sum of the individual endocrine deficiencies. There is no specific sequence in which individual endocrine deficiencies occur. Thus, patients with one endocrine deficiency should be observed over a period of years for development of additional endocrine deficiencies through repeated clinical assessment and measurements of hormone levels. Relatives should be made aware of the diagnosis and screened when appropriate. Measurement of glutamic acid decarboxylase antibodies may be useful in determining risk.

Diagnosis is suggested clinically and confirmed by detecting deficient hormone levels. Measuring autoantibodies to the affected glandular tissue can help differentiate autoimmune polyglandular endocrine dysfunction from that of other causes (eg, tuberculous hypoadrenalism, nonautoimmune hypothyroidism).

Multiple endocrine deficiencies may suggest hypothalamic-pituitary failure. In almost all cases, elevated plasma levels of pituitary tropic hormones demonstrate the peripheral nature of the defect; however, hypothalamic-pituitary insufficiency occasionally occurs as part of type II syndrome.

Asymptomatic patients at risk need not be tested with autoantibodies because such antibodies may persist for years without causing endocrine deficiencies.

Treatment

Treatment of the various individual glandular deficiencies is discussed elsewhere in The Manual. The interaction of multiple deficiencies may complicate treatment.

Chronic mucocutaneous candidiasis usually requires lifelong antifungal therapy. If given early (within the 1st 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.

Untreated, IPEX syndrome is usually fatal in the 1st year of life. The enteropathy leads to diarrhea. 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 produced by a plasma cell dyscrasia (see also Plasma Cell Disorders). Patients may have hepatomegaly, lymphadenopathy, hypogonadism, type 2 diabetes mellitus, primary hypothyroidism, hyperparathyroidism, adrenal insufficiency, and excess production of monoclonal IgA and IgG from plasmacytomas and skin abnormalities (eg, hyperpigmentation, dermal thickening, hirsutism, angiomas, hypertrichosis). Patients may have edema, ascites, pleural effusion, papilledema, and fever. Patients with the syndrome also have increased circulating cytokines (IL-1-β, IL-6), vascular endothelial growth factor, and tumor necrosis factor-α.

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 2005

Content last modified November 2005