Polyglandular deficiency syndromes are characterized by sequential or concurrent 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 1 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 of Polyglandular Deficiency Syndromes
The etiology is most often autoimmune. Risk factors for development of autoimmunity include
Genetic factors
Environmental triggers
Medications
Genetic factors include the AIRE gene mutation, which is causative of type 1, and certain human leukocyte antigen (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.
Immune check point inhibitors, which are used to treat some types of cancer and are associated with autoimmune endocrine disease, including hypophysitis, thyroid disease, primary adrenal insufficiency, and type 1 diabetes mellitus, are a trigger.
Pathophysiology of Polyglandular Deficiency Syndromes
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 of Polyglandular Deficiency Syndromes
Three patterns of autoimmune failure have been described in polyglandular deficiency syndrome (see table Characteristics of Polyglandular Deficiency Syndromes), which likely reflect different autoimmune abnormalities. Some experts combine type 2 and type 3 into a single group. The prevalence of type 2 is about 1 per 1000 whereas type 1 occurs in about 1 per 100,000 (1).
Type 1 polyglandular deficiency
Type 1 polyglandular deficiency, also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), usually begins in childhood. It is caused by mutations in the AIRE gene and is inherited in an autosomal recessive pattern. It is defined by the presence of ≥ 2 of the following:
Adrenal insufficiency (Addison disease)
Candidiasis is usually the initial clinical manifestation, most often occurring in patients < 5 years of age. Hypoparathyroidism occurs next, usually in patients < 10 years old. Lastly, adrenal insufficiency occurs in patients < 15 years. Accompanying endocrine and nonendocrine disorders (see table Characteristics of Polyglandular Deficiency Syndromes) continue to appear at least until patients are about age 40.
Type 2 polyglandular deficiency
Type 2 polyglandular deficiency, also known as Schmidt syndrome, usually occurs in adults; peak incidence is age 30 years. It occurs 3 times more often in women. It is associated with certain human leukocyte antigen (HLA) genotypes and exhibits polygenic inheritance. It typically manifests with the following:
Type 1 diabetes mellitus (autoimmune etiology)
More rare features may also be present (see table Characteristics of Polyglandular Deficiency Syndromes).
Type 3 polyglandular deficiency
Type 3 is glandular failure that usually occurs in adults, particularly middle-aged women. It also is associated with certain HLA genotypes and exhibits polygenic inheritance. It is characterized by
At least one of a variety of other disorders (see table Characteristics of Polyglandular Deficiency Syndromes)
Type 3 does not involve the adrenal cortex.
Classification reference
1. Husebye ES, Anderson MS, Kampe O: Autoimmune polyendocrine syndromes. N Engl J Med 378:1132–1141, 2018. doi: 10.1056/NEJMra1713301
Symptoms and Signs of Polyglandular Deficiency Syndromes
The clinical appearance of patients with polyglandular deficiency syndromes 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 of Polyglandular Deficiency Syndromes
Measurement of hormone levels
Sometimes autoantibody titers
Diagnosis of polyglandular deficiency syndromes 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 or sarcoidosis involving multiple endocrine glands).
Type 1 polyglandular deficiency is associated with autoantibodies against type 1 interferons, and presence of these antibodies suggests the diagnosis, which can be confirmed by mutational analysis of the AIRE gene. Detecting autoantibodies to each affected glandular tissue can help differentiate polyglandular deficiency syndromes 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 polyglandular deficiency syndrome 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. A trial following relatives of patients with type 1 diabetes for development of autoimmunity found antibodies associated with type 1 diabetes, celiac disease, and/or thyroid disease in 21.5% of subjects (1).
Diagnosis reference
1. Winkler C, Jolink M, Knopff A, et al: Age, HLA, and sex define a marked risk of organ-specific autoimmunity in first-degree relatives of patients with type 1 diabetes. Diabetes Care 42:1684–1691, 2019. doi: 10.2337/dc19-0315
Treatment of Polyglandular Deficiency Syndromes
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. For example, treatment of hypothyroidism with thyroid hormone replacement can precipitate an adrenal crisis in patients with undiagnosed adrenal insufficiency.
Chronic mucocutaneous candidiasis associated with type 1 polyglandular deficiency usually requires lifelong antifungal therapy
Clinical trials of interventions to slow the autoimmune process in type 1 diabetes have shown some promise in delaying the complete destruction of insulin1, 2, 3, 4).
Treatment references
1. Cai J, Wu Z, Xu X, et alDiabetes Care 39:149–157, 2016.
2. Haller MJ, Gitelman SE, Gottlieb PA, et al: Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest 125(1):448–455, 2015.
3. Kroger CJ, Clark M, Ke Q, and Tisch RM: Therapies to suppress β cell autoimmunity in type 1 diabetes. Front Immunol 9:1891, 2018. doi: 10.3389/fimmu.2018.01891
4. Nourelden AZ, Elshanbary AA, El-Sherif L, et al: Safety and efficacy of teplizumab for treatment of type one diabetes mellitus: a systemic review and meta-analysis. Endocr Metab Immune Disord Drug Targets 21(10):1895-1904, 2021.
Key Points
Polyglandular deficiency syndromes 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, dietary substances, or drugs.
Polyglandular deficiency syndromes are distinguished by the glands affected.
Treatment involves replacement of deficient hormones.
