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Polyglandular Disorders
Definition
Polyglandular syndromes are disorders of dysfunction and pathology of more than one endocrine gland. These disorders can be classified into neoplastic syndromes with abnormal endocrine cell proliferation and often, but not invariably, hormone hypersecretion, and autoimmune syndromes , in which immune destruction of endocrine cells often results in hypofunction and reduced hormone secretion. Both the neoplastic and autoimmune polyglandular syndromes often have nonendocrine manifestations that are relatively syndrome specific. With the recent recognition of the many nonendocrine components of some autoimmune polyglandular syndromes, especially type 3, the term multiple autoimmune syndromes is increasingly being used.
With few exceptions, the polyglandular syndromes are due to germline mutations of key growth regulatory genes (neoplastic syndromes) or immune regulatory genes (autoimmune syndromes). These disorders must be differentiated from sporadic single–endocrine gland diseases for several reasons. First, recognition of a specific polyglandular syndrome should alert the clinician to look for other endocrine and extra-endocrine manifestations of the syndrome. Although some patients will present with multiple endocrine gland manifestations, some will initially present with only a single affected endocrine gland. Careful family history and screening for other endocrine and characteristic extra-endocrine manifestations are needed in such cases. Second, treatment of polyglandular disease may differ from treatment of individual gland disease. Third, because of the genetic basis of most of these syndromes, a careful family history and, in some cases, screening other family members to allow disease prevention in affected individuals are indicated.
This chapter discusses the best-characterized polyglandular disorders. Other chapters on the anterior pituitary ( Chapter 205 ), thyroid ( Chapter 207 ), adrenal cortex ( Chapter 208 ), adrenal medulla ( Chapter 209 ), pancreatic islets ( Chapters 211 and 213 ), and parathyroids ( Chapter 227 ) should be consulted for more detailed discussion of the diseases of individual glands.
Epidemiology
In the United States, the prevalence of multiple endocrine neoplasia type 1 (MEN 1) is estimated to be between 1 per 10,000 and 1 per 30,000. The total prevalence of MEN2A and B is estimated to be about 1 per 35,000.
Neoplastic Syndromes
Seven distinct neoplastic syndromes involve more than one endocrine gland: MEN 1, multiple endocrine neoplasia types 2A (MEN 2) and 2B (sometimes referred to as MEN 3), multiple endocrine neoplasia type 4 (MEN 4), , multiple endocrine neoplasia type 5 (MEN 5), Carney complex, von Hippel-Lindau disease (VHL), and McCune-Albright syndrome ( Table 212-1 ). Patients with polyglandular neoplastic syndromes typically present with their respective endocrine tumors at a younger age than patients with single-gland sporadic endocrine tumors.
TABLE 212-1
POLYGLANDULAR NEOPLASIA SYNDROMES
| SYNDROME | GENETIC BASIS ∗ | ENDOCRINE TUMORS | NONENDOCRINE FEATURES |
|---|---|---|---|
| MEN 1 | MEN1 | Parathyroid Anterior pituitary Pancreatic islet |
Subcutaneous lipomas Skin collagenomas |
| MEN 2 (A and B) | RET | Medullary thyroid cancer Pheochromocytoma Parathyroid (2A) |
Mucosal neuromas (2B) Megacolon (2B) |
| MEN 4 | CDNK1B | Anterior pituitary Parathyroid |
Renal tumors |
| MEN5 | MAX | Pheochromocytoma Paraganglioma Anterior pituitary |
Chondrosarcoma Lung adenocarcinoma |
| Carney complex | PKAR1A | Adrenal cortex Anterior pituitary Thyroid |
Atrial myxomas Skin lentigines Blue nevi |
| von Hippel-Lindau disease | VHL | Pheochromocytoma Pancreatic islet |
Renal cell cancer CNS hemangioblastoma |
| McCune-Albright syndrome | GNAS (mosaic) | Thyroid Anterior pituitary Adrenal cortex Gonads |
Fibrous dysplasia Café au lait skin lesions |
CNS = central nervous system; MEN = multiple endocrine neoplasia.
∗ With the exception of McCune-Albright, all syndromes are caused by heterozygous germline mutations of the gene listed and show autosomal dominant inheritance.
All but McCune-Albright syndrome are caused by heterozygous germline mutations and are inherited in autosomal dominant fashion. The genes responsible for multiple endocrine neoplasia 1, 4, 5, Carney complex, and von Hippel-Lindau disease act as tumor suppressor genes. Germline loss-of-function mutations in one allele are followed by somatic mutations that inactivate the second normal allele, thereby leading to tumorigenesis. The basis for the tissue-specific expression of both the endocrine and extra-endocrine manifestations of these syndromes is not well understood, but the germline nature of the mutation and the expression of the affected gene in more than one endocrine gland explain the polyglandular aspect of the disorder. Multiple endocrine neoplasia 2A and 2B, in contrast, are caused by germline activating mutations of an oncogene, RET . The pattern of expression of this gene, involving chromaffin cells, helps explain the specific clinical manifestations. McCune-Albright syndrome is caused by a somatic rather than germline mutation that constitutively activates the ubiquitously expressed GNAS gene. This mutation, which may occur early in embryogenesis, leads to unregulated cyclic adenosine monophosphate (cAMP) formation in affected cells. The resultant mosaic distribution of the mutant gene helps explain the pleiotropic manifestations of the disease.
Treatment
Treatment of the polyglandular neoplastic syndromes, both in terms of the neoplastic component and the hormone hypersecretion, poses greater challenges than treatment of individual endocrine tumors. For disorders with high risk of fatal cancer, such as medullary thyroid cancer in multiple endocrine neoplasia 2, early genetic diagnosis and prophylactic surgical removal of the thyroid is indicated. In other disorders such as multiple endocrine neoplasia 1 and Carney complex, less aggressive approaches such as selective tumor resection and pharmacologic treatment to reduce hormone hypersecretion may be more appropriate. More detailed discussion of the clinical features, diagnosis, and treatment of these neoplastic syndromes may be found in other chapters (multiple endocrine neoplasia 1 in Chapter 227 ; multiple endocrine neoplasia 2 and 3 in Chapter 213 ; McCune-Albright syndrome in Chapters 214 and 217 ).
Autoimmune Syndromes
Organ-specific autoimmune disease, characterized by lymphocytic infiltration and organ-specific autoantibodies, commonly results in endocrine hypofunction. Not uncommonly, however, disorders of more than one endocrine gland appear in families or individual patients. Characteristic patterns of disease presentation and genetic inheritance allow the definition of two syndromes with overlapping manifestations ( Table 212-2 ).
TABLE 212-2
CLINICAL FEATURES OF AUTOIMMUNE POLYGLANDULAR SYNDROMES
| FEATURE | TYPE 1 | TYPE 2 |
|---|---|---|
| Mucocutaneous candidiasis | Very common | Not seen |
| Hypoparathyroidism | Common | Rare |
| Addison disease | Common | Common |
| Primary hypogonadism | Common | Occurs |
| Autoimmune thyroid disease | Rare | Common |
| Autoimmune diabetes | Occurs | Common |
| Alopecia | Common | Occurs |
| Keratopathy | Common | Not seen |
| Tympanic membrane calcification | Common | Not seen |
| Hypophysitis | Occurs | Occurs |
| Pernicious anemia | Occurs | Occurs |
| Vitiligo | Occurs | Occurs |
| Malabsorption syndrome | Occurs | Occurs as celiac disease |
| Autoimmune hepatitis | Occurs | Not seen |
| Autoimmune pneumonitis | Occurs | Not seen |
| Myasthenia gravis | Not seen | Occurs |
| Inheritance | Autosomal recessive | HLA association |
| Age at onset | Usually childhood | Usually adulthood |
HLA = human leukocyte antigen.
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