Disorders of the Peripheral Endocrine Glands
The thyroid gland originates during embryogenesis at the base of the tongue, after which cells migrate to the front of the neck to form the mature organ. Thyroid hormone, produced by the thyroid, participates in regulating many aspects of metabolism. If untreated, hypothyroidism may lead to intellectual disability, delayed growth or skeletal development, or severely reduced energy metabolism.[9] Among patients referred to our Endocrinology Service, hypothyroid cases are relatively frequent.[10] A large proportion of these are the result of autoimmune disorders. Nonautoimmune congenital hypothyroidism results in some cases from thyroid dyshormonogenesis. Alternatively, in cases of congenital hypothyroidism due to thyroid organ dysgenesis, thyroid migration is incomplete (thyroid ectopy) or else the thyroid gland is absent (athyreosis).[11–12] These conditions are diagnosed routinely by radioisotope imaging, which shows either the presence of ectopic (sub)lingual thyroid tissues in the throat or else the absence of any thyroid tissue. Ectopic thyroids are typically hormonally active (hence detectable by radioisotope uptake), but are presumably too small to generate enough thyroid hormone for full physiological function. It is unclear whether the ectopic tissues also lack some specific aspects of thyroid function. Ectopic hypothyroidism is sufficiently common that it has been accessible to twin studies. Somewhat surprisingly, monozygotic twins are usually discordant for the phenotype, consistent with a nongenetic (or at least nonheritable) etiology. It is unclear whether the primary defect is in the thyroid primordial cells themselves, the tissue through which these cells must migrate to reach the correct destination or both. Mutations in a number of genes are known to lead to hypothyroidism, mostly encoding enzymes of hormone biosynthesis or metabolism, or transcription factors that are not known to be involved in migration of the embryonic thyroid (e.g., PAX8; Table 1).[13–15]
The parathyroid glands primarily regulate calcium metabolism. As such, disorders of the parathyroid typically involve imbalances in circulating calcium and phosphorus as well as metabolic bone disorders (e.g., mutations in CASR; Table 1). Some genes with mutations causing hypoparathyroidism are known, although many cases remain uncharacterized.[16]
The adrenal glands, situated above the kidneys, play a key role in generating secondary signaling molecules, such as the corticosteroids and steroid sex hormones, that have major effects on development and metabolism. Like the pituitary itself, the adrenals consist of several suborgan compartments with different functional activities including biosynthesis and secretion of steroids (adrenal cortex) and catecholamines (adrenal medulla). Many genes are required for normal adrenal function, including receptors for some pituitary hormones or other signal transducing genes, as well as enzymes responsible for biosynthesis of the hormones of the adrenal cortex, which derive from cholesterol (Table 1).[17]
The pancreas plays a major role in glucose regulation but is not directly controlled by the pituitary. Mutations in genes involved in pancreatic function may cause diabetes, or alternatively hypoglycemia, among other phenotypes (Table 1).
As mentioned previously there are medically important autoimmune disorders that impact on endocrine system function, both genetically complex or else uncharacterized, such as Type 1 diabetes and Hashimoto type hypothyroidism, and monogenic conditions such as APECED (OMIM 240300[7]). Endocrine gland tumors can also cause abnormal hormone production (e.g., multiple endocrine neoplasia [OMIM 131100][7]). The genetics of these types of conditions is beyond the scope of this review.
Personalized Medicine. 2014;11(1):63-78. © 2014 Future Medicine Ltd.
