Commentary

Endocrine disorders can result from defects in hormone production, receptor binding, and postreceptor signaling. Concerning production, there can be an excess or a deficiency in a hormone, or a hormonopathy (e.g., an insulinopathy). In some hormonopathies, the defective hormone is not secreted but leads to apoptotic cell death and an absolute deficiency of the hormone (e.g., permanent neonatal diabetes caused by insulin gene mutations). Autoantibodies that act like hormone agonists can produce states of hyperfunction or hypofunction when acting as receptor antagonists. Autoantibodies that bind to other cell surface receptors can also alter hormone secretion (e.g., agonist autoantibodies directed against the parathyroid's calcium-sensing receptor). An altered ability to sense the environment can produce hormone deficiency (e.g., glucokinase mutations producing maturity-onset diabetes of the young 2). Defects in receptors or signaling typically lead to loss-of-function conditions (e.g., glucocorticoid, mineralocorticoid, or androgen resistance) although gain-of-function mutations do occur (e.g., testotoxicosis or the McCune–Albright syndrome). Receptor gain-of-function mutations allow an interface between the fields of endocrinology and oncology. Endocrine disorders can be due to defective entry of hormones into target tissues (e.g., monocarboxylate transporter 8 mutations). Hormone metabolism can also be disrupted, allowing increased receptor interaction (e.g., apparent mineralocorticoid excess). Defects in postreceptor signaling are extremely prevalent: The underlying disorder in most cases of type 2 diabetes is defective insulin signaling. The distribution of receptor subtypes among tissues can markedly affect the individual's phenotype (e.g., thyroid hormone β receptor vs. α receptor mutations). Lastly, mutations in genes controlling proteins regulated by hormones can produce clinical disease. Examples include nephrogenic diabetes insipidus from aquaporin 2 mutations, vitamin D–resistant rickets from SLC34A37 [solute carrier family 34 (sodium phosphate), member 3] mutations, and mutations in SCNN1B (sodium channel, non–voltage-gated 1, β subunit) or SCNN1G (sodium channel, non–voltage-gated 1, γ subunit) in Liddle syndrome. To maximally assist the clinician, the laboratorian must be aware of the huge variety of defects that can affect the endocrine system. solute carrier family 34 (sodium phosphate), member 3 sodium channel, non–voltage-gated 1, β subunit sodium channel, non–voltage-gated 1, γ subunit.

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