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Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes

Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1802

Correspondence: Address all correspondence and requests for reprints to: Stephen J. Marx, M.D., Building 10, Room 9C-101, National Institutes of Health, 10 Center Drive, MSC 1802, Bethesda, Maryland 20892-1802. E-mail: StephenM{at}intra.niddk.nih.gov

Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it. The gene for a hereditary tumor may contribute also to common tumors. For some syndromes, such as hereditary paraganglioma, several genes can cause a similar syndrome. For other syndromes, such as multiple endocrine neoplasia 2, one gene supports variants of a syndrome. Onset usually begins earlier and in more locations with hereditary than sporadic tumors. Mono- or oligoclonal ("clonal") tumor usually implies a postnatal delay, albeit less delay than for sporadic tumor, to onset and potential for cancer. Hormone excess from a polyclonal tissue shows onset at birth and no benefit from subtotal ablation of the secreting organ. Genes can cause neoplasms through stepwise loss of function, gain of function, or combinations of these. Polyclonal hormonal excess reflects abnormal gene dosage or effect, such as activation or haploinsufficiency. Polyclonal hyperplasia can cause the main endpoint of clinical expression in some syndromes or can be a precursor to clonal progression in others. Gene discovery is usually the first step toward clarifying the molecule and pathway mutated in a syndrome. Most mutated pathways in hormone excess states are only partly understood. The bases for tissue specificity of hormone excess syndromes are usually uncertain. In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter. Polyclonal excess of a hormone is usually from a defect in the sensor system for an extracellular ligand (e.g., calcium, glucose, TSH). The final connections of any of these polyclonal or clonal pathways to hormone secretion have not been identified. In many cases, monoclonal proliferation causes hormone excess, probably as a secondary consequence of accumulation of cells with coincidental hormone-secretory ability.

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