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ABSTRACT

Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to discovery of the usual law of Nature by careful investigation of cases of rarer forms of disease. For it has been found, in almost all things, that what they contain of useful or applicable is hardly perceived unless we are deprived of them, or they become deranged in some way. (Taken from Garrod1 quoting a letter written by William Harvey in 1657 to emphasize the value of studying human variants.)

The medical model of disease holds that manifestations are the result of a process that has a cause. The manifestations of disease are assembled in diagnosis and they constitute a taxonomy. The process which underlies them is the pathogenesis of disease. The cause of disease comprises either an event that overwhelms homeostatic mechanisms (an extrinsic cause) or one that undermines them (an intrinsic cause). Most diseases involve a combination of both (a multifactorial cause).

This text has three unifying themes. The first, and central, theme is that the causes of the diseases described are mutations (intrinsic). Because these mutations are often expressed as disadaptive phenotypes (i.e., clinical manifestations) in the universal environment, they may cause diseases that are simply inherited and classified as Mendelian or single-gene disorders. Some chapters describe more complex causes with non-Mendelian inheritance, as in the cases of Down syndrome (Familial Cardiac Myxomas and Carney Complex, a chromosomal disease) and diabetes mellitus (Genetic: One Word, Several Meanings and Ovarian Cancer, Endometrial Cancer, Cervical Cancer, a multifactorial disease). The discussion of LDL-receptor deficiency (Acknowledgments: Disorders of β- and γ-Amino Acids in Free and Peptide-Linked Forms*) and other lipoprotein disorders illustrates how a disease of heterogeneous etiology (coronary artery disease) is being broken down into its component causes, some cases being caused primarily by a defect in a single gene, and some cases being of multifactorial etiology. The text is now greatly expanded to encompass cancer, in which somatic mutation and environmental exposures play a more prominent role along with germ line mutations. Any of these three factors—germ line mutation, somatic mutation, or environmental factors—may predominate in a single individual or type of cancer. Germ line mutation is the major contributor in retinoblastoma (Oncogenes) and polyposis of the colon or hereditary nonpolyposis colon cancer (Gene Expression Profiling in Cancer and Li-Fraumeni Syndrome). Somatic mutations and environment are usually entwined, but stochastic somatic mutation independent of environment may be more prominent, as perhaps is true for many cases of breast cancer (Retinoblastoma) or pancreatic cancer (Neurofibromatosis 1), while environmental factors causing somatic mutations may be more obvious, as in the case of ...

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