Perspectives in Biology and Medicine

ON LUMPERS AND SPLITTERS, OR THE NOSOLOGY OF GENETIC DISEASE VICTOR A. McKUSICK, M.D.* As Knut Faber pointed out in his Nosography [i], Mendelism contributed much to nosology (the study of the classification of disease) by focusing attention on specific entities. Bacteriology, with its similar emphasis on specific etiology and specific entities, had a comparable effect. One need only recall that a century ago, symptoms such as jaundice, dropsy, and anemia were viewed as entities, in much ofmedicine at least, to realize the nosologic contributions of Mendelism and bacteriology. But the main object here is to review some contemporary problems in the nosology ofgenetic disease. The two leading principles in genetic nosology are pleiotropism and genetic heterogeneity. "Pleiotropism" means multiple effects of a single etiologic factor, for example, a single gene in the genetical use to which the term is usually put. Pleiotropism is the usual, but not the sole, basis for hereditary syndromes. Linkage, that is close situation on the same chromosome of genes for the separate manifestations, is a theoretically unsatisfactory and as yet unproved explanation for Mendelizing syndromes . Because of crossing over, which in time separates even closely situated loci, linkage produces no permanent association of traits in a population. "Genetic heterogeneity" refers to the existence oftwo or more fundamentally distinct entities with essentially one and the same phenotype. Nosologists in all fields tend to be either "lumpers" or "splitters" (Fig. i).1 * Professor of medicine. TheJohns Hopkins University School ofMedicine, Baltimore, Maryland 21205. This paper was presented in part at the First Conference on the Clinical Delineation of Birth Defects, The Johns Hopkins Hospital, May 20, 1968. An article on this subject appears in Clinical Delineation ofBirth Dejects, Vol. V, No. 1, January, 1969. 1 The resemblance of the splitter to the revered Civil War president is a clue to my bias. The cartoons also indicate that splitting is harder work than lumping. 298 Victor A. McKusick · Nosology ofGenetic Disease Perspectives in Biology and Medicine · Winter 1969 Fig. i Fig. 2.—Little People of America convention, Baltimore, July 21, 1968 Psychologists tell us that we find it easier to recognize similarities than differences. Hence a natural tendency to lumping exists. However, geneticists are forced to be splitters because oftheir recurrent encounters with genetic heterogeneity in recent years. The principle of genetic heterogeneity is illustrated by a consideration ofFigure 2, a photograph ofthe national annual meeting ofan organization ofdwarfs and midgets. Clearly, ifone were to undertake a study of the genetics of short stature, or of the physiologic defects underlying short stature, or of other aspects including even the psychologic and sociologie impact ofshort stature, separation ofseparate categories would be necessary. In this absurdly obvious example, genetic heterogeneity is evident even to the casual observer, and the experienced eye can pick out more than a dozen distinct entities. (Of course, heterogeneity can also involve non-genetic bases for the phenotype, so called phenocopies.) Pleiotropism is "many from one"—multiple phenotypic features from one etiologic factor, one gene. Genetic heterogeneity is "one from many" —one and the same or almost the same phenotype from several different etiologic factors. In medical genetics, awareness ofpleiotropism and genetic heterogeneity have developed particularly in the last twenty years, the second a bit later than the first. Looking back on my own work in medical genetics, I recognize that pleiotropism was a leading concern in its earlier stages when I began working, for example, with the Marfan syndrome. Latterly , genetic heterogeneity has become increasingly the focus—for example , in studies ofthe genetic mucopolysaccharidoses and the separation of homocystinuria from the Marfan syndrome. Successive editions of Heritable Disorders ofConnective Tissue [2] illustrate this trend in nosology. In an earlier period, medical genetics suffered from excessive and improper splitting, which was at least partly inadvertent, arising as it did from specialization in medicine. Seeing cases ofone and the same entity, physicians in different specialties were concerned mainly with features falling within their particular purview and often failed to recognize that the feature ofparticular interest to them was merely part ofa syndrome. Examples are angioid streaks ofthe ophthalmologist and pseudoxanthoma elasticum ofthe dermatologist. Thus, medical geneticists have been, and continue to be, lumpers to the...