October 1977 TheJournalofPEDIATRICS
693
. . . but the f a m i l y history was negative At least eight possible explanations make the diagnosis of a genetically determined disorder compatible with a negative family history. In the interests o f the patient, the family, and a clearer understanding o f genetic clinical disorders, it behooves all to respect these possibilities.
Richard C. Juberg, M . D . , Ph.D., D a y t o n , O h i o
SURELY IT HAS NOT been long since you, like me, have listened to the story of a child whose disorder seemed obviously to be genetically determined only to hear the presentation be concluded doubtfully with " . . . but the family history was negative." Did you, like me, shudder at such distrust of clinical evidence, rebel against the insecurity, and then rise to reassure the physician and staff that their diagnositc impression was likely correct regardless of the family history? Regardless of the family history! Strange words coming from a geneticist? Not really. "Regardless of the family history" means to me that the inquirer at least obtained the minimal family history and made a relevant summary' or perhaps had even compiled the maximal family history and constructed a pedigree. Then, after analyzing this information and using knowledge from the literature about the inheritance of the disorder in question, the physician concluded that the diagnosis and its sporadic occurrence in this kindred were entirely compatible. Here I should point out that to come to a clinical conclusion regardless of the family history differs from disregarding the family history. To disregard the family history is a different matter-really unforgivable-for it means that history of the family was not taken or, once taken, even superficially, was given no attention. When the family history is negative in respect to the disorder of the patient, it usually implies that no other member of the family had the same disorder that is generally accepted to be genetically determined. Presum-
From the Department of Pediatrics, Wright State University School of Medicine, and the Children's Medical Center. Reprint address: Children's Medical Center, 1735 Chapel St., Dayton, OH 45404
ably if another related person at any position in the child's pedigree appeared to have the same disorder, then the history would be positive, and the diagnosis would seem more secure. When this is not the case, it is often considered that something is wrong: possibly the diagnosis, maybe the history, or perhaps the genetic interpretation. If the diagnosis is wrong, then not just the judgment of the physician and the wisdom of the staff but also all evidence accumulated from diagnostic studies have pointed in the wrong direction. If the history is mistrusted, then the informants are considered to be inadequately informed, unobservant or unconcerned, or deliberately deceitful. If the genetic interpretation is thought in error, then perhaps either not enough data has been accumulated or the available information has been misinterpreted. Not one of these alternatives, however, need be considered, because there exist at least eight possible explanations for the compatibility of the diagnosis of a genetically determined disorder with a negative family history for the clinical entity. It behooves all to respect these possibilities. Autosomal recessive inheritance, One characteristic of this form of monogenic inheritance is that both parents and more distantly related members of the kindred of the affected person are usually unaffected with the trait. ~ The probability that the disorder will occur in a given sibling is 0.25. With this probability one must realize that by applying the binomial expansion it is evident that even in a large sibship a single affected child is not unusual. X-linked recessive inheritance. Distinct discontinuities in transmission from generation to generation characterize this mode of inheritance. ~ In addition, affected males will be the offspring of carrier females who will tend to produce normal and affected sons in equal numbers; hence, the likelihood of another affected person
Vol. 91, No. 4, pp. 693-694
694
Editor's column
The Journal of Pediatrics October 1977
depends on the number of males in the sibship. Similarly, the likelihood of affected males depends on the number of possible carrier females and the number of their sons. Furthermore, a new mutation leading to the existence of the abnormal gene in a carrier mother is apparently common. Genetic heterogeneity. More than one mode of inheritance has long been recognized for what often appears to be a single clinical entity. For example, retinitis pigmentosa may be transmitted in an autosomal recessive, an autosomal dominant, or an x-linked recessive manner. Recently, autosomal recessive inheritance of multiple epiphyseal dysplasia, the tarda form, and of craniofaciai dysostosis (the Crouzon syndrome) has been reported? ,4 A variant form of inheritance-in effect a new f o r m - c a n always be considered when the diagnosis of the disorder is unquestioned. Such a situation is important in genetic counseling. Spontaneous mutation. For a dominantly transmitted disorder, in which affected ancestors in a direct line of ascent from the index case are to be expected, an affected person resulting from a spontaneous mutation may repreSent an isolated instance in the family. Mutation rates for different disorders appear to be variable, and for some seem to be higher than for others2 Further, the possible relationship between paternal age and the appearance of mutant progeny must be recognized. ~ Nonpenetranee. By definition, penetrance results in phenotypic effect determined by an abnormal gene. Conversely, nonpenetrance produces no phenotypic effect in spite of the presence of the abnormal gene; the abnormal gene is assumed to be present by virtue of the manifest clinical disorder in the parent as well as in the child of the person said to be unaffected-hence, the evidence of nonpentrance i n one generation. Given adequate data for a disorder, t h e likelihood of nonpenetrance is estimable. ~ Expressivity. Variable expressivity or perhaps more understandably, variation in expression, is the phenomenon in which the phenotypic effect of a gene varies from one bearer to another. This apparently results from genetic modifiers, environmental modifiers, sex, age, or some combination of these. Thus, it is important that minor manifestations of a disorder, for instance a syndrome, be sought in seemingly unaffected relatives. The syndromes of facial and cranial anomalies in partie
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cular demonstrate variability in expressionT; a good example is heritable telecanthus? Extramarital paternity. Discreet inquiry concerning the identity of the father of a child with a genetic disorder, presumed to be a sporadic occurrence, should not be considered just as a last resort; those of us, whose business is to construct a pedigree from a detailed family history, recognize the frequency of extramarital parenthood. Knowledge of extramarital paternity of a seemingly sporadic case can make a great difference in formulating a genetic prognosis for the married couple, assuming that the identity of the biologic parent remains unknown. Phenoeopy. By definition, a phenocopy is presumed to be an environmentally determined copy of a genetic disorder. The diagnosis should not be based only upon an accumulation of negative data in respect to a genetic disorder, but upon some positive evidence pointing to an environmental agent, in genetic counseling, recurrence in subsequent siblings is generally considered to be most unlikely. With these possibilities in mind, the next apparently negative family history you hear should not convey negative implications. Rather, you can give careful consideration to reasonable explanations for the sporadic occurrence of a genetically determined disorder. Then, for both your patient and the family there may follow considerable prognostic benefit. REFERENCES 1. Juberg RC: Making the family history relevant, JAMA 220:122, 1972. 2. Neel JV, and Schull WJ: Human heredity, Chicago, 1954, University of Chicago Press. 3. Juberg RC, and H01t JF: Inheritance of multiple epiphyseal dysplasia, tarda, Am J Hum Genet 20:549, 1968. 4. Juberg RC, and Chambers SR: An autosomal recessive form of craniofacial dysostosis (the Crouzon syndrome), J.Med Genet 10:89, 1973. 5. Neel JV: Mutations in the human population, in Burdette WJ, editor: Methodology in human genetics, San Francisco, 1962, Holden-Day, Inc., p 210. 6. Jones KL, Smith DW, Harvey MAS, Hall BD, and Quan L: Older paternal age and fresh gene mutation: Data on additional disorders, J PEDIATR86:84, 1975. 7. Gorlin RJ, Pindborg JJ, and Cohen MM Jr: Syndromes of the head and neck, ed 2, New York, 1976, McGraw-Hill Book Company. 8. Juberg RC, and Hirsch R: Expressivity of heritable telecanthus in five generations of a kindred, Am J Hum Genet 23:547, 1971.
Erratum. In the July, 1977, issue of THE JOURNAL OF PEDIATRICS (91:143, 1977), in the article "Childhood pheochromocytoma" by Ricki G. Robinson, Vincent DeQuattro, Carl M. Grushkin, and Ellin Lieberman, the footnote of Table I should read 2.5 _+ 1.3/~g,and on page 146, lines 25 and 26, the dosages should have read 108 and 129/~g/hour and 164 and 184/~g/hour, respectively. Erratum. In the August, 1977, issue of THE JOURNALOF PEDIATRICS(91:304, 1977), in the article "Supraventricular tachycardia in newborn infants: An approach to therapy" by Victor Whitman, Zvi Friedman, William Berman, Jr., and M. Jeffrey Maisels, Fig. 1 on page 304 is upside down.