Commentary

GENETICS SYNDROMES AND PREDISPOSITIONTO MALIGNANT NEOPLASMS

MICHAEL SWIFT, M.D.

Almost all of the autosomal recessivesyndromes associated with a high inci-dence of malignant neoplasms (ataxiatel-angiectasia), Fanconi anemia, the Bloomsyndrome, xeroderma pigmentosum,the Werner syndrome, Chediak-Higashisyndrome) have dermatological manifes-tations,^ and 2 of them are primarily der-matological.2. 3 While some of thesesyndromes are so rare that an individualclinician may never see a case in his ownpractice, interest in them has grown be-cause heterozygous carriers for each ofthese genes may constitute between 0.2and 1 % of the general population. Thus,genes for certain autosomal recessivesyndromes may also be, in heterozygotes,important in the general population inpredisposing to cancer and leukemia.

Observations

In 8 families of patients with Fanconianemia, we observed a significant in-crease in deaths from cancer and leu-kemia. ' More recently we completed astudy of 27 families of patients withataxia-telangiectasia (AT).5 There was ahighly significant increase in deaths frommalignant neoplasms in blood relativesdy ing below age 75 and an even morestriking increase in deaths from thatcause below age 45. Six of the 27 moth-

From ihe Department of Medicine and theBiological Sciences Research Center, University

of North Carolina School of Medicine,Chapel Hill, North Carolina

ers and 2 of the fathers had had a malig-nancy at the time the study was com-pleted.

We estimated that the risk of an ATheterozygote dying from a malignantneoplasm before age 45 is 5 times greaterthan the risk for an individual in thegeneral population; the risk of AT heter-ozygotes between ages 45 and 75 dy-ing from a malignant neoplasm is in-creased about twofold. The malignancieswhich appear to be associated with theataxia-telangiectasia gene are those ofthe lymphopoietic system, and ovarian,gastric, biliary system, breast and cervicalcarcinomas.

Heterozygotes for the ataxia-telangiec-tasia gene are estimated to comprise 1 %of the general population. At the pres-ent time there is no test to identifycarriers of the AT gene, and the onlyheterozygotes who can be identifiedwith certainty are the parents of affectedchildren. We have counseled the fami-lies in our study and others, seen sub-sequently, about the risk of malignantdisease. Our study does not prove

734 INTERNATIONAL JOURNAL OF DERMATOLOGY December 1975 Vol. 14

beyond all doubt that heterozygotesfor the ataxia-telangiectasia gene havean increased risk of developing canceror leukemia, but must serve as the bestavailable information until a test for theheterozygous state is developed. Withsuch a test the risk of malignancy couldbe measured directly. In counseling thefamilies, we thought that it was impor-tant to urge them to undertake a regularprogram of medical care aimed at detect-ing the neoplasms for which they havean increased risk, while not provokingan excessive and incapacitating fear ofmalignant disease.

Specific Syndromes

We are presently studying about 30families of patients with xeroderma pig-mentosum to see if there is an increasedincidence of malignant disease in heter-ozygous carriers of this gene. While agreat deal is known about abnormalitiesin DNA repair in cells from xerodermapatients,' little is known of manifesta-tions at the cellular or clinical level inheterozygous carriers. The findings fromour clinical studies of xeroderma fami-lies should be ready for analysis in early1976.

Because of the numerical relationshipbetween the frequency of homozygousaffected individuals and heterozygouscarriers in the general population (e.g.,ataxia-telangiectasia homozygotes areabout one in 40,000, while heterozygotesare about one in 100), rare autosomalrecessive syndromes which are associatedwith malignancy can be particularly use-ful in understanding genetic predisposi-tion to cancer and leukemia generally.Despite growing interest in syndromesof this type, there has not been an in-crease over the past 10 years in the num-ber so identified. While there is no apriori reason to think that additional

autosomal recessive syndromes associ-ated with cancer and leukemia will berecognized, it is important to try to iden-tify such syndromes, if they exist. A l -most all of the hundreds of recognizedautosomal recessive syndromes are notknown to be associated with cancer orleukemia. If a patient with one of thesesyndromes does develop a malignancy,the case should be published or reportedto an investigator active in this area. Itwould also be useful for physicians tonote and report instances in which aparent of a child with an autosomal re-cessive syndrome developed a malig-nancy, especially if that neoplasm oc-curred at a relatively early age.

Conclusions

Physicians at the present time cancontribute to research in this area byhelping to identify new associations ofautosomal recessive syndromes with ma-lignant disease. They can use presentlyavailable data to counsel the families ofpatients with those syndromes which, ac-cording to family studies, predispose theheterozygote to a malignancy.

References

1. Reed, W. B., Epstein, W. L., Boder, E., andSedgwick, R., Cutaneous manifestations ofataxia-telangiectasia. JAMA 195:746, 1966.

2. Cerman, J., Bloom's syndrome. I. Ceneticaland clinical observations in the first twenty-seven patients. Am. J. Hum. Cenet. 21:196,1969.

3. Robbins, J. H., Kraemer, K. H., Lutzner, M.A., Festolf, B. W., and Coon, H. G., Xero-derma pigmentosum—An inherited diseasewith sun sensitivity, multiple cutaneous neo-plasms, and abnormal DNA repair. Ann. In-tern. Med. 80:221, 1974.

4. Swift, M., Fanconi's anemia in the geneticsof neoplasia. Nature 230:370, 1971.

5. Swift, M., Sholman, L., Perry, M., and Chase,C, Malignant neoplasms in the families ofpatients with ataxia-telangiectasia. CancerRes. In press.