97

CANCER IN THE FETAL HYDANTOIN SYNDROME

SIR,-Since 1975 the fetal hydantoin syndrome (FHS) has beenregarded as a significant entity in publications on human

teratogenesis. Children exposed in utero to hydantoinanticonvulsants may display abnormalities that include prenataland postnatal growth deficiency, motor and developmentaldelays, mental retardation, characteristic craniofacial anomalies,and distal phalangeal hypoplasial Of infants so exposed, 11% have afull pattern of anomalies and an additional 3107o have someabnormalities consistent with the prenatal effects of hydantoins. 2We report here a child with FHS and neuroblastoma, the fourth

such case in the U.S. to be reported since 1976, born at full term to a25-year-old primigravida who had been treated for a seizure disorderfor 7 years. Anticonvulsant therapy during the pregnancy and forthe three preceding years including phenytoin, primidone, anddiazepam. At no time did the mother use alcohol, tobacco, orother drugs during the pregnancy. Our patient, a boy, presented at31 months of age with metastatic (stage IV) neuroblastoma. Heexhibited several manifestations of FHS, including mild motor anddevelopmental delays; small head circumference (3rd percentile at 2months, compared with 40th percentile and 50th percentile forlength and weight, respectively); ocular hypertelorism; epicanthalfolds; small ears; and very high-arched palate. He died at the age of40 months; his mother has had no further pregnancies.Although it has been estimated that one in 10 000 liveborn infants

will acquire neuroblastoma,3 recent statistics4 lead us to believe thatthis tumour might be more common. From 1973 to 1976neuroblastoma was found in the U.S. approximately 2’ 8 times morefrequently than retinoblastoma, an easily diagnosed tumour forwhich ascertainment is excellent. The vast majority of retino-blastomas will have appeared by the age of 5 or 6 years, a pattern thatalso obtains for neuroblastoma. Since the incidence of retino-blastoma is approximately 1 in 20 0005 we believe that a moreaccurate figure for the incidence of neuroblastoma would be 1 in7100 livebirths. FHS occurs at the rate of 1 in 5000 livebirths so itshould take about 45 years for 4 cases of FHS with neuroblastoma tooccur by chance; in fact, it took no more than 5 years. We concludethat there is a true association of neuroblastoma with FHS-i.e.,that neuroblastoma is a catastrophic, though possibly infrequent,feature of FHS.The four reports of neuroblastoma associated with FHS have

involved phenytoin with phenobarbitone,7,8 with phenobarbitoneplus primidone,9 and (our case) with primidone and diazepam.Primidone is converted to phenobarbitone, in part; this conversionis enhanced in patients taking phen ytoin.1 Increased plasma levelsof phenytoin may result from concurrent use of diazepam. All fourchildren with FHS and neuroblastoma have thus had prenatalexposures to both phenytoin and phenobarbitone. The similarcombinations of drugs in these four cases raise the further questionwhether phenytoin alone, or in combination with phenobarbitone,is the carcinogen. Phenobarbitone may itself be a weak carcinogenor co-carcinogen. 12 The import of a related neural crest neoplasm,

1. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975; 87: 285-902 Hanson JW, Myrianthopoulos NC, Harvey MAS, Smith DW. Risks to the offspring of

women treated with hydantoin convulsants, with emphasis on the fetal hydantoinsyndrome. J Pediatr 1976; 89: 662-68

3. Beckwith JB, Perrin EV In situ neuroblastomas: a contribution to the natural history ofneural crest tumors. Am J Pathol 1963; 43: 1089-1100.

4 Young JL, Heise HW, Silverberg E, Myers MH Cancer incidence, survival andmortality for children under 15 years of age New York: American Cancer Society,1978

5 Knudson AG Retinoblastoma’ a prototypic hereditary neoplasm. Semin Oncol 1978,5:57-60

6 Hanson JW Fetal hydantoin syndrome. In: Bergsma D, ed. Birth defects compendium,2nd ed New York: Liss, 1979: 433-34.

7 Pendergrass TW, Hanson JW. Fetal hydantoin syndrome and neuroblastoma Lancet1976, ii. 150.

8 Sherman S, Roizen N. Fetal hydantoin syndrome and neuroblastoma. Lancet 1976; ii;517

9 Allen RW, Buchler B, Ogden B, Bentley FG, Jung AL. Fetal hydantoin syndrome,neuroblastoma and hemorrhagic disease. Pediatr Res 1980; 14: 530.

10 Fincham RW, Schottelius DD, Sahs AL The influence of diphenylhydantoin onprimidone metabolism. Arch Neurol 1974; 30: 259-262.

11 Kutt H Interactions of antiepileptic drugs. Epilepsia 1975; 16: 393-40212. Gold E, Gordis L, Tonascia J, Szklo M. Increased risk of brain tumors in children

exposed to barbiturates J Natl Cancer Inst 1978; 61: 1031-34

ganglioneuroblastoma, in a 3-year-old13 is confounded by prenatalexposure to both alcohol and phenytoin.Neoplasms other than neuroblastoma in children with FHS

include a rare extrarenal Wilms’ tumour in an infant,’ malignantmesenchymoma in an 18-year-old,ls and a melanoticneuroectodermal tumour of infancy. 16 Furthermore, case reportsand epidemiological studies of patients without prenatal exposureto anticonvulsants but who are themselves treated with hydantoinsto control their seizures, indicate that use of these drugs mayincrease the risk of lymphoma and other tumours.17-21The association of neoplasia with a number of birth defects has

lent credence to the hypothesis that they are causally related andthat such neoplasms originate during embryogenesis, probablyconcomitant with the origin of the developmental defect(s) in thetarget organ(s).22,23 Genetic as well as environmental pathways ofdevelopmental defects and in utero carcinogenesis have beenrecognised.22,24 Phenytoin appears to be the best example to date ofan environmental agent that has independent teratogenic andcarcinogenic properties as well as the propensity to precipitate bothevents during embryogenesis.Laboratory of Cancer Genetics and Cytogenetics,Memorial Sloan-Kettering Cancer Center,New York, N.Y. 10021, U.S.A.

LILA T. EHRENBARDR. S. K. CHAGANTI

CANCER, CHOLESTEROL, CAROTENE,AND TOCOPHEROL

SIR,-Your correspondents (June 20, p. 1371) raise the question ofwhich, if any, of blood retinol, blood carotene, and blood cholesterolare positively or negatively correlated with the onset rates of varioustypes of cancer.Most cholesterol in human blood is found in low density (LDL) or

in high density (HDL) lipoprotein, two types of lipoproteinparticles which have almost exactly opposite physiological roles.LDL delivers cholesterol to cells in peripheral tissues while HDLremoves surplus cholesterol from peripheral tissues. The risk ofdeath from vascular disease is correlated positively with LDLcholesterol but negatively with HDL cholesterol. The totalcholesterol is largely the sum of LDL and HDL cholesterol and forseveral years scientists concerned with the aetiology of vasculardisease have accepted that LDL and HDL cholesterol must beconsidered separately, total cholesterol being merely an easilymeasured but physiologically unsatisfactory approximation to LDLcholesterol. Likewise, if blood cholesterol is any kind of a link in acausal chain that predisposes to any type of cancer, it seems likelythat LDL and HDL cholesterol will be oppositely correlated withcancer risk, so they should, wherever the data permit, be consideredseparately.

-

LDL particles also provide the main delivery system for thecarotenoids and tocopherols (M. S. Brown and J. L. Goldstein,

13. Seeler RA, Israel JN, Royal JE, Kaye CI, Rao S, Abulaban M. Ganglioneuroblastomaand fetal hydantoin-alcohol syndromes. Pediatrics 1979; 63: 524-27

14. Taylor WF, Myers M, Taylor R. Extrarenal Wilms’ tumour in an infant exposed tointrauterine phenytoin. Lancet 1980; ii. 481-82.

15. Blattner WA, Henson DE, Young RC, Fraumeni JF. Malignant mesenchymoma andbirth defects: prenatal exposure to phenytoin JAMA 1977, 238: 334-35.

16. Jimenez JF, Brown RE, Seibert RW, Seibert JJ, Char F. Melanotic ectodermal tumor ofinfancy and fetal hydantoin syndrome Am J Pediatr Hematol Oncol 1981; 3: 9-15

17 Bladé Creixenti J, Segura Porta F, Nogué Xarau S, Soriano Marin E, Garcia SanMiguel J Asociación de enfermedad de Hodgkin e hidantoinas. Comunicacion de unnuevo caso y revision de la literatura. Med Clin (Barcelona) 1980; 75: 24-26.

18. Li FP, Willard DR, Goodman R, Vawter G. Malignant lymphoma after

diphenylhydantoin (Dilantin) therapy. Cancer 1975; 36: 1359-62.19. White SJ, McLean AEM, Howland C. Anticonvulsant drugs and cancer: a cohort study

in patients with severe epilepsy. Lancet 1979; ii: 458-61.20. Jancar J. Anticonvulsant drugs and cancer Lancet 1980; i: 484.21 Clemmesen J, Hjalgrim-Jensen S. Is phenobarbital carcinogenic? A follow-up of 8078

epileptics Ecotoxicol Environ Safety 1978; 1: 457-70.22. Miller RW. Prenatal origins of cancer in man: epidemiological evidence In Tomatis

L, Mohr U, eds Transplacental carcinogenesis. Lyon: International Agency forResearch on Cancer, 1973: 175-81.

23. Napalkov NP Some general considerations of the problem of transplacentalcarcinogenesis. In: Tomatis L, Mohr U, eds. Transplacental carcinogenesis Lyon:International Agency for Research on Cancer, 1973: 1-13.

24 Chaganti RSK, Miller DR, Meyers PA, German J. Cytogenetic evidence of theintraterine origin of acute leukemia in monozygotic twins N Engl J Med 1979;300: 1032-34.