150 their independent survival it is probably essential that such alien practices remain so. It is therefore hardly surprising that there is no call for intervention from unknown outsiders in the care of "desperately ill adults" who might surely be regarded as hopeless cases. Far from being evidence for any breakdown in attitudes to their environment, it seems that the Somali nomads are being remarkably consistent in the expression of their values. There are obvious dangers in making judgements about societies without a sense of their historical perspective. All of us involved in this type of aid or who try to weigh up its value have to face up to the issues. We would concur that the shelters create many problems when they threaten to transform freemoving pastoralists into sedentary cereal eaters and pill-takers. We cannot see that more blankets, clothing, or a dose of preventive medicine will improve their fundamental impact. If the shelters are only refeeding centres, and not destined to have a more lasting effect on pastoral life, then it would seem the best thing for the nomads is that they be released from reliance on them as fast as oossible. 79 Long Acre, Bingham, Notts NG13
ONE DRUG
THERÈSE BLANCHET-COHEN NICHOLAS M. COHEN
8BU
(PHENYTOIN) IN TREATMENT
OF
EPILEPSY
interested in the article by Reynolds et al.’1 because I agree with their desire to reduce, as far as possible, the dose and number of drugs used in epilepsy. I treat epileptics with behaviour disorders, and phenytoin has proved disappointing because of the high incidence of unwanted effects. I am not certain of the reason for this since I use doses well within the usual range. Perhaps the combination with barbiturate (I use either phenobarbitone or primidone) could partly account for my difficulty. I wonder if Dr Reynolds and his colleagues have any observations about this and if they could tell us the type and number of unwanted effects they encountered in their trial.
SIR,—I
was
Special Hospitals Research Unit, Institute of Psychiatry,
JOHN GUNN
London SE5
* * This letter has been shown to Dr gues, whose reply follows.-ED.L.
Reynolds
and his collea-
SIR,-We thank Dr Gunn for his letter and share his
FETAL HYDANTOIN SYNDROME AND NEUROBLASTOMA
SIR,-A pattern of abnormalities referred to as the "fetal hydantoin syndrome" has been described in some infants born to women receiving phenytoin or other hydantoin anticonvul-
during pregnancy.’ Phenytoin may also be oncogenic.2 We have evaluated a child with the fetal hydantoin syndrome who had a fatal neuroblastoma. The association of these events raised the question of a causal relationship between them.
sants
This child was born to an otherwise healthy 24-year-old who had been taking phenytoin and phenobarbitone for a grand-mal seizure disorder since age 14. The pregnancy was complicated by two seizures and was terminated by caesarean section at 43 weeks. Birth-weight was 2950 g. There were no neonatal problems; however, postnatal growth was poor and the infant was mildly developmentally delayed. At 3 years of age she presented with a large abdominal tumour and was admitted to the Children’s Orthopedic Hospital and Medical Center, Seattle. She was below the third percentile for height and weight. Head circumference was 49.1 cm. She displayed numerous features of the fetal hydantoin syndrome including metopic sutural ridging, hypertelorism, ptosis, bilateral epicanthic folds, finger-like thumbs, and hypoplasia of distal phalanges and nails. Despite intensive chemotherapy, radiotherapy, and supportive care, she died from problems related to disseminated intravascular coagulation. Necropsy revealed metastatic neuroblastoma. No other anomalies were found. The association of these findings in a single patient could be due to chance. However, Blake and Fallinger3 have lately suggested that formation of epoxides may be an intermediate step in the metabolism of phenytoin in some individuals. These substances have been reported to be oncogenic.4 This raises the possibility that malignant tumours could be a rare but nonrandom event in individuals exposed to hydantoins prenatally. A search for a maternal history of treatment with hydantoin anticonvulsants during pregnancy in children with neuroblastoma or other childhood malignancies might shed further light on this hypothesis. We would be most interested to hear if others have observed this syndrome in association with malignancies. woman
Division of Hematology/Oncology, Children’s Orthopedic Hospital and Medical Center, Seattle, Washington 98105, U.S.A.
THOMAS W. PENDERGRASS
Division of Medical Genetics, University of Washington School of Medicine
JAMES W. HANSON
con-
about the unwanted effects of phenytoin and other anticonvulsants. Indeed, this was one of the main motivating factors for our study of the value of single drug therapy, as the number of undesirable effects increases with the number of
cern
2
drugs consumed.
Apart from the
acute toxicity noted in our paper, we have any obvious side effects, but, because we believe that many of the undesirable effects are subtle and insidious, we are monitoring the evolution of such chronic toxicity as folate and vitamin D deficiency in our trial, which is continuing, and this aspect will be reported on later. Unlike those of Dr Gunn, our patients did not have behavioural disorders, but we agree with him that both phenytoin and barbiturates can be disappointing in his type of patient, not least because the drugs may aggravate the underlying behaviour disorder.’ In our experience carbamazepine (’Tegretol’) is less troublesome in this erouo of oatients. E. H. REYNOLDS Department of Neurology, D. CHADWICK Institute of Psychiatry, A. W. GALBRAITH London SE5 8AF
not seen
1. 2. 3.
Reynolds, E. H., Chadwick, D., Galbraith, A. W. Lancet, 1976, Reynolds, E. H. Epilepsia, 1975, 16, 319. Trimble, M., Reynolds, E. H. Psychol. Med. 1976, 6, 169.
i, 923.
FLUORIDE AND FLUOROSIS
SIR,-Cook and France’refer to "the W.H.O.’s admission that intakes of from 2 mg per day [of fluoride] can in the long run lead to skeletal fluorosis." In fact, p.239 of the W.H.O. report Fluorides in Human Health states: "At higher levels of ingestion-from 2 to 8 mg daily-when signs of fluorosis appear in teeth mineralised during the ingestion period ...". It is well established that the prevalence of white marks on the teeth resembling those of dental fluorosis is reduced in children who received drinking water fluoridated at 1 p.p.m. during tooth development, compared with those with no additional fluoride. Thus Cook and France’s data would suggest that the figure given in the W.H.O. report cited is too low. Department of Oral Physiology, Dental School, University of Newcastle upon Newcastle NE2 4AJ
Tyne,
W.
M. EDGAR
Hanson, J. W., Smith, D. W. J. Pediat. 1975, 87, 285. Hoover, R., Fraumeni, J. F. in Persons at High Risk of Cancer (edited by J. F. Fraumem); chap. 12. New York, 1975. 3. Blake, D. A., Fallinger, C. Teratology, 1976, 13, 17A. 4. Jerina, D. M., Daly, J. W. Science, 1974, 185, 573. 5. Cook, H. A., France, B. A. Lancet, 1976, i, 1419.
1. 2.
ONE DRUG
THERÈSE BLANCHET-COHEN NICHOLAS M. COHEN
8BU
(PHENYTOIN) IN TREATMENT
OF
EPILEPSY
interested in the article by Reynolds et al.’1 because I agree with their desire to reduce, as far as possible, the dose and number of drugs used in epilepsy. I treat epileptics with behaviour disorders, and phenytoin has proved disappointing because of the high incidence of unwanted effects. I am not certain of the reason for this since I use doses well within the usual range. Perhaps the combination with barbiturate (I use either phenobarbitone or primidone) could partly account for my difficulty. I wonder if Dr Reynolds and his colleagues have any observations about this and if they could tell us the type and number of unwanted effects they encountered in their trial.
SIR,—I
was
Special Hospitals Research Unit, Institute of Psychiatry,
JOHN GUNN
London SE5
* * This letter has been shown to Dr gues, whose reply follows.-ED.L.
Reynolds
and his collea-
SIR,-We thank Dr Gunn for his letter and share his
FETAL HYDANTOIN SYNDROME AND NEUROBLASTOMA
SIR,-A pattern of abnormalities referred to as the "fetal hydantoin syndrome" has been described in some infants born to women receiving phenytoin or other hydantoin anticonvul-
during pregnancy.’ Phenytoin may also be oncogenic.2 We have evaluated a child with the fetal hydantoin syndrome who had a fatal neuroblastoma. The association of these events raised the question of a causal relationship between them.
sants
This child was born to an otherwise healthy 24-year-old who had been taking phenytoin and phenobarbitone for a grand-mal seizure disorder since age 14. The pregnancy was complicated by two seizures and was terminated by caesarean section at 43 weeks. Birth-weight was 2950 g. There were no neonatal problems; however, postnatal growth was poor and the infant was mildly developmentally delayed. At 3 years of age she presented with a large abdominal tumour and was admitted to the Children’s Orthopedic Hospital and Medical Center, Seattle. She was below the third percentile for height and weight. Head circumference was 49.1 cm. She displayed numerous features of the fetal hydantoin syndrome including metopic sutural ridging, hypertelorism, ptosis, bilateral epicanthic folds, finger-like thumbs, and hypoplasia of distal phalanges and nails. Despite intensive chemotherapy, radiotherapy, and supportive care, she died from problems related to disseminated intravascular coagulation. Necropsy revealed metastatic neuroblastoma. No other anomalies were found. The association of these findings in a single patient could be due to chance. However, Blake and Fallinger3 have lately suggested that formation of epoxides may be an intermediate step in the metabolism of phenytoin in some individuals. These substances have been reported to be oncogenic.4 This raises the possibility that malignant tumours could be a rare but nonrandom event in individuals exposed to hydantoins prenatally. A search for a maternal history of treatment with hydantoin anticonvulsants during pregnancy in children with neuroblastoma or other childhood malignancies might shed further light on this hypothesis. We would be most interested to hear if others have observed this syndrome in association with malignancies. woman
Division of Hematology/Oncology, Children’s Orthopedic Hospital and Medical Center, Seattle, Washington 98105, U.S.A.
THOMAS W. PENDERGRASS
Division of Medical Genetics, University of Washington School of Medicine
JAMES W. HANSON
con-
about the unwanted effects of phenytoin and other anticonvulsants. Indeed, this was one of the main motivating factors for our study of the value of single drug therapy, as the number of undesirable effects increases with the number of
cern
2
drugs consumed.
Apart from the
acute toxicity noted in our paper, we have any obvious side effects, but, because we believe that many of the undesirable effects are subtle and insidious, we are monitoring the evolution of such chronic toxicity as folate and vitamin D deficiency in our trial, which is continuing, and this aspect will be reported on later. Unlike those of Dr Gunn, our patients did not have behavioural disorders, but we agree with him that both phenytoin and barbiturates can be disappointing in his type of patient, not least because the drugs may aggravate the underlying behaviour disorder.’ In our experience carbamazepine (’Tegretol’) is less troublesome in this erouo of oatients. E. H. REYNOLDS Department of Neurology, D. CHADWICK Institute of Psychiatry, A. W. GALBRAITH London SE5 8AF
not seen
1. 2. 3.
Reynolds, E. H., Chadwick, D., Galbraith, A. W. Lancet, 1976, Reynolds, E. H. Epilepsia, 1975, 16, 319. Trimble, M., Reynolds, E. H. Psychol. Med. 1976, 6, 169.
i, 923.
FLUORIDE AND FLUOROSIS
SIR,-Cook and France’refer to "the W.H.O.’s admission that intakes of from 2 mg per day [of fluoride] can in the long run lead to skeletal fluorosis." In fact, p.239 of the W.H.O. report Fluorides in Human Health states: "At higher levels of ingestion-from 2 to 8 mg daily-when signs of fluorosis appear in teeth mineralised during the ingestion period ...". It is well established that the prevalence of white marks on the teeth resembling those of dental fluorosis is reduced in children who received drinking water fluoridated at 1 p.p.m. during tooth development, compared with those with no additional fluoride. Thus Cook and France’s data would suggest that the figure given in the W.H.O. report cited is too low. Department of Oral Physiology, Dental School, University of Newcastle upon Newcastle NE2 4AJ
Tyne,
W.
M. EDGAR
Hanson, J. W., Smith, D. W. J. Pediat. 1975, 87, 285. Hoover, R., Fraumeni, J. F. in Persons at High Risk of Cancer (edited by J. F. Fraumem); chap. 12. New York, 1975. 3. Blake, D. A., Fallinger, C. Teratology, 1976, 13, 17A. 4. Jerina, D. M., Daly, J. W. Science, 1974, 185, 573. 5. Cook, H. A., France, B. A. Lancet, 1976, i, 1419.
1. 2.
