212 Evidence continues to accumulate about the involvement of the central nervous system in all shock states and suggesting that the resulting pathophysiological changes involve endocrine and reticuloendothelial as well as the cardiovascular and respiratory systems. Possibly more success would follow treatment directed to the initiating sources rather than to where the end-products of the resulting changes appear. 11 Chelsea Embankment, London SW3 4LE
PRENATAL DIAGNOSIS OF M.S.U.D. IN AMNIOTIC-CELL CULTURE
D. A. BUXTON HOPKIN
ANTENATAL DIAGNOSIS OF MAPLE-SYRUP-URINE DISEASE
SIR,—Maple-syrup-urine disease (M.S.U.D.) is an autosomal recessive disease affecting the degradation of the three branched-chain aminoacids leucine, isoleucine, and valine. The classical form of the disease, if untreated, is rapidly lethal. Treatment is difficult, requiring life-long restriction of the three aminoacids. Parents who have had a child with M.S.U.D. often seek antenatal diagnosis in subsequent pregnancies. The demonstration of the branched-chain ketoacid decarboxylase in cultured amniotic cells suggested the possibility of antenatal diagnosis’ and this was confirmed in a patient from this laboratory’ and by Wendel et al.2 We have now studied eighteen pregnancies at risk for M.S.U.D. The diagnosis can be made with accuracy and confidence, but care is needed with cultures of epithelial cells and with slow-growing cultures. Twelve of the
eighteen specimens investigated were sent from
other
institutions, including four from other countries. Methods of subculhave been previously described.3 Cells were harvested for assay either with a rubber policeman or with a solution of Puck’s saline A containing 0-02% (w/v) edetic acid (E.D.T.A.) and 0.05% (w/v) trypsin (two patients). The E.D.T.A.-trypsin cell suspension was immediately added to one-quarter its volume of calf serum and centrifuged. The cell button was resuspended in buffered saline containing 20% serum and transferred to reaction flasks and centrifuged. The supernatant was ’replaced with reaction mixture and decarboxylase activity was assayed.4 Approximately 4x105 cells are required for assay, but reliable results are obtained with fewer actively growing cells. Most specimens were assayed 3-5 weeks after amniocentesis. ture
Eighteen amniotic-cell cultures were investigated and a diagnosis was made in sixteen, of which four had M.S.U.D., giving the frequency of 25% expected for an autosomal recessive disease. The other twelve assays were normal and in all twelve the postnatal diagnosis was also normal. Details of the remaining six cases (A-F) are given in the table. The diagnosis was confirmed in case B by post-abortion culture and assay of fetal skin fibroblasts. In case A a type-n variant was confirmed after birth by enzyme assay of leucocytes and by clinical course. In case C a macerated fetus was delivered at another institution after abortion with prostaglandin and urea. Culture of fetal tissues failed. In case F the baby was delivered at term; symptoms of M.S.U.D. developed and the infant died in a week. No diagnosis could be made in cases D and E. In both the cells were predominantly epithelial, as they were in 5 other successful cultures. One culture (E) was received from France. Cells grew poorly and an assay was attempted with few cells. No radioactive CO2 was released, but there was also no incorporation of radioactive aminoacids into protein, indicating that the cells were no longer metabolically active. The outcome of this pregnancy is not known. In D the ratio of the ’4C02to radioactivity in protein suggested variant M.S.U.D., but the incorporation of radioactivity into protein was too low to provide confidence in the results. No diagnosis was made and the fetus was aborted at another institution. Cultures were not established from fetal tissue. 1. Dancis, J. in Antenatal Diagnosis (edited by A. Dorfman); p. 123. Chicago, 1972. 2. Wendel, U., Rudiger, H. W., Passarge, E. Humangenetik, 1973, 19, 127. 3. Cox, R. P., Macleod, C. M.J. gen. Physiol. 1962, 45, 439. 4. Dancis, J., Hutzler, J., Cox, R. P. in Tissue Culture, Methods and Applications (edited by P. F. Kruse, Jr. and M. K. Patterson, Jr.) p. 639. New York, 1973.
Amniotic cell cultures that are predominantly fibroblastic have presented no problems with the technique devised for skin fibroblasts.s However, when cultures are predominantly
epithelial they multiply slowly, delaying analysis. Harvesting cells with a rubber policeman, as we have usually done, is associated with a variable, and frequently serious, loss of enzyme activity. The use of E.D.T.A.-trypsin to remove cells from glass surfaces seems to preserve enzyme activity in epithelial cells. We now assay cell suspensions prepared by E.D.T.A.-trypsin treatment of confluent cell monolayers. Intact cells are used because disruption of cells greatly reduces enzyme activity.’ The cells are incubated for 120 min with L-valine-1-14C (specific activity 0-5 µCi/µmol). The evolution of 14C02 provides a measure of the decarboxylase activity and is expressed per mg protein. The simultaneous incorporation of the radioactive aminoacid into protein provides an indication of the number of cells that are assayed and their metabolic activity. The ratio of the 14CO2to 14C-incorporation into protein is the most satis-
factory approach to diagnosis, provided 14C-incorporation per mg protein indicates active cell metabolism. This Service Fund.
study (AM
was
supported by grants
14528 and HD
from the U.S. Public Health
04526) and by the Samuel
Division of Human Genetics, Departments of Medicine and Pediatrics, New York University Medical Center, New York, N.Y. 10016, U.S.A.
A.
Berger
RODY P. Cox
JOEL HUTZLER JOSEPH DANCIS
MATERNAL HYPERTHERMIA AND NEURAL-TUBE DEFECTS
SIR,-Retrospective studies in the north-western United a significant correlation between maternal hyperthermia during the early part of pregnancy and the incidence of anencephalyl and meningomyelocele.2 Our similar study in the mid-southern United States has detected 3 instances of maternal hyperthermia in 45 pregnancies which resulted in children with neural-tube defects (anencephaly, meningomyelocele, spina bifida, or encephalocele). Only births during the past 11 months were included. States have revealed
In
man
the neural tube closes between the 22nd and 28th
gestation. The mothers in this study were questioned particularly about hyperthermia due to illness or prolonged sauna usage during the third, fourth, and fifth weeks of ges-
day
of
tation. This interval
was
chosen because most of the dates of
conception were only approximate. 1 mother reported "quite high" fever lasting 2 or 3 days and caused by streptococcal Elsas, L. J., Priest, J. H. Wheeler, F. B., Danner, D. J., Pask, B. A., Metabolism, 1974, 23, 569. 1. Miller, P., Smith, D. W., Shepard, T. H. Lancet, 1978, i, 519. 2. Chance, P. F., Smith, D. W. ibid. p. 769. 5.
213 at the end of the first month after conception. The infant was born with a thoracolumbar meningomyelocele. The second mother had had influenza for 7 days during the third and fourth weeks after conception with fever that peaked at 40°C. The pregnancy resultedin a child with a nasal encephalocele. A third instance of maternal hyperthermia resulted from sauna usage of 45 min duration on four occasions during the fifth week after conception. On one of these occasions the temperature of the sauna rose to 43 °C. The infant was born with a posterior encephalocele and a meningocele. The control group for this study came from two different sources. Since only 20 matched controls could be obtained (friends or neighbours pregnant at the same time as the mothers of the babies with neural-tube defects), another 28 controls were obtained from a group of women who were in the City of Memphis Hospital after giving birth to normal babies. 1 mother of the 48 controls had had hyperthermia due to pelvic inflammatory disease, but this had been during the sixth week after conception, well after the expected date of closure of the neural tube. Our findings support those of Smith and his colleagues (7 instances of hyperthermia in 63 mothers of infants with anencephalyl and 3 of hyperthermia in 43 mothers of infants with meningomyelocele.2 We suggest that hyperthermia lowers the threshold for the expression of these polygenically inherited neural tube defects. A thorough prospective evaluation of maternal hyperthermia and neural-tube defects is needed.
pharyngitis
,
Department of Pediatrics,
University of
Tennessee Center for the Health Services, Memphis, Tennessee 38163, U.S.A.
LINDA RUTH HALPERIN ROBERT S. WILROY, JR
MATERNAL AGE AND DOWN SYNDROME
SIR,-Substantial data
the maternal-age-specific incidence of Down syndrome and other chromosome aberrations derived from the results of prenatal diagnosis were presented at the 3rd European Prenatal Diagnosis Conference held in Munich in April, 1978. Over thirty centres in Europe (and one in Israel) contributed results from 16 273 pregnancies tested in women 35 years of age and over. On average, the rates for Down syndrome in these pregnancies are 33% above the rates determined from live births. This effect is seen at all maternal ages above 35 years and not just in the 40-44 year old mothers as suggested in your editorial of July 1. In fact, the major effect is seen in the 35-39 year age-group where the rate of 0.84% is 37% above the expected rate; at 40-44 and 45-49 years the rates are 2.31% and 4.87%, respectively, and the increases over the expected rate are 33% and 26%. (In these calculations the maternal age is the age at delivery and not the age at amniocentesis.) These figures show that earlier reports2-4 on the discrepancy between prenatal and postnatal rates were not just chance observations in small samples. Up to two-thirds of the discrepancy may be attributable to fetal loss between 16 weeks’ gestation and term, and some may be due to the selection of older mothers for amniocentesis for reasons other than maternal age.4 An important possibility mentioned in your editorial which has not been sufficiently emphasised in the past, is that the age-specific incidence may have been increasing,56 the effect being most marked in the 35-39 year age-group.? The New York studyl appears to be the most up-to-date live-birth study and this relates to births in 1963-74, whereas most of on
the amniocentesis data have been obtained in 1976-77 and almost all since 1974. Prenatal rates for chromosome aberrations may thus reflect current postnatal rates more closely than is generally supposed. There was much discussion in your correspondence columns of June 17 about which risk to quote to the older mother con-
templating prenatal diagnosis. Epidemiologists seem to prefer to use the risk of the birth of an affected living child, on the grounds of burden to the family and community. However, the parental distress associated with late abortion and stillbirth must not be discounted. Genetic counsellors appreciate that parents want to take account of all the facts. Ideally, these should include up-to-date prenatal and postnatal rates for both Down syndrome and all other chromosome aberrations. With the increasing use of prenatal diagnosis it will soon be difficult to obtain accurate postnatal rates and it may be that the best estimate of this will be the prenatal rate suitably corrected for fetal loss between 16 weeks and term. Maternal-age-specific rates for chromosome aberrations other than Down syndrome are not available from live birth studies, but the Munich data show that they add about 1% to the prenatal rate calculated for Down syndrome in women 35 years of age and over. It seems likely that many obstetricians are deterred from offering amniocentesis to their patients in the 35-39 years age group because they use obsolete and incomplete information and believe the risk of a fetal chromosome abnormality may not be sufficiently different from the risk of fetal loss after amniocentesis to justify the procedure. It would be preferable if all older mothers in need of pre-amniocentesis counselling were given the current age-specific prenatal rates for chromosome
aberrations and
1976, ii, 516. 5. Mikkelsen, M., Fischer, G., Stene, J., Stene, E., Petersen, E. Ann. hum. Genet. 1976, 40, 177. 6. Holloway, S., Emery, A. E. H.J. biosoc. Sci. 1977, 9, 453. 7. Evans, J. A., Hunter, A. G. W., Hamerton, J. L. J. med. Genet. 1978, 15, 43.
advised that up
to
20% of abnormal
research into the maternal-age-specific incidence of chromosome aberrations in late abortions and stillbirths. Department of Medical Genetics, Royal Hospital for Sick Children, Glasgow G3 8SJ
M. A. FERGUSON-SMITH
TREATMENT OF PAGET’S DISEASE
SIR,-Recent letters have raised some important points conthe treatment of Paget’s disease. Professor Milhaud’ advocates a very-low-dose regimen of (porcine) calcitonin which has given favourable therapeutic results. We agree that small doses of calcitonin may relieve pain in some cases of Paget’s disease and that the ideal dosage scheme remains to be established. However, it is clear that higher doses of calcitonin are required to heal the bones in the osteolytic phase of the disease, and low doses cannot be recommended in this situation since they are insufficient to check the advance of the resorptive process. 2-4 Dr Hamdy5 states that the main aim of treating Paget’s disease is to prevent complications and believes that pagetic pain usually responds to ordinary analgesics. Our experience is different. Simple analgesics may relieve mild pagetic pain but are ineffective in the more severe cases. We have seen many patients with frankly pagetic pain (i.e., not associated with concomitant osteoarthritis) who have gained pain relief with calcitonin after conventional analgesics had proved completely ineffective.
cerning
Endocrine Unit,
Royal Postgraduate Medical School, London W12 0HS
1. Hook, E., Chambers, G. C. Birth Defects orig. Art. Ser. 1977, 13 (3A), 123. 2. Ferguson-Smith, M. A. Lancet, 1976, ii, 252. 3. Ferguson-Smith, M. A., Ferguson-Smith, M. E. in Prenatal Diagnosis (edited by A. Boué); p. 81. INSERM, Paris, 1976. 4. Polani, P. E., Alberman, E., Berry, A. C., Blunt, S., Singer, J. D. Lancet,
were
conceptions might be lost between 16 weeks and term. Improvement in this advice can only come from more detailed
IMOGEN M. A. EVANS I. MACINTYRE
Milhaud, G. Lancet, 1978, i, 1153. Doyle, F. H., Pennock, J., Greenberg, P. B., Joplin, G. F., MacIntyre, I. in Endocrinology 1973 (edited by S. Taylor); p. 425. London, 1974. 3. Evans, I. M. A., Doyle, F. H., Banks, L., Pennock, J., Joplin, G. F., MacIn-
1. 2.
tyre, I. in Molecular Endocrinology (edited by I. Maclntyre and M. Szelke); p. 235. Amsterdam, 1977. 4. Nagant de Deuxchaisnes, C., Rombauts-Lindemans, C., Huaux, J. P., Malghem, J., Laldague, B. ibid. p. 213. 5. Hamdy, R. Lancet, 1978, i, 1267.
PRENATAL DIAGNOSIS OF M.S.U.D. IN AMNIOTIC-CELL CULTURE
D. A. BUXTON HOPKIN
ANTENATAL DIAGNOSIS OF MAPLE-SYRUP-URINE DISEASE
SIR,—Maple-syrup-urine disease (M.S.U.D.) is an autosomal recessive disease affecting the degradation of the three branched-chain aminoacids leucine, isoleucine, and valine. The classical form of the disease, if untreated, is rapidly lethal. Treatment is difficult, requiring life-long restriction of the three aminoacids. Parents who have had a child with M.S.U.D. often seek antenatal diagnosis in subsequent pregnancies. The demonstration of the branched-chain ketoacid decarboxylase in cultured amniotic cells suggested the possibility of antenatal diagnosis’ and this was confirmed in a patient from this laboratory’ and by Wendel et al.2 We have now studied eighteen pregnancies at risk for M.S.U.D. The diagnosis can be made with accuracy and confidence, but care is needed with cultures of epithelial cells and with slow-growing cultures. Twelve of the
eighteen specimens investigated were sent from
other
institutions, including four from other countries. Methods of subculhave been previously described.3 Cells were harvested for assay either with a rubber policeman or with a solution of Puck’s saline A containing 0-02% (w/v) edetic acid (E.D.T.A.) and 0.05% (w/v) trypsin (two patients). The E.D.T.A.-trypsin cell suspension was immediately added to one-quarter its volume of calf serum and centrifuged. The cell button was resuspended in buffered saline containing 20% serum and transferred to reaction flasks and centrifuged. The supernatant was ’replaced with reaction mixture and decarboxylase activity was assayed.4 Approximately 4x105 cells are required for assay, but reliable results are obtained with fewer actively growing cells. Most specimens were assayed 3-5 weeks after amniocentesis. ture
Eighteen amniotic-cell cultures were investigated and a diagnosis was made in sixteen, of which four had M.S.U.D., giving the frequency of 25% expected for an autosomal recessive disease. The other twelve assays were normal and in all twelve the postnatal diagnosis was also normal. Details of the remaining six cases (A-F) are given in the table. The diagnosis was confirmed in case B by post-abortion culture and assay of fetal skin fibroblasts. In case A a type-n variant was confirmed after birth by enzyme assay of leucocytes and by clinical course. In case C a macerated fetus was delivered at another institution after abortion with prostaglandin and urea. Culture of fetal tissues failed. In case F the baby was delivered at term; symptoms of M.S.U.D. developed and the infant died in a week. No diagnosis could be made in cases D and E. In both the cells were predominantly epithelial, as they were in 5 other successful cultures. One culture (E) was received from France. Cells grew poorly and an assay was attempted with few cells. No radioactive CO2 was released, but there was also no incorporation of radioactive aminoacids into protein, indicating that the cells were no longer metabolically active. The outcome of this pregnancy is not known. In D the ratio of the ’4C02to radioactivity in protein suggested variant M.S.U.D., but the incorporation of radioactivity into protein was too low to provide confidence in the results. No diagnosis was made and the fetus was aborted at another institution. Cultures were not established from fetal tissue. 1. Dancis, J. in Antenatal Diagnosis (edited by A. Dorfman); p. 123. Chicago, 1972. 2. Wendel, U., Rudiger, H. W., Passarge, E. Humangenetik, 1973, 19, 127. 3. Cox, R. P., Macleod, C. M.J. gen. Physiol. 1962, 45, 439. 4. Dancis, J., Hutzler, J., Cox, R. P. in Tissue Culture, Methods and Applications (edited by P. F. Kruse, Jr. and M. K. Patterson, Jr.) p. 639. New York, 1973.
Amniotic cell cultures that are predominantly fibroblastic have presented no problems with the technique devised for skin fibroblasts.s However, when cultures are predominantly
epithelial they multiply slowly, delaying analysis. Harvesting cells with a rubber policeman, as we have usually done, is associated with a variable, and frequently serious, loss of enzyme activity. The use of E.D.T.A.-trypsin to remove cells from glass surfaces seems to preserve enzyme activity in epithelial cells. We now assay cell suspensions prepared by E.D.T.A.-trypsin treatment of confluent cell monolayers. Intact cells are used because disruption of cells greatly reduces enzyme activity.’ The cells are incubated for 120 min with L-valine-1-14C (specific activity 0-5 µCi/µmol). The evolution of 14C02 provides a measure of the decarboxylase activity and is expressed per mg protein. The simultaneous incorporation of the radioactive aminoacid into protein provides an indication of the number of cells that are assayed and their metabolic activity. The ratio of the 14CO2to 14C-incorporation into protein is the most satis-
factory approach to diagnosis, provided 14C-incorporation per mg protein indicates active cell metabolism. This Service Fund.
study (AM
was
supported by grants
14528 and HD
from the U.S. Public Health
04526) and by the Samuel
Division of Human Genetics, Departments of Medicine and Pediatrics, New York University Medical Center, New York, N.Y. 10016, U.S.A.
A.
Berger
RODY P. Cox
JOEL HUTZLER JOSEPH DANCIS
MATERNAL HYPERTHERMIA AND NEURAL-TUBE DEFECTS
SIR,-Retrospective studies in the north-western United a significant correlation between maternal hyperthermia during the early part of pregnancy and the incidence of anencephalyl and meningomyelocele.2 Our similar study in the mid-southern United States has detected 3 instances of maternal hyperthermia in 45 pregnancies which resulted in children with neural-tube defects (anencephaly, meningomyelocele, spina bifida, or encephalocele). Only births during the past 11 months were included. States have revealed
In
man
the neural tube closes between the 22nd and 28th
gestation. The mothers in this study were questioned particularly about hyperthermia due to illness or prolonged sauna usage during the third, fourth, and fifth weeks of ges-
day
of
tation. This interval
was
chosen because most of the dates of
conception were only approximate. 1 mother reported "quite high" fever lasting 2 or 3 days and caused by streptococcal Elsas, L. J., Priest, J. H. Wheeler, F. B., Danner, D. J., Pask, B. A., Metabolism, 1974, 23, 569. 1. Miller, P., Smith, D. W., Shepard, T. H. Lancet, 1978, i, 519. 2. Chance, P. F., Smith, D. W. ibid. p. 769. 5.
213 at the end of the first month after conception. The infant was born with a thoracolumbar meningomyelocele. The second mother had had influenza for 7 days during the third and fourth weeks after conception with fever that peaked at 40°C. The pregnancy resultedin a child with a nasal encephalocele. A third instance of maternal hyperthermia resulted from sauna usage of 45 min duration on four occasions during the fifth week after conception. On one of these occasions the temperature of the sauna rose to 43 °C. The infant was born with a posterior encephalocele and a meningocele. The control group for this study came from two different sources. Since only 20 matched controls could be obtained (friends or neighbours pregnant at the same time as the mothers of the babies with neural-tube defects), another 28 controls were obtained from a group of women who were in the City of Memphis Hospital after giving birth to normal babies. 1 mother of the 48 controls had had hyperthermia due to pelvic inflammatory disease, but this had been during the sixth week after conception, well after the expected date of closure of the neural tube. Our findings support those of Smith and his colleagues (7 instances of hyperthermia in 63 mothers of infants with anencephalyl and 3 of hyperthermia in 43 mothers of infants with meningomyelocele.2 We suggest that hyperthermia lowers the threshold for the expression of these polygenically inherited neural tube defects. A thorough prospective evaluation of maternal hyperthermia and neural-tube defects is needed.
pharyngitis
,
Department of Pediatrics,
University of
Tennessee Center for the Health Services, Memphis, Tennessee 38163, U.S.A.
LINDA RUTH HALPERIN ROBERT S. WILROY, JR
MATERNAL AGE AND DOWN SYNDROME
SIR,-Substantial data
the maternal-age-specific incidence of Down syndrome and other chromosome aberrations derived from the results of prenatal diagnosis were presented at the 3rd European Prenatal Diagnosis Conference held in Munich in April, 1978. Over thirty centres in Europe (and one in Israel) contributed results from 16 273 pregnancies tested in women 35 years of age and over. On average, the rates for Down syndrome in these pregnancies are 33% above the rates determined from live births. This effect is seen at all maternal ages above 35 years and not just in the 40-44 year old mothers as suggested in your editorial of July 1. In fact, the major effect is seen in the 35-39 year age-group where the rate of 0.84% is 37% above the expected rate; at 40-44 and 45-49 years the rates are 2.31% and 4.87%, respectively, and the increases over the expected rate are 33% and 26%. (In these calculations the maternal age is the age at delivery and not the age at amniocentesis.) These figures show that earlier reports2-4 on the discrepancy between prenatal and postnatal rates were not just chance observations in small samples. Up to two-thirds of the discrepancy may be attributable to fetal loss between 16 weeks’ gestation and term, and some may be due to the selection of older mothers for amniocentesis for reasons other than maternal age.4 An important possibility mentioned in your editorial which has not been sufficiently emphasised in the past, is that the age-specific incidence may have been increasing,56 the effect being most marked in the 35-39 year age-group.? The New York studyl appears to be the most up-to-date live-birth study and this relates to births in 1963-74, whereas most of on
the amniocentesis data have been obtained in 1976-77 and almost all since 1974. Prenatal rates for chromosome aberrations may thus reflect current postnatal rates more closely than is generally supposed. There was much discussion in your correspondence columns of June 17 about which risk to quote to the older mother con-
templating prenatal diagnosis. Epidemiologists seem to prefer to use the risk of the birth of an affected living child, on the grounds of burden to the family and community. However, the parental distress associated with late abortion and stillbirth must not be discounted. Genetic counsellors appreciate that parents want to take account of all the facts. Ideally, these should include up-to-date prenatal and postnatal rates for both Down syndrome and all other chromosome aberrations. With the increasing use of prenatal diagnosis it will soon be difficult to obtain accurate postnatal rates and it may be that the best estimate of this will be the prenatal rate suitably corrected for fetal loss between 16 weeks and term. Maternal-age-specific rates for chromosome aberrations other than Down syndrome are not available from live birth studies, but the Munich data show that they add about 1% to the prenatal rate calculated for Down syndrome in women 35 years of age and over. It seems likely that many obstetricians are deterred from offering amniocentesis to their patients in the 35-39 years age group because they use obsolete and incomplete information and believe the risk of a fetal chromosome abnormality may not be sufficiently different from the risk of fetal loss after amniocentesis to justify the procedure. It would be preferable if all older mothers in need of pre-amniocentesis counselling were given the current age-specific prenatal rates for chromosome
aberrations and
1976, ii, 516. 5. Mikkelsen, M., Fischer, G., Stene, J., Stene, E., Petersen, E. Ann. hum. Genet. 1976, 40, 177. 6. Holloway, S., Emery, A. E. H.J. biosoc. Sci. 1977, 9, 453. 7. Evans, J. A., Hunter, A. G. W., Hamerton, J. L. J. med. Genet. 1978, 15, 43.
advised that up
to
20% of abnormal
research into the maternal-age-specific incidence of chromosome aberrations in late abortions and stillbirths. Department of Medical Genetics, Royal Hospital for Sick Children, Glasgow G3 8SJ
M. A. FERGUSON-SMITH
TREATMENT OF PAGET’S DISEASE
SIR,-Recent letters have raised some important points conthe treatment of Paget’s disease. Professor Milhaud’ advocates a very-low-dose regimen of (porcine) calcitonin which has given favourable therapeutic results. We agree that small doses of calcitonin may relieve pain in some cases of Paget’s disease and that the ideal dosage scheme remains to be established. However, it is clear that higher doses of calcitonin are required to heal the bones in the osteolytic phase of the disease, and low doses cannot be recommended in this situation since they are insufficient to check the advance of the resorptive process. 2-4 Dr Hamdy5 states that the main aim of treating Paget’s disease is to prevent complications and believes that pagetic pain usually responds to ordinary analgesics. Our experience is different. Simple analgesics may relieve mild pagetic pain but are ineffective in the more severe cases. We have seen many patients with frankly pagetic pain (i.e., not associated with concomitant osteoarthritis) who have gained pain relief with calcitonin after conventional analgesics had proved completely ineffective.
cerning
Endocrine Unit,
Royal Postgraduate Medical School, London W12 0HS
1. Hook, E., Chambers, G. C. Birth Defects orig. Art. Ser. 1977, 13 (3A), 123. 2. Ferguson-Smith, M. A. Lancet, 1976, ii, 252. 3. Ferguson-Smith, M. A., Ferguson-Smith, M. E. in Prenatal Diagnosis (edited by A. Boué); p. 81. INSERM, Paris, 1976. 4. Polani, P. E., Alberman, E., Berry, A. C., Blunt, S., Singer, J. D. Lancet,
were
conceptions might be lost between 16 weeks and term. Improvement in this advice can only come from more detailed
IMOGEN M. A. EVANS I. MACINTYRE
Milhaud, G. Lancet, 1978, i, 1153. Doyle, F. H., Pennock, J., Greenberg, P. B., Joplin, G. F., MacIntyre, I. in Endocrinology 1973 (edited by S. Taylor); p. 425. London, 1974. 3. Evans, I. M. A., Doyle, F. H., Banks, L., Pennock, J., Joplin, G. F., MacIn-
1. 2.
tyre, I. in Molecular Endocrinology (edited by I. Maclntyre and M. Szelke); p. 235. Amsterdam, 1977. 4. Nagant de Deuxchaisnes, C., Rombauts-Lindemans, C., Huaux, J. P., Malghem, J., Laldague, B. ibid. p. 213. 5. Hamdy, R. Lancet, 1978, i, 1267.
