- Email: [email protected]
AUTOANTIBODIES IN DOWN'S SYNDROME
497 bone-marrow may increase the number of
isolations
positive
considerably. I am grateful for the technical assistance of Mrs. Elsie Collier. This work was supported by contract DA 18-108-AMC-C-157 (A), U.S. Army Chemical Research and Development Laboratories. Details will be published elsewhere. Albany Medical College, KATHERINE E. FRITZ. Albany, N.Y.
ANTI-MONGOLISM
SIR,-We
are
writing
to
emphasise
an
important
statement
made by Edwards et al., as long ago as 1962, about the adequate investigation of cases with an autosomal abnormality. These workers said that " wherever possible no opinion on the chromosomes of individuals with suspected autosomal abnormalities should be given without examining the parents ".’ Implicit in this statement is the requirement to record tha1 parents were examined even though the findings may have beer
negative. The regrettable tendency
to ignore this advice is nowhere better shown than in the article by Dr. Reisman and his colleagues last week. They may have correctly concluded tha1 the phenotypic abnormalities observed in their case were consequent on the detected genotypic aberration. Since they do not report on the karyotypes of the mother and father, however, their conclusion carries no weight whatsoever. Furthermore the facies of the case they reported appear typical of those regarded as characteristic of renal agenesis.2 We have examinee the chromosomes of a child with renal agenesis and found nc detectable abnormality. W. M. COURT BROWN Medical Research Council, PATRICIA A. JACOBS Clinical Effects of Radiation Research Unit, ANNE L. STEWART. Western General Hospital, Edinburgh 4.
the very interesting article by Dr. last week, it seems appropriate to " case of anti-mongolism " was reported me in 1962 to Dr. J. L. German and Dr. A. G. by personally Beam. The patient was a female, aged 8 years, with an i.Q. of 65. She had a long narrow head, receding chin, downward and outward sloping palpebral fissures, prominent nose, and other features which were the converse of those characteristic of mongolism. The karyotype in lymphocytes was similar to that described by Dr. Reisman and his colleagues, with an abnormal chromosome in the 21-22 group which could be a small ring. There are, thus, at the present time apparently three established instances of this condition. Kennedy-Galton Centre for Mental Retardation Research and Diagnosis, Harperbury Hospital, near St. Albans, L. S. PENROSE. Hertfordshire.
SIR,-With regard
Reisman and his mention that a
to
colleagues
in two stages. In the first stage an immunologically competent cell undergoes a mutation which results in the loss of histocompatibility antigens. In the second stage, normal cells having a full complement of histocompatibility antigens serve as antigenic and hence proliferative stimuli to the abnormal cell. The result is constant unrestrained growth leading to neoplasm of the lymphoid tissue. Schwartz and Beldottihave confirmed this theory by injecting PI hybrid mice with parental spleen cells. Long-term survivors of this graft-versus-host reaction developed lymphoid neoplasms originating in the host tissues. Kaplan and Smithersand Green et al.have suggested that lymphoid neoplasia in man may be due to a cyto-immunological reaction of neoplastic lymphoid cells against the normal hasmatopoietic cells of the host. I believe that, when we culture lymphocytes from a patient with malignant lymphoma, we really perform a mixed culture of two different cell populations-namely, normal lymphocytes together with neoplastic lymphocytes which have undergone mutation. One group of cells stimulates the other, and this explains the high " spontaneous " rate of cell enlargement and mitosis. I have also stimulated cultures of lymphocytes, from patients with lymphoma, with extracts of the patients’ skin. Two patients have been examined with the" technique of Hashem et al. In both, a higher proportion of blast " transformation was found in the cultures stimulated by the patients’ skin extracts than in the control cultures. This project was supported in part by a grant from the Israel Cancer Association Lady Edith Wolfson Research Fund. Oncological Department, Hadassah University Hospital, E. ROBINSON. Jerusalem, Israel.
AUTOANTIBODIES IN DOWN’S SYNDROME SIR,-Our investigation of thyroid autoimmunity in children with Down’s syndrome and in their mothers 10 concerned few subjects and had arisen from systematic investigations on autoimmunity in childhood by Steffen’s antiglobulin-consumption (A.G.C.) test using lyophilised thyroid tissue. Positive results had been obtained previously by Mellon et al.11 using different methods. Meanwhile an unusual frequency of RESULTS OF WITH
A.G.C., T.R.C., AND LATEX-FIXATION TESTS IN CHILDREN DOWN’S SYNDROME, MOTHERS OF SUCH CHILDREN, HEALTHY
CHILDREN, AND MOTHERS
OF HEALTHY CHILDREN
LYMPHOPROLIFERATIVE-DISEASE
Decrease of titre of antiglobulin serum by
LYMPHOCYTES
SIR,-Hirschhorn et al. 3 have reported that cultured lymphocytes of patients with malignant lymphoma show a high spontaneous rate of cell enlargement and mitosis. They suggested that"anergy and hypergammaglobulinaemia observed in patients with lymphoproliferative disorders are being reflected by the behaviour of their cells in vitro ". These findings are confirmed by my studies of lymphocyte cultures 4 from patients with cancer and malignant lymphoma, but I would like to put forward another explanation. Tylersuggested that neoplasms of lymphoid tissue develop 1.
Edwards, J. H., Fraccaro, M., Davies, P., Young,
R. B. Ann. hum.
Genet. 1962, 26, 163. A. R. Pathology of Infancy and Childhood. Edinburgh, 1960. 3. Hirschhorn, K., Schreibman, R. R., Bach, F. H., Siltzbach, L. E. Lancet, 1964, ii, 842. 4. Robinson, E., Horowitz, D. Israel J. med. Sci. (in the press). 5. Tyler, A. J. natn. Cancer Inst. 1960, 25, 1197.
2.
Macgregor,
Titres in all
groups
were
low.
1
or more
titre-steps.
has been found by Saxena and Pryles 12 in children with Down’s syndrome, and by Fialkow et al.13 in mothers of patients with Down’s syndrome. We report here further results. Controls (healthy children and mothers of healthy children) were matched for age with the children with Down’s syndrome and with the mothers of Down’s syndrome children. By using
thyroid autoimmunity
Schwartz, R. S., Beldotti, L. Science, N.Y. 1965, 149, 1511. Kaplan, H. S., Smithers, D. W. Lancet, 1959, ii, 1. Green, I., Inkelas, M., Allen, L. B. ibid. 1960, i, 30. Hashem, N., Hirschhorn, K., Sedlis, E., Holt, L. E., Jr. ibid. 1963, ii, 269. 10. Burgio, G. R., Severi, F., Rossoni, R., Vaccaro, R. Lancet, 1965, i, 166. 11. Mellon, J. P., Pav, B. Y., Green, D. M. J. ment. Defic. Res. 1963, 7, 31. 12. Saxena, K. M., Prvles, C. V. J. Pediat. 1965, 67, 363. 13. Fialkow, P. J., Uchida, I., Hecht, F., Motulsky, A. G. Lancet, 1965, ii, 868. 6. 7. 8. 9.
498
gold, platinum, and selenium in the region, because there were apparently hardly any of these metals in the Arjeplog and Arvidsjaur districts where most of the patients lived. A few years after Waldenstrom’s report in 1937,, however, rich deposits of lead were discovered in the Arjeplog district and
Effect on thyroid autoimmunity of age, as shown by A.G.C. test, in children with Down’s syndrome and mothers of such children (continuous line), and healthy children, and mothers of healthy children (interrupted line).
test, the tanned-red-cell (T.R.C.) test (with thyroantigen), and the latex-fixation test (’ TA-test’, globulin Hyland), we obtained a high proportion of positive results in children with Down’s syndrome, and in mothers of Down’s syndrome children, compared with controls (see accompanying table). A remarkable difference was noticed in the proportion of positive results using different tests; in particular, the lowest proportion of positive results was observed with the latexfixation test-no positive results were observed in control subjects using this test (see accompanying table). Since it is well known that thyroid autoimmunity increases with advancing age, we analysed our cases in this respect by the A.G.C. test (see accompanying figure). In order to discover whether the positive results obtained by the A.G.C. test could be considered specific, 20 positive sera were tested, using lyophilised kidney or heart tissue. The results were only occasionally positive. To discover if the results changed with the passage of time, we repeated the A.G.c. test in 22 subjects after 3-19 months, and the latex-fixation test in 18 subjects after 3-8 months. We noted only a slight difference of intensity of the positive results. It seems clear from these investigations, carried out by three different methods, that thyroid autoimmunity is commoner in subjects with Down’s syndrome and in mothers of Down’s syndrome children than in controls. G. ROBERTO BURGIO FRANCESCA SEVERI Paediatric Clinic, ROBERTO ROSSONI University of Perugia, RENATO VACCARO. Italy.
the
A.G.C.
as
have since been mined there. A man of 54 from the Arjeplog district, who had many relatives with porphyria, had had at least 30 acute attacks in the previous 20 years of the kind usually occurring in acute intermittent porphyria, characterised mainly by abdominal and muscular pain, and distal paralysis in the arms. During an investigation of his family, the patient related that he could not stand the fish he used to catch in lake Aisjaur near his home. A few hours after he ate such food, he would feel sick and nauseated, and vomit, and he said that any kind of fish from this lake made him sick. On the other hand, he could eat any kind of sea fish. Because of the possibility that the lake fish the patient had eaten were exposed to an increased amount of lead, and had accumulated a large amount of the metal in their tissues, examples of the four most common fish in the lake-whitefish
(Coregonus spp.), perch (Perca fluviatilis), pike (Esox lucius), lota)-were examined for their lead-content.
and burbot (Lota
LEAD CONTENT OF FISH IN LAKE
AISJAUR
AND GULF OF BOTHNIA
*‘ In 6 instances two examples of the same fish t 0 = less than z2 mg. lead per kg. tissue.
were
examined.
Control examinations were made of the same species of fish caught in the Gulf of Bothnia at the same time of year and under the same conditions. The results are shown in the accompanying table. The question is whether a high lead-content in the fish caught in lake Aisjaur has an untoward effect on persons with the enzymatic defect assumed to occur in acute intermittent porphyria. It is planned to continue measuring the content of lead in the lake fish and in the persons who eat them every day. I wish to thank Mr. T. Ahrén (Fishery Department, Northern Sweden) for providing me with material for this study. Psychiatric Research Centre, University of Uppsala, ’
ACUTE PORPHYRIA AND LEAD POISONING
SIR,-Dagg et a1.1 have noted striking clinical, biochemical, and pathological likenesses between lead poisoning and acute intermittent porphyria; the most important clinical difference found was the occurrence of ansemia in lead poisoning. Others, including Waldenstrom,2 Haeger-Aronsen,3 and Galambos and Dowda,4have also pointed out the similarity between these two conditions. Some substances, such as barbiturates, sulphonamides, and griseofulvin, are known to precipitate acute attacks of porphyria. Heavy metals other than lead have also been mentioned in connection with porphyria.5 Waldenstrom found a large number of manifest cases of intermittent porphyria among people living along the borders of the Skellefte river in the north of Sweden. He abandoned his hypothesis that this had something to do with the large amounts of arsenic, copper, silver, lead, 1.
2. 3. 4. 5.
Dagg, J., Goldberg, A., Lochhead, A., Smith, J. A. Q. Jl Med. 1965, 34, 163. See Lancet, 1965, ii, 26. Waldenström, J. Acta med. scand. 1937, suppl. 82. Haeger-Aronsen, B. Scand. J. clin. Lab. Invest. 1960, suppl. 47. Galambos, J. T., Dowda, F. W. Am. J. Med. 1959, 27, 803. Peters, H. A. Fedn Proc. Fedn Am. Socs exp. Biol. 1961, 20, 227.
Ulleråker
Hospital, Uppsala, Sweden.
L. WETTERBERG.
RADIOLOGICAL PROCEDURES AND MORBIDITY Dr. GEORGE ANSEL (Department of Radiology, Whiston Hospital, Liverpool) writes: "I am undertaking a national survey of the incidence of major complications of X-ray examinations. I have already written personally to about 600 radiologists asking for details of major complications occurring during 1965. In some cases, however, the radiologist may be unaware of delayed morbidity or long-term effects. If any clinician has details of such cases, it would be helpful if he could send the information to the radiologist concerned or, where this is not feasible, direct to me. I should also be pleased to receive data from any radiologists who may not have
been included in the survey. All information will be treated
strictly confidentially."
isolations
positive
considerably. I am grateful for the technical assistance of Mrs. Elsie Collier. This work was supported by contract DA 18-108-AMC-C-157 (A), U.S. Army Chemical Research and Development Laboratories. Details will be published elsewhere. Albany Medical College, KATHERINE E. FRITZ. Albany, N.Y.
ANTI-MONGOLISM
SIR,-We
are
writing
to
emphasise
an
important
statement
made by Edwards et al., as long ago as 1962, about the adequate investigation of cases with an autosomal abnormality. These workers said that " wherever possible no opinion on the chromosomes of individuals with suspected autosomal abnormalities should be given without examining the parents ".’ Implicit in this statement is the requirement to record tha1 parents were examined even though the findings may have beer
negative. The regrettable tendency
to ignore this advice is nowhere better shown than in the article by Dr. Reisman and his colleagues last week. They may have correctly concluded tha1 the phenotypic abnormalities observed in their case were consequent on the detected genotypic aberration. Since they do not report on the karyotypes of the mother and father, however, their conclusion carries no weight whatsoever. Furthermore the facies of the case they reported appear typical of those regarded as characteristic of renal agenesis.2 We have examinee the chromosomes of a child with renal agenesis and found nc detectable abnormality. W. M. COURT BROWN Medical Research Council, PATRICIA A. JACOBS Clinical Effects of Radiation Research Unit, ANNE L. STEWART. Western General Hospital, Edinburgh 4.
the very interesting article by Dr. last week, it seems appropriate to " case of anti-mongolism " was reported me in 1962 to Dr. J. L. German and Dr. A. G. by personally Beam. The patient was a female, aged 8 years, with an i.Q. of 65. She had a long narrow head, receding chin, downward and outward sloping palpebral fissures, prominent nose, and other features which were the converse of those characteristic of mongolism. The karyotype in lymphocytes was similar to that described by Dr. Reisman and his colleagues, with an abnormal chromosome in the 21-22 group which could be a small ring. There are, thus, at the present time apparently three established instances of this condition. Kennedy-Galton Centre for Mental Retardation Research and Diagnosis, Harperbury Hospital, near St. Albans, L. S. PENROSE. Hertfordshire.
SIR,-With regard
Reisman and his mention that a
to
colleagues
in two stages. In the first stage an immunologically competent cell undergoes a mutation which results in the loss of histocompatibility antigens. In the second stage, normal cells having a full complement of histocompatibility antigens serve as antigenic and hence proliferative stimuli to the abnormal cell. The result is constant unrestrained growth leading to neoplasm of the lymphoid tissue. Schwartz and Beldottihave confirmed this theory by injecting PI hybrid mice with parental spleen cells. Long-term survivors of this graft-versus-host reaction developed lymphoid neoplasms originating in the host tissues. Kaplan and Smithersand Green et al.have suggested that lymphoid neoplasia in man may be due to a cyto-immunological reaction of neoplastic lymphoid cells against the normal hasmatopoietic cells of the host. I believe that, when we culture lymphocytes from a patient with malignant lymphoma, we really perform a mixed culture of two different cell populations-namely, normal lymphocytes together with neoplastic lymphocytes which have undergone mutation. One group of cells stimulates the other, and this explains the high " spontaneous " rate of cell enlargement and mitosis. I have also stimulated cultures of lymphocytes, from patients with lymphoma, with extracts of the patients’ skin. Two patients have been examined with the" technique of Hashem et al. In both, a higher proportion of blast " transformation was found in the cultures stimulated by the patients’ skin extracts than in the control cultures. This project was supported in part by a grant from the Israel Cancer Association Lady Edith Wolfson Research Fund. Oncological Department, Hadassah University Hospital, E. ROBINSON. Jerusalem, Israel.
AUTOANTIBODIES IN DOWN’S SYNDROME SIR,-Our investigation of thyroid autoimmunity in children with Down’s syndrome and in their mothers 10 concerned few subjects and had arisen from systematic investigations on autoimmunity in childhood by Steffen’s antiglobulin-consumption (A.G.C.) test using lyophilised thyroid tissue. Positive results had been obtained previously by Mellon et al.11 using different methods. Meanwhile an unusual frequency of RESULTS OF WITH
A.G.C., T.R.C., AND LATEX-FIXATION TESTS IN CHILDREN DOWN’S SYNDROME, MOTHERS OF SUCH CHILDREN, HEALTHY
CHILDREN, AND MOTHERS
OF HEALTHY CHILDREN
LYMPHOPROLIFERATIVE-DISEASE
Decrease of titre of antiglobulin serum by
LYMPHOCYTES
SIR,-Hirschhorn et al. 3 have reported that cultured lymphocytes of patients with malignant lymphoma show a high spontaneous rate of cell enlargement and mitosis. They suggested that"anergy and hypergammaglobulinaemia observed in patients with lymphoproliferative disorders are being reflected by the behaviour of their cells in vitro ". These findings are confirmed by my studies of lymphocyte cultures 4 from patients with cancer and malignant lymphoma, but I would like to put forward another explanation. Tylersuggested that neoplasms of lymphoid tissue develop 1.
Edwards, J. H., Fraccaro, M., Davies, P., Young,
R. B. Ann. hum.
Genet. 1962, 26, 163. A. R. Pathology of Infancy and Childhood. Edinburgh, 1960. 3. Hirschhorn, K., Schreibman, R. R., Bach, F. H., Siltzbach, L. E. Lancet, 1964, ii, 842. 4. Robinson, E., Horowitz, D. Israel J. med. Sci. (in the press). 5. Tyler, A. J. natn. Cancer Inst. 1960, 25, 1197.
2.
Macgregor,
Titres in all
groups
were
low.
1
or more
titre-steps.
has been found by Saxena and Pryles 12 in children with Down’s syndrome, and by Fialkow et al.13 in mothers of patients with Down’s syndrome. We report here further results. Controls (healthy children and mothers of healthy children) were matched for age with the children with Down’s syndrome and with the mothers of Down’s syndrome children. By using
thyroid autoimmunity
Schwartz, R. S., Beldotti, L. Science, N.Y. 1965, 149, 1511. Kaplan, H. S., Smithers, D. W. Lancet, 1959, ii, 1. Green, I., Inkelas, M., Allen, L. B. ibid. 1960, i, 30. Hashem, N., Hirschhorn, K., Sedlis, E., Holt, L. E., Jr. ibid. 1963, ii, 269. 10. Burgio, G. R., Severi, F., Rossoni, R., Vaccaro, R. Lancet, 1965, i, 166. 11. Mellon, J. P., Pav, B. Y., Green, D. M. J. ment. Defic. Res. 1963, 7, 31. 12. Saxena, K. M., Prvles, C. V. J. Pediat. 1965, 67, 363. 13. Fialkow, P. J., Uchida, I., Hecht, F., Motulsky, A. G. Lancet, 1965, ii, 868. 6. 7. 8. 9.
498
gold, platinum, and selenium in the region, because there were apparently hardly any of these metals in the Arjeplog and Arvidsjaur districts where most of the patients lived. A few years after Waldenstrom’s report in 1937,, however, rich deposits of lead were discovered in the Arjeplog district and
Effect on thyroid autoimmunity of age, as shown by A.G.C. test, in children with Down’s syndrome and mothers of such children (continuous line), and healthy children, and mothers of healthy children (interrupted line).
test, the tanned-red-cell (T.R.C.) test (with thyroantigen), and the latex-fixation test (’ TA-test’, globulin Hyland), we obtained a high proportion of positive results in children with Down’s syndrome, and in mothers of Down’s syndrome children, compared with controls (see accompanying table). A remarkable difference was noticed in the proportion of positive results using different tests; in particular, the lowest proportion of positive results was observed with the latexfixation test-no positive results were observed in control subjects using this test (see accompanying table). Since it is well known that thyroid autoimmunity increases with advancing age, we analysed our cases in this respect by the A.G.C. test (see accompanying figure). In order to discover whether the positive results obtained by the A.G.C. test could be considered specific, 20 positive sera were tested, using lyophilised kidney or heart tissue. The results were only occasionally positive. To discover if the results changed with the passage of time, we repeated the A.G.c. test in 22 subjects after 3-19 months, and the latex-fixation test in 18 subjects after 3-8 months. We noted only a slight difference of intensity of the positive results. It seems clear from these investigations, carried out by three different methods, that thyroid autoimmunity is commoner in subjects with Down’s syndrome and in mothers of Down’s syndrome children than in controls. G. ROBERTO BURGIO FRANCESCA SEVERI Paediatric Clinic, ROBERTO ROSSONI University of Perugia, RENATO VACCARO. Italy.
the
A.G.C.
as
have since been mined there. A man of 54 from the Arjeplog district, who had many relatives with porphyria, had had at least 30 acute attacks in the previous 20 years of the kind usually occurring in acute intermittent porphyria, characterised mainly by abdominal and muscular pain, and distal paralysis in the arms. During an investigation of his family, the patient related that he could not stand the fish he used to catch in lake Aisjaur near his home. A few hours after he ate such food, he would feel sick and nauseated, and vomit, and he said that any kind of fish from this lake made him sick. On the other hand, he could eat any kind of sea fish. Because of the possibility that the lake fish the patient had eaten were exposed to an increased amount of lead, and had accumulated a large amount of the metal in their tissues, examples of the four most common fish in the lake-whitefish
(Coregonus spp.), perch (Perca fluviatilis), pike (Esox lucius), lota)-were examined for their lead-content.
and burbot (Lota
LEAD CONTENT OF FISH IN LAKE
AISJAUR
AND GULF OF BOTHNIA
*‘ In 6 instances two examples of the same fish t 0 = less than z2 mg. lead per kg. tissue.
were
examined.
Control examinations were made of the same species of fish caught in the Gulf of Bothnia at the same time of year and under the same conditions. The results are shown in the accompanying table. The question is whether a high lead-content in the fish caught in lake Aisjaur has an untoward effect on persons with the enzymatic defect assumed to occur in acute intermittent porphyria. It is planned to continue measuring the content of lead in the lake fish and in the persons who eat them every day. I wish to thank Mr. T. Ahrén (Fishery Department, Northern Sweden) for providing me with material for this study. Psychiatric Research Centre, University of Uppsala, ’
ACUTE PORPHYRIA AND LEAD POISONING
SIR,-Dagg et a1.1 have noted striking clinical, biochemical, and pathological likenesses between lead poisoning and acute intermittent porphyria; the most important clinical difference found was the occurrence of ansemia in lead poisoning. Others, including Waldenstrom,2 Haeger-Aronsen,3 and Galambos and Dowda,4have also pointed out the similarity between these two conditions. Some substances, such as barbiturates, sulphonamides, and griseofulvin, are known to precipitate acute attacks of porphyria. Heavy metals other than lead have also been mentioned in connection with porphyria.5 Waldenstrom found a large number of manifest cases of intermittent porphyria among people living along the borders of the Skellefte river in the north of Sweden. He abandoned his hypothesis that this had something to do with the large amounts of arsenic, copper, silver, lead, 1.
2. 3. 4. 5.
Dagg, J., Goldberg, A., Lochhead, A., Smith, J. A. Q. Jl Med. 1965, 34, 163. See Lancet, 1965, ii, 26. Waldenström, J. Acta med. scand. 1937, suppl. 82. Haeger-Aronsen, B. Scand. J. clin. Lab. Invest. 1960, suppl. 47. Galambos, J. T., Dowda, F. W. Am. J. Med. 1959, 27, 803. Peters, H. A. Fedn Proc. Fedn Am. Socs exp. Biol. 1961, 20, 227.
Ulleråker
Hospital, Uppsala, Sweden.
L. WETTERBERG.
RADIOLOGICAL PROCEDURES AND MORBIDITY Dr. GEORGE ANSEL (Department of Radiology, Whiston Hospital, Liverpool) writes: "I am undertaking a national survey of the incidence of major complications of X-ray examinations. I have already written personally to about 600 radiologists asking for details of major complications occurring during 1965. In some cases, however, the radiologist may be unaware of delayed morbidity or long-term effects. If any clinician has details of such cases, it would be helpful if he could send the information to the radiologist concerned or, where this is not feasible, direct to me. I should also be pleased to receive data from any radiologists who may not have
been included in the survey. All information will be treated
strictly confidentially."