- Email: [email protected]
XXX MOSAICISM WITH TURNER STIGMATA
1228
family doctors. Time and again we tell readers to go to the family doctor, assuring them they will receive sympathetic hearing and the help they need. And time and again readers tell us: My doctor hasn’t any time for me, so don’t tell me to go to him "; My doctor won’t explain "; I’ve been to my doctor, and he said there was nothing wrong, but I feel there must be, the way I’m feeling "; and so on. It would be easy to pooh-pooh such comments as the complaints of women who have nothing better to do than sit "
"
"
around and count their symptoms. But I cannot believe that every such comment comes from such people. And even if they did, are they not still in need of help ? A woman who has symptoms that distress her enough to make her write to a magazine is clearly not enjoying good health, however organically sound she may be. One particular type of problem that comes up often in letters is the psychosexual one. Readers cry for help because they are frigid in some degree, or because of their husband’s impotence, premature ejaculation, and similar difficulties. There are also pleas for help on contraception and subfertility. In these cases, the Family Planning Association and the Marriage Guidance Council are of immense value, but there are still those who need the help of the family doctor, and fail to get such help when they seek it. So what are we to do for the people who ask us for advice ? Do we continue to suggest that they return to their family doctors in the teeth of their complaints that family doctors won’t or can’t help ? Let me assure family doctors that the problem is a far from negligible one. Popular magazines enjoy readerships of many millions, and between them get thousands of letters a week, from all over the country. I doubt if there is a doctor anywhere who has not, on his list, patients who have sought the help of magazines. We should not be necessary, but clearly we are. I for one should be deeply grateful if doctors could tell me how to help the people who turn to me, and people like me, for solutions to their problems-problems which, I must repeat, are medical. I know where to send people seeking legal help. I know which equally reliable social agencies exist, and But I must pass the buck on, on medical problems use them. too. Surely it is not good enough for magazines to be the place where the medical buck comes to rest.
CLAIRE RAYNER. TRISOMY 21 OR 22 IN DOWN’S SYNDROME ? SIR,-Since a structural differentiation of chromosomes 21 and 22 is not possible in most cases, autoradiography has been used for identifying these chromosomes. The process of D.N.A. replication of the G-group chromosomes in patients with Down’s syndrome is judged in different ways. The extra chromosome has been found to replicate lateand also both early and late.3 Moreover the relative proportion of weakly and strongly labelled G chromosomes is supposed to change in succeeding states during termination of D.N.A. synthesis.4 We have therefore investigated whether the autoradiographic method is suitable for the identification of the G chromosomes in patients with Down’s syndrome. Three female and two male patients with the regular type of trisomy Gl were examined. 1 flow per ml. tritiated thymidine (specific activity 3 C per mmole) was added to the blood-cultures for 6 hours. The preparations were exposed with Kodak stripping film’AR 10 ’ for 5 days. The different labelling densities over the chromosomes were determined by comparative estimations of the blackened areas carried out by two persons and subdivided into 4 degrees: very strongly labelled, strongly labelled, weakly labelled, and unlabelled. The 56 combinations, resulting from 5 chromosomes and 4 labelling intensities, were divided into 3 groups: group A, with 3 strong and 2 weak Patau, K. Am. J. hum. Genet. 1960, 12, 250. Schmid, W. Cytogenetics, 1963, 2, 175. Yunis, J. J., Hook, E. B., Mayer, M. Lancet, 1965, i, 465. 3. Cave, M. D., Levitsky, J. M. Expl. Cell Res. 1966, 43, 210. 4. Gey, W. Humangenetik, 1966, 2, 246. 1. 2.
group B, with 2 strong and 3 weak labelling types; and group C, with those combinations of types which did not permit a classification of 3:2. From the 5 patients 216 mitoses were examined: 51 (23-6%) in 6 combinations of group A, 31 (14-4%) in 6 combinations of group B, and the remaining 134 mitoses (62-0%) in 44 combinations of group C. Statistically an accumulation in group A and B is demonstrable, but the assumption rA=1, PB=0 cannot be made on these figures. We conclude from these findings that either the termination phases of D.N.A. synthesis for both pairs of group G lie close together or that there is asynchrony of the homologues; the representation of the replication pattern may also be influenced by various methodological factors. Possibly all factors take part in the process. The factors of effectivity, -absorption, and coincidence5 depend perhaps on the condensation of the chromosome, which can vary in the homologues for methodological and biological reasons. For these reasons, and because an altered replication pattern of extra chromosomes is possible, the autoradiographic identification of chromosomes 21 and 22 in patients with Down’s syndrome not only seems questionable but will probably still present difficulties even after the method has been improved.
labelling types;
Details of the of chromosome elsewhere.
findings, with a statistical analysis and description autoradiography and its problems, will be given F. BACK P. DÖRMER P. BAUMANN.
Hæmatology Institute of the Society of Radiation Research in Association with
EURATOM, Munich, Germany. University Institute of Histology and Embryology, Innsbruck, Austria.
E. OLBRICH.
XO/XX/XXX
MOSAICISM WITH TURNER STIGMATA SIR,-We report a new case of triple mosaicism XO/XX/XXX in a 16-year-old girl with Turner stigmata associated with isthmic aortic stenosis and normal puberty. The patient is 4 ft. 7 in. (140 cm.) in height and has a shield chest, widely spaced nipples, short neck, slight webbing and low cervical hairline, low-set ears, micrognathia, cubitus valgus, pigmented naevi, and simian crease on left hand. She has normal sexual characteristics (axillary and pubic hair, breast development) and has menstruated regularly since 15 years of age. Cardiac evaluation and angiocardiography showed isthmic aortic stenosis. Buccal smear showed 2% of positive cells. Leucocytes from peripheral blood were cultured by a modification of the technique of Moorhead et al. with the following results: No. of cells Karyotype XO XX XXX
..
..
..
68 13 19
100
of XO/XX/XXX mosaicism 7-12 have in common the absence of menstruation and cardiovascular anomalies, but recently Vianello and Massino 13 reported a case with this type of mosaicism in a woman who had three children with the following karyotypes: XO, XO/XX, and
Reported
cases
XO/XX/XXX. 5. Perry, R. P. in Methods in Cell Physiology (edited by D. M. Prescott), vol. I. London, 1964. 6. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D., Hungerford, D. A. Expl Cell Res. 1960, 20, 613. 7. Grumbach, M. M., Morishima, A., Chu, E. H. Y. Am. J. Dis. Child.
1961, 102, 691. Hayward, M. D., Cameron, A. H. Lancet, 1961, ii, 623. Jacobs, P. A., Harden, D. G., Buckton, K. E., Court Brown, W. M., King, M. J., MacBride, J. A., MacGregor, T. N., Maclean, N., Fortheringham, A., Isdale, M. ibid. 1961, i, 1183. 10. Carr, D. H., Morishima, A., Barr, M. L., Grumbach, M. M., Luers, T., Boshman, H. W. J. clin. Endocr. 1962, 22, 671. 11. Ferguson-Smith, M. A., Alexander, D. S., Bowen, P., Goodman, R. M., Kaufman, B. N., Jones, H. W., Heller, R. H. Cytogenetics, 1964, 3, 355. 12. Zergollen, L., Hoefnagel, D. Lancet, 1964, i, 1108. 13. Vianello, M. G., Massino, L. Minerva pœdiat. 1965, 17, 26. 8. 9.
1229
Presumably the normal sexual characteristics and menstruation in the present case are due to the presence of a normal XX cell-line and of the XXX cell-line, as in some cases of Turner stigmata with menstruation and an XO/XX karyotype. 14 J. ANTICH M. RIBAS-MUNDÓ Pœdiatric Clinic, PRATS J. of Faculty Medicine, M. FRANCES. J. Barcelona, Spain. MOSAIC DOWN’S SYNDROME SiR,-Matsunaga 15 has suggested that there are two classes of mosaic Down’s syndrome; those with a low proportion of trisomic cells, associated with a normal maternal age-distribution ; and those with a high proportion of trisomic cells, associated with increased maternal age. Dr. Richards (March 25, p. 683) reports his inability to confirm these findings in a large series of Down’s syndrome mosaic patients. In general, the maternal age at birth of such patients has been said to be normal. Chaudhuri and Chaudhuri 16noted that the maternal age in the majority of cases was below 28 years, and Penrose,17 with a somewhat different series of cases, found that the average maternal age was only slightly (and not significantly) raised TRISOMY-21-MOSAIC DOWN’S
SYNDROME
PATIENTS
PRODUCTION OF OFFSPRING WITH
ASCERTAINED BY
21 TRISOMY
above the level in the general population which was chosen for comparison. This finding of normal maternal age is readily ascribable to bias of ascertainment, cytogeneticists being much more likely to see and to carry out chromosome analysis on patients who are the offspring of young mothers, so that the apparent discovery of a particular karyotypic variant associated with normal or decreased maternal age is not surprising. In seven instances known to me, 21-trisomy mosaicism was discovered in an adult as a result of investigation stemming from an affected offspring; these cases are presumably free of the above type of bias. The data on grandmaternal age at time of birth of these adults are given in the accompanying table and are certainly highly suggestive of the same type of maternal-age effect as that seen in " regular " 21 trisomy. In six of these seven cases the mother has been the bearer of the mosaicism. Although the number of these families is as yet very small, the data suggest that male Down’s syndrome mosaic patients may rarely procreate an affected offspring. (The father’s karyotype was ascertained in at least three of the six reported instances of maternal mosaicism, and it seems unlikely, though possible, that these results were produced as a consequence of the mother having been perhaps more often karyotyped than the father.) The situation would thus be analogous to that in translocation carriers-the likeliest explanation for both being perhaps the competitive nature of the events leading to successful fertilisation by the male gamete. Penrose 25 has made a number of observations on types of familial aggregation of Down’s syndrome cases, and of the resemblance between parents and their affected offspring. If these data are to be satisfactorily accounted for by parental mosaicism, it is clear that only maternal mosaicism is significantly effective in the production of affected children. These observations and related fully elsewhere. 26
investigations have been presented
more
Division of Medical Genetics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, U.S.A.
J. PHILIP WELCH.
THE ADVANCE OF CHOLERA SIR,-Cholera, which you discuss in your leading article (April 15, p. 827), has been in the headlines recently, not only because of the "major epidemic" but also because of the controversies on the mechanism of its characteristic symptom, the rice-water diarrhoea. As far as we know, four different mechanisms have been proposed: Virchow’s suggestion 27 of denudation of the intestinal mucosa with consequent loss of plasma, was30 disproved by Gangarosa et al.28; Phillips 2and the Fuhrmans maintained that the vibrio induced paralysis of the sodium pump in the epithelial cells; the hypothesis of others that the blood-vessels in the mucosa of the small bowel became abnormally permeable 31 seemed especially likely since it is possible to extract from the vibrio a non-viable moiety (choleragen) which, injected into the skin of the rabbit, does indeed produce delayed and prolonged vascular leakage 32 ; and it has also been suggested that the vibrio brings about hypersecretion of gastrointestinal hormones, thus indirectly stimulating pancreatic, hepatic, and upper gastro-intestinal secretions.33 *Age of mother patient.
at
time of birth of trisomy-21-mosaic Down’s
syndrome
14. Ferguson-Smith, M. A. J. med. Genet. 1965, 2, 142. 15. Matsunaga, E. in Mongolism (edited by G. E. W. Wolstenholme and R. Porter); p. 73. London, 1967. 16. Chaudhuri, A., Chaudhuri, K. C. J. med. Genet. 1965, 2, 131. 17. Penrose, L. S. in Genetics Today; p. 973. London, 1964. 18. Smith, D. W., Therman, E. M., Pateau, K. A., Inhorn, S. C. Am. J. Dis. Child. 1962, 104, 534. 19. Blank, C. E., Gemmell, E., Casey, M. D., Lord, M. Br. med. J. 1962, ii,
25. 26. 27. 28. 29. 30. 31.
378.
20. 21. 22. 23. 24.
Weinstein, E. D., Warkany, J. J. Pediat. 1963, 63, 599. Verresen, H., van den Berghe, H., Creemers, S. Lancet, 1964, i, 526. Ferrier, S. J. Génét. hum. 1964, 13, 315. Pfeiffer, R. A. Personal communication; Annls Génét. 1966, 9, G-94. Massimo, L. Personal communication. Massimo, L., Borrone, C., Vianello, M. G., Dagna-Bricarelli, F. Lancet, 1967, i, 108.
32. 33.
Penrose, L. S. J. ment. Sci. 1951, 97, 738; Ann. hum. Genet. 1954, 19, 10; Brit. med. Bull. 1961, 17, 184. Welch, J. P., Sigler, A. T. Second Invitational Conference on Human Behaviour Genetics, Louisville, Kentucky, April, 1966. Virchow, R. Gesammelte Abhandlungen auf dem Gebiete der Öffentlichen Medizin; vol. I, p. 151. Berlin, 1879. Gangarosa, E. J., Beisel, W. R., Benyajati, C., Sprinz, H., Piyaratn, P. Am. J. trop. Med. Hyg. 1960, 9, 125. Phillips, R. A. Bull. Wld Hlth Org. 1963, 28, 297. Fuhrman, G. J., Fuhrman, F. A., Nature, Lond. 1960, 188, 71. Sheehy, T. W., Sprinz, H., Augerson, W. S., Formal, S. B. J. Am. med. Ass. 1966, 197, 321. Patnaik, B. K., Ghosh, H. K. Br. J. exp. Path. 1966, 47, 210. Finkelstein, R. A., Nye, S. W., Atthasampunna, P., Charunmethee, P. Lab. Invest. 1966, 15, 1601. Gordon, R. S., Jr. Proceedings of the Cholera Research Symposium; p. 293. Public Health Service Publication no. 1328; Washington, 1965. Greenough, W. B., III. Lancet, 1965, ii, 991.
family doctors. Time and again we tell readers to go to the family doctor, assuring them they will receive sympathetic hearing and the help they need. And time and again readers tell us: My doctor hasn’t any time for me, so don’t tell me to go to him "; My doctor won’t explain "; I’ve been to my doctor, and he said there was nothing wrong, but I feel there must be, the way I’m feeling "; and so on. It would be easy to pooh-pooh such comments as the complaints of women who have nothing better to do than sit "
"
"
around and count their symptoms. But I cannot believe that every such comment comes from such people. And even if they did, are they not still in need of help ? A woman who has symptoms that distress her enough to make her write to a magazine is clearly not enjoying good health, however organically sound she may be. One particular type of problem that comes up often in letters is the psychosexual one. Readers cry for help because they are frigid in some degree, or because of their husband’s impotence, premature ejaculation, and similar difficulties. There are also pleas for help on contraception and subfertility. In these cases, the Family Planning Association and the Marriage Guidance Council are of immense value, but there are still those who need the help of the family doctor, and fail to get such help when they seek it. So what are we to do for the people who ask us for advice ? Do we continue to suggest that they return to their family doctors in the teeth of their complaints that family doctors won’t or can’t help ? Let me assure family doctors that the problem is a far from negligible one. Popular magazines enjoy readerships of many millions, and between them get thousands of letters a week, from all over the country. I doubt if there is a doctor anywhere who has not, on his list, patients who have sought the help of magazines. We should not be necessary, but clearly we are. I for one should be deeply grateful if doctors could tell me how to help the people who turn to me, and people like me, for solutions to their problems-problems which, I must repeat, are medical. I know where to send people seeking legal help. I know which equally reliable social agencies exist, and But I must pass the buck on, on medical problems use them. too. Surely it is not good enough for magazines to be the place where the medical buck comes to rest.
CLAIRE RAYNER. TRISOMY 21 OR 22 IN DOWN’S SYNDROME ? SIR,-Since a structural differentiation of chromosomes 21 and 22 is not possible in most cases, autoradiography has been used for identifying these chromosomes. The process of D.N.A. replication of the G-group chromosomes in patients with Down’s syndrome is judged in different ways. The extra chromosome has been found to replicate lateand also both early and late.3 Moreover the relative proportion of weakly and strongly labelled G chromosomes is supposed to change in succeeding states during termination of D.N.A. synthesis.4 We have therefore investigated whether the autoradiographic method is suitable for the identification of the G chromosomes in patients with Down’s syndrome. Three female and two male patients with the regular type of trisomy Gl were examined. 1 flow per ml. tritiated thymidine (specific activity 3 C per mmole) was added to the blood-cultures for 6 hours. The preparations were exposed with Kodak stripping film’AR 10 ’ for 5 days. The different labelling densities over the chromosomes were determined by comparative estimations of the blackened areas carried out by two persons and subdivided into 4 degrees: very strongly labelled, strongly labelled, weakly labelled, and unlabelled. The 56 combinations, resulting from 5 chromosomes and 4 labelling intensities, were divided into 3 groups: group A, with 3 strong and 2 weak Patau, K. Am. J. hum. Genet. 1960, 12, 250. Schmid, W. Cytogenetics, 1963, 2, 175. Yunis, J. J., Hook, E. B., Mayer, M. Lancet, 1965, i, 465. 3. Cave, M. D., Levitsky, J. M. Expl. Cell Res. 1966, 43, 210. 4. Gey, W. Humangenetik, 1966, 2, 246. 1. 2.
group B, with 2 strong and 3 weak labelling types; and group C, with those combinations of types which did not permit a classification of 3:2. From the 5 patients 216 mitoses were examined: 51 (23-6%) in 6 combinations of group A, 31 (14-4%) in 6 combinations of group B, and the remaining 134 mitoses (62-0%) in 44 combinations of group C. Statistically an accumulation in group A and B is demonstrable, but the assumption rA=1, PB=0 cannot be made on these figures. We conclude from these findings that either the termination phases of D.N.A. synthesis for both pairs of group G lie close together or that there is asynchrony of the homologues; the representation of the replication pattern may also be influenced by various methodological factors. Possibly all factors take part in the process. The factors of effectivity, -absorption, and coincidence5 depend perhaps on the condensation of the chromosome, which can vary in the homologues for methodological and biological reasons. For these reasons, and because an altered replication pattern of extra chromosomes is possible, the autoradiographic identification of chromosomes 21 and 22 in patients with Down’s syndrome not only seems questionable but will probably still present difficulties even after the method has been improved.
labelling types;
Details of the of chromosome elsewhere.
findings, with a statistical analysis and description autoradiography and its problems, will be given F. BACK P. DÖRMER P. BAUMANN.
Hæmatology Institute of the Society of Radiation Research in Association with
EURATOM, Munich, Germany. University Institute of Histology and Embryology, Innsbruck, Austria.
E. OLBRICH.
XO/XX/XXX
MOSAICISM WITH TURNER STIGMATA SIR,-We report a new case of triple mosaicism XO/XX/XXX in a 16-year-old girl with Turner stigmata associated with isthmic aortic stenosis and normal puberty. The patient is 4 ft. 7 in. (140 cm.) in height and has a shield chest, widely spaced nipples, short neck, slight webbing and low cervical hairline, low-set ears, micrognathia, cubitus valgus, pigmented naevi, and simian crease on left hand. She has normal sexual characteristics (axillary and pubic hair, breast development) and has menstruated regularly since 15 years of age. Cardiac evaluation and angiocardiography showed isthmic aortic stenosis. Buccal smear showed 2% of positive cells. Leucocytes from peripheral blood were cultured by a modification of the technique of Moorhead et al. with the following results: No. of cells Karyotype XO XX XXX
..
..
..
68 13 19
100
of XO/XX/XXX mosaicism 7-12 have in common the absence of menstruation and cardiovascular anomalies, but recently Vianello and Massino 13 reported a case with this type of mosaicism in a woman who had three children with the following karyotypes: XO, XO/XX, and
Reported
cases
XO/XX/XXX. 5. Perry, R. P. in Methods in Cell Physiology (edited by D. M. Prescott), vol. I. London, 1964. 6. Moorhead, P. S., Nowell, P. C., Mellman, W. J., Battips, D., Hungerford, D. A. Expl Cell Res. 1960, 20, 613. 7. Grumbach, M. M., Morishima, A., Chu, E. H. Y. Am. J. Dis. Child.
1961, 102, 691. Hayward, M. D., Cameron, A. H. Lancet, 1961, ii, 623. Jacobs, P. A., Harden, D. G., Buckton, K. E., Court Brown, W. M., King, M. J., MacBride, J. A., MacGregor, T. N., Maclean, N., Fortheringham, A., Isdale, M. ibid. 1961, i, 1183. 10. Carr, D. H., Morishima, A., Barr, M. L., Grumbach, M. M., Luers, T., Boshman, H. W. J. clin. Endocr. 1962, 22, 671. 11. Ferguson-Smith, M. A., Alexander, D. S., Bowen, P., Goodman, R. M., Kaufman, B. N., Jones, H. W., Heller, R. H. Cytogenetics, 1964, 3, 355. 12. Zergollen, L., Hoefnagel, D. Lancet, 1964, i, 1108. 13. Vianello, M. G., Massino, L. Minerva pœdiat. 1965, 17, 26. 8. 9.
1229
Presumably the normal sexual characteristics and menstruation in the present case are due to the presence of a normal XX cell-line and of the XXX cell-line, as in some cases of Turner stigmata with menstruation and an XO/XX karyotype. 14 J. ANTICH M. RIBAS-MUNDÓ Pœdiatric Clinic, PRATS J. of Faculty Medicine, M. FRANCES. J. Barcelona, Spain. MOSAIC DOWN’S SYNDROME SiR,-Matsunaga 15 has suggested that there are two classes of mosaic Down’s syndrome; those with a low proportion of trisomic cells, associated with a normal maternal age-distribution ; and those with a high proportion of trisomic cells, associated with increased maternal age. Dr. Richards (March 25, p. 683) reports his inability to confirm these findings in a large series of Down’s syndrome mosaic patients. In general, the maternal age at birth of such patients has been said to be normal. Chaudhuri and Chaudhuri 16noted that the maternal age in the majority of cases was below 28 years, and Penrose,17 with a somewhat different series of cases, found that the average maternal age was only slightly (and not significantly) raised TRISOMY-21-MOSAIC DOWN’S
SYNDROME
PATIENTS
PRODUCTION OF OFFSPRING WITH
ASCERTAINED BY
21 TRISOMY
above the level in the general population which was chosen for comparison. This finding of normal maternal age is readily ascribable to bias of ascertainment, cytogeneticists being much more likely to see and to carry out chromosome analysis on patients who are the offspring of young mothers, so that the apparent discovery of a particular karyotypic variant associated with normal or decreased maternal age is not surprising. In seven instances known to me, 21-trisomy mosaicism was discovered in an adult as a result of investigation stemming from an affected offspring; these cases are presumably free of the above type of bias. The data on grandmaternal age at time of birth of these adults are given in the accompanying table and are certainly highly suggestive of the same type of maternal-age effect as that seen in " regular " 21 trisomy. In six of these seven cases the mother has been the bearer of the mosaicism. Although the number of these families is as yet very small, the data suggest that male Down’s syndrome mosaic patients may rarely procreate an affected offspring. (The father’s karyotype was ascertained in at least three of the six reported instances of maternal mosaicism, and it seems unlikely, though possible, that these results were produced as a consequence of the mother having been perhaps more often karyotyped than the father.) The situation would thus be analogous to that in translocation carriers-the likeliest explanation for both being perhaps the competitive nature of the events leading to successful fertilisation by the male gamete. Penrose 25 has made a number of observations on types of familial aggregation of Down’s syndrome cases, and of the resemblance between parents and their affected offspring. If these data are to be satisfactorily accounted for by parental mosaicism, it is clear that only maternal mosaicism is significantly effective in the production of affected children. These observations and related fully elsewhere. 26
investigations have been presented
more
Division of Medical Genetics, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, U.S.A.
J. PHILIP WELCH.
THE ADVANCE OF CHOLERA SIR,-Cholera, which you discuss in your leading article (April 15, p. 827), has been in the headlines recently, not only because of the "major epidemic" but also because of the controversies on the mechanism of its characteristic symptom, the rice-water diarrhoea. As far as we know, four different mechanisms have been proposed: Virchow’s suggestion 27 of denudation of the intestinal mucosa with consequent loss of plasma, was30 disproved by Gangarosa et al.28; Phillips 2and the Fuhrmans maintained that the vibrio induced paralysis of the sodium pump in the epithelial cells; the hypothesis of others that the blood-vessels in the mucosa of the small bowel became abnormally permeable 31 seemed especially likely since it is possible to extract from the vibrio a non-viable moiety (choleragen) which, injected into the skin of the rabbit, does indeed produce delayed and prolonged vascular leakage 32 ; and it has also been suggested that the vibrio brings about hypersecretion of gastrointestinal hormones, thus indirectly stimulating pancreatic, hepatic, and upper gastro-intestinal secretions.33 *Age of mother patient.
at
time of birth of trisomy-21-mosaic Down’s
syndrome
14. Ferguson-Smith, M. A. J. med. Genet. 1965, 2, 142. 15. Matsunaga, E. in Mongolism (edited by G. E. W. Wolstenholme and R. Porter); p. 73. London, 1967. 16. Chaudhuri, A., Chaudhuri, K. C. J. med. Genet. 1965, 2, 131. 17. Penrose, L. S. in Genetics Today; p. 973. London, 1964. 18. Smith, D. W., Therman, E. M., Pateau, K. A., Inhorn, S. C. Am. J. Dis. Child. 1962, 104, 534. 19. Blank, C. E., Gemmell, E., Casey, M. D., Lord, M. Br. med. J. 1962, ii,
25. 26. 27. 28. 29. 30. 31.
378.
20. 21. 22. 23. 24.
Weinstein, E. D., Warkany, J. J. Pediat. 1963, 63, 599. Verresen, H., van den Berghe, H., Creemers, S. Lancet, 1964, i, 526. Ferrier, S. J. Génét. hum. 1964, 13, 315. Pfeiffer, R. A. Personal communication; Annls Génét. 1966, 9, G-94. Massimo, L. Personal communication. Massimo, L., Borrone, C., Vianello, M. G., Dagna-Bricarelli, F. Lancet, 1967, i, 108.
32. 33.
Penrose, L. S. J. ment. Sci. 1951, 97, 738; Ann. hum. Genet. 1954, 19, 10; Brit. med. Bull. 1961, 17, 184. Welch, J. P., Sigler, A. T. Second Invitational Conference on Human Behaviour Genetics, Louisville, Kentucky, April, 1966. Virchow, R. Gesammelte Abhandlungen auf dem Gebiete der Öffentlichen Medizin; vol. I, p. 151. Berlin, 1879. Gangarosa, E. J., Beisel, W. R., Benyajati, C., Sprinz, H., Piyaratn, P. Am. J. trop. Med. Hyg. 1960, 9, 125. Phillips, R. A. Bull. Wld Hlth Org. 1963, 28, 297. Fuhrman, G. J., Fuhrman, F. A., Nature, Lond. 1960, 188, 71. Sheehy, T. W., Sprinz, H., Augerson, W. S., Formal, S. B. J. Am. med. Ass. 1966, 197, 321. Patnaik, B. K., Ghosh, H. K. Br. J. exp. Path. 1966, 47, 210. Finkelstein, R. A., Nye, S. W., Atthasampunna, P., Charunmethee, P. Lab. Invest. 1966, 15, 1601. Gordon, R. S., Jr. Proceedings of the Cholera Research Symposium; p. 293. Public Health Service Publication no. 1328; Washington, 1965. Greenough, W. B., III. Lancet, 1965, ii, 991.