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TRISOMY 21 OR 22 IN DOWN'S SYNDROME?
831 come to term as
female infants with Turner’s
remainder being aborted spontaneously. This study was supported by the Medical
syndrome, the
Research Council of
ranncin-
Department of Anatomy, McMaster University,
Hamilton, Ontario, Canada.
DAVID H. CARR.
REPRODUCTION AND MEIOSIS IN XYY SIR,- The XYY sex-chromosome constitution is of unusual interest, because it seems to predispose to aggressive behaviour, mental subnormality, and tall stature.l Although XYY males have been reportedno data have been presented to our knowledge on the transmission of the extra Y chromosome to their offspring or on the behaviour of their chromosomes in meiosis. We here present findings on both. We studied the 7 children of an XYY man: 6 sons and 1 daughter. The 6 sons all had normal XY sex-chromosome complements, and the daughter had a normal XX constitution. The index case in the family was the daughter’s only child. This boy, who seems chromosomally normal, has mental
retardation, multiple anomalies, and tyrosinuria due to a newly delineated inborn error, tyrosine-transaminase deficiency.a The finding of XYY sex-chromosome constitution in his grandfather, whose leucocyte cultures do not show mosaicism, was therefore entirely unexpected. The fact that all 6 sons of the XYY man were XY is notable. Four classes of gametes are possible if secondary nondisj unction occurs in the first meiotic division in such males: X, YY, XY, and Y. Union of these gametes with X-bearing ova would produce XX, XYY, XXY, and XY zygotes. Thus, female offspring might all be expected to be normal, whereas 2 of the 3 types of males might be expected to be chromosomally abnormal. Neither XXY nor XYY was observed in the 6 sons, suggesting that selection may occur toward euploidy at either meiotic, gametic, and/or zygotic levels. Meiotic studies were refused by this man, but were subsequently carried out on another XYY male with no known offspring. Two leucocyte cultures and a testicular fibroblast culture showed XYY sex-chromosome constitution with no suggestion of mosaicism. A testicular biopsy-specimen was processed for meiotic studies by a modification of the technique described by Evans et al.4 Spermatogonial metaphases were scarce, but all twenty-two examined seemed to have only one Y chromosome. Seventeen of the twenty-two contained 46 chromosomes; eleven of these were karyotyped and showed a normal XY pattern. Of the non-modal cells, four had 45 chromosomes, which upon karyotyping showed scattered losses, and one had 47 chromosomes but contained only a single Y chromosome. Diakinesis and first-meiotic-metaphase figures were plentiful. Of a hundred and fifty-five cells examined none was clearly found to contain two Y chromosomes. Representative cells shown in the accompanying figure demonstrate several typical configurations of the XY bivalent and the X and Y univalents. Although some of these were initially felt to contain two Y chromosomes, comparison with meiotic figures of four chromosomally normal men showed no discernible differences in the various configurations of the sex chromosomes or in the relative frequencies of each type of configuration. Karyotypes of secondary spermatocytes were difficult to interpret, but thirty-four of thirty-nine figures examined contained 23 chromosomes; the other five contained 24-karyotypes of these did not show conclusive evidence as to the presence or absence of two Y chromosomes. 1.
Jacobs, P. A., Brunton, M., Melville, M. M., Brittain, R. P. Nature, Lond. 1965, 208, 1351. 2. Hauschka, T. S., Hasson, J. E., Goldstein, M. N., Koept, G. F., Sandberg, A. Am. J. hum. Genet. 1962, 14, 22. Tzoneva-Maneva, M. T., Bosajieva, E., Petrov, B. Lancet, 1966, i, 1000. 3. Campbell, R. A., Buist, N. R. M., Jacinto, E. Y., Koler, R. D., Hecht, F., Jones, R. T., Society for Pediatric Research (abstract). Atlantic 4.
City, 1967. Evans, E. P., Breckon, G., Ford, C. E. Cytogenetics, 1964. 3,
289.
Meiotic preparations from
an
XYY male.
Representative diplotene-diakinesis figures showing: (A) XY bivalent with commonly observed J-shaped configuration of the Y chromosome; (B) XY bivalent with folding of the Y chromosome as in (A), but giving the appearance of two separate parallel strands; (C) X and Y univalents separated; (D) examples of X and Y chromofrom other cells. All these configurations from normal XY males. somes
were
also observed in meiotic
preparations
These findings, although preliminary, suggest that selection toward chromosomally normal spermatocytes occurs before meiosis in XYY males. The mechanism responsible for this selection is unknown, but may be related to a similar one known to occur normally in the male creeping vole (Microtus oregoni), in which the somatic cells have an XY sex-chromosome constitution and the germ cells a YO constitution.5 This study was supported in part by grants HD 01343 and CA 07941, and from the Children’s Bureau. Department of Pediatrics, University of Oregon Medical School, Portland, Oregon 97201, and Fairview Hospital and Training Center, Salem, Oregon. Metabolic Division, Children’s Hospital of Los Angeles and Department of Pediatrics, University of Southern California, Los Angeles, California 90027. Department of Pediatrics (Crippled Children’s Division) and Division of Experimental Medicine, University of Oregon Medical School, Portland, Oregon 97201.
U.S. Public Health Service genetics programme grants
HAVELOCK THOMPSON.
JOHN
MELNYK.
FREDERICK HECHT.
TRISOMY 21 OR 22 IN DOWN’S SYNDROME? SIR,-The letter of Dr. Back and his colleagues 6 prompts us to report here a possible method of identifying the G-group chromosome involved in Down’s syndrome. We are specially interested’in the possibility of classifying the meiotic chromosomes in man in the same sequence as the standardised Denver karyotype pattern for mitotic 5. 6.
Ohno, S., Jainchill, J., Stenius, C. ibid. 1963, 2, 232. Back, F., Dormer, P., Baumann, P., Olbrich, E. Lancet, 1967, i, 1228.
832 lesion which overlapped the valve ring, and so prevented the full return of the ball into its seating. There was also evidence of endocarditis involving the mitral valve. R. Y. CARTWRIGHT C. M. MORGANS Royal Devon and Exeter Hospital DAVID B. SHAW. Exeter.
Meiotic
chromosome karyotype from human testicular biopsy to size and chiasma frequency.
arranged according
chromosomes. The accompanying figure shows our karyotype results arranged according to size and chiasma frequency.7 The findings suggest that the two smallest chromo-
structurally at diakinesis, one of them consistently revealing only one chiasma. To determine which of the two G-group chromosomes is involved in Down’s syndrome it would be of value to study testicular biopsy specimens from patients with mitotic-chromosome evidence of G/G translocations. Since translocation chromosomes are readily identifiable at diakinesis,8 it should be possible by this method to determine the specificity of the somes
differ
chromosome in this disorder. the other groups should allow these meiotic chromosomes to be identified by the karyotypes of the mitotic chromosomes, thus making it possible to establish useful karyotypes of the meiotic chromosomes of man. Division of Human Genetics, Georgia Mental Health Institute and ARTHUR FALEK Department of Psychiatry, KAREN J. BACK. Emory University, Atlanta, Georgia.
normal
and
translocated
Analysis of translocations involving
E.C.G. CHANGES IN SCURVY SIR,-While congratulating Dr. Shafar on his interesting report (July 22, p. 176), one cannot help wondering why the possibility of a concomitant potassium depletion, with or without hypokalaemia, should not have found a place in his otherwise excellent and detailed discussion on the pathogenesis of the electrocardiogram (E.C.G.) changes illustrated. The E.C.G. before treatment in case 1 appears to be diagnostic of hypokalaemia,l while that in case 2 may be described as being not incompatible with hypokalaemia. Potassium. depletion with or without hypokalsemia, and with or without a hypokalxmic E.C.G. pattern, is not uncommon in the clinical circumstances detailed in the two cases. A reference to plasma-potassium levels, if available, would be of interest. Potassium therapy can effect the improvement noted in the post-treatment E.c.G.s. It would therefore be pertinent to know whether, during the week of treatment with vitamin C, the patients also received more potassium through food or through medicines administered than before treatment. Although the possible participation of ascorbic-acid deficiency in the production of the E.C.G. changes reported cannot be denied, I feel that the relation of such changes to potassium depletion, being much more clear and well-recognised, is at least as worthy of consideration. University of Kentucky Medical Center, Lexington, Kentucky 40506.
has been shown to Dr. Shafar, who writes possibility of hypokalxmia merits further consideration, although there were no relevant clinical features. Plasma-potassium levels were not estimated on admission in my patients, but will be included in a current investigation of the possible association of electrocardiogram (E.C.G.) changes and low leucocyte vitamin-C levels. No potassium supplements were prescribed in either patient, the sole medication being oral ascorbic acid. Neither patient during the first week in hospital was able to consume more than a very modest amount of the ordinary ward diet, in which fruit cordials are not included. There is little indication that the quantity of potassium thus provided would have sufficed for the correction of any significant degree of deficiency within 7 days, by which time the E.C.G. tracings had reverted to normal."-ED. L.
*** This letter
as
TREATMENT OF Q-FEVER ENDOCARDITIS SIR,-We congratulate Dr. Kristinsson and Professor Bentall (Sept. 30, p. 693) on the survival of their six patients with Q-fever endocarditis. Since they advocate aortic-valve replacement by a Starr-Edwards valve we feel that our recent case of Q-fever endocarditis in a man already fitted with such valve is relevant. A man of 40 with rheumatic aortic-valve disease had a Starr-Edwards valve fitted in the Bristol Royal Infirmary in June, 1966. Despite a stormy postoperative period he made a good recovery and returned to work in February, 1967. Follow-up indicated no clinical evidence of aortic incompetence and the erythrocyte-sedimentation rate (E.S.R.) and haemoglobin level were both normal until July, 1967. At this time he developed fever and malaise, and for the first time since operation there was clinical evidence of aortic incompetence. The E.S.R. on July 3 was 45 mm. in the first hour. Six blood-cultures were sterile and intramuscular penicillin and streptomycin had no effect on the fever. The Q-fever antibody titre was strikingly increased (1/640 phase 1, and 1/1280 phase 2) and on this basis, Q-fever endocarditis was diagnosed. The patient was initially treated with tetracycline, 2 g. a day, and later chloramphenicol was added, but despite these measures he deteriorated and died a fortnight after a
starting
treatment.
puzzled by the fact that have become incompetent. However, necropsy showed that there was a granulomatous 7. Chiarelli, B., Falek, A. Experentia (in the press). Falek, A., Chiarelli, B., Archo ital. Antrop. (in the press). Chiarelli, B., Falek, A., Back, During the patient’s life
the artificial valve
8.
we were
appeared
to
K. J., Cowart, T. Fert. Steril. (in the press). Lindsten, J., Fraccaro, M., Klinger, H. P., Zettergrist, P. Cytogenetics, 1965, 4, 45. Kjessler, B. Karyotype, Meiosis and Spermatogenesis in Man; p. 28. Basle, 1966.
R. N. SARMA
follows: " The
MORTALITY FROM CERVICAL CARCINOMA SIR,-In their article (Sept. 16, p. 605) Dr. Hill and Dr. Adelstein show crude, standardised, and age-specific deathrates from carcinoma of the cervix uteri from 1950 to 1965. They conclude: " Although the picture is necessarily incomplete, the figures indicate a decreasing risk in successive cohorts born between about 1881 and 1911; subsequent cohorts born between about 1911 and 1926 show a reversed, upward trend; and finally in the youngest cohorts, born after about 1926, the trend has changed again and is downwards." They speculate about possible underlying factors. We are inclined to believe that it is dangerous to assess the risks of developing a disease from the mortality data, when cure-rates are not very small. Bailar et a1.2 have demonstrated Surawicz, B., Braun, H. A., Crum, W. B., Kemp, R. L., Wagner, S., Bellet, S. Circulation, 1957, 16, 750. Weaver, W. F., Burchell, H. B. ibid. 1960, 21, 505. 2. Bailar, J. C., III, Thomas L. B., Thomson, A. D., Eisenberg, H., Vick, R. M. U.S. Department of Health, Education and Welfare, monograph no. 19; p. 393. 1966. 1.
female infants with Turner’s
remainder being aborted spontaneously. This study was supported by the Medical
syndrome, the
Research Council of
ranncin-
Department of Anatomy, McMaster University,
Hamilton, Ontario, Canada.
DAVID H. CARR.
REPRODUCTION AND MEIOSIS IN XYY SIR,- The XYY sex-chromosome constitution is of unusual interest, because it seems to predispose to aggressive behaviour, mental subnormality, and tall stature.l Although XYY males have been reportedno data have been presented to our knowledge on the transmission of the extra Y chromosome to their offspring or on the behaviour of their chromosomes in meiosis. We here present findings on both. We studied the 7 children of an XYY man: 6 sons and 1 daughter. The 6 sons all had normal XY sex-chromosome complements, and the daughter had a normal XX constitution. The index case in the family was the daughter’s only child. This boy, who seems chromosomally normal, has mental
retardation, multiple anomalies, and tyrosinuria due to a newly delineated inborn error, tyrosine-transaminase deficiency.a The finding of XYY sex-chromosome constitution in his grandfather, whose leucocyte cultures do not show mosaicism, was therefore entirely unexpected. The fact that all 6 sons of the XYY man were XY is notable. Four classes of gametes are possible if secondary nondisj unction occurs in the first meiotic division in such males: X, YY, XY, and Y. Union of these gametes with X-bearing ova would produce XX, XYY, XXY, and XY zygotes. Thus, female offspring might all be expected to be normal, whereas 2 of the 3 types of males might be expected to be chromosomally abnormal. Neither XXY nor XYY was observed in the 6 sons, suggesting that selection may occur toward euploidy at either meiotic, gametic, and/or zygotic levels. Meiotic studies were refused by this man, but were subsequently carried out on another XYY male with no known offspring. Two leucocyte cultures and a testicular fibroblast culture showed XYY sex-chromosome constitution with no suggestion of mosaicism. A testicular biopsy-specimen was processed for meiotic studies by a modification of the technique described by Evans et al.4 Spermatogonial metaphases were scarce, but all twenty-two examined seemed to have only one Y chromosome. Seventeen of the twenty-two contained 46 chromosomes; eleven of these were karyotyped and showed a normal XY pattern. Of the non-modal cells, four had 45 chromosomes, which upon karyotyping showed scattered losses, and one had 47 chromosomes but contained only a single Y chromosome. Diakinesis and first-meiotic-metaphase figures were plentiful. Of a hundred and fifty-five cells examined none was clearly found to contain two Y chromosomes. Representative cells shown in the accompanying figure demonstrate several typical configurations of the XY bivalent and the X and Y univalents. Although some of these were initially felt to contain two Y chromosomes, comparison with meiotic figures of four chromosomally normal men showed no discernible differences in the various configurations of the sex chromosomes or in the relative frequencies of each type of configuration. Karyotypes of secondary spermatocytes were difficult to interpret, but thirty-four of thirty-nine figures examined contained 23 chromosomes; the other five contained 24-karyotypes of these did not show conclusive evidence as to the presence or absence of two Y chromosomes. 1.
Jacobs, P. A., Brunton, M., Melville, M. M., Brittain, R. P. Nature, Lond. 1965, 208, 1351. 2. Hauschka, T. S., Hasson, J. E., Goldstein, M. N., Koept, G. F., Sandberg, A. Am. J. hum. Genet. 1962, 14, 22. Tzoneva-Maneva, M. T., Bosajieva, E., Petrov, B. Lancet, 1966, i, 1000. 3. Campbell, R. A., Buist, N. R. M., Jacinto, E. Y., Koler, R. D., Hecht, F., Jones, R. T., Society for Pediatric Research (abstract). Atlantic 4.
City, 1967. Evans, E. P., Breckon, G., Ford, C. E. Cytogenetics, 1964. 3,
289.
Meiotic preparations from
an
XYY male.
Representative diplotene-diakinesis figures showing: (A) XY bivalent with commonly observed J-shaped configuration of the Y chromosome; (B) XY bivalent with folding of the Y chromosome as in (A), but giving the appearance of two separate parallel strands; (C) X and Y univalents separated; (D) examples of X and Y chromofrom other cells. All these configurations from normal XY males. somes
were
also observed in meiotic
preparations
These findings, although preliminary, suggest that selection toward chromosomally normal spermatocytes occurs before meiosis in XYY males. The mechanism responsible for this selection is unknown, but may be related to a similar one known to occur normally in the male creeping vole (Microtus oregoni), in which the somatic cells have an XY sex-chromosome constitution and the germ cells a YO constitution.5 This study was supported in part by grants HD 01343 and CA 07941, and from the Children’s Bureau. Department of Pediatrics, University of Oregon Medical School, Portland, Oregon 97201, and Fairview Hospital and Training Center, Salem, Oregon. Metabolic Division, Children’s Hospital of Los Angeles and Department of Pediatrics, University of Southern California, Los Angeles, California 90027. Department of Pediatrics (Crippled Children’s Division) and Division of Experimental Medicine, University of Oregon Medical School, Portland, Oregon 97201.
U.S. Public Health Service genetics programme grants
HAVELOCK THOMPSON.
JOHN
MELNYK.
FREDERICK HECHT.
TRISOMY 21 OR 22 IN DOWN’S SYNDROME? SIR,-The letter of Dr. Back and his colleagues 6 prompts us to report here a possible method of identifying the G-group chromosome involved in Down’s syndrome. We are specially interested’in the possibility of classifying the meiotic chromosomes in man in the same sequence as the standardised Denver karyotype pattern for mitotic 5. 6.
Ohno, S., Jainchill, J., Stenius, C. ibid. 1963, 2, 232. Back, F., Dormer, P., Baumann, P., Olbrich, E. Lancet, 1967, i, 1228.
832 lesion which overlapped the valve ring, and so prevented the full return of the ball into its seating. There was also evidence of endocarditis involving the mitral valve. R. Y. CARTWRIGHT C. M. MORGANS Royal Devon and Exeter Hospital DAVID B. SHAW. Exeter.
Meiotic
chromosome karyotype from human testicular biopsy to size and chiasma frequency.
arranged according
chromosomes. The accompanying figure shows our karyotype results arranged according to size and chiasma frequency.7 The findings suggest that the two smallest chromo-
structurally at diakinesis, one of them consistently revealing only one chiasma. To determine which of the two G-group chromosomes is involved in Down’s syndrome it would be of value to study testicular biopsy specimens from patients with mitotic-chromosome evidence of G/G translocations. Since translocation chromosomes are readily identifiable at diakinesis,8 it should be possible by this method to determine the specificity of the somes
differ
chromosome in this disorder. the other groups should allow these meiotic chromosomes to be identified by the karyotypes of the mitotic chromosomes, thus making it possible to establish useful karyotypes of the meiotic chromosomes of man. Division of Human Genetics, Georgia Mental Health Institute and ARTHUR FALEK Department of Psychiatry, KAREN J. BACK. Emory University, Atlanta, Georgia.
normal
and
translocated
Analysis of translocations involving
E.C.G. CHANGES IN SCURVY SIR,-While congratulating Dr. Shafar on his interesting report (July 22, p. 176), one cannot help wondering why the possibility of a concomitant potassium depletion, with or without hypokalaemia, should not have found a place in his otherwise excellent and detailed discussion on the pathogenesis of the electrocardiogram (E.C.G.) changes illustrated. The E.C.G. before treatment in case 1 appears to be diagnostic of hypokalaemia,l while that in case 2 may be described as being not incompatible with hypokalaemia. Potassium. depletion with or without hypokalsemia, and with or without a hypokalxmic E.C.G. pattern, is not uncommon in the clinical circumstances detailed in the two cases. A reference to plasma-potassium levels, if available, would be of interest. Potassium therapy can effect the improvement noted in the post-treatment E.c.G.s. It would therefore be pertinent to know whether, during the week of treatment with vitamin C, the patients also received more potassium through food or through medicines administered than before treatment. Although the possible participation of ascorbic-acid deficiency in the production of the E.C.G. changes reported cannot be denied, I feel that the relation of such changes to potassium depletion, being much more clear and well-recognised, is at least as worthy of consideration. University of Kentucky Medical Center, Lexington, Kentucky 40506.
has been shown to Dr. Shafar, who writes possibility of hypokalxmia merits further consideration, although there were no relevant clinical features. Plasma-potassium levels were not estimated on admission in my patients, but will be included in a current investigation of the possible association of electrocardiogram (E.C.G.) changes and low leucocyte vitamin-C levels. No potassium supplements were prescribed in either patient, the sole medication being oral ascorbic acid. Neither patient during the first week in hospital was able to consume more than a very modest amount of the ordinary ward diet, in which fruit cordials are not included. There is little indication that the quantity of potassium thus provided would have sufficed for the correction of any significant degree of deficiency within 7 days, by which time the E.C.G. tracings had reverted to normal."-ED. L.
*** This letter
as
TREATMENT OF Q-FEVER ENDOCARDITIS SIR,-We congratulate Dr. Kristinsson and Professor Bentall (Sept. 30, p. 693) on the survival of their six patients with Q-fever endocarditis. Since they advocate aortic-valve replacement by a Starr-Edwards valve we feel that our recent case of Q-fever endocarditis in a man already fitted with such valve is relevant. A man of 40 with rheumatic aortic-valve disease had a Starr-Edwards valve fitted in the Bristol Royal Infirmary in June, 1966. Despite a stormy postoperative period he made a good recovery and returned to work in February, 1967. Follow-up indicated no clinical evidence of aortic incompetence and the erythrocyte-sedimentation rate (E.S.R.) and haemoglobin level were both normal until July, 1967. At this time he developed fever and malaise, and for the first time since operation there was clinical evidence of aortic incompetence. The E.S.R. on July 3 was 45 mm. in the first hour. Six blood-cultures were sterile and intramuscular penicillin and streptomycin had no effect on the fever. The Q-fever antibody titre was strikingly increased (1/640 phase 1, and 1/1280 phase 2) and on this basis, Q-fever endocarditis was diagnosed. The patient was initially treated with tetracycline, 2 g. a day, and later chloramphenicol was added, but despite these measures he deteriorated and died a fortnight after a
starting
treatment.
puzzled by the fact that have become incompetent. However, necropsy showed that there was a granulomatous 7. Chiarelli, B., Falek, A. Experentia (in the press). Falek, A., Chiarelli, B., Archo ital. Antrop. (in the press). Chiarelli, B., Falek, A., Back, During the patient’s life
the artificial valve
8.
we were
appeared
to
K. J., Cowart, T. Fert. Steril. (in the press). Lindsten, J., Fraccaro, M., Klinger, H. P., Zettergrist, P. Cytogenetics, 1965, 4, 45. Kjessler, B. Karyotype, Meiosis and Spermatogenesis in Man; p. 28. Basle, 1966.
R. N. SARMA
follows: " The
MORTALITY FROM CERVICAL CARCINOMA SIR,-In their article (Sept. 16, p. 605) Dr. Hill and Dr. Adelstein show crude, standardised, and age-specific deathrates from carcinoma of the cervix uteri from 1950 to 1965. They conclude: " Although the picture is necessarily incomplete, the figures indicate a decreasing risk in successive cohorts born between about 1881 and 1911; subsequent cohorts born between about 1911 and 1926 show a reversed, upward trend; and finally in the youngest cohorts, born after about 1926, the trend has changed again and is downwards." They speculate about possible underlying factors. We are inclined to believe that it is dangerous to assess the risks of developing a disease from the mortality data, when cure-rates are not very small. Bailar et a1.2 have demonstrated Surawicz, B., Braun, H. A., Crum, W. B., Kemp, R. L., Wagner, S., Bellet, S. Circulation, 1957, 16, 750. Weaver, W. F., Burchell, H. B. ibid. 1960, 21, 505. 2. Bailar, J. C., III, Thomas L. B., Thomson, A. D., Eisenberg, H., Vick, R. M. U.S. Department of Health, Education and Welfare, monograph no. 19; p. 393. 1966. 1.