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AUTOANTIBODIES IN KLINEFELTER'S SYNDROME
748 The incidence of diabetes among the parents and relatives of our patients is as follows:
leucocytes. Patient
(no.)
Age (yr.)
2 3 5
52 20 43
24 25 28 29 31
20 20 27 20 20
Positivechromatin
Diabetes mellitus in: Other relatives Parents (buccal smears) The patient Father 37/100 Mother 18/100 Father and mother Maternal uncle’ 36/100 and grandmother Maternal grandmother 22/100 Father 32/100 Father 19/100 Paternal grandmother 23/100 Mother 17/100 .
..
..
..
..
..
Thus 8 (25%) of 32 patients with Klinefelter’s syndrome have near relatives with diabetes mellitus. Patient no. 2, karyotype XXY,24 is diabetic. Of the patients’ parents, 4 (12-5%) of 32 fathers, and 3 (9%) of 32 mothers, have diabetes mellitusi.e., 7 (11%) of 64 parents are affected, a result coinciding with that found by Dr. Nielsen. 17 Out of these 32 patients with Klinefelter’s syndrome, 13 (41%) are Jewish, including 3 (10%) with diabetes. Endocrinology Centre, Ministry of Social Assistance and Public Health, Godoy Cruz 1221, Buenos Aires, Argentina.
prediabetes in parents of patients with Klinefelter’s and Turner’s syndromes as well as in patients with these syndromes is due to an autoimmune disorder associated with the presence of antibodies against insulin, as recently suggested by Dr. Burch and his colleagues (July 16, p. 170). The correlation between diabetes mellitus and sex hormones,29as well as that found between this disease and prolonged administration of pituitary hormone or extract of purified growth hormone 30 31 in animal experiments, suggests that diabetes mellitus or prediabetes in patients with Klinefelter’s and Turner’s syndromes might be partly due to the sex. hormone changes found in these disorders. More studies of glucose metabolism in patients with Klinefelter’s syndrome as well as in patients with other chromosome abnormalities are, however, needed before any definite conclusion can be drawn about the genetic implications of a possible correlation between non-disjunction and diabetes mellitus and between chromosome abnormalities and diabetes mellitus. Cytogenetic Laboratory, Århus State Hospital, JOHANNES NIELSEN. Risskov, Denmark.
SAMUEL WAIS EMILIO SALVATI. AUTOANTIBODIES IN KLINEFELTER’S SYNDROME
SiR,—The finding of a fairly high frequency of diabetes mellitus in parents of patients with Klinefelter’s syndrome,25 and the possibility of a correlation between diabetes mellitus and Klinefelter’s syndrome similar to that between diabetes mellitus and Turner’s syndrome,26 27 led me to do glucosetolerance tests in 9 of the previously described 25 25 patients with sex chromosomes XXY and XY/XXY, and in 1 patient with XXXY, none of whom had overt diabetes mellitus. Fajans and Conn 28 define a diabetic glucose-tolerance curve as one in which the 1-hour, 1-hour, and 2-hour blood-sugar concentrations are at least 160, 140, and 120 mg. per 100 ml. AGE, WEIGHT, KARYOTYPE, AND RESULTS OF BLOOD GLUCOSE-TOLERANCE TESTS IN 10 PATIENTS WITH KLINEFELTER’S SYNDROME
6 of the 10 patients with Klinefelter’s syndrome had a diabetic glucose-tolerance curve according to these criteria (see accompanying table). This frequency of 60% with such a curve is high compared with one of 0-8% in 127 healthy persons with no diabetic relatives, and of 19% in 438 close relatives of patients with diabetes mellitus.28 Only 1 (no. 12) of the 4 patients who did not have a diabetic glucose-tolerance curve as defined had a completely normal curve. (Patient no. 13 had had a stomach resection.) It will be of special interest to study the possibility whether the tendency to a high frequency of diabetes mellitus or
respectively.
Wais, S., Zapata, A. C., Martinez Montes, E., Salvati, E. Abstracts of Fifth Pan-American Congress of Endocrinology: vol. I; p. 161. Lima, Peru, 1961. 25. Nielsen, J. Lancet, 1966, i, 1376. 26. Forbes, A. P., Engel, E. Metabolism, 1963, 12, 428. 27. Menzinger, G., Fallucca, F., Andreani, D. Lancet, 1966, i, 1269. 28. Fajans, S. S., Conn, J. W. Ann. N. Y. Acad. Sci. 1959, 82, 208.
24.
SIR Dr. Ferguson-Smith and his collaborators (Sept. 10, 566) attribute to us the view that somatic mutation at could determine the development of specific X-linked loci autoimmune disease ". From their finding of a lower incidence of circulating autoantibodies in patients with Klinefelter’s syndrome than in male and female controls, they argue "
p.
...
...
that their results do not seem consistent with the X-linked postulate of Burch and Burwell.32 We should like to comment on their interpretation of their findings. In our view, only certain autoimmune diseases involve somatic mutation of X-linked genes. In the publication33 two which Dr. Ferguson-Smith and his colleagues refer, we cited examples of autoimmune diseases (inflammatory polyarthritis, systemic sclerosis, and systemic lupus erythematosus) in which somatic mutation of particular X-linked genes appear to be pathogenic. But we had previously deduced 33 that the average rate of the random events initiating Hashimoto’s thyroiditis in adults is probably the same in both sexes. This indicates33 that somatic mutation of autosomal rather than X-linked genes should be involved in the initiation of this autoimmune disease. Thyroiditis with similar features occurs also in children and adolescents. Analysis of the sex-specific and age-specific onset-rates 34—37 of this form of the disease indicates that there are at least two predisposing genotypes. As in the genotype predisposing to thyroiditis with predominant onset in adults, it appears that somatic mutation of autosomal genes is again involved. In both sexes, the modal onset age for the first genotype occurs at about 6 years, and for the second at about 12 years. The similarities in the modal onset-ages for both sexes suggest, firstly, that the average rate of the random initiating events is effectively the same in males and females, and, secondly, that the average latent period-i.e., the interval between the completion of initiation through somatic mutation and clinical or symptomatic onset-is also about the same in both sexes. These features are consistent with the hypothesis that juvenile thyroiditis (in both genotypes) is a spontaneous disturbed-tolerance autoimmune disease in which the primary, Houssay, B. A. in Diabetes; p. 233. New York, 1960. Young, F. G. Lancet, 1937, ii, 372. Keterer, B., Randle, P. J., Young, F. G. in Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie; p.127. Berlin, 1957. 32. Burch, P. R. J., Burwell, R. G. Lancet, 1963, ii, 943. 33. Burch, P. R. J., Rowell, N. R. ibid. 1963, ii, 507. 34. Saxena, K. A. Personal communication. 35. Hall, R. Personal communication. 36. Hahn, H. B., Hayles, A. B., Woolner, L. B. Pediatrics, Springfield, 1965, 66, 73. 37. Nilsson, L., Doniach, D. Acta pœdiat., Stockh. 1964, 53, 255.
29. 30. 31.
749 are humoral.38—40 They are likely to pathogenicon autoantibodies electrophoresis with the oc-globulin serum-protein
migrate
41
fraction.40 We suspect that the observed fragmentation of the basement membrane in thyroiditis is a conseperifollicular the of primary autoimmune attack, and that lymphoquence cytes subsequently infiltrate the thyroid acini through the gaps
in this membrane. Our arguments 32 33 38-40 on the aetiology and pathogenesis of autoimmune disease have been based on the evidence for clinically overt disease and not on serological abnormalities. In our view, 33 38 40 disturbances in the immunoglobulin fraction ,e.g., IgA, IgG, and IgM) are never the primary cause of spontaneous disturbed-tolerance autoimmunity; at best their rdation to clinical disease is secondary, at worst (as in aggammastudies of gtobulinsmia) it is non-existent. have a somewhat autoantibodies complicated immunoglobin and indirect connection with our hypothesis of spontaneous
Accordingly,
clinical autoimmunity. Age is in itself an immensely important factor in the development of autoimmunity, and in most adults with Hashimoto’s thyroiditis the onset is after the age of 30 years.33 Dr. FergusonSmith and his colleagues do not detail the age of their patients, although the mean age is given as 323 years; consequently many will not have attained the main thyroiditis age-range". In considering the incidence of autoimmune disease in patients with Klinefelter’s syndrome it must be remembered that they represent a special subpopulation. Following Fialkow’s 42 observation and hypothesis that chromosomal non-disjunction at meiosis is associated with autoimmunity, we have proposed 43 that Klinefelter’s syndrome results from a specific autoimmune attack on parental germ cells. It is well known that certain autoimmune diseases are positively associated, and we have recently argued 44 that negative associationthat is, mutual exclusion-should also be found. To take a simple monogenic example: if alleles aa/aa in homozygous form predispose to disease A, and if the alternative alleles ab/ab at the same autosomal locus predispose to disease B, then diseases A and B will never arise in the same individual. The coefficient of association between diseases A and B will then be -1. On our extension of the Fialkow 42 hypothesis, one of the parents of a patient with Klinefelter’s syndrome may be regarded as having a specific autoimmune disease in which germ cells are the target tissue. This affected parent will be likely to have positively associated autoimmune diseases and unlikely to have negatively associated diseases. Consequently, patients with Klinefelter’s syndrome will tend to inherit such positively and negatively associated predisposinggenotypes. It has been observed 45 that the parents and close relatives of patients with Klinefelter’s syndrome have a raised incidence of diabetes mellitus. From the foregoing arguments it follows that the age-specific onset-rates of diabetes should also be raised in patients with Klinefelter’s syndrome. Turner’s (XO) syndrome may have an autoimmune aetiology, and similar arguments regarding inherited tendencies should apply to such individuals. It is pertinent, therefore, that cllmcal evidence of thyroid disease has been found in three out of twenty-five patients with gonadal dysgenesis, and microscopic evidence of severe chronic thyroiditis was found in four out of nine such cases 46 Significantly, thyroid dysfunction and goitres are often found in Klinefelter’s syndrome.47-49 Further"
’
more, there appears to be
an
association between Turner’s
syndrome and diabetes.5° We agree with Dr. Ferguson-Smith and his colleagues that patients with Klinefelter’s syndrome constitute an important population where autoimmune theory is concerned. If in the XXY form of the syndrome both X-chromosomes in lymphoid growth-control stem cells are at somatic mutational risk, then when age-specific onset-rates of clinically overt autoimmune diseases show a sex difference, the age-pattern (e.g., modal onset age) in patients with the XXY karyotype should follow that observed in populations of XX females. Finally, in considering the details of incidence of autoimmune diseases in any specific subclass of the general population (such as Klinefelter’s, Turner’s, or Down’s syndromes) attention must be given to all the following factors: (1) the incidence of autoimmune diseases in parents; (2) the contribution of sexlinked and autosomal alleles to genotypes predisposing to autoimmune disease; (3) the contribution of sex-linked and autosomal somatic mutations to the pathogenesis of autoimmune disease; (4) the contribution (if any) of X-linkage to the duration of the latent period; (5) age; and (6) the lack of a simple one-to-one correspondence between clinical autoimmune disease and detachable serological abnormalities. P. R. J. BURCH The General Infirmary at Leeds. Robert Jones and Agnes Hunt
Orthopædic Hospital, Oswestry.
N. R. ROWELL.
R. G. BURWELL.
MUSCLE ANTIBODIES IN MYASTHENIA GRAVIS SIR,-Dr. Vetters in his letter (Sept. 10, p. 588) calls attention to the potential clinical value of serological tests for demonstrating presumed autoantibodies to striated muscle as a means of detecting radiologically inapparent thymomas, particularly in patients with myasthenia gravis. We heartily concur in and endorse his worth-while suggestion. The from evidence several laboratories,51 including preponderant ours, is that such anti-striated-muscle reactivity is detectable in concentrations greater than in the control background in 23-62% of patients with myasthenia gravis at large, in almost all patients with myasthenia gravis with associated documented thymomas (57 of 59 cases in our series to date), and in some patients with thymomas who do not have myasthenia gravis (12 of 51 in our published series).52 We, too, are puzzled by the consistent failure of Hoffbrand 53 to detect such serum reactivity in his series of thymoma cases, which include patients with and without myasthenia gravis. Paralleling Dr. Vetters’ experience we have detected significant titres (1:60-1:1920 or greater) of anti-striated-muscle reactivity in sera of several patients with myasthenia gravis, who did not have radiologically demonstrable thymomas, but who did have gross morphological and microscopic evidence of thymomas at subsequent thymectomy or necropsy. Dr. Kermit Osserman, at The Mount Sinai Hospital, New York, has had similar experiences. We know of no instance in which an occult thymoma has been demonstrated in a patient with myasthenia gravis in which anti-striated-muscle reactivity had not been detectable. On the other hand, we have encountered high titres of anti-striated-muscle reactivity in sera of several patients with myasthenia gravis who, at surgery or on postmortem examination, were found not to have thymomas, or for 38. Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. that matter any detectable thymus tissue. In short, we believe 39 Burch, P. R. J., Rowell, N. R. Am. J. Med. 1965, 38, 793. that the absence of anti-striated-muscle reactivity militates 40 Burch, P. R. J., Rowell, N. R. Acta derm.- vener., Stockh. 1965, 45, 366. 41 Irvine, W. J., Muir, A. R. Q. Jl exp. Physiol. 1963, 48, 13. against the possible presence of thymoma; the presence of the 42 Fialkow, P. J. Lancet, 1964, i, 474. same reactivity is suggestive but does not constitute proof of 43 Burch, P. R. J., Rowell. N. R., Burwell, R. G. ibid. July 16, 1966, p. 170. the presence of thymoma. While it would be diagnostically 44 Burch, P. R. J., Rowell, N. R. Br. med. J. Aug. 6, 1966, p. 362. 45 Nielsen, J. Lancet, 1966, i, 1376. convenient, as Dr. Vetters has suggested in his hypothesis, for 46 Williams, E. D., Engel, E., Forbes, A. D. New Eng. J. Med. 1964, 270, anti-A-band reactivity to be exclusively the property of sera 805.
47 Barr, M. L., Shaver,
E. L., Carr, D. H., Plunkett, E. R. J. ment. Defic. Res. 1960, 4, 89. 48 Davis, T.. E., Canfield, C. J., Herman, R. H., Goler, D. New Engl. J. Med. 1963, 268, 178. 49 Carr, D. H., Barr, M. L., Plunkett, E. R., Grumbach, M. M., Morishima, A., Chu, E. H. Y.J. clin. Endocr. Metab. 1961,21,491.
50. Forbes, A. D., Engel, E. Metabolism, 1963, 12, 428. 51. Several contributors to the Myasthenia Gravis Conference Volume. Ann. N.Y. Acad. Sci., 1966. 52. Strauss, A. J. L., Smith, C. W., Cage, G. W., van der Geld, H. W. R., McFarlin, D. E., Barlow, M. Ann. N.Y Acad. Sci. 1966, 135, 557. 53. Hoffbrand, B. I. Thorax, 1966, 21, 263.
leucocytes. Patient
(no.)
Age (yr.)
2 3 5
52 20 43
24 25 28 29 31
20 20 27 20 20
Positivechromatin
Diabetes mellitus in: Other relatives Parents (buccal smears) The patient Father 37/100 Mother 18/100 Father and mother Maternal uncle’ 36/100 and grandmother Maternal grandmother 22/100 Father 32/100 Father 19/100 Paternal grandmother 23/100 Mother 17/100 .
..
..
..
..
..
Thus 8 (25%) of 32 patients with Klinefelter’s syndrome have near relatives with diabetes mellitus. Patient no. 2, karyotype XXY,24 is diabetic. Of the patients’ parents, 4 (12-5%) of 32 fathers, and 3 (9%) of 32 mothers, have diabetes mellitusi.e., 7 (11%) of 64 parents are affected, a result coinciding with that found by Dr. Nielsen. 17 Out of these 32 patients with Klinefelter’s syndrome, 13 (41%) are Jewish, including 3 (10%) with diabetes. Endocrinology Centre, Ministry of Social Assistance and Public Health, Godoy Cruz 1221, Buenos Aires, Argentina.
prediabetes in parents of patients with Klinefelter’s and Turner’s syndromes as well as in patients with these syndromes is due to an autoimmune disorder associated with the presence of antibodies against insulin, as recently suggested by Dr. Burch and his colleagues (July 16, p. 170). The correlation between diabetes mellitus and sex hormones,29as well as that found between this disease and prolonged administration of pituitary hormone or extract of purified growth hormone 30 31 in animal experiments, suggests that diabetes mellitus or prediabetes in patients with Klinefelter’s and Turner’s syndromes might be partly due to the sex. hormone changes found in these disorders. More studies of glucose metabolism in patients with Klinefelter’s syndrome as well as in patients with other chromosome abnormalities are, however, needed before any definite conclusion can be drawn about the genetic implications of a possible correlation between non-disjunction and diabetes mellitus and between chromosome abnormalities and diabetes mellitus. Cytogenetic Laboratory, Århus State Hospital, JOHANNES NIELSEN. Risskov, Denmark.
SAMUEL WAIS EMILIO SALVATI. AUTOANTIBODIES IN KLINEFELTER’S SYNDROME
SiR,—The finding of a fairly high frequency of diabetes mellitus in parents of patients with Klinefelter’s syndrome,25 and the possibility of a correlation between diabetes mellitus and Klinefelter’s syndrome similar to that between diabetes mellitus and Turner’s syndrome,26 27 led me to do glucosetolerance tests in 9 of the previously described 25 25 patients with sex chromosomes XXY and XY/XXY, and in 1 patient with XXXY, none of whom had overt diabetes mellitus. Fajans and Conn 28 define a diabetic glucose-tolerance curve as one in which the 1-hour, 1-hour, and 2-hour blood-sugar concentrations are at least 160, 140, and 120 mg. per 100 ml. AGE, WEIGHT, KARYOTYPE, AND RESULTS OF BLOOD GLUCOSE-TOLERANCE TESTS IN 10 PATIENTS WITH KLINEFELTER’S SYNDROME
6 of the 10 patients with Klinefelter’s syndrome had a diabetic glucose-tolerance curve according to these criteria (see accompanying table). This frequency of 60% with such a curve is high compared with one of 0-8% in 127 healthy persons with no diabetic relatives, and of 19% in 438 close relatives of patients with diabetes mellitus.28 Only 1 (no. 12) of the 4 patients who did not have a diabetic glucose-tolerance curve as defined had a completely normal curve. (Patient no. 13 had had a stomach resection.) It will be of special interest to study the possibility whether the tendency to a high frequency of diabetes mellitus or
respectively.
Wais, S., Zapata, A. C., Martinez Montes, E., Salvati, E. Abstracts of Fifth Pan-American Congress of Endocrinology: vol. I; p. 161. Lima, Peru, 1961. 25. Nielsen, J. Lancet, 1966, i, 1376. 26. Forbes, A. P., Engel, E. Metabolism, 1963, 12, 428. 27. Menzinger, G., Fallucca, F., Andreani, D. Lancet, 1966, i, 1269. 28. Fajans, S. S., Conn, J. W. Ann. N. Y. Acad. Sci. 1959, 82, 208.
24.
SIR Dr. Ferguson-Smith and his collaborators (Sept. 10, 566) attribute to us the view that somatic mutation at could determine the development of specific X-linked loci autoimmune disease ". From their finding of a lower incidence of circulating autoantibodies in patients with Klinefelter’s syndrome than in male and female controls, they argue "
p.
...
...
that their results do not seem consistent with the X-linked postulate of Burch and Burwell.32 We should like to comment on their interpretation of their findings. In our view, only certain autoimmune diseases involve somatic mutation of X-linked genes. In the publication33 two which Dr. Ferguson-Smith and his colleagues refer, we cited examples of autoimmune diseases (inflammatory polyarthritis, systemic sclerosis, and systemic lupus erythematosus) in which somatic mutation of particular X-linked genes appear to be pathogenic. But we had previously deduced 33 that the average rate of the random events initiating Hashimoto’s thyroiditis in adults is probably the same in both sexes. This indicates33 that somatic mutation of autosomal rather than X-linked genes should be involved in the initiation of this autoimmune disease. Thyroiditis with similar features occurs also in children and adolescents. Analysis of the sex-specific and age-specific onset-rates 34—37 of this form of the disease indicates that there are at least two predisposing genotypes. As in the genotype predisposing to thyroiditis with predominant onset in adults, it appears that somatic mutation of autosomal genes is again involved. In both sexes, the modal onset age for the first genotype occurs at about 6 years, and for the second at about 12 years. The similarities in the modal onset-ages for both sexes suggest, firstly, that the average rate of the random initiating events is effectively the same in males and females, and, secondly, that the average latent period-i.e., the interval between the completion of initiation through somatic mutation and clinical or symptomatic onset-is also about the same in both sexes. These features are consistent with the hypothesis that juvenile thyroiditis (in both genotypes) is a spontaneous disturbed-tolerance autoimmune disease in which the primary, Houssay, B. A. in Diabetes; p. 233. New York, 1960. Young, F. G. Lancet, 1937, ii, 372. Keterer, B., Randle, P. J., Young, F. G. in Ergebnisse der Physiologie, biologischen Chemie und experimentellen Pharmakologie; p.127. Berlin, 1957. 32. Burch, P. R. J., Burwell, R. G. Lancet, 1963, ii, 943. 33. Burch, P. R. J., Rowell, N. R. ibid. 1963, ii, 507. 34. Saxena, K. A. Personal communication. 35. Hall, R. Personal communication. 36. Hahn, H. B., Hayles, A. B., Woolner, L. B. Pediatrics, Springfield, 1965, 66, 73. 37. Nilsson, L., Doniach, D. Acta pœdiat., Stockh. 1964, 53, 255.
29. 30. 31.
749 are humoral.38—40 They are likely to pathogenicon autoantibodies electrophoresis with the oc-globulin serum-protein
migrate
41
fraction.40 We suspect that the observed fragmentation of the basement membrane in thyroiditis is a conseperifollicular the of primary autoimmune attack, and that lymphoquence cytes subsequently infiltrate the thyroid acini through the gaps
in this membrane. Our arguments 32 33 38-40 on the aetiology and pathogenesis of autoimmune disease have been based on the evidence for clinically overt disease and not on serological abnormalities. In our view, 33 38 40 disturbances in the immunoglobulin fraction ,e.g., IgA, IgG, and IgM) are never the primary cause of spontaneous disturbed-tolerance autoimmunity; at best their rdation to clinical disease is secondary, at worst (as in aggammastudies of gtobulinsmia) it is non-existent. have a somewhat autoantibodies complicated immunoglobin and indirect connection with our hypothesis of spontaneous
Accordingly,
clinical autoimmunity. Age is in itself an immensely important factor in the development of autoimmunity, and in most adults with Hashimoto’s thyroiditis the onset is after the age of 30 years.33 Dr. FergusonSmith and his colleagues do not detail the age of their patients, although the mean age is given as 323 years; consequently many will not have attained the main thyroiditis age-range". In considering the incidence of autoimmune disease in patients with Klinefelter’s syndrome it must be remembered that they represent a special subpopulation. Following Fialkow’s 42 observation and hypothesis that chromosomal non-disjunction at meiosis is associated with autoimmunity, we have proposed 43 that Klinefelter’s syndrome results from a specific autoimmune attack on parental germ cells. It is well known that certain autoimmune diseases are positively associated, and we have recently argued 44 that negative associationthat is, mutual exclusion-should also be found. To take a simple monogenic example: if alleles aa/aa in homozygous form predispose to disease A, and if the alternative alleles ab/ab at the same autosomal locus predispose to disease B, then diseases A and B will never arise in the same individual. The coefficient of association between diseases A and B will then be -1. On our extension of the Fialkow 42 hypothesis, one of the parents of a patient with Klinefelter’s syndrome may be regarded as having a specific autoimmune disease in which germ cells are the target tissue. This affected parent will be likely to have positively associated autoimmune diseases and unlikely to have negatively associated diseases. Consequently, patients with Klinefelter’s syndrome will tend to inherit such positively and negatively associated predisposinggenotypes. It has been observed 45 that the parents and close relatives of patients with Klinefelter’s syndrome have a raised incidence of diabetes mellitus. From the foregoing arguments it follows that the age-specific onset-rates of diabetes should also be raised in patients with Klinefelter’s syndrome. Turner’s (XO) syndrome may have an autoimmune aetiology, and similar arguments regarding inherited tendencies should apply to such individuals. It is pertinent, therefore, that cllmcal evidence of thyroid disease has been found in three out of twenty-five patients with gonadal dysgenesis, and microscopic evidence of severe chronic thyroiditis was found in four out of nine such cases 46 Significantly, thyroid dysfunction and goitres are often found in Klinefelter’s syndrome.47-49 Further"
’
more, there appears to be
an
association between Turner’s
syndrome and diabetes.5° We agree with Dr. Ferguson-Smith and his colleagues that patients with Klinefelter’s syndrome constitute an important population where autoimmune theory is concerned. If in the XXY form of the syndrome both X-chromosomes in lymphoid growth-control stem cells are at somatic mutational risk, then when age-specific onset-rates of clinically overt autoimmune diseases show a sex difference, the age-pattern (e.g., modal onset age) in patients with the XXY karyotype should follow that observed in populations of XX females. Finally, in considering the details of incidence of autoimmune diseases in any specific subclass of the general population (such as Klinefelter’s, Turner’s, or Down’s syndromes) attention must be given to all the following factors: (1) the incidence of autoimmune diseases in parents; (2) the contribution of sexlinked and autosomal alleles to genotypes predisposing to autoimmune disease; (3) the contribution of sex-linked and autosomal somatic mutations to the pathogenesis of autoimmune disease; (4) the contribution (if any) of X-linkage to the duration of the latent period; (5) age; and (6) the lack of a simple one-to-one correspondence between clinical autoimmune disease and detachable serological abnormalities. P. R. J. BURCH The General Infirmary at Leeds. Robert Jones and Agnes Hunt
Orthopædic Hospital, Oswestry.
N. R. ROWELL.
R. G. BURWELL.
MUSCLE ANTIBODIES IN MYASTHENIA GRAVIS SIR,-Dr. Vetters in his letter (Sept. 10, p. 588) calls attention to the potential clinical value of serological tests for demonstrating presumed autoantibodies to striated muscle as a means of detecting radiologically inapparent thymomas, particularly in patients with myasthenia gravis. We heartily concur in and endorse his worth-while suggestion. The from evidence several laboratories,51 including preponderant ours, is that such anti-striated-muscle reactivity is detectable in concentrations greater than in the control background in 23-62% of patients with myasthenia gravis at large, in almost all patients with myasthenia gravis with associated documented thymomas (57 of 59 cases in our series to date), and in some patients with thymomas who do not have myasthenia gravis (12 of 51 in our published series).52 We, too, are puzzled by the consistent failure of Hoffbrand 53 to detect such serum reactivity in his series of thymoma cases, which include patients with and without myasthenia gravis. Paralleling Dr. Vetters’ experience we have detected significant titres (1:60-1:1920 or greater) of anti-striated-muscle reactivity in sera of several patients with myasthenia gravis, who did not have radiologically demonstrable thymomas, but who did have gross morphological and microscopic evidence of thymomas at subsequent thymectomy or necropsy. Dr. Kermit Osserman, at The Mount Sinai Hospital, New York, has had similar experiences. We know of no instance in which an occult thymoma has been demonstrated in a patient with myasthenia gravis in which anti-striated-muscle reactivity had not been detectable. On the other hand, we have encountered high titres of anti-striated-muscle reactivity in sera of several patients with myasthenia gravis who, at surgery or on postmortem examination, were found not to have thymomas, or for 38. Burch, P. R. J., Burwell, R. G. Q. Rev. Biol. 1965, 40, 252. that matter any detectable thymus tissue. In short, we believe 39 Burch, P. R. J., Rowell, N. R. Am. J. Med. 1965, 38, 793. that the absence of anti-striated-muscle reactivity militates 40 Burch, P. R. J., Rowell, N. R. Acta derm.- vener., Stockh. 1965, 45, 366. 41 Irvine, W. J., Muir, A. R. Q. Jl exp. Physiol. 1963, 48, 13. against the possible presence of thymoma; the presence of the 42 Fialkow, P. J. Lancet, 1964, i, 474. same reactivity is suggestive but does not constitute proof of 43 Burch, P. R. J., Rowell. N. R., Burwell, R. G. ibid. July 16, 1966, p. 170. the presence of thymoma. While it would be diagnostically 44 Burch, P. R. J., Rowell, N. R. Br. med. J. Aug. 6, 1966, p. 362. 45 Nielsen, J. Lancet, 1966, i, 1376. convenient, as Dr. Vetters has suggested in his hypothesis, for 46 Williams, E. D., Engel, E., Forbes, A. D. New Eng. J. Med. 1964, 270, anti-A-band reactivity to be exclusively the property of sera 805.
47 Barr, M. L., Shaver,
E. L., Carr, D. H., Plunkett, E. R. J. ment. Defic. Res. 1960, 4, 89. 48 Davis, T.. E., Canfield, C. J., Herman, R. H., Goler, D. New Engl. J. Med. 1963, 268, 178. 49 Carr, D. H., Barr, M. L., Plunkett, E. R., Grumbach, M. M., Morishima, A., Chu, E. H. Y.J. clin. Endocr. Metab. 1961,21,491.
50. Forbes, A. D., Engel, E. Metabolism, 1963, 12, 428. 51. Several contributors to the Myasthenia Gravis Conference Volume. Ann. N.Y. Acad. Sci., 1966. 52. Strauss, A. J. L., Smith, C. W., Cage, G. W., van der Geld, H. W. R., McFarlin, D. E., Barlow, M. Ann. N.Y Acad. Sci. 1966, 135, 557. 53. Hoffbrand, B. I. Thorax, 1966, 21, 263.