- Email: [email protected]
XY GONADAL DYSGENESIS
27
who either underwent surgery within 9 days of a haemorrhage or who when operated on had not fully recovered from the effect of the hxmorrhage. This emphasises that waiting can lessen the risks of an operation; the price is that more patients will rebleed before operation so that the overall results are no better. A decade ago, it was proposed that antifibrinolytic therapy might protect a patient against rebleeding and make delayed surgery safer.5 In the past year it has even been suggested, though with little supporting evidence, that such treatment might confer lasting protection, making surgery unnecessary.6 The value of antifibrinolytic therapy within the first two weeks is still debated; two recent randomised controlled studies of antifibrinolytic therapy reached conflicting conclusions.7 8 Do the results in the Mayo series represent an improvement on the natural history of the disease? The chances that a patient with a ruptured aneurysm may die are governed by two factors-how long he has already survived since his hsemorrhage, and whether consciousness is impaired or there are other major deficits. Information about these two features can be used to calculate the expected mortality in a series of patients,9 but this method was not applied to the Mayo series. Instead, Sundt and Whisnant contrasted the mortality of about 20% at 1 month, which they observed in 42 patients admitted to the Mayo Clinic on the day after haemorrhage, with one of over 40%, which was found in 50 patients drawn from a survey of the population of Rochester, Minnesota, and who had survived for at least one day after a subarachnoid haemorrhage. Although the two groups were thus selected carefully to ensure that they were compared at similar intervals after a hmmorrhage, there is not sufficient information about other important factors, such as the clinical grades in the two groups and the treatment received by the population series (which was observed between 1955and 1969 and so antedates the surgical series), to put the validity of the comparison beyond doubt. We need reliable, up-to-date statistics about patients with a ruptured aneurysm, because what we advise depends upon careful weighing of the risks of surgery against those of spontaneous bleeding and ischaemia. Until lately it seemed that we had to take into account only the risks within the first few months after rupture and that the chances of rebleeding thereafter could be neglected. Now a longer timespan has to be considered: once an aneurysm has ruptured there is persisting risk of rebleeding for at least ten years-a risk of about 3.5% per year.10 This longer time-scale has highlighted the importance of a patient’s age; there has been controversy about the advisability of surgical management in the over-60s.11 12 The case for surgery in younger patients has become clearer-particularly if the patient is a woman of childbearing age, because pregnancy may 3. 4. 5. 6. 7.
Sundt, T.M., Whisnant, J. P. New Engl. J. Med 1978, 299, Skultety, F. M., Nishioka, H.J. Neurosurg. 1966, 25, 683. Mullan, S., Dawley, J. ibid. 1968, 28, 21. Maurice-Williams, R. S. Br. med. J. 1978, i, 945. van
Rossum, J., Wintzen, A. R., Endtz, L. J.,
et
116.
al. Ann. Neurol.
1977, 2,
242. 8.
Fodstad, H., Liliequist, B., Schannong, M.,
et
al.
Surg.
Neurol. 1978,
10,
9
9.
Alvord, E. C. Jnr., Loeser, J. D., Bailey, W. L., et al. Archs Neurol. 1972, 27, 273. 10. Winn, H. R., Richardson, A. E., Jane, J. A. Ann. Neurol. 1977, 1, 358. 11Marundale, B., Garfield, J. Br. med. J. 1978, i, 465. 12. Sengupta, R. P., Lassman, L. P., Hankinson, J. ibid. 1978, ii, 246.
increase the risk of subarachnoid hxmorrhage,13 as may smoking and the use of oral contraceptives. 14 What lies ahead? Improved prevention of rebleeding may encourage even more delayed, and thus safer, surgery ; this seems the likely pattern in the immediate future. Eventually, the fruits of research into pathophysiological mechanisms may permit early surgery without the risk of precipitating cerebral infarction, thereby lessening the chance of rebleeding. The advantages of surgical management over the natural history will then become even clearer. Meanwhile many patients, once they learn of the Sword of Damocles which will hang over their heads perhaps for the rest of their lives, insist despite the risks, on an operation. The timing of the operation still calls for delicate surgical judgment.
XY GONADAL DYSGENESIS
other mammals the Y chromosome normally necessary for the development of the testis, and when the chromosome is absent the embryonic gonad differentiates into an ovary. Occasionally the testis fails to develop despite an apparently normal XY sex-chromosome complement, and the resultant condition is known as XY gonadal dysgenesis. The patients are reared as girls but never menstruate. Their gonads are dysgenetic and consequently the secondary sexual characteristics do not appear. The internal and external IN
man
and
most
is
genitalia, although immature, female; male
are
unquestionably
absent and there is no evidence of masculinisation. Such patients differ from those with 45,X gonadal dysgenesis in being of normal stature, or even eunuchoid, and by being free from any of the other stigmata associated with Turner’s syndrome. Most cases are sporadic but there are now a few reports of families with several affected members. 1-7 The data gathered from these scattered families suggest that in most the mode of inheritance involves an X-linked recessive gene. An autosomal gene cannot be ruled out, but transmission is definitely not via the Y chromosome. It is inferred from this evidence that in normal testicular development there must be interaction between a genetic determinant on the Y chromosome and one located elsewhere, probably on the X. According to one suggestion, the gene product which determines formation of testes is a male-specific plasma membrane protein known as the H-Y antigenand Ghosh and others9 now report the absence of this antigen in three women with XY gonadal dysgenesis. The testing of other women with this disorder awaits standardisation of the technique.7 The histological appearances of the streak gonads in structures are
13. Robinson, J. L., Hall, C. J., Sedzimir, C. B.J. Neurosurg. 1972, 36, 27. 14. Petiti, D. B., Winger, D Lancet, 1978, ii, 234. 1. Cohen, M. M. and Shaw, M. W. New Engl. J. Med. 1965, 272, 1083. 2. Sternberg, W. H., Barclay, D. L., Kloepfer, H. W. ibid. 1968, 278, 695. 3. Espiner, E. A., Veale, A. M. O., Sands, V. E., Fitzgerald, P. H. ibid. 1970,
283, 6. Chemke, J., Carmichael, R., Stewart, J M., Geer, R. H., Robinson, A. J. med. Genet. 1970, 7, 105 5. Simpson, J. L., German, J. Am. J. hum. Genet. 1970, 22, 24 6. Simpson, J. L., Christakos, A. S., Honvith, M., Silverman, F. S. Birth Defects, orig. Art. Ser 1971, 7, 215. 7. German, J., Sunpson, J. L., Chagonti, R. S. K., Summitt, R. L., Reid, L. B., Merkatz, I. R. Science, 1978, 202, 53. 8. Wachtal, S. S., Ohno, S., Koo, G. C., Boyse, E. A. Nature, 1975, 257, 235. 9. Ghosh. S. N., Shah, P. N., Gharpure, H. M. ibid 1978. 276, 180. 4.
28
gonadal dysgenesis are the same as those in adults with Turner’s syndrome. In early 45,X embryos the
XY
ovary looks normal, but at birth the number of follicles and germ cells is greatly reduced and by the age of puberty the ovary has been completely replaced by fibrous tissue. There have been no published descriptions of the embryonic gonad in XY gonadal dysgenesis but, on the assumption that the streak gonad of the
adult is an end-result of the same processes as in Turner’s syndrome, we can take it that hemizygosity-of X-borne factors interferes with the survival of a normal ovary into reproductive years. Since it is only in germ cells that gene loci will be active in both X chromosomes, homozygosity of X-borne genes is essential to normal oogenesis and consequently to normal ovarian develop-
ment.7 10
11
SURMA AND LEAD-POISONING SURMA is a fine powder which is applied to the consurface of the eyelids, in the same way that mascara is applied to the outer surface. Its name is derived from the Urdu word for antimony but Eastern pharmacopoeias contain prescriptions which include salts of antimony, zinc, and lead. Galena (lead sulphide) is now the most frequently used ore and it is often combined with camphor or menthol to induce lacrimation. The use: of surma for medical and cosmetic purposes can be traced back over many centuries. Nowadays it is used mainly as a cosmetic, but many Asians regard it also as a good remedy for eye strain and soreness and a good
junctival
hygienic measure. The possibility of lead-poisoning from the use of surma was first raised by Warley et al.1 in 1968. Their report of an Asian child with lead encephalopathy resulted in a warning notice from the Home Office,2and importers of the material were asked to restrict supplies voluntarily. Subsequent reports, however, indicated that Asian children were still at risk,3-5 and the suspected association between the use of surma and increased bloodlead was confirmed by Ali et al. in Asian children studied in Nottingham. Although direct absorption across the conjunctival membrane was thought possible, these workers judged lacrimation, eye-rubbing, and fingersucking to be important. In 1976 an E.E.C. directive on cosmetic products7, required member States to prohibit the marketing of products containing lead and other listed chemicals. The Cosmetic Products Regulations 1978 are Britain’s response. These regulations, under the Consumer Protection Act 1961 but also under the European Communities Act 1972, require that a cosmetic product shall not be liable to damage human health when applied under normal conditions. Surma and other lead-containing cosmetics are prohibited from Jan. 1, 1979. Another 10. Hamerton, J. L. ibid. 1968, 219, 910. 11. Lyon, M. F. Proc. R . Soc. B. 1974, 187, 243. 1. Warley, M. A., Blackledge, P , O’Gorman, P. Br. med. J. 1968, i, 117. 2. Lead Poison Warning. Home Office Press notice, Sept. 1968. 3. Snodgrass, G. J. A. I., Ziderman, D. A., Gulati, V., Richards, J. Br. med.
E.E.C. directive8 indicates that a member State should take action to trace the source when the blood-level of lead exceeds 35 ug/dl in more than 2% of a population sample. 16% of the surma-using children in the Nottingham study had a blood-lead greater than this. There must remain some doubt as to whether these regulations will prove effective. Ali et a1.6 found that most of the Asians in their study obtained supplies of surma from friends or relatives visiting from abroad. A POLICY FOR SUSPECTED SQUINT
squint in babies and young children is a great problem for general practitioners and infant-welSUSPECTED
fare services. The incidence of loss of binocular function and, more important, of irreversible amblyopia is directly related to the time elapsing between onset and treatment, and bears little relation to the size of the deviation. In many cases, however, even an ophthalmologist or an orthoptist has difficulty in deciding whether or not a true strabismus is present. Epicanthus in the infant may give the illusion of squint, and not uncommonly the two coexist. Genuine squints are often intermittent when they start, and may be difficult or even impossible to elicit at a single consultation. As a result, a series of follow-up examinations is conducted until the matter can be settled one way or the other. Such a policy may be counterproductive if it increases waiting-lists and thereby delays the identification and treatment of the genuine squint. Can we justify the policy of following-up young children with suspected squint, unconfirmed by cover testing? A study by Jacobs’ certainly raises doubts. In 331 children with possible but unconfirmed strabismus at first examination, a striking correlation was shown between the prevalence of abnormal refraction and the later confirmation of strabismus. Among 243 children with refractions of +1-5dioptres or under (low-grade hypermetropia being a normal state in the young child) only 1-7% proved to be true squinters whereas in 77 ametropes whose refraction exceeded +1-5dioptres, strabismus was later confirmed in 24%. There were only 2 myopes, myopia being uncommon in the very young. With the modern techniques for demonstration of equal vision in the slightly older but still illiterate child, and with the simple tests for binocular function, there now seems little reason for the ophthalmologist or infant-welfare clinic to follow every child with a suspected squint. A thorough first examination seems capable of identifying a group, comprising about three-quarters of those whose squint cannot be confirmed at first contact, in whom the probability of squint later being confirmed is actually less than that in the total child population at risk (at age six the prevalence is 5-6%2). In this group repeated examinations are clearly a waste of effort. A selective policy on these lines would lighten the work of school clinics and specialist ophthalmic services and might thereby encourage more liberal first-time referrals - avoiding the policy of "wait and see" without properspecialist assessment, which is still sometimes followed and which may delay treatment of the genuine squint.
J. 1973, iv, 230. 4. Betts, P. R., Astley, R., Raine, D. N. ibid. 1973, i, 402. 5. Josephs, D. S. Publ. Hlth, 1977, 91, 133. 6. Ali, A. R., Smales, O. R. C., Aslam, J. Br. med. J. 1978, ii, 915. 7. Council Directive no. 76/768/EEC. Offic. J. Europ. Communities, L262.
8. Council Directive no. 7/312.EEC. ibid. L105/a. 1. Jacobs, H. B. Br. J. Ophthal. 1978, 62, 763. 2. Graham, P. A. ibid. 1974, 58, 224.
who either underwent surgery within 9 days of a haemorrhage or who when operated on had not fully recovered from the effect of the hxmorrhage. This emphasises that waiting can lessen the risks of an operation; the price is that more patients will rebleed before operation so that the overall results are no better. A decade ago, it was proposed that antifibrinolytic therapy might protect a patient against rebleeding and make delayed surgery safer.5 In the past year it has even been suggested, though with little supporting evidence, that such treatment might confer lasting protection, making surgery unnecessary.6 The value of antifibrinolytic therapy within the first two weeks is still debated; two recent randomised controlled studies of antifibrinolytic therapy reached conflicting conclusions.7 8 Do the results in the Mayo series represent an improvement on the natural history of the disease? The chances that a patient with a ruptured aneurysm may die are governed by two factors-how long he has already survived since his hsemorrhage, and whether consciousness is impaired or there are other major deficits. Information about these two features can be used to calculate the expected mortality in a series of patients,9 but this method was not applied to the Mayo series. Instead, Sundt and Whisnant contrasted the mortality of about 20% at 1 month, which they observed in 42 patients admitted to the Mayo Clinic on the day after haemorrhage, with one of over 40%, which was found in 50 patients drawn from a survey of the population of Rochester, Minnesota, and who had survived for at least one day after a subarachnoid haemorrhage. Although the two groups were thus selected carefully to ensure that they were compared at similar intervals after a hmmorrhage, there is not sufficient information about other important factors, such as the clinical grades in the two groups and the treatment received by the population series (which was observed between 1955and 1969 and so antedates the surgical series), to put the validity of the comparison beyond doubt. We need reliable, up-to-date statistics about patients with a ruptured aneurysm, because what we advise depends upon careful weighing of the risks of surgery against those of spontaneous bleeding and ischaemia. Until lately it seemed that we had to take into account only the risks within the first few months after rupture and that the chances of rebleeding thereafter could be neglected. Now a longer timespan has to be considered: once an aneurysm has ruptured there is persisting risk of rebleeding for at least ten years-a risk of about 3.5% per year.10 This longer time-scale has highlighted the importance of a patient’s age; there has been controversy about the advisability of surgical management in the over-60s.11 12 The case for surgery in younger patients has become clearer-particularly if the patient is a woman of childbearing age, because pregnancy may 3. 4. 5. 6. 7.
Sundt, T.M., Whisnant, J. P. New Engl. J. Med 1978, 299, Skultety, F. M., Nishioka, H.J. Neurosurg. 1966, 25, 683. Mullan, S., Dawley, J. ibid. 1968, 28, 21. Maurice-Williams, R. S. Br. med. J. 1978, i, 945. van
Rossum, J., Wintzen, A. R., Endtz, L. J.,
et
116.
al. Ann. Neurol.
1977, 2,
242. 8.
Fodstad, H., Liliequist, B., Schannong, M.,
et
al.
Surg.
Neurol. 1978,
10,
9
9.
Alvord, E. C. Jnr., Loeser, J. D., Bailey, W. L., et al. Archs Neurol. 1972, 27, 273. 10. Winn, H. R., Richardson, A. E., Jane, J. A. Ann. Neurol. 1977, 1, 358. 11Marundale, B., Garfield, J. Br. med. J. 1978, i, 465. 12. Sengupta, R. P., Lassman, L. P., Hankinson, J. ibid. 1978, ii, 246.
increase the risk of subarachnoid hxmorrhage,13 as may smoking and the use of oral contraceptives. 14 What lies ahead? Improved prevention of rebleeding may encourage even more delayed, and thus safer, surgery ; this seems the likely pattern in the immediate future. Eventually, the fruits of research into pathophysiological mechanisms may permit early surgery without the risk of precipitating cerebral infarction, thereby lessening the chance of rebleeding. The advantages of surgical management over the natural history will then become even clearer. Meanwhile many patients, once they learn of the Sword of Damocles which will hang over their heads perhaps for the rest of their lives, insist despite the risks, on an operation. The timing of the operation still calls for delicate surgical judgment.
XY GONADAL DYSGENESIS
other mammals the Y chromosome normally necessary for the development of the testis, and when the chromosome is absent the embryonic gonad differentiates into an ovary. Occasionally the testis fails to develop despite an apparently normal XY sex-chromosome complement, and the resultant condition is known as XY gonadal dysgenesis. The patients are reared as girls but never menstruate. Their gonads are dysgenetic and consequently the secondary sexual characteristics do not appear. The internal and external IN
man
and
most
is
genitalia, although immature, female; male
are
unquestionably
absent and there is no evidence of masculinisation. Such patients differ from those with 45,X gonadal dysgenesis in being of normal stature, or even eunuchoid, and by being free from any of the other stigmata associated with Turner’s syndrome. Most cases are sporadic but there are now a few reports of families with several affected members. 1-7 The data gathered from these scattered families suggest that in most the mode of inheritance involves an X-linked recessive gene. An autosomal gene cannot be ruled out, but transmission is definitely not via the Y chromosome. It is inferred from this evidence that in normal testicular development there must be interaction between a genetic determinant on the Y chromosome and one located elsewhere, probably on the X. According to one suggestion, the gene product which determines formation of testes is a male-specific plasma membrane protein known as the H-Y antigenand Ghosh and others9 now report the absence of this antigen in three women with XY gonadal dysgenesis. The testing of other women with this disorder awaits standardisation of the technique.7 The histological appearances of the streak gonads in structures are
13. Robinson, J. L., Hall, C. J., Sedzimir, C. B.J. Neurosurg. 1972, 36, 27. 14. Petiti, D. B., Winger, D Lancet, 1978, ii, 234. 1. Cohen, M. M. and Shaw, M. W. New Engl. J. Med. 1965, 272, 1083. 2. Sternberg, W. H., Barclay, D. L., Kloepfer, H. W. ibid. 1968, 278, 695. 3. Espiner, E. A., Veale, A. M. O., Sands, V. E., Fitzgerald, P. H. ibid. 1970,
283, 6. Chemke, J., Carmichael, R., Stewart, J M., Geer, R. H., Robinson, A. J. med. Genet. 1970, 7, 105 5. Simpson, J. L., German, J. Am. J. hum. Genet. 1970, 22, 24 6. Simpson, J. L., Christakos, A. S., Honvith, M., Silverman, F. S. Birth Defects, orig. Art. Ser 1971, 7, 215. 7. German, J., Sunpson, J. L., Chagonti, R. S. K., Summitt, R. L., Reid, L. B., Merkatz, I. R. Science, 1978, 202, 53. 8. Wachtal, S. S., Ohno, S., Koo, G. C., Boyse, E. A. Nature, 1975, 257, 235. 9. Ghosh. S. N., Shah, P. N., Gharpure, H. M. ibid 1978. 276, 180. 4.
28
gonadal dysgenesis are the same as those in adults with Turner’s syndrome. In early 45,X embryos the
XY
ovary looks normal, but at birth the number of follicles and germ cells is greatly reduced and by the age of puberty the ovary has been completely replaced by fibrous tissue. There have been no published descriptions of the embryonic gonad in XY gonadal dysgenesis but, on the assumption that the streak gonad of the
adult is an end-result of the same processes as in Turner’s syndrome, we can take it that hemizygosity-of X-borne factors interferes with the survival of a normal ovary into reproductive years. Since it is only in germ cells that gene loci will be active in both X chromosomes, homozygosity of X-borne genes is essential to normal oogenesis and consequently to normal ovarian develop-
ment.7 10
11
SURMA AND LEAD-POISONING SURMA is a fine powder which is applied to the consurface of the eyelids, in the same way that mascara is applied to the outer surface. Its name is derived from the Urdu word for antimony but Eastern pharmacopoeias contain prescriptions which include salts of antimony, zinc, and lead. Galena (lead sulphide) is now the most frequently used ore and it is often combined with camphor or menthol to induce lacrimation. The use: of surma for medical and cosmetic purposes can be traced back over many centuries. Nowadays it is used mainly as a cosmetic, but many Asians regard it also as a good remedy for eye strain and soreness and a good
junctival
hygienic measure. The possibility of lead-poisoning from the use of surma was first raised by Warley et al.1 in 1968. Their report of an Asian child with lead encephalopathy resulted in a warning notice from the Home Office,2and importers of the material were asked to restrict supplies voluntarily. Subsequent reports, however, indicated that Asian children were still at risk,3-5 and the suspected association between the use of surma and increased bloodlead was confirmed by Ali et al. in Asian children studied in Nottingham. Although direct absorption across the conjunctival membrane was thought possible, these workers judged lacrimation, eye-rubbing, and fingersucking to be important. In 1976 an E.E.C. directive on cosmetic products7, required member States to prohibit the marketing of products containing lead and other listed chemicals. The Cosmetic Products Regulations 1978 are Britain’s response. These regulations, under the Consumer Protection Act 1961 but also under the European Communities Act 1972, require that a cosmetic product shall not be liable to damage human health when applied under normal conditions. Surma and other lead-containing cosmetics are prohibited from Jan. 1, 1979. Another 10. Hamerton, J. L. ibid. 1968, 219, 910. 11. Lyon, M. F. Proc. R . Soc. B. 1974, 187, 243. 1. Warley, M. A., Blackledge, P , O’Gorman, P. Br. med. J. 1968, i, 117. 2. Lead Poison Warning. Home Office Press notice, Sept. 1968. 3. Snodgrass, G. J. A. I., Ziderman, D. A., Gulati, V., Richards, J. Br. med.
E.E.C. directive8 indicates that a member State should take action to trace the source when the blood-level of lead exceeds 35 ug/dl in more than 2% of a population sample. 16% of the surma-using children in the Nottingham study had a blood-lead greater than this. There must remain some doubt as to whether these regulations will prove effective. Ali et a1.6 found that most of the Asians in their study obtained supplies of surma from friends or relatives visiting from abroad. A POLICY FOR SUSPECTED SQUINT
squint in babies and young children is a great problem for general practitioners and infant-welSUSPECTED
fare services. The incidence of loss of binocular function and, more important, of irreversible amblyopia is directly related to the time elapsing between onset and treatment, and bears little relation to the size of the deviation. In many cases, however, even an ophthalmologist or an orthoptist has difficulty in deciding whether or not a true strabismus is present. Epicanthus in the infant may give the illusion of squint, and not uncommonly the two coexist. Genuine squints are often intermittent when they start, and may be difficult or even impossible to elicit at a single consultation. As a result, a series of follow-up examinations is conducted until the matter can be settled one way or the other. Such a policy may be counterproductive if it increases waiting-lists and thereby delays the identification and treatment of the genuine squint. Can we justify the policy of following-up young children with suspected squint, unconfirmed by cover testing? A study by Jacobs’ certainly raises doubts. In 331 children with possible but unconfirmed strabismus at first examination, a striking correlation was shown between the prevalence of abnormal refraction and the later confirmation of strabismus. Among 243 children with refractions of +1-5dioptres or under (low-grade hypermetropia being a normal state in the young child) only 1-7% proved to be true squinters whereas in 77 ametropes whose refraction exceeded +1-5dioptres, strabismus was later confirmed in 24%. There were only 2 myopes, myopia being uncommon in the very young. With the modern techniques for demonstration of equal vision in the slightly older but still illiterate child, and with the simple tests for binocular function, there now seems little reason for the ophthalmologist or infant-welfare clinic to follow every child with a suspected squint. A thorough first examination seems capable of identifying a group, comprising about three-quarters of those whose squint cannot be confirmed at first contact, in whom the probability of squint later being confirmed is actually less than that in the total child population at risk (at age six the prevalence is 5-6%2). In this group repeated examinations are clearly a waste of effort. A selective policy on these lines would lighten the work of school clinics and specialist ophthalmic services and might thereby encourage more liberal first-time referrals - avoiding the policy of "wait and see" without properspecialist assessment, which is still sometimes followed and which may delay treatment of the genuine squint.
J. 1973, iv, 230. 4. Betts, P. R., Astley, R., Raine, D. N. ibid. 1973, i, 402. 5. Josephs, D. S. Publ. Hlth, 1977, 91, 133. 6. Ali, A. R., Smales, O. R. C., Aslam, J. Br. med. J. 1978, ii, 915. 7. Council Directive no. 76/768/EEC. Offic. J. Europ. Communities, L262.
8. Council Directive no. 7/312.EEC. ibid. L105/a. 1. Jacobs, H. B. Br. J. Ophthal. 1978, 62, 763. 2. Graham, P. A. ibid. 1974, 58, 224.