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PSEUDO-PSEUDOHYPOPARATHYROIDISM DUE TO UNEQUAL CROSSING-OVER ?
879
(1) p(SPH)z. would be zero since P replaces H in the presence S-i.e., P. tBTM.gMK’M and H. influenzae would not be expected 1 to exist together in a sputum without Staph. aureus. (2) p(SPH)z, would be zero since S or P would be expected to be present in c.F. sputum. Doggett has defined c.F. sputum as having Staph. aureus and/or Ps. aeruginosa.’ (3) p(SPH)z, would be small though not necessarily zero since P is hypothesised to be the terminal flora. Doggett’ and Kilbourn et al.s found Ps. aeruginosa (mucoid) to be the predominant species in the pulmonary tree just before death. (4) p(SPH)z. would be zero since c.F. sputum is typically infected by one or more of the three species. of
The bacterial species found in a single sputum specimen from each of 40 patients with C.F. seen at the University of Oregon Medical School were as follows:
The above data add further support Burns and May.
to
the
hypothesis
of
J. P. KILBOURN. H.A.A. AT THE BARBER’S ? and with almost every patient, the anaesthetist contaminates his fingers with the patient’s blood when changing syringes on an intravenous needle. Several times a week he may give blood-transfusions. Often he must have small breaks in the skin around the nails or finger tips-tiny open wounds. Yet hepatitis is not, I believe, an occupational hazard among anaesthetists as it is in renal units. Whv ?
SIR,-Every day,
J. G. BOURNE. STERILISATION BY HYSTERECTOMY SiR,-In discussing hysterectomy as a method of contraception and as a technique for iatrogenic abortion, Mr. Williams (Sept. 19, p. 608) states, " In a healthy young woman, however, there are circumstances when hysterectomy is unwise and not likely to please the patient." As a family doctor I take a rather more extreme position: provided that serious disease has been excluded by a D and c, I encourage my patients to put up with minor symptoms and strongly advise them not to have a hysterectomy unless it is essential to maintain good health. In my view it is inadvisable to adopt the attitude that the only purpose of the womb is to bear children, and that, if a woman is beyond childbearing age or does not want children, she is better off without her womb since it is a potential centre of disease. Unsatisfactory coitus, and even total frigidity, may be an occasional consequence of hysterectomy-particularly total hysterectomy. The causes are partly psychological and partly physical. The womb, like the breasts, is an essential aspect of a woman’s femininity. After hysterectomy a woman may feel she has experienced a loss or humiliation. She may complain of " not being the woman she was ". A woman secure in her adult female identity may make a good adjustment to the loss of her womb, whereas, in an insecure woman, it may be a minor tragedy. Total, unlike subtotal, hysterectomy, leads to shortening of the vagina, and, if the vagina is naturally short, this may cause some difficulty in coitus. Cervical secretions are also lost, which may lead to dryness during coitus. I wonder whether there has been too much of a swing towards total
hysterectomy. R. N. EBBING.
7.
Doggett,
R. G.
Appl. Microbiol. 1969, 18, 936.
PSEUDO-PSEUDOHYPOPARATHYROIDISM DUE TO UNEQUAL CROSSING-OVER ?
SIR,-We have lately
seen
two
unrelated girls with
monosomy X who also showed clinical evidence of pseudopseudohypoparathyroidism (P.P.H.). One patient had a 45,X karyotype, and the other was a 45,X/46,XX mosaic. A review of similar cases in the literature suggests that the relationship may be more than fortuitous.
Case 1.-This girl was seen at age 8 years 5 months because of short stature and obesity (her height and weight were at the 50th percentile respectively for 6 years and 10 1/2 years). She had begun to gain weight rapidly at age 4. At age 7 years 2 months she had had an operation to correct a right exotropia. There was no history of convulsions or tetany. When seen by us she had the phenotypic appearance of P.P.H. rather than Turner’s syndrome round-faced obesity, strabismus (corrected), shortened metacarpals (especially the 4th), and mottled, pigmented lesions over large areas of the thighs and feet. Her obesity had been resistant to a low-calorie diet-another characteristic of P.P.H. Buccal smear for sex-chromatin showed no cells with Barr bodies. A karyotype prepared from
peripheral leucocytes was 45,X. Case 2.-This 17-year-old girl
was investigated because of sexual infantilism. There had been no tetany or convulsions. Her weight was 71-3 kg. and height 142 cm. She had rounded facies. A strabismus had been corrected surgically. The hands showed the fat fingers with wide fingernails seen in P.P.H. (similar to the photographs published by Ray and Gardner’). X-ray studies revealed bilateral shortening of the 4th and especially the 5th metacarpals. Serum-calcium was 5-5 meq. per litre, and seruminorganic-phosphorus 4-6 mg. per 100 ml. 53 cells were karyotyped from leucocyte cultures: 21 showed a 46,XX constitution and 32 showed 45,X. A buccal smear revealed 7% cells positive for sex-chromatin. In 1964 Schwarz2 reviewed seven recorded cases of chromatin-negative gonadal dysgenesis associated with the findings of P.P.H. Our two patients raise the total to nine cases. Mann et awl. found a total of 45 cases of P.P.H. reported in the literature up to 1962. Accordingly, we believe that the number of cases of monosomy X with coexistent P.P.H. is disproportionately large compared with the total of P.P.H. cases and cannot be accidental. We suggest that monosomy X may be associated with evocation of the phenotype of P.P.H. due to monosomy of that portion of the pairing segment of the X chromosome carrying the genes for P.P.H., in a manner similar to the evocation of the congenital defects and short stature of Turner’s syndrome by monosomy of the normal alleles of the pairing segment. In P.P.H., however, it is proposed that unequal crossing-over has resulted in abnormal position effects, so that monosomy of the pairing segment makes it more likely that the phenotype of these abnormally positioned alleles will be expressed. It has been suggested that the genes controlling many of the physical manifestations of XO Turner’s syndrome are located on the pairing segment 4,5 of the short arms6 of the X chromosome, and that the genes controlling the physical changes in XY " male Turner’s syndrome " are located in the homologous pairing loci of the Y chromosome. 6 The " overlapping zone " of physical findings between
Ray E. W., Gardner, L. I. Pediatrics, Springfield, 1959, 23, 520. Schwarz, G. Pseudohypoparathyreoidismus und Pseudo-Pseudohypoparathyreoidismus. Berlin, 1964. 3. Mann, J. B., Alterman, S., Gorman Hills, A. Ann. intern. Med. 1962, 56, 315. 4. Ford, C. E. in Intersexuality (edited by C. Overzier); p. 86. New York, 1963. 5. Ferrier, P. Revue méd. Suisse romande, 1964, no. 3, 192. 6. Ferguson-Smith, M. J. med. Genet. 1965, 2, 142.
1. 2.
880 classical Turner’s syndrome and classical P.p.H.2,7 suggests that adjacent genetic loci are involved, with perhaps some sharing of common loci (e.g., for brachymetacarpalia) on the pairing segment. The recorded examples of maleto-male transmission in P.P.H. and in pseudohypoparathyroidism (P.H.), as well as in familial brachymetacarpalia, suggest that the genes controlling metacarpal growth may be located in homologous loci of the pairing segment of the X and Y chromosomes. Accordingly, it is proposed that the pattern of inheritance in P.H./P.P.H. represents a form of partial sex-linkage in man.8 It is suggested that the mechanism may be unequal crossing-over of genes between the pairing segments on the short arms of the X and Y chromosomes, in a manner similar to the situation at the bar locus in Drosophila. In the bar mutations varying genotypes and phenotypes are produced, depending on the position effect of the duplication or triplication of region 16-A of the resulting chromatid. Such an hypothesis could explain the varying phenotypes within a family with P.H. or P.P.H.; one family member may show the full syndrome whereas a sibling or parent may exhibit only short metacarpals. Not only duplications but also intrachromosomal inversions or deletions could affect the pairing segments to produce the to us
P.H./P.P.H. phenotypes. Another, similar, way of viewing the proposed pattern of inheritance in P.H./P.P.H. is the multi-cistron-assembly-line hypothesis suggested to explain pseudo-allelism seen at the lozenge loci in Drosophila.1O The several alleles of lozenge seem to form a tandem assembly line which acts on consecutive steps in the biosynthesis of a compound essential for normal development of certain body structures. If the alleles in the tandem assembly line are out of order spatially the biosynthesis does not take place correctly.
cedure using ’pHisoHex ’ scrubs. Since then there have been no further infections in our dialysis centre, though one patient who treats himself at home did become septic. We agree with Dr. Levi and his colleagues that infection in arteriovenous fistulas is preventable, but we should also like to mention, as they did not, that dialysis patients with fistulas are less prone to serious infective complications than patients with silastic-teflon shunts. Department of Medicine, D. J. SHERRARD. University of Washington, Seattle.
SMALLER G CHROMOSOMES IN THE BONE-MARROW CELLS OF HEAVILY IRRADIATED ATOMIC-BOMB SURVIVORS SIR,-Stable types of chromosome aberrations, including smaller G chromosomes morphologically similar to the Ph’ chromosome in chronic myelocytic leukaemia, were found in bone-marrow cells from individuals who were heavily exposed to radiation from an atomic bomb 25 years earlier, but who had as yet no evidence of leukxmic or hsmatological disorders (table I). Of the total of 74 survivors examined, 13 had been within 1000 m. of the hypocentre of the explosion, and 41 between 1001 and 2000 m. The remaining 20 had been between 2001 and 3000 m. 17 people who had not been exposed and had no haematological disorders were used as controls. TABLE I-CHROMOSOME ABERRATIONS IN BONE-MARROW CELLS OF ATOMIC-BOMB SURVIVORS
This study was supported in part by research grant AM-02504 from the National Institute of Arthritis and Metabolic Diseases, U.S. Public Health Service. The author is indebted to Dr. Salma R. Assemany for helpful suggestions during the course of this study. Thanks are due to Mr. Richard L. Neu for interpretation of the karyotypes, and to Miss Saddie King for technical assistance. Observations on case 2 were made through the kindness of Dr. Arnold M. Moses. Genetic and Endocrine Unit, Department of Pediatrics, State University of New York, Upstate Medical Center,
Syracuse, N.Y. 13210,
TABLE II-HISTORY AND CLINICAL DIAGNOSES OF PATIENTS WITH ABNORMAL CHROMOSOMES
LYTT I. GARDNER
U.S.A.
INFECTIONS IN HÆMODIALYSIS PATIENTS SiR,—The report by Dr. Levi and his colleagues (Aug. 8,
288) recalls our own experience. In our dialysis unit sixteen patients have used arteriovenous fistulas for periods of 1 to 34 months, and eighteen patients use silastic-’ Teflon’ shunts. The patients using fistulas have had a total of three p.
episodes
of
septicaemia—all
due
to
Staphylococcus
aureus.
These occurred after 14,10 and 3 months of fistula dialysis. Two had pustules at a needle site, while the third did not. The third case was complicated by a septic arthritis due to Staph. aureus, but all three responded to antibiotics. None of the fistulas were removed. Over the same period septicxmia was much more frequent in the patients with cannulas, and, in addition, there were more serious complications. There were two cases of bacterial endocarditis and one of septic pulmonary embolus. 14 months ago a fistula patient developed an infection for the second time, and we instituted a vigorous cleansing pro7. 8. 9. 10.
Nagant de Deuxchaisnes, C. Schweiz. med. Wschr. 1959, 89, 1239. Haldane, J. B. S. Ann. Eugen. 1936, 7, 28. Bridges, C. B. Science, 1936, 83, 210. Green, M. M. Green, K. C. Proc. natn. Acad. Sci. U.S.A. 1949, 35, 586.
4 of the 13 heavily exposed people had a total of seven types of stable chromosome abnormality: case 1 46,XY,
Dq--; case 2 46,XY, inv(Ap + q -), 46,XYGq-, 48,XY, Cp -, D -, G+,G+,G+, case 3 46,XX,Cp-; case4 46,XY, inv (Ap+q-), 46,XY, Gq-. None of those who had been more than 1000 m. from the hypocentre had chromosome abnormalities. The histories and clinical details of the subjects with abnormal chromosomes are shown in table n. None of the patients with smaller G chromosomes has any evidence of leukaemia, even though they had all had moderate or severe radiation sickness after the explosion. In case 2 the bone-marrow was rechecked a year after the
(1) p(SPH)z. would be zero since P replaces H in the presence S-i.e., P. tBTM.gMK’M and H. influenzae would not be expected 1 to exist together in a sputum without Staph. aureus. (2) p(SPH)z, would be zero since S or P would be expected to be present in c.F. sputum. Doggett has defined c.F. sputum as having Staph. aureus and/or Ps. aeruginosa.’ (3) p(SPH)z, would be small though not necessarily zero since P is hypothesised to be the terminal flora. Doggett’ and Kilbourn et al.s found Ps. aeruginosa (mucoid) to be the predominant species in the pulmonary tree just before death. (4) p(SPH)z. would be zero since c.F. sputum is typically infected by one or more of the three species. of
The bacterial species found in a single sputum specimen from each of 40 patients with C.F. seen at the University of Oregon Medical School were as follows:
The above data add further support Burns and May.
to
the
hypothesis
of
J. P. KILBOURN. H.A.A. AT THE BARBER’S ? and with almost every patient, the anaesthetist contaminates his fingers with the patient’s blood when changing syringes on an intravenous needle. Several times a week he may give blood-transfusions. Often he must have small breaks in the skin around the nails or finger tips-tiny open wounds. Yet hepatitis is not, I believe, an occupational hazard among anaesthetists as it is in renal units. Whv ?
SIR,-Every day,
J. G. BOURNE. STERILISATION BY HYSTERECTOMY SiR,-In discussing hysterectomy as a method of contraception and as a technique for iatrogenic abortion, Mr. Williams (Sept. 19, p. 608) states, " In a healthy young woman, however, there are circumstances when hysterectomy is unwise and not likely to please the patient." As a family doctor I take a rather more extreme position: provided that serious disease has been excluded by a D and c, I encourage my patients to put up with minor symptoms and strongly advise them not to have a hysterectomy unless it is essential to maintain good health. In my view it is inadvisable to adopt the attitude that the only purpose of the womb is to bear children, and that, if a woman is beyond childbearing age or does not want children, she is better off without her womb since it is a potential centre of disease. Unsatisfactory coitus, and even total frigidity, may be an occasional consequence of hysterectomy-particularly total hysterectomy. The causes are partly psychological and partly physical. The womb, like the breasts, is an essential aspect of a woman’s femininity. After hysterectomy a woman may feel she has experienced a loss or humiliation. She may complain of " not being the woman she was ". A woman secure in her adult female identity may make a good adjustment to the loss of her womb, whereas, in an insecure woman, it may be a minor tragedy. Total, unlike subtotal, hysterectomy, leads to shortening of the vagina, and, if the vagina is naturally short, this may cause some difficulty in coitus. Cervical secretions are also lost, which may lead to dryness during coitus. I wonder whether there has been too much of a swing towards total
hysterectomy. R. N. EBBING.
7.
Doggett,
R. G.
Appl. Microbiol. 1969, 18, 936.
PSEUDO-PSEUDOHYPOPARATHYROIDISM DUE TO UNEQUAL CROSSING-OVER ?
SIR,-We have lately
seen
two
unrelated girls with
monosomy X who also showed clinical evidence of pseudopseudohypoparathyroidism (P.P.H.). One patient had a 45,X karyotype, and the other was a 45,X/46,XX mosaic. A review of similar cases in the literature suggests that the relationship may be more than fortuitous.
Case 1.-This girl was seen at age 8 years 5 months because of short stature and obesity (her height and weight were at the 50th percentile respectively for 6 years and 10 1/2 years). She had begun to gain weight rapidly at age 4. At age 7 years 2 months she had had an operation to correct a right exotropia. There was no history of convulsions or tetany. When seen by us she had the phenotypic appearance of P.P.H. rather than Turner’s syndrome round-faced obesity, strabismus (corrected), shortened metacarpals (especially the 4th), and mottled, pigmented lesions over large areas of the thighs and feet. Her obesity had been resistant to a low-calorie diet-another characteristic of P.P.H. Buccal smear for sex-chromatin showed no cells with Barr bodies. A karyotype prepared from
peripheral leucocytes was 45,X. Case 2.-This 17-year-old girl
was investigated because of sexual infantilism. There had been no tetany or convulsions. Her weight was 71-3 kg. and height 142 cm. She had rounded facies. A strabismus had been corrected surgically. The hands showed the fat fingers with wide fingernails seen in P.P.H. (similar to the photographs published by Ray and Gardner’). X-ray studies revealed bilateral shortening of the 4th and especially the 5th metacarpals. Serum-calcium was 5-5 meq. per litre, and seruminorganic-phosphorus 4-6 mg. per 100 ml. 53 cells were karyotyped from leucocyte cultures: 21 showed a 46,XX constitution and 32 showed 45,X. A buccal smear revealed 7% cells positive for sex-chromatin. In 1964 Schwarz2 reviewed seven recorded cases of chromatin-negative gonadal dysgenesis associated with the findings of P.P.H. Our two patients raise the total to nine cases. Mann et awl. found a total of 45 cases of P.P.H. reported in the literature up to 1962. Accordingly, we believe that the number of cases of monosomy X with coexistent P.P.H. is disproportionately large compared with the total of P.P.H. cases and cannot be accidental. We suggest that monosomy X may be associated with evocation of the phenotype of P.P.H. due to monosomy of that portion of the pairing segment of the X chromosome carrying the genes for P.P.H., in a manner similar to the evocation of the congenital defects and short stature of Turner’s syndrome by monosomy of the normal alleles of the pairing segment. In P.P.H., however, it is proposed that unequal crossing-over has resulted in abnormal position effects, so that monosomy of the pairing segment makes it more likely that the phenotype of these abnormally positioned alleles will be expressed. It has been suggested that the genes controlling many of the physical manifestations of XO Turner’s syndrome are located on the pairing segment 4,5 of the short arms6 of the X chromosome, and that the genes controlling the physical changes in XY " male Turner’s syndrome " are located in the homologous pairing loci of the Y chromosome. 6 The " overlapping zone " of physical findings between
Ray E. W., Gardner, L. I. Pediatrics, Springfield, 1959, 23, 520. Schwarz, G. Pseudohypoparathyreoidismus und Pseudo-Pseudohypoparathyreoidismus. Berlin, 1964. 3. Mann, J. B., Alterman, S., Gorman Hills, A. Ann. intern. Med. 1962, 56, 315. 4. Ford, C. E. in Intersexuality (edited by C. Overzier); p. 86. New York, 1963. 5. Ferrier, P. Revue méd. Suisse romande, 1964, no. 3, 192. 6. Ferguson-Smith, M. J. med. Genet. 1965, 2, 142.
1. 2.
880 classical Turner’s syndrome and classical P.p.H.2,7 suggests that adjacent genetic loci are involved, with perhaps some sharing of common loci (e.g., for brachymetacarpalia) on the pairing segment. The recorded examples of maleto-male transmission in P.P.H. and in pseudohypoparathyroidism (P.H.), as well as in familial brachymetacarpalia, suggest that the genes controlling metacarpal growth may be located in homologous loci of the pairing segment of the X and Y chromosomes. Accordingly, it is proposed that the pattern of inheritance in P.H./P.P.H. represents a form of partial sex-linkage in man.8 It is suggested that the mechanism may be unequal crossing-over of genes between the pairing segments on the short arms of the X and Y chromosomes, in a manner similar to the situation at the bar locus in Drosophila. In the bar mutations varying genotypes and phenotypes are produced, depending on the position effect of the duplication or triplication of region 16-A of the resulting chromatid. Such an hypothesis could explain the varying phenotypes within a family with P.H. or P.P.H.; one family member may show the full syndrome whereas a sibling or parent may exhibit only short metacarpals. Not only duplications but also intrachromosomal inversions or deletions could affect the pairing segments to produce the to us
P.H./P.P.H. phenotypes. Another, similar, way of viewing the proposed pattern of inheritance in P.H./P.P.H. is the multi-cistron-assembly-line hypothesis suggested to explain pseudo-allelism seen at the lozenge loci in Drosophila.1O The several alleles of lozenge seem to form a tandem assembly line which acts on consecutive steps in the biosynthesis of a compound essential for normal development of certain body structures. If the alleles in the tandem assembly line are out of order spatially the biosynthesis does not take place correctly.
cedure using ’pHisoHex ’ scrubs. Since then there have been no further infections in our dialysis centre, though one patient who treats himself at home did become septic. We agree with Dr. Levi and his colleagues that infection in arteriovenous fistulas is preventable, but we should also like to mention, as they did not, that dialysis patients with fistulas are less prone to serious infective complications than patients with silastic-teflon shunts. Department of Medicine, D. J. SHERRARD. University of Washington, Seattle.
SMALLER G CHROMOSOMES IN THE BONE-MARROW CELLS OF HEAVILY IRRADIATED ATOMIC-BOMB SURVIVORS SIR,-Stable types of chromosome aberrations, including smaller G chromosomes morphologically similar to the Ph’ chromosome in chronic myelocytic leukaemia, were found in bone-marrow cells from individuals who were heavily exposed to radiation from an atomic bomb 25 years earlier, but who had as yet no evidence of leukxmic or hsmatological disorders (table I). Of the total of 74 survivors examined, 13 had been within 1000 m. of the hypocentre of the explosion, and 41 between 1001 and 2000 m. The remaining 20 had been between 2001 and 3000 m. 17 people who had not been exposed and had no haematological disorders were used as controls. TABLE I-CHROMOSOME ABERRATIONS IN BONE-MARROW CELLS OF ATOMIC-BOMB SURVIVORS
This study was supported in part by research grant AM-02504 from the National Institute of Arthritis and Metabolic Diseases, U.S. Public Health Service. The author is indebted to Dr. Salma R. Assemany for helpful suggestions during the course of this study. Thanks are due to Mr. Richard L. Neu for interpretation of the karyotypes, and to Miss Saddie King for technical assistance. Observations on case 2 were made through the kindness of Dr. Arnold M. Moses. Genetic and Endocrine Unit, Department of Pediatrics, State University of New York, Upstate Medical Center,
Syracuse, N.Y. 13210,
TABLE II-HISTORY AND CLINICAL DIAGNOSES OF PATIENTS WITH ABNORMAL CHROMOSOMES
LYTT I. GARDNER
U.S.A.
INFECTIONS IN HÆMODIALYSIS PATIENTS SiR,—The report by Dr. Levi and his colleagues (Aug. 8,
288) recalls our own experience. In our dialysis unit sixteen patients have used arteriovenous fistulas for periods of 1 to 34 months, and eighteen patients use silastic-’ Teflon’ shunts. The patients using fistulas have had a total of three p.
episodes
of
septicaemia—all
due
to
Staphylococcus
aureus.
These occurred after 14,10 and 3 months of fistula dialysis. Two had pustules at a needle site, while the third did not. The third case was complicated by a septic arthritis due to Staph. aureus, but all three responded to antibiotics. None of the fistulas were removed. Over the same period septicxmia was much more frequent in the patients with cannulas, and, in addition, there were more serious complications. There were two cases of bacterial endocarditis and one of septic pulmonary embolus. 14 months ago a fistula patient developed an infection for the second time, and we instituted a vigorous cleansing pro7. 8. 9. 10.
Nagant de Deuxchaisnes, C. Schweiz. med. Wschr. 1959, 89, 1239. Haldane, J. B. S. Ann. Eugen. 1936, 7, 28. Bridges, C. B. Science, 1936, 83, 210. Green, M. M. Green, K. C. Proc. natn. Acad. Sci. U.S.A. 1949, 35, 586.
4 of the 13 heavily exposed people had a total of seven types of stable chromosome abnormality: case 1 46,XY,
Dq--; case 2 46,XY, inv(Ap + q -), 46,XYGq-, 48,XY, Cp -, D -, G+,G+,G+, case 3 46,XX,Cp-; case4 46,XY, inv (Ap+q-), 46,XY, Gq-. None of those who had been more than 1000 m. from the hypocentre had chromosome abnormalities. The histories and clinical details of the subjects with abnormal chromosomes are shown in table n. None of the patients with smaller G chromosomes has any evidence of leukaemia, even though they had all had moderate or severe radiation sickness after the explosion. In case 2 the bone-marrow was rechecked a year after the