- Email: [email protected]
ELECTROLYTE ABNORMALITIES IN PORPHYRIA
1082 Case 6.-This boy, born in 1959, was a second child. " No thumbs, no anus." He died on the 1st day of life. Cases 1 and 2 closely resemble the cases described by Dr. Say and Dr. Gerald, with the exception that they had not polydactyly, but ectrodactyly of the thumb. Cases 3 and 4 also had anal atresia, and had respectively, ectrodactyly and abnormality " of thumb, but it is not known whether they had anomalies of vertebras and ribs. The resemblance of the 4 cases to each other, and the relationship to the triad of anomalies observed by Dr. Say and Dr. Gerald, suggest that their proposed syndrome includes ectrodactyly and polydactyly as interchangeable limb deformities. Polydactyly or ectrodactyly, anal atresia, and abnormalities of the vertebral column thus appear to present a clinical entity. My findings bring the proposed syndrome into closer morphological relationship to the mutant " dominant hemimelia " in mice, in which ectrodactylism is even more common than polydactylism. This relationship seems to be further confined by absence of the spleen, a constant sign in dominant hemimelia, in case 5. But I am not sure whether this case actually belongs to the same triad as cases 1 and 2 (or cases 1-4), since the presence of vertebral anomalies is doubtful (no X-rays available), and since a septal defect of the heart was not found in the cases of Dr. Say and Dr. Gerald and the rest of my own "
that " normal " secretion or " normal " plasmaconcentrations persist in the face of hypo-osmolality of serum, ordinarily commensurate with hyponatraemia. That many patients with porphyria have normal serum-sodium concentrations (and, as Dr. Gupta tells us, normal serum-A.D.H.) gives no clue as to whether the syndrome of inappropriate secretion of A.D.H. is present. The presence of a small amount of A.D.H. when there should be none would be quite sufficient to account for all the features of the syndrome." To show this one would need to give the patient an amount of water which, if it is not normally excreted, will produce clear hyponatrxmia. In porphyria, it is often not normally excreted, and so lowers serum-osmolality. It is at this point that an assay of serum A.D.H. would be of value. All the evidence suggests that with water-loads serum-A.D.H. remains " normal " in the syndrome of inappropriate secretion of A.D.H. instead of falling (and often becoming undetectable) as it does in normal subjects, who, of course, consequently excrete the water-load. Department of Endocrinology, National Heart Institute, FREDERIC C. BARTTER. Bethesda, Maryland, U.S.A.
implies
INTRAVASCULAR COAGULATION AND HYALINE-MEMBRANE DISEASE
cases.
ectrodactyly of thumb and anal atresia, but there is no evidence that this drug also causes vertebral and rib anomalies. So far, only for patient 6, who was born in 1959 when thalidomide was available, and for whom we have no X-rays of the spine, may this drug be considered as the underlying cause. The other 5 patients were born before 1958 or after 1962, so that thalidomide can be excluded as an xtiological factor. Thalidomide may
Cases 1-4
cause
related to 315,902 live-born and stillborn incidence of 1.3 per 100,000. In the administrative area 6f Munster (1950-57) incidence of anal atresia was 1-6, and that of ectrodactyly roughly 0-2 per 10,000 total births. From these estimates the combined occurrence of both anomalies by chance can be calculated as 0-0003 per 100,000, an expected figure which is significantly different from the observed value.8 The aetiology of the presumptive syndrome is unknown. The observation of Fuhrmann et al. seems to suggest a genetic basis.4 Case 1, with his normal dizygotic twin brother, gives no information on genetic or environmental influences. The next step will be family investigations, which will be completed for my own patients in the near future. are
children, giving
an
A more detailed description of my observations will be published elsewhere. The investigations are supported by the Skeletregister at this institute, based on a grant by the Deutsche Forschungsgemeinschaft. Cases 1, 2, and 5 are described by courtesy of Dr. Pfeiffer, Munster. Institute of Human Genetics, University of Münster, West
Germany.
W. TÜNTE.
ELECTROLYTE ABNORMALITIES IN PORPHYRIA SIR,-Dr. Ridley and Dr. Cameron (Oct. 19, p. 872) discuss the appearance of hyponatrxmia in patients with acute intermittent porphyria as a result of " excessive secretion of antidiuretic hormone (A.D.H.) ". Dr. Gupta in reply (Nov. 2, p. 971) notes that he found normal plasma and urinary A.D.H. in a patient with porphyria who had normal serum-electrolytes. Whereas I would heartily support Dr. Gupta’s subsequent plea for objective laboratory data to clarify the diagnosis, I would suggest that the data he has supplied do nothing to resolve the question. It was originally suggested that the secretion of A.D.H. in porphyria was, not excessive, but "inappropriate". 9 I’ This 8. 9. 10.
Stevens, W. L. J. Genet. 1942, 43, 301. Hellman, E. S., Tschudy, D. P., Bartter, F. C. Am. J. Med. 1962, 32, 734. Ludwig, G. D., Goldberg, M. Ann. N.Y. Acad. Sci. 1963, 104, 710.
Six,-The hypothesis of Dr. Stark and his colleagues on the of hyaline-membrane disease (H.M.D.) seems valid for the child described by him.12 In that case, however, there was an exceptional situation in which the essential point was premature abruptio placentx with the influx of thromboplastic
aetiology
material into the child. A few similar cases have been reported,13-15 but in the great majority of cases of H.M.D. in premature infants the birth history does not permit the assumption that such an event has taken place. Our own coagulation studies on 96 premature infants with H.M.D. certainly do not allow the conclusion that the disease generally occurs as a consequence of intravascular coagulation. Our investigations showed, inter alia, that the immunologically determined plasma-fibrinogen levels of 11 survivors from H.M.D. were not significantly lower than those of 21 healthy premature infants. Nor did fibrinolytic activity, similarly determined by an immunological method, differ significantly between the two groups. 9 premature infants with H.M.D. who died had significantly lower fibrinogen values, but all had cerebral haemorrhages. Those factors consumed in coagulation -prothrombin, factor v, factor vii, and thrombocytes-were not significantly depressed in premature infants with H.M.D. as compared with a healthy control group. However, fatal cases with cerebral haemorrhage had significantly lower values than survivors from H.M.D.16 Similar results have been published elsewhere. 17 111a The therapy recommended by Dr. Stark and his colleagues has essentially been used already; a significant reduction in mortality was not achieved. 18 19 The hypothesis of Dr. Stark and his colleagues therefore applies only to the individual cases described. In most premature infants with H.M.D. the exact mechanism of the disease remains obscure. W. SCHENCK D. KARITZKY Universitats-Kinderklinik, W. PRINGSHEIM im Freiburg Breisgau, W. KÜNZER. Germany. Bartter, F. C., Schwartz, W. B. Am. J. Med. 1967, 42, 790. Stark, C. R., Abramson, D., Erkan, V. Lancet, 1968, i, 1180. Boyd, J. F. Archs Dis. Childh. 1967, 42, 401. Leissring, J. C., Verlicky, L. N. Am. J. Dis. Child. 1968, 115, 100. Edson, R. J., Blaese, R. M., White, J. G., Krivit, K. J. Pediat. 1968, 72, 342. 16. Kabus, K., Schenck, W., Kunzer, W. Z. Kinderheilk. (in the press.) 17. Ambrus, C. M., Weintraub, D. H., Dunphy, D., Dowd, J. E., Pickren, J. W., Niswander, K. R., Ambrus, J. L. Pediatrics, Springfield, 1963, 32, 10. 18. Ambrus, C. M., Weintraub, D. H., Ambrus, J. L. ibid. 1966, 38, 231. 19. Markarian, M., Githens, J. H., Jackson, J. J., Bannon, A. E., Lindley, A., Rosenblut, E., Martorell, R., Lubchenco, L. O. Am. J. Dis. Child. 1967, 113, 312.
11. 12. 13. 14. 15.
that " normal " secretion or " normal " plasmaconcentrations persist in the face of hypo-osmolality of serum, ordinarily commensurate with hyponatraemia. That many patients with porphyria have normal serum-sodium concentrations (and, as Dr. Gupta tells us, normal serum-A.D.H.) gives no clue as to whether the syndrome of inappropriate secretion of A.D.H. is present. The presence of a small amount of A.D.H. when there should be none would be quite sufficient to account for all the features of the syndrome." To show this one would need to give the patient an amount of water which, if it is not normally excreted, will produce clear hyponatrxmia. In porphyria, it is often not normally excreted, and so lowers serum-osmolality. It is at this point that an assay of serum A.D.H. would be of value. All the evidence suggests that with water-loads serum-A.D.H. remains " normal " in the syndrome of inappropriate secretion of A.D.H. instead of falling (and often becoming undetectable) as it does in normal subjects, who, of course, consequently excrete the water-load. Department of Endocrinology, National Heart Institute, FREDERIC C. BARTTER. Bethesda, Maryland, U.S.A.
implies
INTRAVASCULAR COAGULATION AND HYALINE-MEMBRANE DISEASE
cases.
ectrodactyly of thumb and anal atresia, but there is no evidence that this drug also causes vertebral and rib anomalies. So far, only for patient 6, who was born in 1959 when thalidomide was available, and for whom we have no X-rays of the spine, may this drug be considered as the underlying cause. The other 5 patients were born before 1958 or after 1962, so that thalidomide can be excluded as an xtiological factor. Thalidomide may
Cases 1-4
cause
related to 315,902 live-born and stillborn incidence of 1.3 per 100,000. In the administrative area 6f Munster (1950-57) incidence of anal atresia was 1-6, and that of ectrodactyly roughly 0-2 per 10,000 total births. From these estimates the combined occurrence of both anomalies by chance can be calculated as 0-0003 per 100,000, an expected figure which is significantly different from the observed value.8 The aetiology of the presumptive syndrome is unknown. The observation of Fuhrmann et al. seems to suggest a genetic basis.4 Case 1, with his normal dizygotic twin brother, gives no information on genetic or environmental influences. The next step will be family investigations, which will be completed for my own patients in the near future. are
children, giving
an
A more detailed description of my observations will be published elsewhere. The investigations are supported by the Skeletregister at this institute, based on a grant by the Deutsche Forschungsgemeinschaft. Cases 1, 2, and 5 are described by courtesy of Dr. Pfeiffer, Munster. Institute of Human Genetics, University of Münster, West
Germany.
W. TÜNTE.
ELECTROLYTE ABNORMALITIES IN PORPHYRIA SIR,-Dr. Ridley and Dr. Cameron (Oct. 19, p. 872) discuss the appearance of hyponatrxmia in patients with acute intermittent porphyria as a result of " excessive secretion of antidiuretic hormone (A.D.H.) ". Dr. Gupta in reply (Nov. 2, p. 971) notes that he found normal plasma and urinary A.D.H. in a patient with porphyria who had normal serum-electrolytes. Whereas I would heartily support Dr. Gupta’s subsequent plea for objective laboratory data to clarify the diagnosis, I would suggest that the data he has supplied do nothing to resolve the question. It was originally suggested that the secretion of A.D.H. in porphyria was, not excessive, but "inappropriate". 9 I’ This 8. 9. 10.
Stevens, W. L. J. Genet. 1942, 43, 301. Hellman, E. S., Tschudy, D. P., Bartter, F. C. Am. J. Med. 1962, 32, 734. Ludwig, G. D., Goldberg, M. Ann. N.Y. Acad. Sci. 1963, 104, 710.
Six,-The hypothesis of Dr. Stark and his colleagues on the of hyaline-membrane disease (H.M.D.) seems valid for the child described by him.12 In that case, however, there was an exceptional situation in which the essential point was premature abruptio placentx with the influx of thromboplastic
aetiology
material into the child. A few similar cases have been reported,13-15 but in the great majority of cases of H.M.D. in premature infants the birth history does not permit the assumption that such an event has taken place. Our own coagulation studies on 96 premature infants with H.M.D. certainly do not allow the conclusion that the disease generally occurs as a consequence of intravascular coagulation. Our investigations showed, inter alia, that the immunologically determined plasma-fibrinogen levels of 11 survivors from H.M.D. were not significantly lower than those of 21 healthy premature infants. Nor did fibrinolytic activity, similarly determined by an immunological method, differ significantly between the two groups. 9 premature infants with H.M.D. who died had significantly lower fibrinogen values, but all had cerebral haemorrhages. Those factors consumed in coagulation -prothrombin, factor v, factor vii, and thrombocytes-were not significantly depressed in premature infants with H.M.D. as compared with a healthy control group. However, fatal cases with cerebral haemorrhage had significantly lower values than survivors from H.M.D.16 Similar results have been published elsewhere. 17 111a The therapy recommended by Dr. Stark and his colleagues has essentially been used already; a significant reduction in mortality was not achieved. 18 19 The hypothesis of Dr. Stark and his colleagues therefore applies only to the individual cases described. In most premature infants with H.M.D. the exact mechanism of the disease remains obscure. W. SCHENCK D. KARITZKY Universitats-Kinderklinik, W. PRINGSHEIM im Freiburg Breisgau, W. KÜNZER. Germany. Bartter, F. C., Schwartz, W. B. Am. J. Med. 1967, 42, 790. Stark, C. R., Abramson, D., Erkan, V. Lancet, 1968, i, 1180. Boyd, J. F. Archs Dis. Childh. 1967, 42, 401. Leissring, J. C., Verlicky, L. N. Am. J. Dis. Child. 1968, 115, 100. Edson, R. J., Blaese, R. M., White, J. G., Krivit, K. J. Pediat. 1968, 72, 342. 16. Kabus, K., Schenck, W., Kunzer, W. Z. Kinderheilk. (in the press.) 17. Ambrus, C. M., Weintraub, D. H., Dunphy, D., Dowd, J. E., Pickren, J. W., Niswander, K. R., Ambrus, J. L. Pediatrics, Springfield, 1963, 32, 10. 18. Ambrus, C. M., Weintraub, D. H., Ambrus, J. L. ibid. 1966, 38, 231. 19. Markarian, M., Githens, J. H., Jackson, J. J., Bannon, A. E., Lindley, A., Rosenblut, E., Martorell, R., Lubchenco, L. O. Am. J. Dis. Child. 1967, 113, 312.
11. 12. 13. 14. 15.