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RADIOACTIVE-IODINE STUDIES IN NON-ENDEMIC GOITROUS CRETINISM
403 have been given. Little alternativeemployment is available even now for pneumoconiotic miners in South Wales. The 10 Grenfell factories for those disabled from pneumoconiosis had, by 1952, provided work for only 148. Disablement benefit, on average, amounts to no more than 7s. 6d. per week. There are probably over 5000 certified pneumoconiotics employed in the mines of South Wales today. It is true that they are all supposed to be working under ’’approved conditions "-but are they in fact? In 4ny case, the obvious and ideal solution is that miners found to be suffering from certifiable degrees of pneumoconiosis should be guaranteed suitable alternative employment without loss of earnings. There must surely be an element of gambling with human life and health when miners with pneumoconiosis are encouraged to continue working in the pits. " Certain it is that the present methods of disposal from not calculated of miners suffering pneumoconiosis are to increase the number of recruits to this vitally important aaaurances
which
they
which was not iodine.
Finally,
Hengoed, Glamorganshire.
T. FRANCIS FRANICIS JARMAN.
RADIOACTIVE-IODINE STUDIES IN NONENDEMIC GOITROUS CRETINISM SIR,—We wish to thank Mr. Oliver and Dr. Ellis (July 18) and Dr. Costa (July 25) for their comments on our article in your issue of June 6. We agree with Mr. Oliver and Dr. Ellis that examination of the full urinary excretion curves in our cases indicates their unusual nature, and supports our opinion that there was a block in the synthesis of the thyroid hormone. We also agree that isolated radioactive-iodine tracer studies may be misleading. Our finding in hypothyroidism of substantial amounts of protein-bound p31 might, without reference to the clinical state of the patients, have been too readily accepted as evidence of thyrotoxicosis. The unusual nature of our cases was, of course, obvious on clinical observation alone, and we consider that when the clinical assessment indicates that a case of thyroid dysfunction is in some way out of the ordinary it is well worth investigating the patient by gland-uptake, plasma-iodine, and urine-excretion studies combined and in as much detail as possible. The conclusion that amounts of protein-bound p31 above 0.4% per litre of plasma indicate thyrotoxicosis 1 and the assumption that protein-bound iodine is essentially circulating thyroid hormone are usually true. That they are not invariably so may be diagnostically inconvenient but physiologically intriguing and supports our plea that detailed investigations should be made to determine the true identity of the substances which we are measuring. In relation to our finding of an unidentified iodinated complex in goitrous cretinism, it is interesting to note that Robbins et a1.2 have recently found, in the serum of patients with thyroid carcinoma who had received therapeutic doses of radioactiveiodine, an iodine component, entirely precipitable with the serum-proteins and only partially soluble in butyl alcohol, which is neither thyroxine or triiodotliyronine. We were interested to read of Dr. Costa’s findings in endemic and familial cretins. His finding of thyroxine in the serum of an endemic cretin who has been given iodine is, of course, what one would expect provided the enlarged and iodine-deprived thyroid gland retains some functional capacity. It was the apparent absence of thyroxine in the plasma of. one of our non-endemic goitrous cretins which, with other observations, led us to conclude that in these patients there was an intrinsic defect in hormone synthesis within a thyroid gland 1. Macgregor, A. G., Miller, H., Blaney, P. J., Whimster, W. S. Brit. med. J. 1953, ii, 21. 2. Robbins, J., Rall, J. E., Rawson, R. W. J. clin. Endocrin. 1953, 13, 852.
of
an
adequate supply
wish to comment upon Dr. Costa’s
use
of
of
"hypothyroid," "euthyroid," and " hyperIn our opinion, these terms should continue, past, to refer to the clinical state of the patient
the terms
thyroid."
in the and should not be used to refer to the functional state of the thyroid gland. As Dr. Costa points out, a cretin may have an overactive and hyperplastic thyroid gland, but he is a cretin because the gland is failing to produce or liberate sufficient thyroid hormone to meet the needs of the tissues ; such a patient is in a hypothyroid state and we do not think the term hyperthyroidism " should be used in these circumstances. E. M. MCGIRR Royal Infirmary and Royal J. H. HUTCHISON. Hospital for Sick Children, Glasgow. as
"
"
industry.
we
being deprived
THE KIDNEY AND METABOLIC DISEASE
SIR,—Your leading article of July 25 demonstrates the growing uncertainty about the exact interpretation of the so-called Fanconi syndrome. This term is being increasingly used to describe a wide variety of symptoms and signs, and the application of findings in one group of cases to another is making confusion worse confounded. Fanconi, in his original publication,! describes nephrotic-glycosurio dwarfism with hypophosphataemic his syndrome, and amplifies rickets " as his description later by the inclusion of cystine storage2 and general aminoaciduria 3 as further important features. How diffuse and ill-defined this syndrome becomes in the absence of one or two of the essential features (especially cystine storage and aminoaciduria) 4is illustrated in the excellent survey by McCune et al. They divided 39 cases from the literature into 10 different groups, based on the combination of two or more cardinal symptoms ; and they concluded that, if applied to so wide a variety of syndromes, the disease is " no sharply definable "
characterising
clinical
entity." position has syndrome in adults The
become still more confused since a with some, but by no means all, of the above characteristics has also been named Fanconi syndrome, and since findings in this condition are freely taken as applicable to the children’s disease. "
Thus, you quote as a typical case of Fanconi syndrome in adults " the patient of Cooke et al.,5 though there was no mention of aminoaciduria in this case, the patient was not dwarfed, and the necropsy revealed no cystine storage. Cystine storage has in fact never been shown in adults, but it was an essential feature of every one of the 21 patients we have observed so far in childhood ; and the consistency of this finding prompted us to define them as suffering from " cystine" or, more storage disease with aminoaciduria and dwarfism briefly, from Lignao-Fanconi disease. Lignac 6 was the first The other to describe in detail cystine-storage disease. essential feature of this condition, besides dwarfing, is aminoaciduria of a characteristic pattern,7 which is different from that described by Anderson et ai. 8 in their adult patient. If adult cases of Fanconi syndrome are still called typical, despite absence of such essential features, what exactly does the name mean ? How far the findings in Lignac-Fanconi disease or in other Fanconi syndromes are primarily due to proximal tubular dysfunction is still a matter of conjecture. Cystine storage cannot be explained in this way. Darmady’s elegant demonstration9 of morphological tubular changes does not confirm 1. Fanconi, G. Jb. Kinderheilk. 1936, 147, 299. 2. Fanconi, G. Helv. pœdiat. acta, 1946, 1, 183. 3. Fanconi, G., Bickel, H. Ibid, 1949, 4, 359. 4. McCune, D. J., Mason, H. H., Clarke, H. T. Amer. J. Dis. Child. 1943, 65, 81. 5. Cooke, W. T., Barclay, J. A., Govan, A. D. T., Nagley, L. Arch. intern. Med. 1947, 80, 147. 6. Lignac, G. O. E. Dtsch. Arch. klin. Med. 1924, 145, 139. 7. Bickel, H., Smallwood, W. C., Smellie, J. M., Hickmans, E. M. Acta pœdiat., Stockh. 1953, 42, suppl. 90. 8. Anderson, I. A., Miller, A., Kenny, A. P. Quart. J. Med. 1952, 21, 33. 9. Clay, R. D., Darmady, E. M., Hawkins, M. J. Path. Bact. 1953, 65, 551.
which
they
which was not iodine.
Finally,
Hengoed, Glamorganshire.
T. FRANCIS FRANICIS JARMAN.
RADIOACTIVE-IODINE STUDIES IN NONENDEMIC GOITROUS CRETINISM SIR,—We wish to thank Mr. Oliver and Dr. Ellis (July 18) and Dr. Costa (July 25) for their comments on our article in your issue of June 6. We agree with Mr. Oliver and Dr. Ellis that examination of the full urinary excretion curves in our cases indicates their unusual nature, and supports our opinion that there was a block in the synthesis of the thyroid hormone. We also agree that isolated radioactive-iodine tracer studies may be misleading. Our finding in hypothyroidism of substantial amounts of protein-bound p31 might, without reference to the clinical state of the patients, have been too readily accepted as evidence of thyrotoxicosis. The unusual nature of our cases was, of course, obvious on clinical observation alone, and we consider that when the clinical assessment indicates that a case of thyroid dysfunction is in some way out of the ordinary it is well worth investigating the patient by gland-uptake, plasma-iodine, and urine-excretion studies combined and in as much detail as possible. The conclusion that amounts of protein-bound p31 above 0.4% per litre of plasma indicate thyrotoxicosis 1 and the assumption that protein-bound iodine is essentially circulating thyroid hormone are usually true. That they are not invariably so may be diagnostically inconvenient but physiologically intriguing and supports our plea that detailed investigations should be made to determine the true identity of the substances which we are measuring. In relation to our finding of an unidentified iodinated complex in goitrous cretinism, it is interesting to note that Robbins et a1.2 have recently found, in the serum of patients with thyroid carcinoma who had received therapeutic doses of radioactiveiodine, an iodine component, entirely precipitable with the serum-proteins and only partially soluble in butyl alcohol, which is neither thyroxine or triiodotliyronine. We were interested to read of Dr. Costa’s findings in endemic and familial cretins. His finding of thyroxine in the serum of an endemic cretin who has been given iodine is, of course, what one would expect provided the enlarged and iodine-deprived thyroid gland retains some functional capacity. It was the apparent absence of thyroxine in the plasma of. one of our non-endemic goitrous cretins which, with other observations, led us to conclude that in these patients there was an intrinsic defect in hormone synthesis within a thyroid gland 1. Macgregor, A. G., Miller, H., Blaney, P. J., Whimster, W. S. Brit. med. J. 1953, ii, 21. 2. Robbins, J., Rall, J. E., Rawson, R. W. J. clin. Endocrin. 1953, 13, 852.
of
an
adequate supply
wish to comment upon Dr. Costa’s
use
of
of
"hypothyroid," "euthyroid," and " hyperIn our opinion, these terms should continue, past, to refer to the clinical state of the patient
the terms
thyroid."
in the and should not be used to refer to the functional state of the thyroid gland. As Dr. Costa points out, a cretin may have an overactive and hyperplastic thyroid gland, but he is a cretin because the gland is failing to produce or liberate sufficient thyroid hormone to meet the needs of the tissues ; such a patient is in a hypothyroid state and we do not think the term hyperthyroidism " should be used in these circumstances. E. M. MCGIRR Royal Infirmary and Royal J. H. HUTCHISON. Hospital for Sick Children, Glasgow. as
"
"
industry.
we
being deprived
THE KIDNEY AND METABOLIC DISEASE
SIR,—Your leading article of July 25 demonstrates the growing uncertainty about the exact interpretation of the so-called Fanconi syndrome. This term is being increasingly used to describe a wide variety of symptoms and signs, and the application of findings in one group of cases to another is making confusion worse confounded. Fanconi, in his original publication,! describes nephrotic-glycosurio dwarfism with hypophosphataemic his syndrome, and amplifies rickets " as his description later by the inclusion of cystine storage2 and general aminoaciduria 3 as further important features. How diffuse and ill-defined this syndrome becomes in the absence of one or two of the essential features (especially cystine storage and aminoaciduria) 4is illustrated in the excellent survey by McCune et al. They divided 39 cases from the literature into 10 different groups, based on the combination of two or more cardinal symptoms ; and they concluded that, if applied to so wide a variety of syndromes, the disease is " no sharply definable "
characterising
clinical
entity." position has syndrome in adults The
become still more confused since a with some, but by no means all, of the above characteristics has also been named Fanconi syndrome, and since findings in this condition are freely taken as applicable to the children’s disease. "
Thus, you quote as a typical case of Fanconi syndrome in adults " the patient of Cooke et al.,5 though there was no mention of aminoaciduria in this case, the patient was not dwarfed, and the necropsy revealed no cystine storage. Cystine storage has in fact never been shown in adults, but it was an essential feature of every one of the 21 patients we have observed so far in childhood ; and the consistency of this finding prompted us to define them as suffering from " cystine" or, more storage disease with aminoaciduria and dwarfism briefly, from Lignao-Fanconi disease. Lignac 6 was the first The other to describe in detail cystine-storage disease. essential feature of this condition, besides dwarfing, is aminoaciduria of a characteristic pattern,7 which is different from that described by Anderson et ai. 8 in their adult patient. If adult cases of Fanconi syndrome are still called typical, despite absence of such essential features, what exactly does the name mean ? How far the findings in Lignac-Fanconi disease or in other Fanconi syndromes are primarily due to proximal tubular dysfunction is still a matter of conjecture. Cystine storage cannot be explained in this way. Darmady’s elegant demonstration9 of morphological tubular changes does not confirm 1. Fanconi, G. Jb. Kinderheilk. 1936, 147, 299. 2. Fanconi, G. Helv. pœdiat. acta, 1946, 1, 183. 3. Fanconi, G., Bickel, H. Ibid, 1949, 4, 359. 4. McCune, D. J., Mason, H. H., Clarke, H. T. Amer. J. Dis. Child. 1943, 65, 81. 5. Cooke, W. T., Barclay, J. A., Govan, A. D. T., Nagley, L. Arch. intern. Med. 1947, 80, 147. 6. Lignac, G. O. E. Dtsch. Arch. klin. Med. 1924, 145, 139. 7. Bickel, H., Smallwood, W. C., Smellie, J. M., Hickmans, E. M. Acta pœdiat., Stockh. 1953, 42, suppl. 90. 8. Anderson, I. A., Miller, A., Kenny, A. P. Quart. J. Med. 1952, 21, 33. 9. Clay, R. D., Darmady, E. M., Hawkins, M. J. Path. Bact. 1953, 65, 551.