Postgrad Med J: first published as 10.1136/pgmj.36.417.425 on 1 July 1960. Downloaded from

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INBORN ERRORS OF IODINE METABOLISM W. R. TROTTER, D.M., M.R.C.P. The Medical Unit, University College Hospital Medical School, London, W.C.I

Garrod,4 in I908, introduced the term ' inborn during the growing period can be plainly seen. errors of metabolism' to describe biochemical When the degree of is severe the abnormalities which were genetically determined, child's whole development, physical and mental, present throughout life and relatively non-lethal. is drastically slowed down; and the characteristic He suggested that it would ultimately be possible puffy face, thick lips, large tongue and dry, to attribute the biochemical aberrations found in coarse skin appear. The extent to which thyroxine these conditions to specific enzyme defects. synthesis is interfered with may, however, vary Recent work5 has confirmed the validity of within wide limits in this group of cases. Occa- Garrod's ideas to a remarkable extent, and has sionally one of the less severely affected cases may extended them to a considerably greater range of escape detection during childhood, and present conditions than the four originally considered by during adult life with the evidence of past hypo- him (albinism, alcaptanuria, and pento- thyroidism clearly shown by the infantile propor- suria). One of the most fruitful of these exten- tions, distorted head femoral and enlarged pitu- by copyright. sions has been to certain types of disease.16 itary fossa.17 These defects (collectively known as ' sporadic The cases with the grossest metabolic errors goitrous cretinism ') conform extremely well to were naturally enough the first to be studied and Garrod's definition, for they are hereditary, con- described.16. More recently, however, it has genital, persist through life, and are relatively become apparent that the biochemical defect need non-lethal. The fact that they are accompanied not be severe enough to cause manifest hypo- by gross structural changes (, cretinism) thyroidism. In fact, the compensatory hyper- does not by any means exclude them from the trophy and hyperplasia of the thyroid may enable group defined for these structural the gland to by Garrod, produce normal quantities of http://pmj.bmj.com/ changes are merely anatomical reflections of the thyroxine. In that case, the only manifestation of underlying biochemical defect. Although existing the inborn error is a goitre which is not clinically evidence cannot be regarded as conclusive, most distinguishable from any other type of simple authors are agreed that the biochemical defects goitre. Like other it is initially diffuse, consist essentially of absence or inadequacy of but with the passage of time it becomes nodular. one or more of the enzyme systems which collec- The best example of this type of euthyroid goitre, tively enable the thyroid gland to produce its caused by an inborn error of metabolism, is to be hormones (thyroxine and triiodothyronine). found in the group of cases in which it is asso- on September 29, 2021 by guest. Protected ciated with congenital deafness. The first cases Clinical Aspects of this type were described by Pendred'0 in I896 It is easy enough to deduce from physiological and are most conveniently referred to by his principles what the clinical effects of a block in name. Persons afflicted with Pendred's syndrome thyroxine synthesis will be. The first effect of the are usually euthyroid, but may be hypothyroid. resulting low levels of circulating thyroxine is The goitre usually appears in middle childhood, stimulation of the anterior pituitary to produce histologically shows marked hyperplasia and has more of its thyroid-stimulating hormone (T.S.H.). an inveterate tendency to recur after a partial This causes hyperplasia and hypertrophy of the thyroidectomy. The deafness is present from thyroid, and a goitre is formed. Hence the goitre birth, usually symmetrical and most marked for may not unreasonably be regarded as an attempt high tones, and may be severe enough to cause to compensate for the block in thyroxine synthesis. deaf-mutism. In the cases described as sporadic goitrous cretins, It is qxtremely probable that there are other this attempt at compensation has clearly failed, types of"defect capable of causing goitre without and- the usual manifestations of hypothyroidism hypothyroidism. Pendred's syndrome is unusually 426 POSTGRADUATE MEDICAL JOURNAL yuly I960Postgrad Med J: first published as 10.1136/pgmj.36.417.425 on 1 July 1960. Downloaded from X 1)Dr l j

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FiG. I.-Schematic representation of iodine metabolism. I - =iodide; 12=free iodine; 11IT =mono-iodotyrosine; DIT-di-iodotyrosine; T3 = tri-iodo- thyronine; T4=thyroxine. A, B and C represent sites at which genetically-determined enzyme defects are believed by copyright. to occur. easy to identify merely because the associated type of inborn error. This therapy should be deafness provides a convenient ' marker.' We given whether signs of hypothyroidism are present can, however, from a study of Pendred's syndrome, or not, and should be maintained throughout life. deduce certain characteristics of a goitre due to an The best guide to dosage is to find the smallest inborn error of metabolism, which should enable dose which will completely inhibit radio-iodine us to suspect this type of defect even in the uptake. Our practice is to start with i-thyroxinehttp://pmj.bmj.com/ absence of hypothyroidism. These are the presence O.I mg. daily (a more reliable preparation than of marked histological hyperplasia, a tendency for dried thyroid) and to measure 1321 uptake after the goitre to recur after partial thyroidectomy about a month. If uptake is still present the daily and the occurrence of goitre in the patient's sibs. dose is increased by o. i mg. per month until Any of these features should suggest that detailed suppression is achieved. biochemical studies of thyroid function might be rewarding. Biochemical Aspects on September 29, 2021 by guest. Protected The identification of goitres due to inborn A simplified version of the main pathways of errors is not merely an academic exercise, for iodine metabolism is shown in Fig. i. The three even in the absence of hypothyroidism treatment sites at which genetically-determined enzyme with thyroxine is well worth while. This treat- failure is thought to occur are indicated at A, ment is effective in reducing thyroid size, provided B and C. the goitre is still in the diffuse stage. Even when The defect at site A is both the best under- it has become nodular (as is usually the case in stood and the easiest to demonstrate. It is widely adult subjects) it is very probable that treatment accepted that iodide has to be oxidized to iodine with thyroxine will prevent further growth of the before it can form organic compounds, such as goitre. If a nodular goitre of this type has to be iodotyrosines. The enzyme responsible for this dealt with by partial thyroidectomy on account of oxidation has never been isolated, but is generally pressure symptoms it is essential that the patient believed to be a peroxidase. If this enzyme is should be treated with thyroxine subsequently to defective iodide necessarily accumulates within prevent recurrence. Hence it can be said that the thyroid. Its presence there is readily demon- thyroxine (or thyroid extract) should be given to strable in patients by giving an oral or intravenous any patient with a goitre caused by one or other tracer dose of radio-iodine followed 1-4 hours Postgrad Med J: first published as 10.1136/pgmj.36.417.425 on 1 July 1960. Downloaded from July I960 TROTTER: Inborn Errors of Iodine Metabolism 427 PERCHLORATE TEST.

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60 10 so qo 50 550 MINUTES AFTEA I FIG. 2.-Effect of an oral dose of 400 mg. of potassium perchlorate on thyroid counting rate, when by copyright. given to a patient with Pendred's syndrome one hour after an oral tracer dose of 1321. The counting rate falls steeply as perchlorate ion discharges unbound labelled iodide from the thyroid. later by 400 mg. of potassium perchlorate or by metabolite, having a thiourea-like action, rather i g. of potassium thiocyanate. If the concentra- than to an actual deficiency of the enzyme itself. tion of labelled iodine within the thyroid is This hypothesis is not as yet supported by any measured by serial counting over the gland, a direct evidence. sharp fall in thyroid counting-rate following the A defect at site B in the diagram is much more http://pmj.bmj.com/ administration of perchlorate indicates that an difficult to identify by current techniques. Here appreciable proportion of the radio-iodine was in it is supposed that mono- and di-iodotyrosines are the form of iodide (Fig. 2). This in turn shows formed in the normal way, but are unable to that the thyroid's capacity to oxidize iodide to couple together to form tri-iodothyronine and iodine is severely limited. When this defect occurs thyroxine. A fundamental difficulty is that we do naturally it is generally presumed that the oxida- not know whether a specific enzyme is required tion enzyme (' peroxidase') is absent or inade- for this step or not; the coupling of di-iodo- on September 29, 2021 by guest. Protected quate. In the cases described as goitrous cretins tyrosine derivatives can occur in vitro in the by Stanbury and Hedge13 it seems likely that the absence of enzymes.11 It will be obvious from enzyme was entirely missing, for all the radio- the diagram that a defect at site B will be revealed iodine could be discharged from the thyroid. by a ' build-up ' of mono- and di-iodotyrosines However, incomplete defects of the same type within the thyroid. This indeed occurred in the (without cretinism) are much more common; a two cases in which site B defects have been partial discharge of radio-iodine following per- postulated.156 18 Unfortunately, a similar build-up chlorate is a characteristic feature of Pendred's of iodotyrosines is also seen in site C defects. syndrome.3' 8, 9 It should be noted that the There is therefore no critical test available now for same type of biochemical defect can be induced the identification of site B defects. temporarily in any type of subject by thiourea Site C defects, due to absence of the de- derivatives, or other anti-thyroid drugs with a iodinating enzyme, are more securely established, similar action.2 9,17 Hence it is possible that the but some puzzling features still remain unex- inefficiency of the oxidative enzyme in Pendred's plained. The existence of an enzyme which syndrome might be the result of a circulating specifically de-iodinates mono- and di-iodotyrosine Postgrad Med J: first published as 10.1136/pgmj.36.417.425 on 1 July 1960. Downloaded from 428 POSTGRADUATE MEDICAL JOURNAL July 196o Two INTERMARRIED FAMILIES C4ARRYNCrG THE PENDRED .

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KEy by copyright. * AFFECTE D O UN-PFFECreD FIG. 3.-Pedigree of two unrelated cases of Pendred's syndrome who married each other, showing the characteristic recessive mode of inheritance. Assortative mating is not uncommon in deaf populations. is well established (deiodinase, dehalogenase). It exogenous labelled mono- or di-iodotyrosine is can be seen from Fig. i that the coupling of not deiodinated by the tissues generally, so that a iodotyrosines to form iodothyronines occurs substantial proportion of the administered ma-http://pmj.bmj.com/ within the thyroglobulin molecule. However, not terial appears unchanged in the urine.7, 8,14 all the iodotyrosines are actually converted into It is obvious from Fig. i that there are other iodothyronines; when the thyroglobulin molecule possible sites at which enzyme blocks might occur. is hydrolysed by thyroid protease, much free For instance, before hormone synthesis can begin mono- and di-iodothyronine is released within iodide must be held within the thyroid at a con- the gland. The deiodinase acts on these free siderably higher concentration than in blood. iodotyrosines and liberates their iodine as iodide. This process must require energy, and probably on September 29, 2021 by guest. Protected This iodide then re-enters the synthetic cycle. the help of an enzyme. No defect of this mechan- Absence of deiodinase obviously has two effects: ism has as yet been identified. Similarly, the it diminishes the amount of iodide available for final step in hormone production is the enzymic hormone synthesis, and it floods the gland with proteolysis of thyroglobulin, with the release of free iodotyrosines, which also appear in excess in thyroxine and triiodothyronine into the blood. the blood and urine. It is not clear which of Defects of this enzyme have not yet been found these effects is the more important from the point either. of view of hormone production; one would not Another biochemical aberration, not as yet expect that iodine deficiency induced in this way related to any known or suspected enzyme system, would be severe enough to cause hypothyroidism. has been described by DeGroot and Stanbury.' Proof that a patient lacks deiodinase can only be They described five patients with goitrous cre- afforded by direct demonstration that his excised tinism, and referred to reports of probably similar goitre cannot deiodinate iodotyrosines; this has cases in the literature. This variety, which also been shown to be so in two cases.7, 8, 12 However, seems to be genetically determined, is charac- lack of thyroid deiodinase can be inferred if terized by the presence in the serum of an iodine- Postgrad Med J: first published as 10.1136/pgmj.36.417.425 on 1 July 1960. Downloaded from July I 960 TROTTER: Inborn Errors of Iodine Metabolism 429 containing substance, probably a polypeptide, rarities. It is indeed clear that genetically-deter- -which is insoluble in butanol. The existence of mined defects severe enough to cause nearly this substance may indicate a defect in thyro- complete hypothyroidism are exceedingly un- globulin synthesis resulting in the formation of a common. However, it now seems certain that precursor or variant which is metabolically inert, the same (or at least a closely related) defect can and which leaks out readily into the circulation. cause Pendred's syndome. The site A defect in Iodine is thus diverted from the normal pathway this syndrome is not usually severe enough to leading to thyroglobulin into a metabolic blind cause hypothyroidism. The occurrence of a con- tilley. venient ' marker' in the form of congenital deaf-, ness makes it possible to form some estimate of Genetic Aspects the population frequency of this condition; this Site A defects are inherited in a strictly recessive is of the order of I 5 to 30 per million. We fashion.3' 9,13 Cases occur only in single genera- cannot as yet assess the prevalence of other types tions, and (after allowing for inadequate ascer- of inherited thyroid defect, and it may well be tainment) the ratio of affected: unaffected sibs is that there are others still to be discovered. It is, very near to the expected i: 3. There seems to however, unlikely that the sum total of inborn be an excessive consanguinity rate among the errors of metabolism will ever account for a parents of cases. There is no evidence of sex substantial proportion of simple goitres. The linkage and the abnormal gene is able to manifest main reason for this inference is that such goitres itself with equal facility in males and females. rarely recur after partial thyroidectomy; hence it In Pendred's syndrome it is probable that a gene is unlikely that the thyroid is under the constant defect at the same locus is responsible for both T.S.H. stimulation, which is the inevitable sequel deafness and the thyroid enzyme defect. Hetero- of a block in thyroxine synthesis. It is of some zygotes for the defective gene cannot at present practical importance to be able to recognize goitres be identified. A typical pedigree of two families due to inborn errors, because they are so readily with Pendred's syndrome is shown in Fig. 3. controlled with thyroxine. The main interest of Nothing useful can be said about the inheritance these conditions is, however, that they provide an by copyright. of site B defects because insufficient cases have opportunity for studying the long and complex been described. sequence of events which leads from mutant gene Site C defects are inherited in the same manner to specialized enzyme. as site A defects, i.e. as an autosomal recessive.16 Hutchison and McGirr6 have described no less REFERENCES I. DEGROOT, L. J., and STANBURY, J. B. (i959), Amer. 7. than ten goitrous cretins in a group of inter- Med., 27, 586. married Scottish tinkers, and subsequent studies 2. EDWARDS, D. A. W., ROWLANDS, E. N., and TROTTER, W. R. (I954), Lancet, ii, 1051. confirmed that the underlying biochemical defect 3. FRASER, G. R., MORGANS, M. E., and TROTTER, W. R. was a lack of deiodinase.7, 8 This highly inbred (I960), Quart. jt. Med. (to be published). http://pmj.bmj.com/ 4. GARROD, A. E. (I908), Lancet, ii, I, 73, 142, 214. isolated community provided an ideal setting for 5. HARRIS, H. (i959), 'Human Biochemical Genetics,' Cam- the manifestation of a gene of recessive type. bridge University Press. 6. HUTCHISON, J. H., and McGIRR, E. M. (1956), Lancet, Although heterozygotes carrying the defective L, 1035. gene could not be identified clinically, McGirr 7. McGIRR, E. M., HUTCHISON, J. H., and CLEMENT, 8 W. E. (I959), Ibid., ii, 823. et al.7' think they have been able to recognize 8. McGIRR, E. M., HUTCHISON, J. H., and CLEMENT, them by their slightly impaired ability to de- W. E. (I959), Scot. Med. 7., 4, 107. 9. MORGANS, M. E., and TROTTER, W. R. (I958), Lancet, iodinate an oral dose of labelled mono-iodotyro- i, 607. on September 29, 2021 by guest. Protected sine. Stanbury et al.'4 found that some relatives Io. PENDRED, V. (I896), Ibid., ii, 532. of a Dutch goitrous cretin (with the same type of xi. PITT-RIVERS, R. (I948), Biochem. J., 43, 223. 12. QUERIDO, A., STANBURY, J. B., KASSENAAR, A. A. H., biochemical defect) had goitres and also were and MEIJER, J. W. A. (I956), _7. clin. Endocr., I6, I096. unable to deiodinate iodotyrosines as completely 13. STANBURY, J. B., and HEDGE, A. N. (I950), Ibid., 10,1471. 14. STANBURY, J. B., MEIJER, J. W. A., and KASSENAAR, as other people. A. A. H. (I956), Ibid., I6, 848. I5. STANBURY, J. B., OHELA, K., and PITT-RIVERS, R. Discussion (1955), Ibid., I15, 54- x6. STANBURY, J. B., and McGIRR, E. M. (1957), Amer. . When goitrous cretins were first shown to Med., 22, 712. belong to Garrod's group of inborn errors of 17. TROTTER, W. R. (I957), Postgrad. med. Y., 33, 338. I8. WERNER, S. C., BLOCK, R. J., MANDL, R. H., and metabolisnm, they wvere regarded as extreme KASSENAAR, A. A. H. (I957), . clin. Endocr., 17, 817.