Postgrad. med. J. (May 1968) 44, 398-403.

Hypothyroidism due to enzyme defects

E. M. McGIRRB.Sc., M.D., F.R.C.P. (Lond., Glasg. and Edin.)

JOHN A. THOMSONM.B., M.R.C.P.(Lond.), M.R.C.P.(Glasg.)

Professor of Medicine, Muirhead Chair Senior Registr,University Department of Medicine, Royal Infirmary, Glasgow, C.4

SummaryDefects in thyroid hormone production, trans-

port and utilization are classified.Particular attention is given to inherited intra-

thyroidal defects in hormone synthesis whichimpair thyroid function and lead to goitreformation and hypothyroidism. Anomalies in bio-synthesis may also result from disease or drugs.

Reference is made to the derangement ofiodine metabolism that results from iodine de-ficiency and from insufficient TSH.

Illustrative clinical problems with regard totransport and utilization are quoted, and it isinferred that they lie in rather neglected areas.Throughout an attempt has been made to show

how the clinical problems that are encounteredin practice may, by the techniques of investiga-tion available to us, be related to the theoreticallist of defects that are included in the classifi-cation.

IntroductionThe thyroid hormones thyroxine (T4) and tri-

iodothyronine (T3) play a dominant role in con-trolling metabolism and are essential for normalgrowth and development in childhood. The clini-cal features and laboratory findings indicative ofhypothyroidism appear when the amounts ofthese hormones available to organs, tissues andcells are insufficient.The term dyshormonogenesis implies a dis-

turbance of normal hormone production. Whileit may be due to lack of the driving force ofthyrotrophin (TSH), as in pituitary hypothyroid-ism, or to insufficiency of dietary iodine, as inendemic cretinism, it is especially applied tothose patients whose condition is due to a defectin the intrathyroidal mechanisms, in particularto those whose condition is due to an inheritedanomaly in thyroid hormone synthesis. Theo-retically, hypothyroidism may also result from adefect in the mechanism for transporting T4 andT3 from the thyroid gland to the peripheraltissues, and from a defect in tissue cells which

renders them incapable of responding to normallevels of T4 and T8 in the blood.Whatever the cause the clinical features of

hypothyroidism are identical. They are, however,modified by the age of the patient. If hypo-thyroidism develops in utero or the early monthsafter birth mental retardation as well as physicalstunting may result unless the condition is quickyrecognized and adequate treatment instituted.While the common 'athyroidic' or 'dysgenetic'cretin and adult patient with primary hypo-thyroidism are non-goitrous, the patient whosecondition is due to enzymatic dyshormono-genesis is goitrous. Some patients with dyshor-monogenesis remain euthyroid, while others be-come hypothyroid, presumably depending on theseverity of their defect. Most cases are familialand where data are sufficient the evidence favoursthe opinion that the defects are inherited assimple recessive autosomal characteristics. Cer-tainly such a conclusion is fully justified for theorganification (Fraser, Morgans & Trotter, 1960)and iodotyrosine deiodinase or dehalogenaseHutchison and McGirr, 1956) defects.The various defects postulated in the synthesis,

transport and utilization of the thyroid hormonesmay be classified as follows.

A. Defects in biosynthesis(a) Intrathyroidal defects: these may be dueto:

1. defective trapping of iodide by the thy-roid gland

2. defective organification and utilization ofthe iodine to form monoidotyrosine (MIT)and diiodotyrosine (DIT)

3. defective coupling of MIT and DIT toform T3 and T4

4. defective deiodination of MIT and DITwith their consequent loss in the urinedue to iodotyrosine deiodinase deficiency

5. defective production of thyroglobulinwith the formation of an abnormal iodi-nated protein

ar

Protected by copyright.

on Septem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.44.511.398 on 1 May 1968. D

ownloaded from

Hypothyroidism due to enzyme defects6. defective proteolysis of thyroglobulin7. miscellaneous and ill-defined defects

(b) Iodine deficiency(c) Deficient production of TSH

B. Defects in the transport of T4 and T3 fromthe thyroid gland to the peripheral tissues

1. plasma binding proteins increased2. plasma binding proteins decreased

C. Defects in the tissue cells1. ? deficiency of cellular binding proteins2. ? failure of mechanism for transportation

of T4 and T3 across the cell membrane.3. ? refractory end organ response by the

tissues.In this paper we propose in the main to dis-

cuss intrathyroidal defects in thyroid hormonesynthesis. We shall, however, briefly refer to theother topics where they appear to us relevant toour theme.

Intrathyroidal defectsThe stages involved in the production of T3

and T4 are fairly well understood in broad out-line, although the minute details of the processesinvolved are not. It is envisaged that iodine istrapped by the thyroid probably in the form ofiodide; that iodide is then oxidized to some'active' form of iodine which is then bound totyrosine in thyroglobulin to give MIT and DIT;that MIT and DIT are then joined together togive To and T4 within the thyroglobulin mole-cule. As hormone is required the thyroglobulinis broken down by proteolytic enzymes to re-lease T3 and T4 which pass into the peripheralblood. MIT and DIT are also released by a

similar mechanism but their iodine is removedby a special enzyme (iodotyrosine deiodinase or

dehalogenase) and is conserved for re-use withinthe thyroid.

Defective iodine trapping is a very rare causeof goitrous hypothyroidism having been des-cribed on only two occasions (Stanbury & Chap-man, 1960; Wolff, Thomson & Robbins, 1964).This defect is diagnosed by demonstrating theabsence of significant accumulation of radio-iodine in the thyroid area. The salivary glandsalso normally trap iodine. In patients with thetrapping defect the salivary glands are also de-fective in this function. The ratio of the radio-activity of a sample of saliva and of plasmaobtained simultaneously after a tracer dose ofradioiodine in them is approximately unitywhereas in normal subjects it is about 20: 1.The administration of potassium iodide in phar-macological doses may raise the plasma inorganiciodide of such a patient sufficiently to permit

iodide to penetrate the thyroid cell by passivediffusion and so allow sufficient hormone to beproduced to make the patient euthyroid.

Failure of organification was the first defectto be described by Stanbury & Hedge (1950).It is readily detected after the administration ofradioiodine. The iodine which has been accumu-lated but not utilized to form MIT and DIT iseasily dischargeable by perchlorate or thiocy-anate. There appears to be a defect in the per-oxidase enzyme system. Failure of organificationmay be associated with a high tone nerve deaf-ness (Pendred's syndrome). Patients with Pen-dred's syndrome frequently remain euthyroid.

Defective coupling of MIT and DIT hasbeen occasionally and tentatively propounded(Stanbury, Ohela & Pitt-Rivers, 1955; Stanbury,1966). The precise details of coupling are un-known. It has never been shown to be an enzy-matic process, and indeed it may depend uponthe molecules of MIT and DIT being in thecorrect geometric positions on the thyroglobulinmolecule. Such an arrangement could well beupset if the thyroglobulin molecule was abnor-mal, or if the gland was very iodine deficientresulting in the molecules of MIT and DIT beingtoo far apart to permit their coupling (Joseph& Job, 1958). This latter explanation seems un-likely because the coupling process is normal inother dyshormonogenetic goitres which are just asiodine deficient. Other mechanisms of couplinghave been postulated. For example it has beensuggested that coupling may occur between onemolecule of DIT and one of diiodophenyl-pyruvic acid (DIIPPA). We ourselves have seena patient with a presumptive coupling defect witha pattern of iodoamino acids in the thyroid con-sistent with the presence of the pyruvic acid ana-logues of the iodotyrosines (Murray et al., 1965a).Recently Surks, Weinbach & Volpert (1967) havedescribed DIIPPA in the rat thyroid. In practicemost cases claimed to have a coupling defecthave been examples of goitrous hypothyroidismin which other known defects of thyroid hor-mone synthesis have been eliminated. The thy-roid glands at operation 48-72 hr after radio-iodine administration have been shown to con-tain abundant MIT and DIT but little or noT3 or T4. Otherwise the diagnosis has been madeon the basis of negative criteria. A more positivediagnostic approach awaits eludication of thecoupling mechanism.When the iodotyrosine enzyme system is de-

fective MIT and DIT escape in large amountsfrom the thyroid gland into the blood and thenceinto the urine taking their iodine with them.Individuals with this defect constituted the first

399P

rotected by copyright. on S

eptember 29, 2020 by guest.

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.511.398 on 1 M

ay 1968. Dow

nloaded from

E. M. McGirr and John A. Thomson

group of patients with dyshormonogenesis seenby the authors. The precise diagnosis is readilymade by demonstrating that such subjects ex-crete in the urine a substantial amount of orallyor intravenously administered M131T or D131Tas iodotyrosine and do not break down thesecompounds so that iodide is the main excretionproduct as occurs in normal individuals. Thedefect is confirmed by showing that thyroidtissue obtained at operation is unable to deiodi-nate added iodotyrosines in vitro. Cases havebeen described in which the thyroid gland wasunable to deiodinate iodotyrosines but the peri-pheral blood was able to do so (Kusakabe &Miyake, 1964). Presumably in this situation someof the iodine liberated by peripheral deiodin-ation can be conserved provided the thyroidenlarges: or, expressed in another way, the needfor more iodine conservation and more frequentrecycling through the incompetent thyroid tomake good the loss from the thyroid of theiodotyrosines leads to goitre formation. Furtherwork in such partial cases is required before sucha speculative explanation can be accepted asestablished.Our experience of the iodotyrosine deiodinase

or dehalogenase defect has been in the mainwith two large kindreds (Hutchison & McGirr,1956; Murray et al., 1965b), one of tinker stockfrom the West of Scotland and the other, appar-ently unrelated, from Dumfries. In both thesefamilies genetic studies showed that the defectwas transmitted as an autosomal recessive char-acteristic; some of the apparently unaffectedrelatives were shown to have minor defects in thedeiodination of MIT. The thyroid gland of oneof our patients unconnected with the above fami-lies showed a histological picture indicative ofneoplasia (McGirr et al., 1959). Crooks, Greig& Branwood (1963) have described a similarcase.

Many patients have been described who pro-duce an abnormal iodinated protein. Indeed thisis probably the commonest defect, though thereports of individual groups of workers such asourselves tend to be biased by a misleadinglyhigh proportion of one anomaly which by chancecomes their way. Several different types of ab-normal iodoprotein have been reported. Insteadof normal thyroglobulin these patients producea protein which runs on paper electrophoresis inthe position of serum albumin or even in ad-vance of the albumin band-pre-albumin. Insome cases more than one type of abnormalprotein is present (Murray et al., 1965a). Thesepatients usually present with familial goitre andare as likely to be euthyroid as hypothyroid.

Radioiodine studies give a 'thyrotoxic' patternof rapid trapping of 131! and an elevated pro-tein-bound 131I (PB31!I) at 48 hr. ThePB81I consists of an abnormal iodinated pro-tein which cannot be extracted with butanol: theBE'31! is low. The diagnosis is confirmed byexamination of the electrophoretic pattern of thethyroid proteins, and by their ultracentrifugationwhich reveals the presence of a light-weightiodoprotein. It seems likely that in time morerefined techniques will delineate more clearly thevarious anomalies that are at present includedin the broad term, iodoprotein defect.

It is at least theoretically possible that thefinding of an abnormal iodinated protein mayon occasion reflect not the production of anabnormal protein but rather be due to a defectin the proteolytic enzyme system responsible forbreaking down thyroglobulin. Two patients inthis category have been described by Pittman &Pittman (1966) and we consider that we haveseen one further case in our own clinic. Thetechniques for assessing protease activity in thethyroid are, however, unsatisfactory. There aresampling problems too and it has to be remem-bered that the activity of only a small portionof the thyroid gland is measured. It seems reason-able therefore to state that although it is likelythat such a defect exists there is as yet no con-clusive proof of its existence.

Despite the use of a whole variety of tech-niques available at present for the elucidationof defects in thyroid metabolism some cases re-main obscure. We (Murray et al., 1966) recentlyreported a family in which goitre was apparentlyinherited through five generations in an auto-somal dominant fashion. All tests available tous were applied to the in vivo and in vitro studyof the thyroids of these patients with negativeresults. It is debatable whether they should beincluded with dyshormonogenetic cases. Thegoitres were unusual in that even at an early agethey showed unusual calcification. Their histo-logy did not show the gross and generalizedhyperplasia and the pleomorphism usually asso-ciated with dyshormonogenetic goitres. Indeedthe picture was in many ways similar to thatseen in a long-standing non-toxic goitre in anelderly individual.

Dyshormonogenesis though seen in its mosttypical form in the group of cases we have dis-cussed is not an exclusive feature of inheritedintrathyroidal defects in hormone biosynthesis.Blocks of hormone synthesis with goitre forma-tion and with or without the features of hypo-thyroidism may result from goitrogens, whethernaturally occurring or iatrogenic. In certain dis-

400P

rotected by copyright. on S

eptember 29, 2020 by guest.

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.511.398 on 1 M

ay 1968. Dow

nloaded from

Hypothyroidism due to enzyme defectsease processes anomalies in synthesis are com-monly found. For example in Hashimoto's auto-immune thyroiditis a minor defect in organifica-tion is found in about half the cases and an ab-normal iodoprotein in the majority (Murray &McGirr, 1960). An abnormal iodoprotein maybe found in thyroid cancer and occasionally innon-toxic goitre (Pitt-Rivers & Tata, 1960).

Iodine deficiencyIodine deficiency produces characteristic

changes in iodine metabolism (Wayne, Kontras& Alexander, 1964) with a low value for plasmainorganic iodine (PII), and increased thyroidavidity for tracer doses of radioiodine. Thepattern of hormonogenesis is altered with an in-creased amount of MIT relative to DIT and ofiodotyrosines relative to iodothyronines.Endemic goitre is the classical example of the

result of severe iodine deficiency, but there aregood reasons to believe that other factors areoften if not usually also involved. Genetic pre-disposition seems to be especially important inendemic cretinism, but there is also an individualfactor as far as the goitre itself is concerned. Inendemic areas non-goitrous individuals can beshown by present-day techniques to be as iodinedeficient as those who are goitrous (Malamoset al., 1966). Furthermore up to the age of pub-erty goitre is equally common in males andfemales but after puberty goitre is more commonin females.Anomalies in iodine metabolism may some-

times occur in endemic goitres but whether theyare a consequence or a cause of the cellularhyperplasia is unknown. The goitre may allowas much inorganic iodine to leak from it as ituses in hormone production (Ermans, Dumont& Bastenie, 1963). Iodotyrosines are sometimesdetected in the circulation, and so are butanol-insoluble iodoproteins (Soto et al., 1967). Re-cently in the sera of a group of patients studiedin an endemic goitre region in the Argentine,Soto et al. (1967) found a very high incidenceof positive tests for antithyroglobulin antibodies.They explained the development of goitre insome individuals and not in others on the basisof a preestablished genetically determined, dim-inished immunological tolerance. Whether suchfindings in endemic areas are the exception orthe rule is obviously as yet unknown.

In many but not all hospital patients seen inthis country with sporadic goitre iodine meta-bolism assumes an iodine deficiency pattern(Wayne et al., 1964), which suggests that iodinedeficiency may be a significant cause of sporadicgoitre. By contrast, otherwise healthy individuals

in a community whose thyroids have enlargedsufficiently to be visible and palpable but who donot have large goitres do not appear to be iodinedeficient (Greig et al., 1967). This finding andother bits of evidence including the observationthat sporadic goitres are more common in femalesand that hormone synthesis may be deranged inthem (Pitt-Rivers, Hubble & Hoather, 1957) aswell as in cases of familial goitre (McGirr, 1960)indicate that factors other than iodine deficiencyare involved in the development of sporadicgoitre.Deficient production of TSH

If the supply of TSH is inadequate the wholemechanism of trapping iodine and synthesizingthe thyroid hormones becomes defective. Thethyroid becomes less avid for iodine and it hasdifficulty in producing iodotyrosines, particularlydiiodotyrosine, and iodothyronines. The modeof action of TSH on the thyroid is poorly under-stood. Deficiency of TSH in the adult is likelyto be accompanied by evidence of deficiency ofother anterior pituitary factors, particularlyACTH and the gonadotrophins. Occasionally inchildhood there is an isolated deficiency of TSHleading to secondary hypothyroidism.Defects in the transport of T3 and T4The thyroid hormones travel in the peripheral

blood bound to plasma proteins. The one withthe highest specificity for T4 is an interalphaglobulin called thyroxine binding globulin (TBG)The other binding proteins are albumin, whichhas a large binding capacity but low specificityand thyroid binding pre-albumin (TBPA) a bind-ing protein running in front of albumin on paperelectrophoresis. This latter protein is subject toalteration in acute non-thyroidal illness (Oppen-heimer et al., 1963). T3 is rather less firmlybound to TBG than T4 and is not bound at allto TBPA. This is thought to account, at leastin part, for the more rapid clinical effect of T3as compared to T4.

Patients have been described with lowered TBGlevels in association with thyrotoxicosis (Lemar-chand-Beraud, Assayah & Vanotti, 1964; Cava-lieri, 1961) or without thyroid abnormality(Tanaka & Starr, 1959); with increased TBGlevels in association with hypothyroidism (Lem-archand-Beraud et al., 1964) or without clinicalthyroid abnormality (Florsheim et al., 1962). TheTBG level is also elevated in pregnancy andfollowing the administration of oestrogens (in-cluding oral contraceptives) and is lowered bydrugs of the hydantoin series and by androgens.

Alterations in the TBG levels do not seem tobe causally related to clinically abnormal thy-

401P

rotected by copyright. on S

eptember 29, 2020 by guest.

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.511.398 on 1 M

ay 1968. Dow

nloaded from

E. M. McGirr and John A. Thomson

roid states but are usually diagnosed by thefinding of a PBI level in the serum which is outof keeping with the clinical status of the patient,thus leading to more exact estimations of theTBG capacity being performed. It must be pre-sumed that an equilibrium is reached in thesepatients between the binding proteins of theplasma, the circulating free thyroxine and thecellular binding proteins which allows a normallevel of free thyroxine to be offered to thecells.Both diminished levels of TBG and elevated

levels of TBG have been reported in severalmembers of a family. The pedigrees of the af-fected families are consistent with each of thesetraits being transmitted by X-chromosome linkeddominant inheritance (Nikolai & Seal, 1967;Jones & Seal, 1967).Peripheral defects

Theoretically there could be at least three typesof peripheral defect:

(1) defective binding proteins in the peripheraltissues to accept thyroxine from theplasma

(2) failure of the mechanism for transportingthe hormones across the cell membrane tothe site of action

(3) failure of the peripheral tissues to respondThere are no techniques at present available

by which such mechanisms may be studied anddefects detected and elucidated. Our shortcom-ings are unfortunate as there certainly seem to bepatients, as some of the following examplesshow, who have some peripheral defect whichcannot at present be clearly delineated. A peri-pheral defect was suggested by us (Hutchison,Arneil & McGirr, 1957) to be present in a cretinwho failed to respond to dry thyroid, which wehad good reason to believe was potent, but re-sponded to triiodothyronine. Unfortunately theresponse to thyroxine was not tested.

Recently we described patients with dyshor-monogenetic goitres of the iodotyrosine deiodi-nase (dehalogenase) type, who showed abnormalhandling of intravenously administered s3lI-T4without there being any significant change inTBG levels (Thomson & Wallace, 1966).An apparent lack of response to the circulat-

ing thyroid hormones has been noted as a fami-lial disorder in several members of a family whohad high PB127I and BE127I levels, who wereeuthyroid, and who had normal TBG levels(Refetoff, De Wind & De Groot, 1967). Thesefindings were associated with stippled epiphyses,which could not be related to a previous episodeof hypothyroidism, and with deaf-mutism.

A contrasting abnormality has been suggestedby Luft et al. (1962) who described a patientwith hypermetabolism but with a normal PB127I.They postulated that there was a defect at themitochondrial level which resulted in a loss ofcapacity for respiratory control at a subcellularlevel.Though the case material appears fragmentary

and the investigations, by virtue of a lack ofappropriate techniques, are limited we considerthat some reference to clinical problems in rela-tion to hormone transport and peripheral utili-zation is desirable if for no other reason thanto direct attention to them and the need fortheir more intensive study.

ConclusionsThe assertion that dyshormonogenesis plays a

fundamental aetiological role in the evolution ofthyroid dysfunction is certainly true for inheritedintrathyroidal defects of hormone synthesis. Pre-sumably in these cases difficulty in hormoneproduction leads to overactivity of the anteriorpituitary, increased production of TSH with con-sequent thyroid hyperplasia and enlargement whichin greater or lesser degree compensates for itsfundamental inefficiency. We find as a result theclinical conditions of familial goitre or sporadic(non-endemic) goitrous cretinism and hypothyroi-dism.Where the dyshormonogenesis is a result of

or is associated with other conditions such asHashimoto's autoimmune thyroiditis or iodinedeficiency the aetiological contribution of thedyshormonogenesis to the clinical and metabolicstatus of the affected individual is uncertain. Itis, however, important to an understanding ofthe pathogenesis of such conditions that weshould be aware that there may be an accom-panying derangement in thyroid function andthat in appropriate circumstances we should beprepared to study it with a view to assessing itssignificance and relationship to the primary con-dition.

Theoretical considerations suggest that morethought and investigational effort should be de-voted to the study of hormone transport andperipheral utilization. Past investigations, parti-cularly in the latter field, have been hamperedby inadequate techniques. Undoubtedly defectsof transport occur and there is evidence thatsome of them are hereditary. So far, however,they have not been shown to be responsible forgoitre production or hypothyroidism. Most ifnot all of the reports which suggest defects inutilization have so far been more speculative thanfactual.

402P

rotected by copyright. on S

eptember 29, 2020 by guest.

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.44.511.398 on 1 M

ay 1968. Dow

nloaded from

Hypothyroidism due to enzyme defects 403

ReferencesCAVALIERI, R.R. (1961) Hyperthyroidism and decreased

thyroxine binding by serum proteins. J. clin. Endocr. 21,1455.

CROOKS, J., GREIG, W.R. & BRANWOOD, A.W. (1963) Dyshor-monogenesis and carcinoma of the thyroid gland. Scot.med. J. 8, 303.

ERMANS, A.M., DUMONT, J.E. & BASTENIE, P.A. (1963)Thyroid function in a goitrous endemic: II. Non-hormonaliodine escape from the goitrous gland. J. clin. Endocr. 23,550.

FLORSHEIM, W.H., DOWLING, J.T., MEISTER, L. & BODFISH,R.E. (1962) Familial elevation of serum thyroxine bindingcapacity. J. clin. Endocr. 22, 735.

FRASER, G.R., MORGANS, M.E. & TROTTER, W.R. (1960)The syndrome of sporadic goitre and congenital deafness.Quart. J. Med. 29, 279.

GREIG, W.R., BOYLE, J.A., DUNCAN, A., NICOL, J., GRAY,M.J.B., BUCHANAN, W.W. & McGIRR, E.M. (1967)Genetic and non-genetic factors in simple goitre. Evidencefrom a twin study. Quart. J. Med. 142, 175.

HUTCHISON, J.H. & McGIRR, E.M. (1956) Sporadic non-endemic goitrous cretinism. Hereditary transmission.Lancet, i, 1035.

HuTCHISON, J.H., ARNEIL, G.C. & MCGIRR, E.M. (1957)Deficiency of an extra-thyroid enzyme in sporadic cretin-ism. Lancet, ii, 314.

JONES, J.E. & SEAL, U.S. (1967) X-chromosome linked in-heritance of elevated thyroxine-binding globulin. J. clin.Endocr. 27, 1521.

JOSEPH, R. & JOB, J.C. (1958) Congenital hypothyroidism withanomaly of iodotyrosine condensation: familial incidence:physiopathological discussion. Arch. franc. Pediat. 15, 464.

KUSAKABE, T. & MIYAKE, T. (1964) Thyroidal deiodinationdefect in three sisters with simple goitre. J. clin. Endocr.24, 456.

LEMARCHAND-BERAUD, TH., ASSAYAH, M.-R. & VANoTrI, A.(1964) Alteration of thyroxine-binding protein in clinicallyhypo- and hyper-thyroid patients with normal PBI level.Acta endocr. (Kbh.), 45, 99.

LUFr, R., IKKOS, D., PALMIRI, G., ERNSTER, L. & AFZELIUS,B. (1962) A case of severe hypermetabolism of nonthyroidorigin with a defect in the maintenance of mitochondrialrespiratory control: A correlated clinical, biochemical andmorphological study. J. clin. Invest. 41, 1776.

McGIRR, E.M. (1960) Clinical Endocrinology (Ed. by E. B.Astwood), vol. 1, p. 133. Grune & Stratton, New York.

MCGIRR, E.M., CLEMENT, W.E., CURRIE, A.R. & KENNEDY,J.S. (1959) Impaired dehalogenase activity as a cause ofgoitre with malignant change. Scot. med. J. 4, 232.

MALAMOS, B., MIRAS, K., KOUTRAS, D.A., KOSTAMIS, P.,BINOPOULOS, D., MANTZOS, J., LEVIs, G., RIGOPOULOS, G.,ZEREFOS, N. & TASSOPOULOS, C.N. (1966) Endemic goiterin Greece: metabolic studies. J. clin. Endocr. 26, 696.

MURRAY, I.P.C. & MCGIRR, E.M. (1960) Radioactiveiodine studies in the diagnosis of Hashimoto's thyroiditis.Brit. med. J. 1, 838.

MURRAY, I.P.C., MCGIRR, E.M., THOMSON, J.A. & HUTrCm-SON, J.H. (1965a) Current Topics in Thyroid Research(Ed. by C. Cassano and M. Andreoli), p. 813. AcademicPress, New York.

MURRAY, I.P.C., THOMSON, J.A., MCGIRR, E.M., WALLACE,T.J., MACDONALD, E.M. & MACCABE, H.J. (1956b) Absentand defective iodotyrosine deiodination in a family, someof whose members are goitrous cretins. Lancet, i, 183.

MURRAY, I.P.C., THOMSON, J.A., MCGIRR, E.M., MAC-DONALD, E.M., KENNEDY, J.S. & MCLENNAN, I. (1966)Unusual familial goitre associated with intrathyroidalcalcification. J. clin. Endocr. 26, 1039.

NIKOLAI, T.F. & SEAL, U.S. (1967) X-chromosome linkedinheritance of thyroxine binding globulin deficiency. J. clin.Endocr. 27, 1515.

OPPENHEIMER, J.H., SQUEF, R., SuRKs, M. & HAUER, H.(1963) Binding of thyroxine by serum proteins evaluatedby equilibrium dialysis and electrophoretic techniques.Alterations in non thyroidal illness. J. clin. Invest. 42, 1769.

PITTMAN, C.S. & PITTMAN, J.A. (1966) A study of the thyro-globulin, thyroidal protease and iodoproteins in twocongenital goitrous cretins. Amer. J. Med. 40, 49.

Prir-RIVERS, R., HUBBLE, D. & HOATHER, W.H. (1957) Achromatographic study of thyroidal iodine metabolism innon-toxic nodular goitre. J. clin. Endocr. 17, 1313.

PITT-RIVERS, R. & TATA, J.R. (1960) The Chemistry ofThyroid Disease. Thomas, Springfield, Illinois.

REFETOFF, S., DEWIND, L.T. & DE GROOT, L.J. (1967)Familial syndrome combining deaf mutusm, stippledepiphyses, goiter and abnormally high PBI: possibletarget organ refractoriness to thyroid hormone. J. clin.Endocr. 27, 279.

SoTo, R.J., IMAs, B., BRUNENGO, A.M. & GOLDBERG, D.(1967) Endemic goiter in Misiones, Argentina; patho-physiology related to immunological phenomena. J. clin.Endocr. 27, 1581.

STANBURY, J.B. (1966) The Metabolic Basis of InheritedDisease (Ed. by J. B. Stanbury, J. B. Wyngaarden, andD. S. Fredrickson), p. 215. McGraw-Hill, New York.

STANBURY, J.B. & CHAPMAN, E.M. (1960) Congenitalhypothyroidism with goitre. Absence of an iodide-con-centrating mechanism. Lancet, i, 1162.

STANBURY, J.B. & HEDGE, A.H. (1950) A study of a familyof goitrous cretins. J. clin. Endocr. 10, 1471.

STANBURY, J.B., OHELA, K. & PITT-RIVERS, R. (1955) Themetabolism of iodine in 2 goitrous cretins compared withthat in 2 patients receiving methimazole. J. clin. Endocr.15, 54.

SURKS, M.I., WEINBACH, S. & VOLPERT, E.M. (1967) Paperpresented at the Annual meeting of the American ThyroidAssociation, Ann Arbor, September 1967.

TANAKA, S., STARR, P. (1959) Clinical observations on serumglobulin thyroxine-binding capacity, using a simplifiedtechnique. J. clin. Endocr. 19, 84.

THOMSON, J.A. & WALLACE, T.J. (1966) Anomalous valuesfor the half-life of radiothyroxine in dyshormonogeneticgoiter. J. clin. Endocr. 26, 875.

WAYNE, E.J., KOUTRAS, D.A. & ALEXANDER, W.D. (1964)Clinical Aspects of Iodine Metabolism. Blackwell ScientificPublications, Oxford.

WOLFF, J., THOMSON, R.H. & ROBBINS, J. (1964) Congenitalgoitrous cretinism due to the absence of iodide-concen-trating ability. J. clin. Endocr. 24, 699.

Protected by copyright.

on Septem

ber 29, 2020 by guest.http://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.44.511.398 on 1 May 1968. D

ownloaded from