ACROMEGALY and GIGANTISM Including a NEW SYNDROME in CHILDHOOD by S

Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 201

ACROMEGALY AND GIGANTISM Including A NEW SYNDROME IN CHILDHOOD By S. LEONARD SIMPSON, M.A., M.D.(Cantab.), F.R.C.P.(Lond.) Physician (with charge of Endocrine & Diabetic Clinics), Willesden General Hospital ; Endocrinologist, Princess Louise Children's Hospital; Consultant Endocrinologist, St. Mary's Hospital

The characteristic endocrine giant is a patient his eighteenth birthday, i80 cm. (6 ft.), and at 22 with an eosinophil adenoma of the anterior years, 224 cm. (7 ft. 6 in.). Extreme prognathism pituitary gland, the hypersecretion of growth hor- and coarsening of the features were indicative mone having been operative before union of the of acromegaly, but the bones remained slender. ephiphyses of the long bones and subsequently The genitals were entirely infantile, and no producing the added complication of acromegaly secondary sexual characteristics were present. if the hypersecretion continues in late adolescence The sella turcica was deformed and three times or adult life. In relatively minor degree both the normal size. gigantism and acromegaly occur more frequently Acromegaly, not unexpectedly, tends to occur without an actual eosinophil adenoma and tend to in tall people and Davidoff (1926) found in one have a high incidence in some families and indeed series that the average height of men before the in some races, e.g. the Swedes. These are ob- disease commenced was 6 ft. 2 in., and in women viously genetically determined variations of nor- 5 ft. 6 in.

mality. by copyright. Clinical accounts of gigantism go back to 1567 Acromegaly and the Thyroid (quoted by Sternberg, 1897), but fables and folk- The thyroid gland may be appreciably enlarged lore carry them back to much earlier times and in acromegaly and the basal metabolism moderately we may include the biblical tale of Goliath and raised. If there is any truth in the pituitary thyro- David. Pierre Marie used the name 'acro- trophic cause of thyrotoxicosis, it might well be megalie ' in i866, Minkowski connected the disease substantiated by typical findings in acromegaly, with the pituitary gland in 1887, and Benda but clinical thyrotoxicosis is a rarity, especially the associated it with the eosinophil cells in I900. picture of Graves' disease. Cushing and Davidoff and Davidoff established found an increased basal metabolism

Cushing (1927) firmly (1927) http://pmj.bmj.com/ the relation with eosinophil cell adenoma, or hyper- (average i8 per cent.) in 49 of 72 cases of acro- plasia; and Cushing in 1912 recorded an interest- megaly. Davis (I940) in a series of 135 cases (of ing case of acromegaly in a man of 33, with a a total of i66 cases) found an average increase of primary cerebellar cystic tumour, a secondary i8 per cent. in 16 cases, and an average decrease hydrocephalus, and hyperplasia of the eosinophil of minus 7 per cent. in 17 cases, the remaining 2 cells of the anterior pituitary gland. being normal. He found enlargement of the It is not the author's intention to spend time on thyroid gland in 86 of the i66 cases and obvious the conventional descriptions of these disorders adenomata in 53 of these 86 cases, the adenomata on September 26, 2021 by guest. Protected which are to be found in any good textbook, but varying from small nodules to large tumours that rather to draw attention to less obvious features caused tracheal compression. As to correlation, and problems. the group of cases in which the thyroid gland con- Acromegaly does not usually manifest itself tained definite adenomata comprised the cases in until adolescence or adult life, the excess of growth which there was the greatest increase of meta- hormone having its initial point of action on the bolism (mean B.M.R. plus 24 per cent.); in the epiphyseal cartilage of the long bones. However, group of cases in which the thyroid gland was pal- Atkinson (I93I) recorded one case at the age of pable, the B.M.R. average was plus i per cent.; eight years and noted in the literature 25 cases in and the group in which the thyroid was not pal- childhood. F. Mainzer and E. Yalausis (I937) pable clinically had an average B.M.R. of plus 9 describe a case of giantism and acromegaly in a per cent. Resection of the thyroid gland was boy of 14 following a severe fall, concussion and carried out in 27 cases for 'one or more of the unconsciousness for three days. This was fol- following reasons :-respiratory obstruction, pre- lowed by progressive weakness and very rapid sent in 7 cases; evidence of hyperthyroidism, growth, although there was no measurement until present in 24 cases, and hypertensive heart disease Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 202 POSTGRADUATE MEDICAL JOURNAL April 1950 in association with hyperthyroidism which was also varies in intensity with the spontaneous present in 5 cases.' There were five deaths in the variations in the course of the primary acromegaly. series, and Davis regards these cases as poor sur- The diabetes of acromegaly may be very resistant gical risks. The B.M.R. after thyroidectomy was to insulin and several hundred units may be re- recorded in only 12 cases and of these it decreased quired daily. The renal threshold may be high in io and was unchanged in 2. The decrease and frequent blood sugars essential for an accurate varied from 2 to 53 with an average of 13 per assay of the severity of the disorder. Fasting blood cent. sugars may be normal or near normal and yet be Fortunately, only five patients received pre- followed by a severe diabetic type of carbohydrate operative iodine so that the pathological anatomy tolerance curve. Polyuria, polyphagia and poly- of the thyroid gland was undistorted. In no less dipsia may be symptoms of acromegaly even in the than 23 cases the histological picture was des- absence of diabetes. Coggeshall and Root (I940) cribed as ' adenoma in colloid thyroid'; in I as describe I6 cases of diabetes mellitus in acro- colloid thyroid gland, and in 3 only as diffuse megalics of which 3 died in diabetic coma. The parehchymatous hypertrophy. Cushing and average interval between the onset of acromegaly Davidoff (1927) found that surgical removal of a and diabetes was nine years, but varied between pituitary eosinophil adenoma in patients with one and 22 years. Three of their cases were acromegaly, goitre and raised B.M.R. resulted in a secondary to giantism without acromegaly. They fall of B.M.R. as striking as the effect of thy- quote White's findings to the effect that a con- roidectomy. It would therefore appear probable siderable proportion of diabetic children are that the thyrotropic hormone is secreted in excess above the average height at the onset of their in acromegaly, and we then must ask ourselves the diabetes and also show earlier bony, dental and question why does it in the majority of cases sexual development. This obviously raises the produce a colloid adenomatous goitre and not the question of the primary pituitary origin of or- diffuse parenchymatous hyperplasia of Graves' dinary diabetes mellitus. disease ? We cannot reject the thyrotropic by copyright. stimulus mechanism theory of Graves' disease Acromegaly and the Parathyroids since injection of thyrotropic hormone in some Bauer and Aub (1940) reviewed the experimental species of animals does produce this hyperplrsia and clinical evidence of correlation between the picture. We must, therefore, conclude that the two. An alkaline extract of the anterior pituitary character of the response of the thyroid gland is at gland caused hypertrophy ofthe parathyroid glands least as important a factor as the stimulus. in rabbits and rats. They noted a case reported by The above facts gleaned from acromegaly, as Scriver and Bryan of acromegaly with osteoporosis well as others learned from certain types of and a negative calcium balance, and studied four in own series. found an Cushing's disease, cannot be ignored in any acromegalics their They http://pmj.bmj.com/ attempts to theorize about the problems of toxic increased urinary excretion of calcium and phos- goitre. phorus but no change in faecal or serum values. They excluded hyperthyroidism as a factor, as in Acromegaly and Diabetes Mellitus this disorder the faecal as well as the urinary ex- The occurrence of diabetes mellitus as a com- cretion of calcium and phosphorus is increased. plication of acromegaly has long been known, and They found that the excretion of calcium varied the work of Young (1937) on the pituitary dia- with the phase of activity of the acromegaly and betogenic hormone gives a theoretical basis for the could be reduced by deep radiation of the pituitary on September 26, 2021 by guest. Protected clinical facts. Cushing and Davidoff (I927) gland, but did not regard proof of secondary found 12 cases of diabetes mellitus in a group of hyperfunction of the parathyroids as absolute. o00 acromegalics. It is often stated that the diabetes of acromegaly is relatively mild and in- Acromegaly and the Gonads nocuous, but in a series of autopsies Cushing and In adults there may be an initial increase in Davidoff (1927) found that of 44 acromegalics no libido and potency, but soon impotence follows, less than ii died in diabetic coma. The initial or it may be one of the earliest symptoms. These diabetes may well be entirely pituitary in origin, two phases may also be found in adolescence, and but later there is probably degeneration of the in spite of normal or large genitals there may be islets as in Young's dogs, and a superimposed incomplete secondary sexual characteristics. Fur- pancreatic diabetes. At this later stage treatment ther, with apparently normal sexual development, of the acromegaly would have no influence on the there may be delayed union of the epiphyses so that severity of the diabetes. In the earlier stages, not a rapid spurt in growth may occur at the age of 20 only may successful treatment of the acromegaly or more. In the female, amenorrhoea is common, abolish or improve the diabetes, but the diabetes but anovular menstruation and menorrhagia occur Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from April 1950 SIMPSON: Acromegaly and Gigantism 203 as well as normal menstruation. The thymus and was found to contain an excess of posterior gland is often enlarged. pituitary antidiuretic hormone. Further, this excess disappeared with successful radiotherapy to Racial Acromegaly and Gigantism the pituitary gland and at the same time the Allowing for individual variations and for the water balance returned to normal (Ellinger, Hare absence of clear-cut ethnological divisions, there is and Simpson, I937). It was therefore postulated no doubt that some races are tall, others are short. that hyperactivity of the posterior pituitary gland Evidence for an underlying pituitary mechanism was present and the name diabetes tenuifluus w.ts is forthcoming in the greater incidence of mild given to the disorder (Simpson, I948). The acromegalic features in some of the taller, big- sweating was assumed to be secondary. It is boned European races. difficult to know why the posterior pituitary

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··--I-.-,...,.6.,.,wspp.:. .· ·. r _Illr 8 :· :· ·;·-..a Fig. :.- Racial Acromegaly. A, aged 24 years, just prior to onset of acromegaly; B, aged 33 years, when first seen; C, aged 38 years. Note startling negroid changes in features, especially the nose, lips and forehead, also the pig- mentatio:n and darker frizzier hair. (Reproduced hb, kind permission of Drs. Goldberg and Lisser.) The negro race is on the whole a tall race, and gland should be hyperactive in acromegaly, a demonstrates what might be regarded as acro- disease of the anterior pituitary; and more easy to http://pmj.bmj.com/ megaloid features in the facies, e.g. thick lips and comprehend why diabetes insipidus sometimes broad nose. Without speculating on its more occurs as a complication, the pars nervosa being general significance, Goldberg and Lisser (I942) destroyed by an invading eosinophil adenoma. describe a case of acromegaly in a woman of 33 of Nevertheless, such hyperfunction is possible as in American parents of French-Norwegian extrac- the adrenal, where a neuroblastoma of the medulla tion. There was probably also an undetermined may rarely stimulate the cortex to produce some admixture, not at all in her of virilism, due to negroid apparent early degree presumably secondary on September 26, 2021 by guest. Protected features. After the onset of acromegaly, her hyperfunction of the cortex. appearance became frankly negroid (Fig. I). There is, however, an alternative explanation of these findings, namely that excessive perspiration, Excessive Perspiration in Acromegaly in the same way as dehydration or absence of fluid Cushing and Davidoff (I927) reported ex- intake, stimulates the posterior pituitary to cessive perspiration in no less than 60 per cent. physiological hyperfunction. of acromegalics and its degree appears to vary with the phase of activity of the primary disease. The Course and Treatment of Acromegaly Its cause is uncertain, but it may be associated and its Biochemical Control with the excessive development and hyperfunction The course of acromegaly is variable. Its active of the sweat glands. In one such case the writer phase may give way to an involutionary or ex- was impressed by the fact that there was an haustion phase. Certainly excessive muscular associated positive water balance, more fluid being strength may be evident initially and may be fol- taken than was excreted. This may have been lowed by marked weakness. The author ventures caused by the perspiration but, to test an alterative to suggest that in Biblical times Goliath's victories hypothesis, the cerebrospinal fluid was examined were obtained in the active phase of his disease Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 204 POSTGRADUATE MEDICAL JOURNAL April 1950 and that David was lucky enough to meet him raised in the active phase of the disease. They after weakness had set in. In more modern times note that serum phosphorus is also raised during we have seen a European acromegalic boxer reach childhood growth and falls in post-puberty growth, the heavyweight championship class and retire which observations, coupled with the depression prematurely for physical reasons. The same of serum phosphorus in acromegalics by testos- phenomenon is found in some forms of giantism. terone and/or oestrogens, led them to the hypo- The phase of excessive strength must, in the thesis that there is a pituitary type of growth author's view, be attributed to androgen secretion associated with high serum phosphorus and a by the adrenal cortex, comparable to that in the steroid type (or phase) of growth associated with Herculean type of sexual precocity. If such normal serum phosphorus. Their normal range of abnormal strength persists during the phase of im- serum phosphorus was 3 to 4 mgm. per cent., and potence we are dealing with a paradox in which values in their acromegalics were in the neighbour- perhaps simultaneous hypersecretion of adrenal hood of 5 mg. per cent. or higher (4 mg. per cent. oestrogens plays a part. might be considered the normal limit for most In general, the waxing and waning of acro- laboratories). They confirm Albright's observa- megaly gives no cause for complacency, for pro- tion that the serum phosphatase is not raised in gress of the disease is grievous and ultimately fatal. acromegaly, with the exception of one male acro- Surgical removal of a pituitary adenoma is a megalic giant aged 20, with open epiphyses, who radical measure giving good results in the hands had a persistent elevation of the phosphatase. of experts, although haemorrhage may be trouble- This group of investigators, working in Professor some and even fatal. Increasing optic atrophy Herbert Evans' laboratories in California, were may be considered an indication for surgery. also able to demonstrate an excess of growth hor- Irradiation of the pituitary gland is a comparatively mone in the serum of their acromegalics, and its safe procedure and its effectiveness may well be parallel fluctuation with the serum phosphorus explored initially (Hurxthal, et al., I949). Ellis during treatment. Contrary to many reports, they

(i949) recently reviewed the literature, indicating also found that with an adequate diet, their acro-by copyright. a favourable response in some 50 per cent. of megalics were on positive calcium, phosphorus and cases, and recorded his own encouraging results, nitrogen balance. The suggested dosage for hor- preferring moderate doses of 1,200 to 1,800 r. to mone therapy of acromegalics is given as 25 to the heavier dosages up to 3,000 r. previously em- 50 mg. of testosterone injected daily for the male, ployed. He believes that if irradiation fails, radon and 0.3 mg. of ethinyl oestradiol daily by mouth seeds should be given a trial before surgery, but fo the female. Improvement is claimed. the danger of haemorrhage in the course of im- planting radon seeds into a pituitary eosinophil Gigantism adenoma is by no means negligible (Northfield, Moderate gigantism is not uncommon and is http://pmj.bmj.com/ I949). Claims have been made for the inhibition usually associated with considerable muscular of the pituitary by large doses of oestradiol and strength. This is probably due to the large testosterone, a somewhat tentative medical ap- quantity of androgens secreted by the overactive proach of symptomatic benefit. Schrire and adrenals, with or without multiple adenoma forma- Sharpey-Schafer (I938) point out that pituitary tion, the adrenal activity being secondary to activity may be judged by the quantities of creatine f pituitary hyperfunction. The muscular strength and creatinine in the urine, and the effect of of a gigantic acromegalic boxer has already been testosterone and oestradiol by the resulting mentioned. Gigantism is, however, not necessarily on September 26, 2021 by guest. Protected diminution in these quantities. Schrire (1948) also complicated by acromegaly and the associated uses creatine and creatinine to study the degree of strength may endure throughout life. Recently activity of the hyperpituitarism at any phase. Thus we have seen a team of overseas golfers whose ex- he found that in active giantism and acromegaly, ceptional skill was paralleled by their exceptional creatinine is excreted in large quantities, creatine height, strength and muscular development. Their often in excessive amounts, but both inconsistently. hands were big and enfolded the golf club in an He and Sharpey-Schafer (1938) also drew atten- embracing powerful grip. One physically minia- tion to the fact that pituitary gonadotropic hor- ture British golfer defeated their most massive mone increases creatinine excretion, whilst thyro- representative by greater skill and timing, but tropic hormone promotes creatine excretion. that does not negative the above general im- Kinsell, Michaels, Li and Larsen (I948) use pressions or the obvious advantages, other things the serum inorganic phosphorus as an index of being equal, of hyperfunctioning pituitary and pituitary hyperfunction and effectiveness of treat- adrenal glands within physiological limits. ment after acknowledging the original discovery of As to historical giants, Gibbon in the second Albright that serum inorganic phosphorus is edition (i776) of his classical work gives the Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from April 1950 SIMPSON: Acromegaly and Gigantism 205 following description of a young Thracian peasant almost physiological limits, resulting in virile who was later to become the Emperor and in- attractive personalities. Many a ' he-man ' of the human tyrant Maximin. Having floored in films owes his box office attraction to his pituitary succession i6 of the stoutest camp followers at the gigantic skeletal development, his resolute prog- military games he, on the following day, attracted nathic lower jaw and his deep vibrant voice, the notice of the Emperor Alexander Severus by emanating from an overdeveloped acromegalic easily keeping pace with him on horseback over a larynx. long distance. Asked by the Emperor whether he would wrestle after his race, he was at once Acromegaly in Childhood and Adolescence matched against seven of the strongest soldiers in Atkinson (193I) collected no less than 32 cases the Army simultaneously, and gained the verdict from the literature of which he accepts 25-15 with ease. His stature, according to Gibbon, ex- males and io females. The disease usually com- ceeded 8 ft. He could draw a loaded wagon, break menced at about the age of puberty, e.g. 12 years, a horse's leg with his fist, crumble stones in his but there was one case at six years, that described hand and tear up trees by the roots. His appetite by Walker: a male, aged six years, with both was in keeping with his strength, for he would acromegaly and gigantism; rapid growth after drink an amphora (about 7 gal.) of wine and eat measles, especially of the hands and feet; no 30 to 40 lb. of meat daily. Wrestling, incidently, enlargement of the lower jaw; progressive loss of continues to be a sport which attracts relative sight of right eye from age of eight (suggesting giants with or without acromegalic features. eosinophil adenoma and optic atrophy). Another It might well be argued that tall people are not patient was aged seven, also with acromegaly always strong and some are definitely weaker than complicating gigantism; and another aged eight. the average. This may be clinical evidence for the 1 would like to describe briefly here the in- existence of a pituitary growth hormone un- sidious onset of acromegaly in a male patient associated with a pituitary adrenotrophic hormone. about the time of chronological puberty, with Since some such cases later develop acromegalic some interesting features and paradoxes. The by copyright. features, the author is inclined to recognize such a patient (Fig. 2) was first seen by me having just group. In others, however, who have a late reached the age of 17. His father was 5 ft. i in., puberty and grow to excessive height because their the mother was tall, and all her male folk over 6 ft. epiphyses remain ununited unduly long even into The patient weighed I4 lb. at birth. He was the third decade and whose genitals do not respond always a tall boy and at i6 his height was 73 in. and to gonadotrophic hormone, there appears to be a his weight 152 lb. His breasts enlarged at the primary hypogonadism. In such cases, the small age of 15 and his voice broke at i6, but in a few genitals in adolescence justify the name eunuch- months returned to his boyish high pitch. He oids, but mild cases are too numerous to be re- experienced some erections but no emissions. He http://pmj.bmj.com/ garded as pathological, and their ultimate spon- wvas always very tired and wanted to be with his taneous sexual development may be quite normal. parents all the time. His hands and feet were very Adolescent acromegalics, in whom there is also large (boots size 12), and his features thickened. delayed puberty and delayed union of the His genitals were of adult size. He had plentiful epiphyses permitting an excess of growth hor- pubic hair but limited horizontally as in the female. mone to act on the long bones over an excessive Axillary hair was present with hair on the legs, period of time, form an intermediate but none on the face. The were group. 17-ketosteroids on September 26, 2021 by guest. Protected Where gigantism is due to a pituitary eosinophil normal (13.6 mg. per day). Nevertheless the im- adenoma, optic atrophy is not uncommon. In plantation of 800 mg. testosterone minimized the one girl of 14 seen in out-patients because of un- gynaecomastia, increased the frequency of erec- duly rapid growth (5 ft. 1 in.) and some enlarge- tions and increased the muscular strength. The ment of the hands, papilloedema was a surprising photograph was taken before treatment. X-rays finding. A ventriculogram revealed dilatation of showed the pituitary fossa to be slightly enlarged the third ventricle; and the autopsy, after a cere- and the epiphyses of the long bones to be united. bral operation, showed stenosis of the aqueduct of One would hazard that the adrenals were hyper- Sylvius by an astrocytoma. This patient had red plastic and were secreting oestrogens as well as abdominal lineae distensae and some facial androgens. Clinically this was a case of gigantism plethora, but a normal red cell count. The and acromegaly with delayed incomplete puberty pituitary gland was apparently normal on histo- and gynaecomastia. logical examination, although one must assume From the wealth of clinical material in Cushing's excessive secretion of growth hormone. 1912 monographs on the pituitary body, two cases Gigantism, or giantism, is often associated with are chosen to illustrate interesting aspects. Case mild acromegaly within what might be termed 21 illustrates the genetic factor in gigantism and Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 206 POSTGRADUATE MEDICAL JOURNAL April 1950 acromegaly and evidence at childbirth of things to very big woman (which complicates the story), but come. The patient, a male, came under Cushing's the first child was too large to be born, the second care at the age of 48 with gross acromegaly. His weighed I7 lb. at birth, the third was said to be maternal grandfather was a giant, famous in his enormous and died soon after. The onset of native land of Hungary, but his parents were acromegaly was apparently insidious in adult life. average. At birth he was said to be as large as a Case 32 was seen by Cushing at the age of 36 child of one year of age and extraordinarily fat, measuring 8 ft. 3 in. and with acromegalic features. the fatness preventing him walking until the age of The patient, a male, began to grow rapidly at I5, three. At the age of 12 he was 6 ft. in height and but never developed facial, axillary or body hair of Herculean strength. At the age of 15 severe except a few pubic hairs. The genitalia were in- headaches commenced. There is no note about fantile and the testicles atrophic with no inter- puberty, but sexual function appears to have been stitial cells and few atrophic tubules. The adrenals at least normal. At the age of 27 he married a were diminutive and difficult to locate. (In two other patients, one with persistent excessive hairiness in a male, signs of Addison's disease in- '' ...... cluding pigmentation were present in the hypo- pituitary phase of the disease.) One of the writer's male acromegalics was 7 ft. 6 in. at the age of 21 and 8 ft. 3 in. at the present age of 25. .::::: .:::: Case 30, a male, illustrates that in spite of ...... normal sexual the ::: apparent development epiphyses ::::: ::::::::::::.:· remain since the from 6 ft. ·::::.:,,;:::::::::'i;::." ';;; may open patient grew to 6 ft. 2 in in his twenty-ninth year, when acro-

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.... ·;...... :,: :: ....:iiii!Ui~l; Case i, a male, showed from very rapid growth by copyright. :'i[:.::::::::::::::::::::::::::...... ;:;:.. ..::i':?'?.!.. .'i..... the age of 13 (6 ft. 4 in.). At 19 he developed un- controlled libido sexualis, whilst at 27 he was ...... ::.::::.. :-... .. ::: '·· Iii:ii::"':"~::::[:...... acromegalic and had lost all libido. .:======..... Cushing incidentally describes a girl of 24 who began to grow rapidly in height and to put on fat, also developing sleepiness, polydipsia and polyphagia. Autopsy of the skull showed ' an unusual :::: ::: ::':::::::::::::::::: i: i,·:::i:::i;:::;.: cell sarcoma,' flattening the pituitary fossa. :: ...., .... : :: '::iliii:iiiiiiiil:lilli· Hirsutism http://pmj.bmj.com/ 'ii··iliiiiil!iiii'lil'i~iilii: ":ii' :'i::l::ii:: ...... ::: .ii .. {:,::.:· i:,.:::.ii:::::::::::: .:::::i::::::::: ::: ·:.:':"il!iiii.:::::;I The author has seen at least five cases in which hirsutism followed acromegaly, and a sixth in which hirsutism was associated with mild ...... i:ii:;::i. n g;;%iil::::til· and The mechanism is a :::l:·...iiii·iii i!tii:iiiitL;...... l: gigantism acromegaly...... : cs:in-iiiiiiiliiiiiili'ii ... secondary hyperplasia with multiple adenoma in the adrenal cortex and hypersecretion of androgens. The first was a woman of 32 who developed on September 26, 2021 by guest. Protected acromegaly at the age of 23 and hirsutism at the age of 27, particularly of the face but also on thighs and abdomen (Simpson, 1948) (Fig. 4). She also had a symptomless goitre. The second (Fig. 5) was a woman of 60 under treatment for hypertension (200/I30) and cardiac failure, complicating her acromegaly. This started in early life, a sister stating that the patient always had an enormous appetite and large hands and feet. The hairiness was present from the age of 30 or before. Her I7-ketosteroids were 2 to 3 mg. per day on one occasion, and 4 to 5 mg. per day two weeks later; the thyroid was grossly enlarged. The third Fig. 2.-Acromegaly in a boy of 17, with incomplete patient was a woman of 33 years suffering from puberty and gynaecomastia. delusional insanity. She was admitted to a mental Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from April 1950 SIMPSON: Acromegaly and Gigantism 207 drome in males from the ill-defined collection of fat boys and from Fr6hlich's or pseudo-Fr6hlich's syndrome. Its characteristics were:-puberty was delayed some years, the patient was fat, often from birth, the pubic hair was late in appearing and was limited horizontally as in the female, the facial skin was smooth and of fine texture as in the female, facial hair appeared late and remained scvnty, the trunk was relatively free from hair, the hips were broad in relation to the shoulders, the gait was somewhat waddling, the stance and tem- perament were feminine and the patients were not 'iiiirlr:! ii good at games. The author gave the syndrome the name of adipose gynandrism and suggested that it was of pituitary or hypothalmic pituitary origin, that it differed from Fr6hlich's syndrome in that sexual maturity developed spontaneously although belatedly, and that the patients were fertile and could reproduce themselves. (Gonadotrophins were effective if used to accelerate genital development.) Lineae distensae were present and frequently purple. Their height varied and they might be tall. In the photograph illustrating the syndrome (Fig. 7) the boy of eight has a height of 52 in. compared with an average of 48 in. In the classical Frohlich's the are syndrome patients sub-by copyright. normal in height. This and allied syndromes both in males and females have been studied further. Thus a boy of 10o years with infantile penis and one descended testicle of infantile dimension, measured 58½ in. (average 53 in.) and weighed 141 lb. (average 70 lb.). He was 7 lb. at birth but soon put on weight. He was always taller than children of his own Fig. 3.-Gigantism with mild acromegaly in a male aged His father was 6 ft. and his 25 (author's case). Enlarged pituitary fossa and age. thin, mother http://pmj.bmj.com/ bilateral optic atrophy. Height, 7 ft. 6 in. Boots, average. He was emotional and had tempera- size 17. mental outbursts, suggesting perhaps a hypothalmic lesion. He had a feminine appearance, hospital with acute mania, hallucinations and de- big pelvis, waddling gait and apparent develop- lusions. There was a scar of a previous thyroidec- ment of breasts. He had no lineae distensae when tomy. The I7-ketosteroids were unexpectedly first seen but six months later developed purple low, 1.5 and 3.I mg. per day, and the plasma phos- lineae distensae on the lower abdomen and thighs. phorous 3 mg. She made a spontaneous recovery Unfortunately he was treated with gonadotrophins on September 26, 2021 by guest. Protected from her mental state, but has not been seen since. and descent of the testes with acceleration of sexual The sixth (Fig. 6) was a very unusual case, a maturity resulted. woman of 21, with big bones and on the tall side Another lad of 17, complaining of adiposity and for a woman, 65 in., with some prognathism, who 15 st. 4 lb. in weight, was always some inches developed amenorrhoea and hirsutism at the age of taller than his average contemporaries, but now i6. The I7-ketosteroids were very high (I40 mg.) only 5 ft. 8½ in., showed all epiphyses of the long and a large right adrenal adenocarcinoma was re- bones completely united. He was said to have moved. Menstruation returned but hirsutism per- been a very big baby. His voice broke at I4 and sisted. Ten years later the ketosteroids remained pubic and axillary hair developed, although none high (70 mg.) but laparotomy failed to reveal an was present on the face even at 17. His penis was ovarian or adrenal neoplasm. of normal size and the testicles small, but a large hydrocele was present on the left side. The re- Augmented Growth in Childhood, a New markable feature, about which the patient was Syndrome (Adipose Gynandrism and Gynism) much distressed, was numerous dark red striae on In I948 the author attempted to separate a syn- abdomen, thighs, shoulders, breasts, and back, Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 208 POSTGRADUATE MEDICAL JOURNAL April 1950

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Fig. 4.-Acromegaly with secondary virilism and goitre. (a) The patient aged 20, and (b) aged 32. which appeared at the age of 15, although a few In females there appears to be a parallel syn- red horizontal striae across the back were present drome to which the author's attention was drawn by from the age of seven. The number and wide the presence of red or purple lineae distensae. A distribution of these striae was much greater than point of interest is that these red lineae distensae could be the of and become white in the course of the of

explained by degree adiposity, may period http://pmj.bmj.com/ another more direct factor in their production observation before, during or after puberty. Some appears probable. examples have been:- Another male patient weighed 8- lb. at birth A.L., first seen at the age of eight, height but soon became overweight (Fig. 8). From the 4 ft. 2i in. (average 4 ft.), weight 104 lb. (average age of 3 to the age of o he approximated to 53 lb.), red lineae distensae on abdomen and normal weight, but then again began to put on buttocks, bluish mottling of legs, B.P. I26/90. weight and at I3 weighed 2o st. Seen at the age of One year later the lineae were white and had i6 he weighed 32 st. and was 5 ft. 9j in. in height. largely disappeared. She had lost 12 lb. in weight. on September 26, 2021 by guest. Protected He was said to be always taller by some inches than E.H. (Fig. 9), after measles at seven, gained his average contemporaries. The body was gener- rapidly in height and weight. Monthly nose bleed- ally hairless, but a few soft hairs were present on ing from 9 to 13, when menstruation started. Seen the pubis, axillae and chin. The genitals were of at the age of 12, height 5 ft. 3 in. (average 4 ft. 9 in.), average size. His voice was high pitched, his weight 210 lb. (average 82 lb.), some lower pubic pelvis broad. His blood pressure was 200/120. and axillary hair present; breasts large; B.P. Deep red lineae distensae were present over the II0/70. During the second half of her thirteenth buttocks, abdomen and breasts. The epiphyses of year her height remained at 5 ft. 5 in. and her the long bones were nearly united and the bone epiphyses were united, although they were un- age given radiologically as I8. The carbohydrate united six months previously. At I21 purple tolerance test showed a flat curve 41, 92, 83, 63, lineae distensae appeared on the abdomen. At 96 mg. Blood cholesterol was 195 mg.; 17- I3 these became white, while at the same time red ketosteroids 9.8 mg. per 24 hours; i i-oxysteroids, ones appeared on the breasts. crude, 2.8 mg., fractionated, I.o mg., i.e. slightly B.McC., obese since an attack of scarlet fever above normal. at the age of eight. Seen at the age of o years II Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from April 1950 SIMPSON: Acromegaly and Gigantism 209

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Fig. 5.-Woman aged 60 with Acromegaly starting at by copyright. puberty, and hirsutism at the age of 30. Note large adenomatous goitre. See text. months, height 5 ft. (average 4 ft. 6 in.), weight 128 lb. (average 70 lb.); B.P. I28/74. Red lineae Fig. 6.-Virilism. Woman aged 2I at time of photo- distensae on abdomen and buttocks. No graph. Menstruation was normal from age 14 to pubic i6, when amenorrhoea developed, together with hair. Seen nine months later, 5 ft. 4 in., 122 lb.; hirsutism, deepening of voice, and increase of red lineae distensae pale pink and white. weight. Radiography after uroselectan showed a M.W., following measles at three years of age right adrenal tumour, which was removed (age 21), to become fat. First seen at ten of after which menstruation became regular once http://pmj.bmj.com/ began years more but hirsutism persisted. The I7-ketosteroids age, height 4 ft. 9 in. (average 4 ft. 4 in.), weight were very high (I43 mg. per day) before operation 150 lb. (average 64 lb.); no pubic hair, multiple and, although reduced by more than 50 per cent., red lineae distensae on breasts and hips. One still remain very high, namely 60 mg. per day as later ft. i lb. The red lineae are compared with the normal of 5 to 12 mg. This year 4 in., 155 explains the persistent hirsutism 8 years after now quite white. operation, and the probability of adrenal hyper- The syndrome in girls therefore may be de- plasia. or neoplasm in the remaining gland. A fined as excessive in primary pituitary stimulas was Ten adiposity, height childhood postulated. on September 26, 2021 by guest. Protected but ultimate not excessive because of years later laparotomy did not reveal any neoplasm height early in the pelvis or adrenal areas. The left adrenal union of epiphyses, normal or early menstruation was moderately enlarged. and secondary sexual characteristics, and red or purple lineae distensae which may become white or disappear. The syndrome may commence in a female. Of course, the term adipose after measles or scarlet fever, suggesting a hypo- gynandrism cannot be applied to these girls and thalmic mechanism. In this connection purple for the moment nomenclature is left until further lineae distensae have been noted following observation and thought has been given to their meningitis treated by streptomycin. There seems clinical observation, but there seems little doubt little doubt that this syndrome in girls is not un- that we are approaching a clinical, if not a patho- related to the syndrome in boys, and probably logical basis for classification of adipose children has the same pathology. The delayed puberty or and adolescence. As the feminine characteristics relative infantalism in boys as distinct from girls are normally present or accentuated in the female is paradoxical but so is the feminism of an adrenal types, one might tentatively use the term adipose tumour in an adult male compared with virilism gynism in contrast to adipose gynandrism. Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 210 POSTGRADUATE MEDICAL JOURNAL April I950o s....-?'

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;...... 1h.Se by copyright. http://pmj.bmj.com/ Fig. 7.-Adipose Gynandrism. Author's original case. Boy aged 8 and subsequently aged 15. Delayed but spontaneous sexual maturity with persistence of feminine characteristics. Note wide pelvis and breasts.

The clinical and pathological situation is, how- (average 3 ft. 8 in.) and her weight 6i lb. (average ever, still complex. Thus, for example, are lineae 45 lb.). She was fat in the face, chest, abdomen distensae an essential part of the syndromes, and and breasts, and was somewhat plethoric. She on September 26, 2021 by guest. Protected must they be red or purple ? If so, what is the had long dark hair (more than i I in. in length) diagnosis before they have appeared, after they on forearms, legs and back of neck, but no pubic turn white or disappear ? Is excessive rate of hair. The mother stated that hair was present growth at certain phases sufficient or essential for 'all over the body' from one year of age. No the diagnosis and is an advanced (radiologically lineae distensae were present. The mother is determined) bone age an essential feature ? Fur- tall (5 ft. 6 in.) and plump, and says she was of ther study must answer these questions but, as similar build to the child as a girl, but never had with other endocrine syndromes, there is no sharp (and has not) any hair on the trunk or limbs. All dividing line between the full syndrome and the her men folk are tall but her husband was average. various intermediate and less complete forms. Since red lineae distensae are a feature of The girls or adolescent women in this series did Cushing's syndrome, the question arises whether not suffer from hirsutism at the time of examina- the group of cases described above can be said to tion, but this factor may arise in cases not very represent Cushing's syndrome in childhood. They dissimilar. Thus a girl of six years was seen have not shown diabetic carbohydrate tolerance because of adiposity. Her height was 4 ft. i in. curves or osteoporosis of bones, but plethora, Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from April 1950 SIMPSON: Acromegaly and Gigantism 211

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Fig. 8.-Adipose Gynandrism at the age of 3, 8 and I6 years. Weight 32 stone; scanty pubic and axillary hair; genitals of average size but voice high-pitched; red lineae distensae; wide pelvis and breasts. (See text.) http://pmj.bmj.com/ polycythaemia and (or) hypertension have oc- Cushing's Syndrome in Childhood in Rela- casionally been present. They do not have sub- tion to Growth cutaneous haemorrhages or gross cutis marmorata Of Cushing's twelve original cases of young of the anterior tibial skin region, but as with many adults he observes that the female patients all fat children they may have a bluish red mottling of appear to have been definitely undersized, the the outer upper arm and buttocks, and this may tallest being 5 ft. 3 in. and the shortest 4 ft. 9 in., also be present on the thighs and lower legs, whereas this was not true of the males and two on September 26, 2021 by guest. Protected sometimes with marble pattern appearance. Re- were tall, 6 ft. i 2 in. and 6 ft. o in. However, the cently it has been noted that adrenocorticotropic onset in these was mostly in adolescence. His hormone, or cortisone, produces pink abdominal case 5 was that of Oppenheimer and Fishberg lineae distensae (McNee, I950) and increases (1924), a girl of 12 who at the age of five gained weight when used in patients with rheumatoid 75 lb. in a year; at the age of ii she showed arthritis; and Li (1950) has found experimentally plethora, drowsiness, hair on the face, pubis and that pure adrenocorticotropic hormone results in axillae, no menstruation, diabetes mellitus and fat deposition in tissues and liver, at the expense of hypertension I90/130. She died at 12 and no protein, but is antagonistic to the growth hormone. height or bone radiology is given, but she was A brief comparative review of Cushing's syndrome described as 'an undersized child.' Chute, in childhood may not be irrelevant, since a Robinson and Donohue (1949), review Cushing's probable explanation of the above syndrome is a syndrome in childhood and describe a girl of eight pituitary-adrenal overactivity involving hyper- who was normal until the age of four and then secretion of adrenal oestrogens, I I-oxysteroids and became fat and ceased to grow. She did not other hormones. menstruate but pubic hair appeared at the age of Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 212 POSTGRADUATE MEDICAL JOURNAL April 1950

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Fig. 9a.-Adipose Gynism. Girl aged 13, illustrating adipose gynism (see text). Note height above normal; large areola of nipple; plethoric face, and (not well shown) purple lineae distensae. by copyright. Fig. 9b.-Same case. X-ray of knee-joint, aged 13 years. Fig. gc.-Same case. Aged 14 years, showing epiphyses almost closed. http://pmj.bmj.com/ on September 26, 2021 by guest. Protected

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b. (1. Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from April 1950 SIMPSON: Acromegaly and Gigantism AI3 seven. Purple striae were present on abdomen Cushing's syndrome in childhood can only be and thigh, and the face was congested. B.P. settled by further study. 148/o00. At the age of eight her height was With presenting sexual precocity in boys and 3 ft. 8 in. (average 4 ft.) and weight 65 lb. (average girls, whatever the cause, e.g. third ventricle or 53 lb.). Her ketosteroids were raised for a child hypothalamic tumours, adrenal tumour, interstitial k6.2 mg.), osteoporosis was present and there was a cell tumour of the testis, granulosa cell tumours or delayed fall in the carbohydrate tolerance curve. hyperplasia of the ovaries, there is nearly always The adrenals were enlarged and contained nodular an increased growth rate, an advanced bone age adenomata. Removal of one proved fatal. The and premature union of the epiphyses so that the pituitary showed Crooke's changes in the basophil abnormally tall child becomes an adult dwarf if cells. There was no note as to bone age or the lesion is of a character which permits adult life premature closure of epiphyses. to be reached. Biologically it would appear that Walters, Wilder and Kepler (1934) describe a excessive or premature secretion of androgens or girl of nine who was normal until the age of four, oestrogens, whether their source be the gonads or when her mother noticed development of the adrenals or both, is responsible for the above breasts, general growth of hair all over her body growth and bone changes. Our therapeutic ex- and face and deepening of the voice. A year later perience in dwarfism and infantilism suggests that she developed pubic hair and enlarged external androgens are much more potent than oestrogens genitals and clitoris. At eight she menstruated in stimulating growth, but that the oestrogens may once. Her facial appearance was adult, her be more important than the androgens in deter- height 4 ft. 5 in. (average 4 ft. 2 in.), and weight mining epiphyseal closure. Both boys and girls 103 lb. (average 58 lb.); obesity, purple striae on may have a spurt of growth at the time of puberty, the abdomen, thighs and buttocks; B.P. 132/97. but in a proportion of girls growth ceases within a A large left adrenal adenocarcinoma was success- year or so of the first menstruation owing to fully removed with relief of symptoms. The closure of the epiphyses whereas in males this authors considered the height within normal limits, rarely occurs before the age of 17. by copyright. but it is above average and the usually given nor- Figs. 4 and 7 are reproduced from Dr. Leonard mals include tall girls with endocrine tendencies. Simpson's book, 'Major Endocrine Disorders,' The bone age radiologically was I2. by kind permission of the Oxford University Crooke and Callow (1939) describe a girl of Press. six with an adrenal tumour and Cushing's syndrome in which the height was average (3 ft. 8 in.), and another of I2 without adrenal tumour whose ADDENDUM height was subnormal (4 ft., average 4 ft. 9 in.). Since this article I have received a

writing http://pmj.bmj.com/ It would 'therefore seem that Cushing's syn- personal communication from Dr. R. G. Sprague drome in girls is associated with average or sub- which supplements my reference in the above normal height, only occasionally with height above article to McNee's American impressions. average, and with normal or advanced bone age. Sprague's letter refers to experience at the Mayo In males, Cushing's syndrome in childhood is Clinic to the effect that cortisone can produce, or rare, but is associated with an increased rate of in some cases intensify, red or purple lineae dis- growth. Forbes, Gustina and Postoloff (I943) tensae, and that the effect varies with the intensity describe 27 cases under i6 in the literature, 17 of treatment and the cessation of same. It appears on September 26, 2021 by guest. Protected girls and Io boys. Of these boys, one aged 15 to me that these observations are of considerable with the full syndrome, was 5 ft. 8 in. in height importance, far beyond the sphere of endocrine (average 5 ft. 4 in.), and was sexually mature with therapy in which they have been recorded. They testes showing spermatogenesis. They consider would indicate that in any patient in which that premature sexual maturity occurs in boys and coloured lineae distensae appeared, or were girls with Cushing's syndrome. However, Joseph- present, it can be concluded with a reasonable son (I936) describes a case in a boy of 17 which measure of confidence that the adrenal glands are commenced probably at the age of io when he secreting an excess of cortisone, and that their became very fat, in which the genitals were in- hyperfunction is therefore playing an important fantile and the general appearance unvirile. part in the pathology of the condition observed. Puberty had not occurred and an adrenal tumour It is my view that this will permit the diagnosis of was present. hypercorticalism, primary or secondary to hyper- These cases show some of the phenomena which pituitarism, in a number of conditions as well as have to be explained. Whether adipose gynandrism the classical syndrome to which the name of and gynism are really minor manifestations of Cushing's syndrome has been applied. Postgrad Med J: first published as 10.1136/pgmj.26.294.201 on 1 April 1950. Downloaded from 214 POSTGRADUATE MEDICAL JOURNAL April 1950 BIBLIOGRAPHY ALBRIGHT, F., SMITH, P. H., and FRASER, R. (1942), J. Clin. GO]LDB)ERG, M. B., and LISSER, H. (1942), J. Ciin. Endo- Endocrinology, 2, 37. crinology, 2, 477. ATKINSON, F. R. B. (193I), Brit. J. of Children's Diseases, 28, HURXTHAL, L. M., HARE H. F. E., HORRASE, G., and 121. POPPEN J. L. (1949) .. Clin. Endocrinology, 9, 126. BAUER, W., and AUB, J. C. (1941), . Clin. Invest., 20, 295. JOSEPHSON, B. Acta. Med. Scand., go, 38s. CHUTE, A. L., ROBINSON, G. C., and DONOHUE, W. L. KINSELL, L. W.,(1936),MICHAELS, G. D., LI, C. H., and LARSEN (I949), . Paediatrics, 34, I. W. E. (1948), J. Clin. Endocrinology, 8, 1013. COGGESHALL, C., and ROOT, H. F. (1940), Endocrinology, LI, C. H. (I950), Lancet, , 213. 26, I. MAINZER, F., and YALAUSIS, E. (I937), Folia Clin. Orient., CROOKE, A. C., and CALLOW, R. K. (I939), Quart.7. Med., I, 37. 8, 233. McNEE J. W. (95o), Brit. Med. J., I, 113. CUSHING, H. (1912), 'The Pituitary Body and its Disorders,' NORTHFIELD,D . W. C. (949), Proc. Roy. Soc. Med., 42. 84 J. B. Lippincott & Co. Philadelphia. OPPENHEIMER, B. S., and FISHBERG, A. M. (I924), Arch. CUSHING, H., and DAVIDOFF, L. M. (1927), 'Rockefeller Int. Med., 34, 631. Institute for Medical Research Monographs,' New York. SCHRIRE, J., and SHARPEY-SCHAFER, E. P. (1938), Clinical DAVIDOFF, L. M. (1926), Endocrinology, 10, 461. Science, 3, 413. DAVIS, A. C. (1940), 'Transactions of Amer. Assoc. for Study SCHRIRE, J. (1948), J. Endocrinology (Gt. Britain), 5, 274. of Goitre. SIMPSON, S. L. (1948), 'Major Endocrine Disorders,' Oxford ELLINGER, P., HARE, D. C., and SIMPSON, S. L. (I937), University Press, London. Quart. Y. Med., 6, 241. TURNER, H. H. (1938), Endocrinology, 23 566. ELLIS F. (949), Proc. Roy. Soc. Med., 42, 853. WALTERS, W., WILDER, M., and KEPLER, E. J. (1934), FORBES, J. E., GUSTINA, F. G., and POSTOLOFF, A. V. Annals of Surgery Oct. p. 670. (I943), Amer. J. Dis. Child., 45, 593. YOUNG, F. G. (1937), Lancet, 2, 372.

DIABETES INSIPIDUS By A. A. G. LEWIS, B.Sc., M.D., M.R.C.P. Saltwell Research Fellow, the Royal College of Physicians

From the Medical Professorial Unit, The Middlesex Hospital by copyright.

Thomas Willis, in I682, distinguished between when and where their illness began and may say saccharine and non-saccharine diabetes. Frank (in that the thirst occurred after some particular 1794) defined diabetes insipidus as a long-continued, food had been eaten. Sometimes a shock or an abnormally-increased secretion of non-saccharine accident may be blamed. urine, not caused by renal disease. It is now In severe cases the thirst is extreme, the patient known to be due to a failure of water reabsorption developing a dry mouth if he abstains from fluid by the renal tubules as the result of an ineffective for more than an hour or so. Very often the http://pmj.bmj.com/ level of circulating anti-diuretic hormone (ADH). thirst seems to be abnormal in quality as well. It Cases where the renal tubules can be shown to be may be described in dramatic terms, the patient insensitive to the action of the hormone occur emphasizing the 'burning sensation' in the extremely rarely (Williams, I946). mouth and throat. Sipping water is only a tem- porary palliative however; the patient often feels Clinical Picture compelled to drink a large quantity of water- Diabetes insipidus may occur at any age, but is he feels he must' drain the glass to the dregs' or more common in the young. In Jones' series of 'get it right down inside.' Water is often pre- on September 26, 2021 by guest. Protected 42 cases (I944), 17 occurred in the first ten years of ferred to all other fluids and some patients be- life. Males are more often affected than come connoisseurs of water, preferring that from females. one source to that from another in flavour. Many The onset is usually insidious, the patient find iced water more satisfying. noticing a tendency to thirst and dryness of the Deprived of water, the sufferer may go to any mouth, with polyuria and nocturia. There may lengths to get fluid, drinking from flower vases, be some loss of appetite, and the dryness of the puddles or fountains, or filling his mouth with mouth may make mastication difficult and food snow, or even drinking his own urine. It is not less appetizing. Loss of weight may occur, though surprising that some of these patients, constantly some cases gain. Loss of appetite and exhaustion tortured by thirst, unable to follow any normal from loss of sleep may lead to emaciation in severe occupation on account of the polyuria and pre- cases. Occasionally the appetite is increased. vented from sleeping for more than an hour or so In a few cases the onset is sudden and dramatic at a time, should develop neurotic symptoms. with intense, unquenchable thlrst and polyuria. Headaches, apathy, weakness, inability to con- These patients may remember for years exactly centrate, irritability and insomnia may be com-