THE ELECTROCARDIOGRAM IN MALES WITH EXTRA Y CHROMOSOMES

1106 In assessing the effect of a gluten-free diet upon the rash it is important to distinguish a decreased requirement of dapsone as a result of improved absorption from a direct effect of the diet upon the skin. Complete control of the rash without dapsone would exclude the first possibility and could therefore be accepted as evidence of such a direct effect. Our evidence is that a gluten-free diet is without effect on the dermatosis; moreover, we have found no decrease in the dose of dapsone required to control the rash. Fluctuations in dosage of the order described in the three patients reported by Fry et al.

(1968)

spontaneously. Because severe enteropathy is common in patients with dermatitis herpetiformis it is now essential to carry out full small-intestinal investigations in all patients with this skin disease. Our findings indicate that reliance on history is inadequate. As in other patients with the coeliac syndrome the severity of the enteropathy must govern the intensity of the therapy, and in addition to replacement of vitamins and minerals a gluten-free diet should be given for a trial period. Dapsone should be given at the same time to control the rash. may

occur

We thank the consultants of the Newcastle upon Tyne hospitals and the North East Region who referred patients to us, Mrs. S. K. Piggott, Mr. J. R. MacLennan, and Mr. J. A. Stewart for valuable technical assistance, Prof. A. L. Latner in whose department the biochemical estimations were carried out, and Dr. C. L. Warrick for his help with the radiological investigations. The Medical Research Council provided a grant. Requests for reprints should be addressed to S. S. REFERENCES B. (1966) Gut, 7, 569. Fraser, N. G., Murray, D., Alexander, J. O’D. (1967) Br. J. Derm. 79, 509. Fry, L., Kier, P., McMinn, R. M. H., Cowan, J. D., Hoffbrand, A. V. (1967) Lancet, ii, 729. McMinn, R. M. H., Cowan, J., Hoffbrand, A. V. (1968) ibid. i, 557. Laws, J. W., Spencer, J., Neale, G. (1967) Br. J. Radiol. 40, 594. Marks, J., Shuster, S., Watson, A. J. (1966) Lancet, ii, 1280. Marks, R., Whittle, M. W., Beard, R. J., Robertson, W. B., Gold, S. G. (1968) Br. med. J. i, 582. McMichael, H. B., Webb, J., Dawson, A. M. (1965) Lancet, i, 717 Pink, I. J., Creamer, B. (1967) ibid. i, 300. Roe, J. H., Rice, E. W. (1948) J. biol. Chem. 173, 507. Rubin, L. E., Brandborg, L. L., Flick, A. L., MacDonald, W. C., Parkins. R. A., Parmentier, C. M., Phelph, P., Stribhibhadh, S., Trier, J. S. (1962) Ciba Fdn Study Grp no. 14. Schilling, R. F. (1953) J. Lab. clin. Med. 42, 860. Shuster, S. (1967a) in Proceedings of the 3rd Symposium on Advanced Medicine. London. — (1967b) Lancet, i, 907. Marks, J. (1965) ibid. i, 1367. — Watson, A. J., Marks, J. (1967) Br. med. J. iii, 458. Stewart, J. S., Pollock, D. J., Hoffbrand, A. V., Mollin, D. L., Booth, C. C. (1967) Q. Jl Med. 36, 425. van de Kamer, J. H., Huinink, H. ten Bokkel, Weyers, H. A. (1949) J. biol. Chem. 177, 347. van Tongeren, J. H. M., van der Staak, W. J. B. M., Schillings, P. H. M. (1967) Lancet, i, 218.

Creamer,

—

—

Addendum

Patient no. 1 has died in another hospital, where she had been admitted for acute abdominal pain. At operation the distal jejunum was found to be grossly thickened and there were two small perforations on its antimesenteric border. No biopsy specimen was taken at operation and unfortunately the jejunal-biopsy specimen which had been taken one year previously was from the upper jejunum. There was no post-mortem examination but it seems likely that the perforations were a result of the long-standing

enteropathy.

THE ELECTROCARDIOGRAM IN MALES WITH EXTRA Y CHROMOSOMES W. H. PRICE M.B., B.Sc. Wales, M.R.C.P.E. OF THE MEDICAL RESEARCH

COUNCIL,

CLINICAL AND POPULATION CYTOGENETICS RESEARCH WESTERN GENERAL

UNIT,

HOSPITAL, EDINBURGH 4

The electrocardiogram (E.C.G.) has been examined in twenty males with the 47, XYY chromosome complement and in suitably matched controls. Males with the 47,XYY chromosome complement were found to have prolonged P-R intervals, an increased incidence of secondary R waves in lead V1, and notching with reduction in the size of the s wave in V1. These findings are discussed and it is suggested that cardiac conduction, and atrioventricular conduction in particular, is influenced by the possession of a Y chromosome, the P-R interval in the E.C.G. being longer in males with one Y chromosome than in females and even longer in males with two Y chromosomes.

Sum ary

Introduction

DURING the clinical examination of males with sexchromosome abnormalities identified in chromosome surveys of mental subnormality hospitals (Court Brown, Price, and Jacobs 1968) one male with the chromosome complement 47,XYY was found to have congenital cyanotic heart-disease. At cardiac catheterisation he was shown to have an atrial septal defect, pulmonary stenosis, and a bidirectional shunt at atrial level. This patient also had a first-degree heart block with a P-R interval of 0-36 second. This electrocardiographic (E.C.G.) finding is consistent with the congenital abnormality of atrial septal defect (10% of such cases may have prolonged P-R intervals) but intervals of more than 0-24 second are rare in this defect (Wood 1962). The finding therefore prompted the examination of the E.c.G.s in other patients with the 47,XYY karyotype and because these men are on average unusually tall and mentally backward, the E.c.G.s of tall men from mentalsubnormality hospitals with known 46,XY karyotype were studied for comparison. The E.c.G.s of chromatinpositive males with extra X chromosomes but only one Y chromosome were also examined for comparison. Patients and Methods A clinical examination and a conventional 12-lead E.C.G. (leads i, II, III, aVR, aVL, aVF, V,-,,) was carried out on each male. XYY Males There were twenty men in this group. Eighteen had a 47,XYY karyotype and the other two were mosaics, 46,XY/ 47,XYY and 45,X/47,XYY. Eighteen were identified in mental hospitals or mental-subnormality hospitals where they were detained mainly on account of their behaviour disorders, one was identified in an epileptic colony, and the other, a 46,XY/ 47,XYY mosaic in a survey of males being examined for radiation damage following the intra-arterial administration of thorium dioxide (’ Thorotrast’) for cerebral angiography. Sixteen of the twenty patients were 6 ft. (180 cm.) or more in height and the mean (±s.D.) age of the whole group was 37-2

(± 12-9)

years.

Control Males with a Normal Chromosome Karyotype The control group consisted of twenty-eight tall mentally subnormal males who were found to have normal chromosomes during surveys of males 6 ft. or over in height at three mental-

subnormality hospitals.

These

were

hospitals

at

which thirteen

1107 P-R INTERVALS IN MALES WITH SEX-CHROMOSOME ABNORMALITIES, MATCHED CONTROLS AND HEALTHY MALES AND FEMALES (SIMONSON

1961)

development. All the chromatin-positive males had clinical features of hypogonadism. E.C.G.

Abnormalities which were observed in XYY males prolongation of the r-R interval, the presence of secondary R waves in V u and reduction in the size and notching of the s wave in Vi.

were

P-R Interval

intervals were measured in standard extremity leads P-R interval seemed to be prolonged the measurements were checked by subtracting the longest QRS interval in standard leads from the longest PS interval in these leads. In the group of XYY males as a whole the mean interval was 0-184 (±0-035) second (table). In six of these men (30%) the P-R interval exceeded the generally accepted upper limit of normal (fig. 1). By contrast in the control group the mean value for the P-R interval was 0-155 (:0’021) second and in none of P-R

and when the of the XYY males were identified. Their mean age was 32-4 (:9-7) years. Chromatin-positive Males Of the fourteen chromatin-positive males whose E.C.G.S were studied one had a 48,XXXY chromosome complement, eleven had 47,XXY complement, and two were 46,XY/47,XXY mosaics. Thirteen of the fourteen were identified at mentalsubnormality hospitals and one at an endocrine clinic. The mean age of this group was 53-1 (±17’5) years. Results

Clinical Examination On examination of the cardiovascular system one patient (22/68), a man with a 47,XYY karyotype, had a short early diastolic murmur, at the left sternal edge. Pulse, blood-pressure, cardiac impulse, and heart sounds were normal; the E.C.G. showed a secondary R wave in VI but there was no evidence of right or left ventricular hypertrophy. The cardiac outline was normal on chest X-ray. The cause of the murmur has not yet been determined. All the other patients examined had no clinical abnormality of the cardiovascular system and the 47,XYY and their controls had no serious abnormality of physical

Fig. 2-Lead V. in four males with 47,XYY karyotype who had secondary R waves.

these men was the interval greater than 0.2 second. The difference in the mean P-R intervals of the XYY males and their controls is highly significant (p < 0,001). In chromatin-positive males the mean P-R interval was 0.169 (±0-013) second. Because of the known increase in length of the P-R interval in males over the age of 50 years (Simonson 1961) and the greater age of the chromatin-positive males, the P-R interval in this group could not be compared with that of the XYY males and their controls. No patient had a P-R interval greater than 0-2 second.

Secondary R Waves in Fi Four males with a 47,XYY karyotype including the patient with an early diastolic murmur, had secondary R waves in VI (fig. 2). One of these men had a P-R interval of 0-22 second but the other three had no other evidence of delayed conduction. None of the control 46,XY males had a secondary R wave in Viand the incidence of this finding amongst 47,XYY males is significant at the 5 % level. Among the chromatin positive men, one had a secondary R wave in Vl. Reduced Size and

Fig.

1-A standard lead and lead Vx from the E.C.G. of each of six males with 47.XYY in whom the P-R interval exceeded 0’2 second.

karyotype The

case

numbers

are

the

patients’

numbers in the

registry of abnormal karyotypes.

Notching of S in V1 and reduction in the size of Notching the deflection were frequently observed in V in patients with XYY sex-chromosome complement. Thus in the sixteen men with RS complexes in Vi, seven had notching of the s wave. Notching was, however, also noted in seven of the twenty-eight XY males. In both the 47,XYY and 46,XY groups notching was accompanied by reduction in the size of the s deflection, but in the group

1108

of XYY males as a whole the size of the s wave in V was significantly less than in the XY group. Thus in only three of the twenty XYY males was the s deflection greater than 1 mV whereas it exceeded 1 mV in seventeen of the twenty-eight XY males. The mean size of the s deflection in twenty XYY males was 0-77 (±0-36) mV which is significantly less than the mean value of 1-27 (±0-45) mV in the control group (p < 0,001). In chromatin-positive males notching of s in V was not observed but the size of the s wave was reduced, the mean value being 0-77 (±0-27) mV which is significantly less (p < 0’001) than in the control group of 46,XY males. Discussion

No clinical evidence of a cardiac abnormality was obtained which could account for the E.c.. findings in the 47,XYY males. Unlike the patient who prompted this investigation none had evidence of an atrial septal defect with which secondary R waves in V and slight prolongation of the P-R interval are associated. Secondary R waves in V are not uncommon in persons with healthy hearts and were found in nine out of a hundred male subjects examined by Said and Bryant (1956) and in 5-5% of six hundred and forty-nine men examined by Simonson (1961). The incidence of 20% in the 47,XYY males studied was significantly higher than in the control group and would also seem to be higher than the " normal " incidence. It is of particular interest that Simonson (1961) found the incidence in three hundred and eleven women to be less (2-3%) than in men. Small and notched s waves in V are common variants of the normal E.C.G. but in this series of XYY males they The size of the s wave seem to be unusually common. was significantly reduced in the 47,XYY males and also in the chromatin positive males. The only difference between the V ventricular complex in these two chromosome groups was the higher incidence, in the 47,XYY males, of secondary R waves and notching of the s both of which appear to contribute to a reduction in the size of In his study of healthy men and women Simonson s. (1961) found the amplitude of s in V1 to be lower in women than in men but the significance of the difference is not given. The most striking finding in the series was the slight but undoubtedly significant prolongation of the P-R interval in XYY men when compared with men in the same age range and who were matched for height and intelligence. The mean of 0-184 (±0-35) second is also longer than the value of 0-163 (±0-018) found by Simonson (1961) among healthy males in the same age range. Furthermore the findings of 30% (6 of the 20) of XYY males to have P-R intervals greater than 0-2 second differs from the findings by Hiss and Lamb (1962) in 122,043 U.S. male Air Force personnel ranging in age from 16 to over 50 among whom only 0-65% showed a P-R interval greater than 0-2 second. The possibility that the prolonged P-R interval was associated with the increased height and mental subnormality of males with a 47,XYY karyotype was considered. For this reason the 46,XY males selected as controls were comparable in age, stature, and intelligence and it is clearly significant that not one of the controls had a P-R interval greater than 0-2 second, and that in only one of the twenty-eight was it equal to 0-2 second. The P-R interval in the chromatin-positive men was not significantly longer than in the 46,XY controls, but

in three hundred and eleven women studied by Simonson (1961) the mean P-R interval was 0-156 (±0-021) second which was significantly shorter than in the six hundred and forty-nine men. These findings suggest that the length of the P-R interval may be directly related to the number of Y chromosomes and that its increased length in XYY males represents a dosage effect of two Y chromosomes.

The possibility that cardiac conduction in man is influenced by the Y chromosome will be further investigated and a detailed analysis of the E.c.G. in subjects with various sex-chromosome complements will be reported elsewhere. I thank Dr. A. H. Kitchin for the results of the cardiac catheterisame to study the E.c.G.s of their patients, and Prof. W. M. Court Brown and Dr. P. A. Jacobs for their help and encouragement and Mr. P. G. Smith for the

tion and all those physicians who allowed statistical

analysis.

REFERENCES Court Brown, W. M., Price, W. H., Jacobs, P. A. (1968) Br. med. J. i, 325. Hiss, R. G., Lamb., L. E. (1962) Circulation, 25, 947. Said, S. I., Bryant, J. M. (1956) ibid. 14, 993. Simonson, E. (1961) Differentiation Between Normal and Abnormal in Electrocardiography. St. Louis, Missouri. Wood, P. (1962) Diseases of the Heart and Circulation. London.

RELATIVE VALUE OF CENTRAL-VENOUSPRESSURE MONITORING AND BLOOD-VOLUME MEASUREMENT IN THE MANAGEMENT OF SHOCK W. G. PROUT Lond., F.R.C.S.

M.B.

FORMERLY SURGICAL REGISTRAR, ST. PETER’S HOSPITAL, CHERTSEY*

The blood-volume

Summary central

venous

was

measured and the

pressure monitored in

sixteen patients in a state of shock, with a view to assessing the relative merits of these two methods. Bloodvolume measurements indicated that after circulatory upset the volume of blood required to maintain a satisfactory circulation often exceeded the predicted " normal " volume. Monitoring of central venous pressure did not always reveal alterations in bloodvolume, but provided a useful means of assessing the circulatory needs, and the safety of rapid intravenous infusion. Introduction

MANY of the larger centres have teams which deal exclusively with shock; but in the smaller hospitals this approach is impracticable. Recently the measurement of central venous pressure (c.v.p.) and of blood-volume (B.v.) has been simplified, and this study was performed in an attempt to assess the relative merits of these two methods in a peripheral hospital where prolonged or detailed measurements could not routinely be performed. Material and Methods

patients were observed; all were hypotensive. They included in the series after failing to respond to appropriate intravenous therapy, or if they were judged clinically to be "poor risk" patients in whom infusion might prove particularly hazardous. c.v.p. was measured from the midthoracic point, using a disposable venous manometer (Baxter). A large-bore 16

were

•

Present address: St.

Mary’s Hospital, Portsmouth.