CRANIAL SYNOSTOSIS IN JOB’S SYNDROME et al.’ described two girls with recur"cold" staphylococcal abscesses, chronic purulent sinusitis and otitis media, eczematoid skin lesions, and chronic pulmonary disease. No defect in neutrophil phagocytic or bactericidal function was indentified, thus distinguishing these patients from children with chronic granulomatous disease. This entity was named "Job’s syndrome". Pabst et al.2 noted extreme hyperimmunoglobulinaemia E in a girl with Job’s syndrome as well as defective in-vivo neutrophil chemotaxis. These findings were extended by Buckley et al. when they described two adolescent boys with the clinical aspects of Job’s syndrome as well as coarse facies, eosinophilia, and very high serum-IgE concentrations. These boys also had depressed invivo cellular immunity and antibody formation. Later reports4-6 suggested that a defect in neutrophil chemotaxis might br related to the undue susceptibility to bacterial infection. Since these initial reports, other children have been described with recurrent infections, most often due to Staphylococcus aureus but also occasionally with Candida albicans, hyperimmunoglobulinsemia E, and defective neutrophil chemotaxis .1,8

SIR,-In 1966, Davis

SIR,-A "thalidomide" child with agenesis of the appendix,


We report three boys who have recurrent infections and serum-IgE levels who also have a striking physical


finding not previously reported-namely, cranial synostosis. This abnormality was clinically obvious in a child seen in New York City in January, 1977. This boy had had corrective cranial surgery when he was 4 years old and had been extensively investigated in Sao Paulo in 1975. A child with a similar cranial defect who also had surgical correction at age 4 years has been followed up at Emory University in Atlanta since 1964. A third boy was seen in New York in March, 1977. His cranial defect had not been noted before; it was concealed by his thick, long hair. A prominent sagittal suture was easily palpated, and premature fusion was confirmed on X-ray. We will describe these three cases in detail later, but we believe that cranial abnormalities should be looked for in other children with Job’s syndrome. These abnormalities may provide a clue to the basic mechanism underlying the recurrent infections and the most consistent immunological aberration, the impaited regulation of immunoglobulin E. Skeletal abnormalities have been associated with other immune-deficiency diseases (e.g., short-limbed dwarfism, cartilage-hair hypoplasia, and adenosine-deaminase deficiency). This seems unlikely to be due to chance. Patieni investigation CA19267.

supported Dy U.S.

Memorial Sloan-Kettering Cancer Centre, New York, N.Y. 10021, U.S.A.

Public Health Service grant


Escola Paulista de Medicina, São Paulo, Brasil


Center for Disease Control, Atlanta



Emory University Medical School, Atlanta



Davis, S. D., Schaller, J., Wedgwood, R. J. Lancet, 1966, i, 1013. Pabst, H. F., Holmes, B., Quie, P. G., Gewurz, H., Rodey, G., Good, R. A. Soc. pediat. Res. 1971, 5, 380. 3. Buckley, R. H., Wray, B. B., Belmaker, E. Z. Pediatrics, 1972, 49, 59. 4. Clark, R. A., Root, R. K., Kimball, H. R., Kirkpatrick, C. H. Ann. intern. Med. 1973, 78, 515. 5. Hill, H. R., Quie, P. G. Lancet, 1974, i, 183. 6. Hill, H. R., Quie, P. G., Pabst, H. F., Ochs, H. D., Clark, R. A., Klebanoff, S. J., Wedgwood, R. J. ibid. 1974, ii, 617. 7. Buckley, R. H., Fiscus, S. A. J. clin. Invest. 1975, 55, 157. 8. Snyderman, R., Buckley, R. H. Clin. Res. 1975, 23, 25A. 1. 2.

due to maternal ingestion of the drug, has lately been described.’ We have come across the case-record of another child who, at operation, had agenesis of the appendix while also having physical defects which could be related to thalidomide ingestion by her mother. A 6-year-old female (born February, 1962) was admitted with central abdominal pain of 24 h duration which later shifted to the right iliac fossa. At operation no appendix could be found despite a careful search of the ileocmcal region, and enlarged mesenteric lymph-nodes were noted. The caecum was normal so the appendicular agenesis was Collins’ type in (the commonest).2 She made an uneventful recovery. On scrutiny of her medical records recently we noted that she had been treated for severe anorectal stenosis by operation and repeated dilation before she was 2 and that she had small pits in both ears with some deformity. Since her mother had taken ’Distaval’ while pregnant the child’s physical anomalies are most likely to be thalidomide-induced and can be graded C2D3 with disability group 9/10.3 Surgeons seeing patients with thalidomide-related anomalies should bear in mind the possibility of agenesis of the appendix when dealing with the acute abdomen.




Cottage Hospital, Kelso, Roxburghshire


SIR,-The mother of 7-year-old identical twin girls, one of whom has reduction deformities of both forearms and hands, the other being anatomically normal, states that the deformed child sweats excessively. The excessive sweating is particularly prominent about the head and neck. Sweat-measurement tests with starch and iodine powder confirm that the child with reduction deformities does sweat more than her sister. Questioning a group of parents of other children with reduction deformities confirms this mother’s observation. The parents also state that the deformed limb appears to be hypersensitive to pressure, and I have confirmed this. The increase in sweating seems out of proportion to the reduction of total body-surface area caused by the deformities. It would be interesting to know if synhidrosis occurs in all children with reduction deformities. If synhidrosis is confirmed as a feature of children with congenital reduction deformities it will be likely that they also have dysautonomia. Foundation 41, Women’s Hospital, Sydney, New South Wales 2010, Australia



SIR,-Dr Fletcher (March 18, p. 600) suggests that ultrasonic scanning of all pregnant women is desirable to reduce the number of X-rays necessary in pregnancy but that this is not possible on economic grounds. I agree that all pregnant women should be ultrasonically scanned, not only on the grounds stated but also because such a policy will give early information on placental site, dates, and possible intrauterine growth retardation. Real-time scanning also provides a quick method of screening for neural-tube defects, though the accuracy of this method of screening has not been determined. If the 1. 2. 3.

Shand, J. E. G., Bremner, D. N. Br. J. Surg. 1977, 64, 203. Collins, D. C. Am. J. Surg. 1951, 82, 689. Smithells, R. W. Br. med. J. 1973, i, 269.


x-fetoprotein level is used for be dated accurately, and


such an



the pregnancy be

scan seems to

the best method for this. Fletcher puts the costs at £ 10 000 per year for 3000 patients; this is only 3-33 per patient, a very small sum compared with the total average cost of a pregnancy to the N.H.S. The establishment of accurate dates and the early detection or exclusion of placenta prsevia might reduce the average number of days spent in hospital during a pregnancy, and this saving may more than offset the cost of the ultrasonic service. If even a proportion of cases of spina bifida are detected before 22 weeks, and the pregnancies terminated as a result, the saving to the N.H.S. will be considerable. These points should be impressed upon administrators. Department of Radiology, East

Glamorgan General Hospital



SiR,—j-adrenergic stimulation increases parathyroid hor(P.T.H.) secretion by activating adenyl cyclase. Adrenaline (epinephrine) and isoproterenol stimulation of P.T.H. secretion from isolated parathyroid cells can be blocked by propranolol.’ This &bgr;-adrenergic effect appears to be independent of calcium since &bgr;-blockade does not alter the tissue response to calcium and high calcium concentrations do not suppress the response to &bgr;-stimulation.2 Systemic isoproterenol mone

and adrenaline in the rat also increase P.T.H. secretion, which can be blocked by propranolol. In man, intradermal adrenaline or isoproterenol raise serum-p.T.H. whereas intravenous propranolol decreases the circulating basal level of P.T.H.4 These effects appear to be independent of changes in serumcalcium since the therapeutic doses of adrenaline and isoproterenol used in asthma raise serum-p.T.H. without affecting serum-calcium.5 Our study of a single patient with hyperparathyroidism suggests that the &bgr;-adrenergic influences in normal individuals continue to operate in states of overproduction of P.T.H. The patient, a 49-year-old male, had angina pectoris and hyperparathyroidism. On first examination, serum-calcium was 11.8 mg/dl (normal 8-5-10-5), serum-phosphorus was normal (3.0 mg/dl) and total protein, serum-albumin, plasma-creatinine, and plasma-alkaline-phosphatase were normal. In repeated tests on 5 different days, his serum-calcium was 10.8-12.4 mg/dl. P.T.H. levels, measured by a carboxy terminal assay at the Nichols Institute, were 317 and 375 jjdeq/ml when serum-calcium was 11.0 and 10.8 mg/dl, respectively (normal P.T.H. by this assay is 25-90 µleq/ml for normal serum-calcium). Moderate osteopenia of the spine was noted on

X-ray. The patient’s angina could not be controlled with nitroglycerin derivatives but propranolol (120 mg/day) brought relief from pain. P.T.H. and serum-calcium measured monthly during propranolol therapy were 79p.leq/ml and 10.6mg/dl, respectively ; 99 and 10.3; 102 and 9-7. Propranolol reduced both P.T.H. and serum-calcium to near normal. We cannot be certain that this patient had primary hyperparathyroidism-the recurrent severe angina may have chronically increased adrenergic activity, resulting in excessive P.T.H. secretion. The treatment for hyperparathyroid patients with mild hypercalcsemia who are without symptoms is controversial ; both surgery and close medical follow-up have been advocated for primary hyperparathyroidism. Our experience with this patient suggests that propranolol reduces P.T.H. and 1. Sherwood, L. M., Abe, M. J. clin. Invest. 1972, 51, 292A. 2. Kukreja, S. C., and others. Proc. Soc. exp. Biol. Med. 1976, 151, 326. 3. Harney, A. N., and others. Clin. Res. 1977, 25, 563A. 4. Kukreja, S. C., and others. J. clin. Endocrin. Metab. 1975, 10, 478. 5. Williams, G. A., and others. Clin. Res. 1974, 22, 652A.

serum-calcium in hyperparathyroidism. p-blockade should be tested more widely in symptom-free patients with biochemical evidence of slight primary hyperparathyroidism and the incidence of hyperparathyroidism in patients with chronic adrenergic overactivity should be determined. University Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania 19107, U.S.A.




SIR,-We read with interest the comments by Professor George (April 1, p. 715) about our Feb. 25 paper on low-dose propranolol. We dispute the existence, not of the hepatic-first pass effect for propranolol, but only of a threshold for this effect. The need to saturate this threshold with an oral dose of 30 mg has been emphasised by Nies and Shand.’ We made no attempt to calculate areas beneath concentration-time curves in our study : indeed we clearly state that only a single plasma-propranolol was determined in each subject. However, both Chidsey et al. and Gomeni et al.,3 using gas/liquid chromatography have done pharmacokinetic studies and did estimate areas beneath concentration-time curves, and neither group could find evidence of a saturable threshold effect. Gomeni et al. found no difference in the bioavailability of oral doses of 10, 20, and 40 mg. However, in neither of these studies was an attempt made to quantitate beta-adrenoceptor blockade. The data from our study are presented against this background of uncertainty regarding a threshold effect. We found unequivocal evidence of the blockade of cardiac and renal receptors both at rest and after a standardised isoprenaline challenge. At this time plasma-propranolol concentrations were below the accurate detection limits of the fluorimetric assay, upon which most of the classical views on the pharmacokinetics of propranolol are based.4-6 George also states that our observation of betaadrenoceptor blockade by this very low dose of oral propranolol is not new, citing the studies of Patersen et al.6and Leonetti et al.’ yet, as he states, these workers gave doses of 40 mg (i.e., eight times the dose we used). We cannot accept George’s statement that the fixed-dose isoprenaline technique "does not contribute findings which are of clinical significance". Firstly, this technique permits an assessment of the effect of beta-blockers on both cardiac and renal beta-adrenoceptors,8 and this may be particularly relevant to the study of hypertension. Secondly, it is arguable that isoprenaline challenge such as the one used more faithfully reproduces the bursts of adenergic activity provoked by motorcar driving, sexual activity, and even violin playing. The classical technique of assessing beta-blockade by the determination of isoprenaline dose-ratios has obvious merit, but it is difficult to see the relevance of a five or even fifty fold increase in the dose of isoprenaline required to restore a given increase in heartrate, to the effects of endogenous catecholamines released during life’s stresses. Moreover, Chidsey et al.9 have demonstrated clear pharmacological effects at blood levels only 2-3 times those we observed. Thus median effective doses (E.D.50) for the suppression of exercise tachycardia and of plasma-renin were only 8 and 11 ng/ml, respectively. We tentatively suggested that these low-dose effects deserve further study, particularly in that they might contribute to our understanding of the mechanisms of action of beta-blockers. Nies, A. S. Shand, A. G. Circulation, 1975, 52, 6. Chidsey, C. A., and others ibid p. 313. 3. Gomeni, R., Bianchetti, G., Sega, R., Morselli, P. L. J. Pharmacokin. Biopharm. 1977, 5, 183. 4. Shand, D. G., Rangno, R. E., Evans, G. H. Pharmacology, 1972, 8, 244. 5. Shand, D. G., and others Drug Metab. Dispos. 1973, i, 679. 6. Paterson, J. W., and others Eur. J. clin. Pharmac. 1970, 2, 127. 7. Leonetti, G., and others Clin. Sci. mol. Med. 1975, 48, 491. 8. Davies, R., and others Clin. Endocr. 1977, 6, 345. 9. Chidsey, C. A., and others Postgrad. med. J. 1976, 52, suppl. 4, p. 26. 1. 2.

Is fetal radiography really necessary?

826 AGENESIS OF APPENDIX: A FURTHER THALIDOMIDE ANOMALY CRANIAL SYNOSTOSIS IN JOB’S SYNDROME et al.’ described two girls with recur"cold" staphylococ...
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