X-LINKED ICHTHYOSIS DUE TO STEROID-SULPHATASE DEFICIENCY

70

lymphoma "malignant plasmacytoma" or at postulate the origin of the tumour from B lymphocytes.21 However, Rappaport, in his original description of Mediterranean lymphoma,22 emphasised that there was no morphological evidence that the lymphomas were histogenetically related to the diffuse plasma-cell infiltration, although in a more recent publicaranean

least

to

tion23 he has claimed that the tumour cells show a similar staining with antisera to alpha chain as the nonneoplastic plasma-cell infiltrate. We would criticise this observation on the grounds that the sections were not trypsinised and the antisera were used at low dilution. Furthermore, the findings do not exclude non-specific uptake of alpha chains by the tumour cells. It is clear from other reports2,3 that the histology of Mediterranean lymphoma varies and that a significant number of such tumours are pleomorphic "reticulum-cell sarcomas". In view of the epidemiological implications it is important to determine if some, or all, of these tumours are of the same type as those described in this paper.

Characterisation of the specific malignant process associated with malabsorption should help to clarify the relationship between intestinal lymphoma and coeliac disease. According to the criteria of Thompson24 and Cooke and Asquith,25 a jejunal-biopsy specimen showing severe villous atrophy and crypt hyperplasia is diagnostic of coeliac disease, and hence these workers would consider all the cases presented in this report to be adult coeliac disease. However, if biopsy-proven gluten sensitivity is the accepted criterion for the diagnosis of coeliac disease, then none of our patients qualify for that diagnosis. The confusion is compounded by the statement of Sleisenger and Brandborg2’ that malabsorption caused

by lymphoma

respond transiently to a gluten-free diet. To resolve the question of the specific relationship between coeliac disease and lymphoma, patients presenting with the type of lymphoma described here should be carefully studied for objective evidence of gluten sensitivity and for the presence of histocompatibility antigens HLA B8 and DW3, which are associated with coeliac dismay

ease. 28,29 chronic jejunal ulcers were present in5 of our cases, and 3 of these presented as ulcerative jejunitis, a condition thought to be associated with coeliac disease in much the same way as is lymphoma. In 2 of these patients foci of pleomorphic lymphoma were found only after an intensive histological search. A link between ulcerative jejunitis and lymphoma has already been suggested 30,31and our cases further support this. Moreover, characterisation of the lymphoma as malignant histiocytosis may explain the pathogenesis of ulcerative jejunitis, since the bases of ulcers not associated with pleomorphic tumour often contained sheets of morphologically normal, or only marginally atypical histiocytes, and aggregations of similar cells were seen at intervals in intact mucosa. Tumour cells in malignant histiocytosis may look deceptively benign,32 and conceivably a diffuse infiltrate of malignant histiocytes, either alone or in association with reactive inflammation, may be the cause of malabsorption, analogous to the "pre-

Non-specific

lymphomatous" phase of mycosis fungoides. The characterisation of these cases of intestinal lymphoma as malignant histiocytosis has an important bearing on treatment, since local treatment, whether sur-

gery, radiotherapy, or both, will clearly not be curative. Successful chemotherapy for malignant histiocytosis has been reported,33 and similar treatment is probably indicated when the disease affects the intestine.

Requests for reprints should

be addressed

to

P.I.

REFERENCES

Fairley, N. H., Mackie, F. P. Br. med. J. 1937, i, 375. Al-Saleem, T., Al-Bahrani, Z. Cancer, N.Y. 1973, 31, 291. Nasr, K., Haghighi, P., Bakshanded, K., Abadi, P., Lahimgarzardeh, A. Dig. Dis. 1976, 21, 313. 4. Isaacson, P., Wright, D. H. Unpublished. 5. Sternberger, L. A. in Immunocytochemistry; p.129. Englewood Cliff, New 1. 2. 3.

6. 7.

Jersey, 1974. Huang, S, Minassian, H., More, J. D. Lab. Invest. 1976, 35, 383. Byrne, G. E., Rappaport, H. in Gann Monograph on Cancer (edited by K. Akazaki et al.); vol. 15, p.145. Tokyo, 1973.

8. 9.

Abele, D. C., Griffin, T. B. Archs Derm. 1972, 106, 319. Viathianathan, I., Fishkin, S., Gruben, J. E. Am. J. clin. Path. 1967, 47,

Research

160. 10.

Chawla, S. K., Lopresti,

P.

A., Burdman, D., Sileo, A., Govoni, A. F., Smu-

lewicz, J. J. Am. J. Gastroent. N.Y. 1975, 63, 129. 11. Macgillivray, J. B., Duthie, J. S. J. clin. Path. 1977, 30, 120. 12. Comes, J. S. Proc. R. Soc. Med. 1967, 60, 732. 13. Thompson, H. J. clin. Path. 1974, 27, 710. 14. Henry, K., Farrer-Brown, G. Histopathology, 1977, 1, 53. 15. Lancet, 1977, i, 1191. 16. Chambers, T. J. J. Path. 1977, 122, 163. 17. Mason, D. Y., Labaume, S., Preud’Homme,

J. L. Clin. exp. Immun. 1977, 29, 413. 18. Taylor, C. R. Eur. J. Cancer, 1976, 12, 61. 19. Lukes, R. J., Collins, R. D. Cancer, N.Y. 1974, 34, 1488. 20. Galian, A., Lecestre, M. J., Scotto, J., Bognel, C., Matuchansky, C., Rambaud, J. C. ibid. 1977, 39, 2081. 21. Lewin, K. J., Kahn, L. B., Nouis, B. H. ibid. 1976, 38, 2511. 22. Rappaport, H., Ramot, B., Hulu, N., Park, J. C. ibid. 1972, 29, 1502. 23. Pangalis, G. A., Rappaport, H. Lancet, 1977, ii, 880. 24. Thompson, H. in Current Topics in Pathology (edited by B. C. Morson); p.49. Berlin, 1976. 25. Cooke, W. T., Asquith, P. Clins Gastroent. 1974, 3, 3. 26. Eidelman, S., Parkins, A., Rubin, C. E. Medicine, Baltimore, 1966, 45, 111. 27. Sleisenger, M. H., Brandborg, L. L. Malabsorption; p.195. Philadelphia, 1977. 28.

Falchuk,

Z.

M., Rogentine, G. N., Stroker, W. J. clin. Invest. 1972, 51,

1602.

Keuning, J. J., Pena, A. S., van Leeuwen, A., van Hooff, J. P., van Rood, J. J. Lancet, 1976, i, 506. 30. Hourihane, D. O’B., Weir, D. G. Gastroenterology, 1970, 59, 130. 31. Whitehead, R. Gut, 1968, 9, 569. 32. Rappaport, H. Atlas of Tumor Pathology; p.48. Washington, D.C., 1966. 33. Stein, R. S., Morgan, E. M., Byrne, G. C. Cancer, N.Y. 1976, 38, 1083. 29.

X-LINKED ICHTHYOSIS DUE TO STEROID-SULPHATASE DEFICIENCY LARRY J. SHAPIRO

ROBERTA WEISS

Division of Medical Genetics, Department of Pediatrics, U.C.L.A. School of Medicine, Harbor General Hospital Campus, Torrance, California, U.S.A.

DIANNE WEBSTER Section

of Cytogenetics, Princess Mary Laboratory, Auckland Hospital, Auckland, New Zealand

JOHN T. FRANCE Postgraduate School of Obstetrics and Gynæcology, National Women’s Hospital, Auckland, New Zealand

Summary

An assay of cultured skin fibroblasts identified several individuals with

3&bgr;-hydroxysteroid-sulphate sulphatase deficiency. All patients with this inborn error of metabolism had clinically apparent ichthyosis and a family history of this skin disorder compatible with X-linked inheritance. It is concluded that steroid-sulphatase deficiency is the bio-

71

chemical basis of

at

least

some cases

of X-linked ich-

thyosis. Introduction DEFICIENCY of the microsomal hydrolase 3[3-hydroxysteroid sulphate sulphatase is an inborn error of sulphated-steroid metabolism in man.1-5 Original clinical descriptions of this entity focused on prenatal and perinatal manifestations. Pregnancies in which the placenta was subsequently shown to have reduced steroid-sulphatase

characterised by extraordinarily low and serum cestriol concentrations. In addition, in many of these pregnancies there was a failure of normal parturitional mechanisms and delivery by cxsarean section was not uncommon. Placental steroid-sulphatase activity is important for the desulphation of various steroidal precursors, a necessary step in the biosynthesis by the placenta of the large amounts ofoestrogens produced in pregnancy. This de-conjugation seems also to be critical for the transport of these steroids among maternal, placental, and fetal compartments. The discovery of pregnancies with very low oestriol production due to a deficiency of placental steroid-sulphatase activity helped to establish these links. All affected pregnancies reported to date have involved"male infants who appeared to be clinically normal after birih. We used cultured fibroblasts from the male infant in such an affected pregnancy to demonstrate that steroidsulphatase deficiency in these patients affects somatic tissues other than the placenta, and persists throughout life.3 It therefore seemed possible that some phenotypic expression of this enzymopathy might be demonstrable postnatally. We investigated two families in which placental steroid-sulphatase activity had been abnormally low in some pregnancies and found that several other members of these families were reported to have had X-liriked ichthyosis.

activity

were

maternal

urinary

Material and Methods The first

patient ever reported to have placental steroid-sulphatase deficiency is a member of a New Zealand family (family K).’ Two other younger siblings had a similar abnormality.l.2 The F family in Torrance, California, in which the results of steroid-sulphatase assays of the placenta and cultured skin fibroblasts have been described elsewhere,3 were also investigated. All available members of these two families were seen and examined by one of us and a dermatologist. Family members also described several individuals with ichthyosis who were dead or could not be examined. Fibroblast lines were established and maintained in conventional fashion.6 All assays were performed at similar passage number, cell density, and time after subculture. Dehydroepiandrosterone-

sulphate (D.H.E.A.s.)-sulphatase activity was assayed in fibrohomogenates as described elsewhere.3 Cholesterol sulphatase was assayed in these patients’ cells and there was complete correlation with the D.H.E.A.s.-sulphatase data.7 blast

Results In both families

(figs. 1 and 2) ichthyosis seemed to X-linked trait affecting males only, segregate autosomal dominant transmission with sexalthough limited expression cannot be excluded. In those individuals in whom ichthyosis developed, the skin had usually appeared normal at birth, and first appeared abnormal at about 3 months of age. After this ichthyosis seemed to persist for life. The trunk and extensor surfaces of the as

an

Fig.

1-K

family pedigree. Individuals with clinical ichthyosis

/’

are indicated by filled-in symbols. A slash denotes a case in which the placenta was steroid-sulphatase deficient. Levels of cholesterol-sulphatase activity in skin fibroblasts for each individual tested are shown below in italics. Normal levels of steroid-sulphatase activity in this assay are 4.64:t 1.99 pmole

desulphated/mg protein/h (n= 11).

-

l Fig. 2-F family pedigree. as in Symbols fig. 1. extremities were most involved. Individual 11-5 in the F family had a slit-lamp ophthalmological examination and was found to have deep corneal opacities identical with those described by Sever et al. in patients with X-linked ichthyosis.8 All individuals with deficient fibroblast cholesterolsulphatase activity had clinical ichthyosis. All those with normal levels of sulphatase activity had no skin disease. Patients n!-9 in the F family and 11-2 in the K family, although presumably obligate heterozygotes for the mutant sulphatase gene, had low normal levels of cholesterol-sulphatase activity in their fibroblasts. Furthermore, careful clinical examination did not disclose any patches of discernibly ichthyotic skin as might be anticipated in an X-linked dermatological condition with lyonisation. Several of the sulphatase-deficient individuals identified through the development of ichthyosis and fibroblast studies were born after the spontaneous onset of labour and without a cxsarean section being

necessary.

Discussion

Ichthyosis is a term which describes the clinical findings in a group of inherited and sporadic, non-inflammatory skin diseases.9 The

inherited variexhibit autosomal dominant, ichthyosis may recessive, or X-linked inheritance in various families.9 Clinical heterogeneity has been recognised even within the X-linked varieties of ichthyosis, with two and perhaps three variant forms being delineated. 10,11 X-linked ichthyosis is quite common, occurring in 1 in 6190 males in Englandl2 and 1 in 5200 males in Israel.13 The gene for at least some varieties of X-linked ichthyosis seems to be moderately closely linked with the gene for the Xg more common

eties of

blood-group substance.9 Ichthyosis is the only recognised postnatal clinical abnormality in patients with steroid-sulphatase de-

72

Culture of skin fibroblasts allowed us to identify affected individuals long after their placentas were no longer available for study. The exact relation between sulphated-steroid metabolism and ichthyosis in our patients is uncertain. However, the skin is an important organ in steroid biotransformation in man. Whole-skin explants from healthy people can sulphate exogenous dehydroepiandrosterone to dehydroepiandrosterone sulphate14 and have sulphatase activity capable of hydrolysing 3p-OH-steroid sulphates.15 It therefore seems reasonable to suggest that diminished steroid-sulphatase activity could alter metabolism in skin. However, steroid-sulphatase deficiency may only be fortuitously associated with ichthyosis, perhaps through close linkage of X-chromosomal genes. This seems unlikely for two reasons. First, ichthyosis and steroid-sulphatase deficiency occurred together in two ethnically and geographically separated families and were also found together in one other family known to us.16 Two other infants with placental sulphatase deficiency studied in the Netherlands also had ichthyosis "of the X-linked type" .17,18 A causal relation between steroidsulphatase deficiency and ichthyosis accords with the observation that patients with the rare autosomal recessive disorder of multiple sulphatase deficiency who have very low levels of lysosomal arylsulphatase A and B, iduronate sulphatase, and heparan-N-sulphatase also have very low levels of steroid sulphatase.1,19,20 Many of these patients seem to have ichthyosis as well.21,22 Therefore it seems that steroid-sulphatase deficiency and ichthyosis are probably causally related.

ficiency.

We thank Dr D. M. Rowan and Dr D. A. Scolly of the Skin Clinic, Auckland Hospital for their assistance with dermatological assessments and skin biopsies, and Mrs Elizabeth Torres for assistance in preparation of the paper. This study was supported in part by N.LG.M.S. Training Grant 1T32M07414-01, National Foundation Genetics Center Grant C-114 and Basil O’Connor starter research grant 5-6from the National Foundation-March of Dimes.

Requests for reprints should be addressed to L. S., Division of Medical Genetics, Harbor General Hospital, Torrance, California, U.S.A. REFERENCES 1. France, J. T., Liggins, G. C. J. clin. Endocr. Metab. 1969, 29, 138. 2. France, J. T., Downey, J. A., McNaught, R. W., Seddon, R. J., Liggins, G. C. Excerpta med. int Congr. ser. 1976, no. 403, 2, 319. 3. Shapiro, L. J., Cousins, L., Fluharty, A. L., Stevens, R. L., Kihara, H.

Pediat. Res. 1977, 11, 894. 4. France, J. T., Seddon, R. J., Liggins, G. C. J. clin. Endocr. Metab. 1973, 36, 1. 5. Fleigner, J. R. H., Schindler, I., Brown, J. B. J. Obstet. Gynæc. Br. Commonw. 1972, 79, 810. 6. Cantz, M., Kresse, H., Barton, R. W., Neufeld, E. F. Meth. Enzymol. 1972, 28, 884. 7. Shapiro, L. J., Weiss, R. Excerpta med. int. Congr. ser. 1977, no. 426, p. 57 (abstr.). 8. Sever, R. J., Frost, P., Weinstein, G. J. Am med. Ass. 1968, 206, 2283. 9. Goldsmith, L. A. Prog. med. Genet. 1976, 1, 185. 10. Passarge, E., Post, B., Schopt, E. in Birth Defects Original (edited by D. Bergsma); vol VII, no. 8, part XII, p.46. Baltimore, 1971. 11. Fitch, N., Segool, R., Ferenczy, A., Cohen, H. Clin. Genet. 1976, 9, 71. 12. Wells, R. S., Kerr, C. B. Br. med. J. 1966,  , 947. 13. Ziprkowski, L., Feinstein, H. Br. J. Derm. 1972, 86, 1. 14. Gallegos, A. J., Berliner, D. L. J. clin. Endocr. Metab. 1967, 27, 1214. 15. Kim, M. H., Herman, W. L. ibid. 1968, 28, 187. 16. France, J. T. Unpublished. 17. Jobsis, A. E., van Duuren, C. Y., de Vries, G. P., Koppe, J. G., Rijiken, Y., van Kempen, M. J., de Groot, W. P Ned. Tijdschr. Geneesk. 1976, 120, 1980. 18. 19. 20. 21. 22.

Koppe, J. G., Rijiken, Y., Jobsis, A. C., Marinkovic-Ilsen, H. Excerpta med. int. Congr. ser. 1977, no. 426, p. 57 (abstr.). Murphy, J. V., Wolfe, J. H., Balzs, E. A., Moser, H. in Lipid Storage Diseases (edited by J. Bernsohn and H. J. Grassman); p. 67. New York, 1971. Eto, Y., Wiesmann, U. N., Carson, J. H., Herschkowitz, N. N. Archs Neurol. 1974, 30, 153. Moser, H. W in Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson); p. 668. New York, 1972. Neufeld, E. F., Aylsworth, A. Personal communication.

UPRIGHT POSTURE AND THE EFFICIENCY OF LABOUR A. A. CALDER J. MCMANUS University Department of Obstetrics and Gynæcology, Glasgow Royal Maternity Hospital, Rottenrow, T.

Glasgow G4 0NA The claim that an upright maternal posture during labour improves the efficiency of the uterus to the benefit of both mother and fetus has been investigated in a randomised prospective study. 40 patients undergoing induction of labour were allocated to a recumbent group or an upright group. No differences were found between the groups in the length of labour, mode of delivery, requirements of oxytocic and analgesic drugs, or fetal and neonatal condition. Our data do not support calls to change conventional intrapartum nursing attitudes.

Summary

Introduction Mendez-Bauer and

colleagues’

have claimed that the

efficiency of labour is greatly improved if the mother adopts an upright posture. In their study, primigravidas in spontaneous labour were asked to alternate every 30 minutes between the dorsal supine and the standing position. They claimed that the upright position was associated with an increase in uterine activity in 50% of paa considerable shortening of labour, and a reduction in the mother’s need for analgesia. Dunn2 supported this view and criticised the conventional obstetric practice of nursing patients in a recumbent position dur-

tients,

ing labour. We have conducted a randomised prospective study of the influence of maternal posture on labour. The patients had labour induced and consequently were in hos-

pital throughout labour, making possible accurate assessment and data collection. We compared the results in patients randomly allocated to a group nursed in the lateral recumbent position throughout labour and a group who were encouraged to remain upright. Patients and Methods 40 patients were studied, of whom 20 were primigravidas and 20 were having their second or third confinement. All gave informed consent to participation in the study. Within each category the patients were randomly allocated to a recumbent or upright management, so that there were four groups of 10 patients (table I). In every case the gestational age was 38 weeks or more, and the cervical score3 was six or greater. No multiple pregnancies or breech presentations were included. The groups were well matched for gestational age, cervical TABLE I-DETAILS OF PATIENTS