753 series treated with cyclophospharelapses. Both figures are higher than the 3-10% incidence of relapse usually reported.2-4 Immunosuppression during the acute attack may actually encourage relapse. It has been said that A.c.T.H. is superior to prednisolone in the treatment of Guillain-Barre syndrome" but there appears to be no objective evidence to support this view and some hold an opposing view. Furthermore we do not know of other situations where A.C.T.H. has been clearly shown to be superior to prednisolone. In Bell’s palsy the reverse has been found: prednisolone 80 mg daily was more effective than A.c.T.H. 60 units daily in reducing the degree of denervation. 18 ’It seems unlikely that A.C.T.H. would succeed in Guillain-Barre syndrome where prednisolone has failed. According to the classical hypothesis acute inflammatory polyneuropathy is caused by a cell-mediated immune response to peripheral nerve antigens analogous to the mechanism demonstrated in experimental allergic encephalomyelitis and thought to operate in experimental allergic neuritis.t5 Steroids and immunosuppressive agents are effective in the treatment of experimental allergic encephalomyelitis’9 and they might be expected to be beneficial in experimental allergic neuritis although this has not been satisfactorily demonstrated. Our finding that prednisolone delays rather than enhances improvement is unexpected. Several factors could contribute to this outcome. Firstly, by the time clinical symptoms appear the immune response may already have reached a stage when it cannot be suppressed. Secondly, any reduction of oedema which occurs with steroids may be relatively unimportant in the peripheral nerve compared with the central neuraxis and steroids may actually slow repair. Thirdly, steroids could inhibit the suppressor T and B cell mechanisms which normally operate to limit the disease. Finally, if the disease is due to an immune response to a persistent viral infection, steroids may prolong the infection. Instances of acute inflammatory neuropathy occurring in patients with reduced cell-mediated immunity associated with Hodgkin’s disease,20 or with immunosuppression after renal transplantation 21 have been reported; cases associated with Cushing’s syndrome have also been
patients
in
a recent
mide16 there
were
4
recorded. 22
SYSTEMIC LUPUS ERYTHEMATOSUS AND LYMPHOMA A. A. DAWSON WILLIAM WALKER
J. A. GREEN
Departments of Medicine and Therapeutics, University of Aberdeen In 4 women lymphomas developed 2 months to 12 years after the onset of systemic lupus erythematosus. An association between the two diseases had previously been reported in 14 cases, in 6 of which the lymphoma either preceded or was diagnosed at the same time as the autoimmune disease. In systemic lupus erythematosus early biopsy of suspect lymph-nodes is recommended.
Summary
Introduction THE association between autoimmune disease and
malignancy is well known. Up to 20% of patients with dermatomyositis have an underlying carcinoma, and other non-organ-specific autoimmune diseases-Sjogren’s syndrome, polyarteritis nodosa, and rheumatoid arthritis-have been associated with lymphoid malignancies.2-4 14 cases of systemic lupus erythematosus (S.L.E.) and lymphoma are documented, the diagnoses being made simultaneously in 44-6 and lymphoma preceding the s.L.E. in 2.46 This paper describes 4 more patients with established S.L.E. in whom lymphoma subsequently developed. The diagnosis of S.L.E. was made on the basis of clinical and laboratory findings. The temporal course of the disease was defined by the terms s.L.E. onset for the time of the first significant symptom and zero time (to) for the time at which treatment for S.L.E. was decided.7 A definite histological diagnosis of Hodgkin’s disease, non-
DR HUGHES AND OTHERS: REFERENCES
2.
3.
Our results provide no grounds for the use of steroids in the management of acute inflammatory neuropathy since the prognosis is not improved, the rate of recovery is slowed, and the chance of relapse may be increased. Careful nursing, physiotherapy, and attention to the risk of ventilatory failure and circulatory complications remain the mainstay of treatment.
We thank Prof P. Armitage for his advice, Sister I. Dillon and staff of the Batten Unit, National Hospital for Nervous Diseases, for their assistance in holding the central register, the Medical Research Council for financial support and the physicians who entered patients to the trial (Dr J. N. Blau, Dr J. H. J. Durston, Dr A. G. Freeman, Dr W. W. Gooddy, Dr M. Green, Dr B. P. Harold, Dr P. K. P. Harvey, Dr A. P. Hopkins, Dr J. M. B. Hughes, Dr N. Jones, Dr R. S. Kocen, Dr N. J. Legg, Dr 1. C. K. Mackenzie, Prof. J. Marshall, Dr J. N. Milnes, Dr B. G. R. Nevilie, Dr B. G. Parsons Smith, Prof. R. J. Robinson, Dr R. W. Ross Russell, Dr P. Rudge, Dr G. Hillas Smith).
References at foot of next column
Kurland, L. T., Mulder, D. W. Neurology, Minneap., 1973, 23, 1269. Wiederholt, W. C., Mulder, D. W., Lambert, E. H. Proc. Mayo Clin. 1964, 39, 427. McLeod, J. G., Walsh, J. C., Prineas, J. W., Pollard, J. D. J. neurol. Sci.,
1. Lesser, R. P., Hauser, W. A.,
4. 5.
1976, 27, 145. Löffel, N. B., Rossi, L. N., Mumenthaler, M., Lütschg, J., Ludin, H. P. ibid. 1977, 33, 71. Dowling, P. C., Menonna, J. P., Cook, S. D. J. Am. med. Ass. 1977, 238, 317.
6. 7.
Jackson, R. H., Miller, H., Schapira, K. Br. med. J. 1957, i, 480. Gilpin, S. F., Moersch, F. P., Kernohan, J. W. Archs Neurol. Psychiat., Chicago, 1936, 35, 937. 8. Heller, G. L., De Jong, R. N. Archs Neurol., Chicago, 1963, 8, 179. 9. Bammer, H., Schaltenbrand, G. Münch. med. Wschr. 1965, 107, 1629. 10. Prineas, J. Acta neurol. scand. 1970, 46, (suppl. 44),1 11. Marshall, J. Brain, 1963, 86, 55. 12. Frick, E., Angstwurm, H. Munch. med. Wschr. 1968, 110, 1265. 13. Goodall, J. A. D., Kosmidis, J. C., Geddes, A. M. Lancet, 1974, i, 524. 14. Swick, H. M., McQuillen, M. P. Neurology, Minneap 1976, 26, 205. 15. Arnason, B. G. W. in Peripheral Neuropathy Vol II, (edited by P. J. Dyck, P. K. Thomas and E. H. Lambert); p. 1110. Philadelphia, 1975. 16. Rosen, A. D., Vastola, E. F. J. neurol. Sci. 1976, 30, 179. 17. Walton, J. N. in Brain’s Diseases of the Nervous System; p. 952. Oxford, 1977. 18. Taverner, D., Cohen, S. B., Hutchinson, B. C. Br. med. J. 1971, iv, 20. 19. Hughes, R. A. C., Leibowitz, S. L. in Immunology in Medicine (edited by E. J. Holborow and W. G. Reeves); p. 878, New York: 1977. 20. Lisak, R. P., Mitchell, M., Zweiman, B, Orrechio, E., Asbury, A. K. Ann Neurol. 1977, 1, 72. 21. Drachman, D. A., Paterson, P. Y., Berlin, B., Roguska, J. Neurology, Minneap. 1970, 20, 390. 22. Bresler, R., Johnson, C. T. Ann. intern. Med. 1959, 50, 1298.
754
Hodgkin’s lymphoma, was
taken
as
or chronic lymphocytic leukxmia the time of onset of lymphoma.
Case-reports Case A In a 22-year-old woman severe photodermatitis of the extremities developed in August, 1963. Antinuclear factor (A.N.F.) was weakly positive, and a skin biopsy showed a non-specific perifollicular focal dermatitis. In August, 1964, she had vascular purpura, cardiac triple rhythm, and an aortic systolic ejection murmur. Investigation showed: hxmoglobin 8.11 g/dl, white blood-cells 2.7-8-0x10/1, platelets 60-100xl0"/l, erythrocyte sedimentation-rate (E.S.R.) 75 mm/h, no L.E. cells, strongly positive A.N.F., T-wave changes in the chest leads on electrocardiography (E.C.G.), and diminished pulmonary transfer factor. Small nodes were found in the neck and axilla. Relapses over the next 10 years responded to short courses of prednisolone, and skin biopsy during one episode showed a non-specific vasculitis. L.E. cells were found intermittently. Axillary and supraclavicular lymphadenopathy appeared in June, 1974, and initially resolved with prednisolone, but it progressed again and in December, 1975, histological assessment showed non-Hodgkin’s lymphoma of nodular well-differentiated type. Investigation showed clinical stage-ila disease, and since mantle radiotherapy both diseases have remained -
quiescent. Case B A 50-year-old woman presented in May, 1963, with nephrotic syndrome and mild hypertension. Investigation showed: full blood-count normal, serum-urea 6 mmol/1, proteinuria 12 g/1, urinary red-cell casts, E.S.R. 103 mm/h, A.N.F. negative. Needle biopsy of kidney showed a progressive sclerosing glomerulonephritis. On a low-salt, high-protein diet and 20 mg prednisolone daily, her condition improved, although bilateral retinal-vein thromboses developed in June, 1964. A photoder-
matitis in June, 1965, was controlled with barrier cream after a short course of local steroids. Prednisolone therapy was withdrawn in 1965, and over the next 11 years chronic renal failure slowly developed, the serum-urea rising to 13.3 mmol/[. Mild hypertension was controlled with methyldopa. In June, 1976, painless axillary, submandibular, and cervical lymphadenopathy was noted and proved on node biopsy to be a nodular well-differentiated lymphocytic lymphoma. Investigation by lymphangiography, gallium-67 scan, and marrow biopsy showed no other evidence of disease. The A.N.F. was weakly positive and the anti-D.N.A.-antibody titre rose to 25 units/ml. With mantle radiotherapy the lymphadenopathy regressed, and for the past 21 months the patient has been well except for Raynaud’s phenomenon, a serum-urea of 23 mmol/1, and moderate proteinuria.
Case C
56-year-old woman presented in October, 1970, with bruising and gastrointestinal and retinal hxmorrhages. Laboratory investigations showed: haemoglobin 10.8 g/dl, white blood-cells 3-7xl0"/l, platelets 4xlO9/1, A.N.F. negative. Marrow aspirate was compatible with idiopathic thrombocytopenic purpura, and the patient was treated by splenectomy after unsuccessful treatment with high-dose prednisolone and azathioprine. The platelet-count remained normal for 4 years without drug therapy until relapse (platelets 9x10/1) in April, 1974, which was treated with further prednisolone, azathioprine, and corticotrophin. Arthropathy developed in May, 1975, together with soft-tissue swelling of the hands and Raynaud’s phenomenon. This was followed by malaise, fever, pericarditis, and pleural effusions. These features, together with positive A.N.F., L.E. cells, and anti-D.N.A.-antibody titre of 34 units/ml, formed the basis for a diagnosis of S.L.E. She remained fairly well for 2 years on azathioprine and steroids until September, 1977, when bilateral axillary lymphadenopathy was noted, associated with a relapse of the arthropathy and Raynaud’s phenomenon. A lymph-node biopsy in December, 1977, showed A
DETAILS OF PATIENTS WITH S.L.E. FOLLOWED BY LYMPHOMA
* present series. t alive at stated survival. to=firm clinical diagnosis ofs.L.B. c.L.L.=chronic lymphocytic leukxmia.
c.T.=cytotoxic therapy. N.H.L.=non-Hodgkin’s lymphoma. R.T.=radiotherapy.
755
Hodgkin’s disease of mixed cellularity, and mediastinal node enlargement was found on X-ray. Clinical staging was ns, and treatment with mantle radiotherapy was given, but she died suddenly at home 3 months later with presumptive evidence of overwhelming infection. Necropsy was not done. Case D A
28-year-old
ment
woman
presented
in
September, 1976, with
of sharp retrosternal pain aggravated by moveand associated with dyspnoea, palpitations, muscular
sudden
onset
aches, arthralgia, dysphagia, Raynaud’s phenomenon, fever, and sweating. Further inquiry elicited a 6-month history of malaise, weight-loss, and secondary amenorrhrea. On examination she
was
tachypnoea.
pyrexial (39°C) with sinus tachycardia and was 56 mm/h, and .c.G. showed s.T. elevan, aVF, V4-6’ Serum-immunoglobulins were nor-
E.S.R.
tion in leads i, mal, and blood-cultures, throat swab, Paul Bunnell test, A.N.F.,
cells, and antistreptolysin-0 titre were all negative. A diagnosis of pericarditis of presumed viral origin was made, and her condition improved then relapsed 5 days later. A widespread purpuric rash and loud pleuropericardial friction were present, and small cervical and axillary nodes were palpable. Hemoglobin had fallen to 9.9 g/dl, but the platelet and leucocyte counts were normal. A fixed high titre of antibody to Coxsackie B4 virus and an eightfold rise in the titre of anti-parainfluenza-virus antibody were observed. Skin biopsy showed a non-specific vasculitis. Symptoms were controlled with 40 mg prednisolone daily, but the lymphadenopathy progressed, and in November, 1976, a large axillary node showing the features of Hodgkin’s disease of mixed cell type was excised. Gallium-67 scanning, bone-marrow trephine, laparotomy, and splenectomy showed no other evidence of disease, and the extent was classified as stage UB. Telecobalt therapy was given to the supradiaphragmatic lymph-node areas, and there has been no clinical recurrence of the Hodgkin’s disease to date. Over the past 16 months she has been well despite an antiD.N.A.-antibody titre of 35 units/ml. L.E.
Discussion The clinical distinction between such
an
ill-defined
entity as s.L.E. and the rheumatic manifestations of malignant disease can be difficult, and in lymphomas this difficulty is compounded by their histological and serological similarities to S.L.E.l The 4 cases previously reported in which both diseases were diagnosed simultaneously4-6 and the 2 cases in which the lymphoma preceded S.L.E. by 2 and 4 years respectively46 all had evidence of extensive lymphomatous involvement, and the systemic symptoms could perhaps be explained by chronic tumour-derived antigenxmia giving rise to immune-complex and antinuclear-antibody formation. Although many patients would not have been investigated further once malignant disease was diagnosed, the lack of other reported cases is surprising. The label "systemic manifestation of malignant disease" may too often have been regarded as a diagnosis rather than as a stimulus to further thought on the pathophysiology of cancer. As has been proved with ectopically produced hormones, an interesting syndrome may later give rise to a useful marker of malignancy. All 12 patients in whom s.L.E. preceded lymphoma (see accompanying table) were women. The mean age at first
36 years, and at to 41 years. Lymphoma diagnosed at mean age 46. S.L.E. preceded the development of lymphoma by 2 months to 12 years. 4 cases were Hodgkin’s disease, and 8 were classified as non-Hodgkin’s lymphoma. There is much eviS.L.E.
symptom was
was
dence that the common factor underlying the association could be immunodeficiency. Patients with primary immunodeficiency disorders have an incidence of malignancy 10 000 times greater than expected,8 and a high proportion of these tumours are lymphomas. Delayed hypersensitivity and T and B cell function are impaired in S.L.E.,9 and genetic lesions located in the major histocompatibility complex adjacent to the postulated immune-response genes produce a disease similar to S.L.E.I0 NZB/BL mice spontaneously acquire an s.L.E.-like disease with glomerulonephritis, A.N.F., and L.E. cells, and they have a high incidence of lymphomas.11 Current concepts favour suppressor-T-cell dysfunction as the primary lesion in s.L.E.,12 13 predisposing to abnormal B-cell proliferation in response to an extrinsic antigen or autoantigen. Most non-Hodgkin’s lymphomas are thought to be of B-cell origin. A role for virus infection either as an initiator of the antigenic stimulation or as an opportunistic or latent infection causing malignant transformation of the primed lymphoid cells has been suggested. 12 Virus-like particles have been seen in s.L.E. lesions,14 and raised EpsteinBarr-virus titres have been recorded in S.L.E.15 as well as in Hodgkin’s disease and other lymphomas.16 A murine leuksemia virus produces an s.L.E.-like disease and lymphoma in neonatal mice.17 The immunosuppressive effect of the drugs used to treat the S.L.E. is another factor to be considered, but the evidence implicating azathioprine in the development of tumours is inconclusive,18 19 and the drug was used in only a minority of the patients with S.L.E. and lymphoma so far described. The widespread use of steroids in other conditions without lymphoid tumours being reported makes a causal relationship unlikely. S.L.E. is not a rare disease, and it is surprising that lymphomas are not more often reported if this is indeed a true association. The relation of S.L.E. to the subsequent development of lymphoma may be regarded as facilitation of the neoplastic process by the autoimmune disorder, however the former is initiated. It is even possible that chronic autoimmune and lymphoreticular neoplasms are all manifestations of one basic underlying pathological process-perhaps virus infection in a genetically susceptible host. Benign lymphadenopathy in autoimmune disease, immunoblastic lymphadenopathy, and lymphoma could then be regarded as forming a spectrum of diseases with a common oetiology. 20 21 We thank Dr D. S. Short and Dr R. A. Main for their management of patients A, B, and D. ’
Requests of Medicine,
help
in the
for
reprints should be addressed to J. A. G., Department University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD. REFERENCES
1. 2.
Calabro, J. J. Arthritis Rheum. 1967, 10, 553. Razis, D. V., Diamond, H. D., Craver, L. F. Am. J.
med. Sci.
1959, 238,
327. 3. Talal, N., Bunim, J. J. Am. J. Med. 1964, 36, 529. 4. Miller, D. G. Am. J. intern. Med 1967, 66, 507 5. Howqua, J., Mackay, I. R. Blood, 1963, 22, 191. 6. Cammarata, R. J., Rodman, G. P., Jensen, W. N. Archs intern. Med.
1963, 111, 330. 7. Canoso, J. J., Cohen, A. A. Arthritis Rheum. 1974, 17, 383. 8. Gatti, R.A., Good, R.A. Cancer, 1971, 28, 89 9. Schneider, J., Chin. W., Friou, G. J., Cooper, S. M., Harding, B., Hill, R. L., Quismorio, F. P. Clin. exp. Immun. 1975, 20, 187. 10 Hauptmann, G., Grosshaus, E., Held, E. Annls Derm. Syph 1974, 101, 479.
756 ENZYMATIC BASIS OF TYPICAL X-LINKED
ICHTHYOSIS LARRY J. SHAPIRO ROBERTA WEISS MELODIE M. BUXMAN JACLYN VIDGOFF ROBERT L. DIMOND Division of Medical Genetics, Department of Pediatrics, U.C.L.A. School of Medicine-Harbor General Hospital, Torrance, California; and Department of Dermatology and Division of Medical Genetics, University of Oregon, Health Science Centre, Portland, Oregon, U.S.A.
JAMES A. ROLLER St. John’s Hospital for Diseases
R. S. WELLS
of the Skin, London
Steroid sulphatase activity was determined in cultured fibroblasts from 25 individuals with X-linked ichthyosis from four countries. All those with X-linked disease had markedly reduced enzyme levels compared with controls and patients with other types of ichthyosis. X-linked ichthyosis seems to be the result of a common mutation affecting the expression of steroid-sulphatase activity.
Summary
some other cases of X-linked ichthyosis, we undertook the present collaborative study and found that steroid-sulphatase deficiency appears to be the cause of many, and perhaps all, cases of X-linked ichthyosis in families from all over the world.
for
Patients and Methods Patients with various types of ichthyosis were recruited from several centres. Skin-biopsy specimens were obtained and cultured fibroblasts were grown as described elsewhere.s Control fibroblast lines were obtained from patients undergoing diagnostic skin biopsy for other reasons. Each patient was examined by an experienced dermatologist; family history was obtained, and their disease was classified on the basis of clinical, histological, and genetic criteria. Biopsy specimens from some patients were prepared for electron microscopy and examined as previously described.6 The samples were coded and sent to Torrance, California, for measurement of steroid-sulphatase activity. Assays were conducted without knowledge of
the dermatological diagnosis. Confluent fibroblast cultures at early passage, were harvested from T-75 flasks. Cells were washed and suspended in 0.05 mol/I "tris"-HCl buffer containing 10 mg/dl sodium CHOLESTEROL-SULPHATASE ACTIVITY IN NORMAL AND ABNORMAL
Introduction
ICHTHYOSIS is a descriptive term for the clinical findings in several genetic and sporadically occurring skin diseases. Although several rarer forms of ichthyosis have been associated with complex syndromes, lamellar ichthyosis, ichthyosis vulgaris, and X-linked ichthyosis are not uncommon disorders. Investigations of normal and abnormal keratinisation in an attempt to clarify the pathogenesis of these conditions have not met with much success. Furthermore, clinical differentiation between autosomal dominant ichthyosis vulgaris, autosomal recessive lamellar ichthyosis, and X-linked ichthyosis has been dependent upon physical distribution, size and colour of scales, histological appearance of and family history.23 Overlap between groups makes accurate diagnosis and genetic counselling difficult. When studying two families with steroid-sulphatase deficiency, we noted that individuals who had this inborn error of metabolism had a dermatosis clinically and genetically similar to X-linked ichthyosis.4 To assess the possibility that this enzymopathy might be responsible
biopsy specimens,
11. 12. 13. 14.
Mellors, R. C. Blood, 1966, 27, 435. Schwartz, R. S. Lancet, 1972, i, 1266.
Steinberg, A. D. Arthritis Rheum. 1974, 17, 11. Grausz, H., Earley, L. E., Stephens, B. G. New Engl. J. Med. 1970, 283,
506. 15. Evans, A. S., Niederman, J. C., Rothfield, N. F. Arthritis Rheum. 1971, 14, 160. 16. Epstein, M. A., Achong, B. A. A. Rev. Microbiol. 1973, 27, 413. 17. Crocker, B. P., Del Villano, B. C., Jensen, F. C., Lerner, R. A., Dixon, F. J.J. exp. Med. 1974, 140, 1028. 18. Hoover, R., Fraumeni, J. F. Lancet, 1973, ii, 55. 19. Casey, T. P. Clin. exp. Immun. 1968, 3, 305. 20. Lukes, R. J., Tindle, B. H. New Engl. J. Med. 1975, 292, 1. 21. Fizzera, G., Moran, E.M., Rappaport, H. Am. J. Med. 1975, 59, 803. 22. Nilsen, L. B., Missal, M. E., Condemi, J. J. Cancer, 1967, 20, 1930. 23. Smith, C. K., Cassidy, J.T., Bale, G.G. Am. J. Med. 1970, 48, 113. 24. Andreev, V. C., Zlathov, N. B. Br. J. Derm. 1968, 80, 503. 25. Lipsmeyer, E. A. Arthritis. Rheum. 1972, 15, 183. 26. Walden, P. A. M., Phibaliths, P. E., Joekes, A. M., Bagshawe, K. D. Clin.
Nephrol. 1977, 8, 317.
SKIN FIBROBLASTS
patients
in
a recent
mide16 there
were
4
recorded. 22
SYSTEMIC LUPUS ERYTHEMATOSUS AND LYMPHOMA A. A. DAWSON WILLIAM WALKER
J. A. GREEN
Departments of Medicine and Therapeutics, University of Aberdeen In 4 women lymphomas developed 2 months to 12 years after the onset of systemic lupus erythematosus. An association between the two diseases had previously been reported in 14 cases, in 6 of which the lymphoma either preceded or was diagnosed at the same time as the autoimmune disease. In systemic lupus erythematosus early biopsy of suspect lymph-nodes is recommended.
Summary
Introduction THE association between autoimmune disease and
malignancy is well known. Up to 20% of patients with dermatomyositis have an underlying carcinoma, and other non-organ-specific autoimmune diseases-Sjogren’s syndrome, polyarteritis nodosa, and rheumatoid arthritis-have been associated with lymphoid malignancies.2-4 14 cases of systemic lupus erythematosus (S.L.E.) and lymphoma are documented, the diagnoses being made simultaneously in 44-6 and lymphoma preceding the s.L.E. in 2.46 This paper describes 4 more patients with established S.L.E. in whom lymphoma subsequently developed. The diagnosis of S.L.E. was made on the basis of clinical and laboratory findings. The temporal course of the disease was defined by the terms s.L.E. onset for the time of the first significant symptom and zero time (to) for the time at which treatment for S.L.E. was decided.7 A definite histological diagnosis of Hodgkin’s disease, non-
DR HUGHES AND OTHERS: REFERENCES
2.
3.
Our results provide no grounds for the use of steroids in the management of acute inflammatory neuropathy since the prognosis is not improved, the rate of recovery is slowed, and the chance of relapse may be increased. Careful nursing, physiotherapy, and attention to the risk of ventilatory failure and circulatory complications remain the mainstay of treatment.
We thank Prof P. Armitage for his advice, Sister I. Dillon and staff of the Batten Unit, National Hospital for Nervous Diseases, for their assistance in holding the central register, the Medical Research Council for financial support and the physicians who entered patients to the trial (Dr J. N. Blau, Dr J. H. J. Durston, Dr A. G. Freeman, Dr W. W. Gooddy, Dr M. Green, Dr B. P. Harold, Dr P. K. P. Harvey, Dr A. P. Hopkins, Dr J. M. B. Hughes, Dr N. Jones, Dr R. S. Kocen, Dr N. J. Legg, Dr 1. C. K. Mackenzie, Prof. J. Marshall, Dr J. N. Milnes, Dr B. G. R. Nevilie, Dr B. G. Parsons Smith, Prof. R. J. Robinson, Dr R. W. Ross Russell, Dr P. Rudge, Dr G. Hillas Smith).
References at foot of next column
Kurland, L. T., Mulder, D. W. Neurology, Minneap., 1973, 23, 1269. Wiederholt, W. C., Mulder, D. W., Lambert, E. H. Proc. Mayo Clin. 1964, 39, 427. McLeod, J. G., Walsh, J. C., Prineas, J. W., Pollard, J. D. J. neurol. Sci.,
1. Lesser, R. P., Hauser, W. A.,
4. 5.
1976, 27, 145. Löffel, N. B., Rossi, L. N., Mumenthaler, M., Lütschg, J., Ludin, H. P. ibid. 1977, 33, 71. Dowling, P. C., Menonna, J. P., Cook, S. D. J. Am. med. Ass. 1977, 238, 317.
6. 7.
Jackson, R. H., Miller, H., Schapira, K. Br. med. J. 1957, i, 480. Gilpin, S. F., Moersch, F. P., Kernohan, J. W. Archs Neurol. Psychiat., Chicago, 1936, 35, 937. 8. Heller, G. L., De Jong, R. N. Archs Neurol., Chicago, 1963, 8, 179. 9. Bammer, H., Schaltenbrand, G. Münch. med. Wschr. 1965, 107, 1629. 10. Prineas, J. Acta neurol. scand. 1970, 46, (suppl. 44),1 11. Marshall, J. Brain, 1963, 86, 55. 12. Frick, E., Angstwurm, H. Munch. med. Wschr. 1968, 110, 1265. 13. Goodall, J. A. D., Kosmidis, J. C., Geddes, A. M. Lancet, 1974, i, 524. 14. Swick, H. M., McQuillen, M. P. Neurology, Minneap 1976, 26, 205. 15. Arnason, B. G. W. in Peripheral Neuropathy Vol II, (edited by P. J. Dyck, P. K. Thomas and E. H. Lambert); p. 1110. Philadelphia, 1975. 16. Rosen, A. D., Vastola, E. F. J. neurol. Sci. 1976, 30, 179. 17. Walton, J. N. in Brain’s Diseases of the Nervous System; p. 952. Oxford, 1977. 18. Taverner, D., Cohen, S. B., Hutchinson, B. C. Br. med. J. 1971, iv, 20. 19. Hughes, R. A. C., Leibowitz, S. L. in Immunology in Medicine (edited by E. J. Holborow and W. G. Reeves); p. 878, New York: 1977. 20. Lisak, R. P., Mitchell, M., Zweiman, B, Orrechio, E., Asbury, A. K. Ann Neurol. 1977, 1, 72. 21. Drachman, D. A., Paterson, P. Y., Berlin, B., Roguska, J. Neurology, Minneap. 1970, 20, 390. 22. Bresler, R., Johnson, C. T. Ann. intern. Med. 1959, 50, 1298.
754
Hodgkin’s lymphoma, was
taken
as
or chronic lymphocytic leukxmia the time of onset of lymphoma.
Case-reports Case A In a 22-year-old woman severe photodermatitis of the extremities developed in August, 1963. Antinuclear factor (A.N.F.) was weakly positive, and a skin biopsy showed a non-specific perifollicular focal dermatitis. In August, 1964, she had vascular purpura, cardiac triple rhythm, and an aortic systolic ejection murmur. Investigation showed: hxmoglobin 8.11 g/dl, white blood-cells 2.7-8-0x10/1, platelets 60-100xl0"/l, erythrocyte sedimentation-rate (E.S.R.) 75 mm/h, no L.E. cells, strongly positive A.N.F., T-wave changes in the chest leads on electrocardiography (E.C.G.), and diminished pulmonary transfer factor. Small nodes were found in the neck and axilla. Relapses over the next 10 years responded to short courses of prednisolone, and skin biopsy during one episode showed a non-specific vasculitis. L.E. cells were found intermittently. Axillary and supraclavicular lymphadenopathy appeared in June, 1974, and initially resolved with prednisolone, but it progressed again and in December, 1975, histological assessment showed non-Hodgkin’s lymphoma of nodular well-differentiated type. Investigation showed clinical stage-ila disease, and since mantle radiotherapy both diseases have remained -
quiescent. Case B A 50-year-old woman presented in May, 1963, with nephrotic syndrome and mild hypertension. Investigation showed: full blood-count normal, serum-urea 6 mmol/1, proteinuria 12 g/1, urinary red-cell casts, E.S.R. 103 mm/h, A.N.F. negative. Needle biopsy of kidney showed a progressive sclerosing glomerulonephritis. On a low-salt, high-protein diet and 20 mg prednisolone daily, her condition improved, although bilateral retinal-vein thromboses developed in June, 1964. A photoder-
matitis in June, 1965, was controlled with barrier cream after a short course of local steroids. Prednisolone therapy was withdrawn in 1965, and over the next 11 years chronic renal failure slowly developed, the serum-urea rising to 13.3 mmol/[. Mild hypertension was controlled with methyldopa. In June, 1976, painless axillary, submandibular, and cervical lymphadenopathy was noted and proved on node biopsy to be a nodular well-differentiated lymphocytic lymphoma. Investigation by lymphangiography, gallium-67 scan, and marrow biopsy showed no other evidence of disease. The A.N.F. was weakly positive and the anti-D.N.A.-antibody titre rose to 25 units/ml. With mantle radiotherapy the lymphadenopathy regressed, and for the past 21 months the patient has been well except for Raynaud’s phenomenon, a serum-urea of 23 mmol/1, and moderate proteinuria.
Case C
56-year-old woman presented in October, 1970, with bruising and gastrointestinal and retinal hxmorrhages. Laboratory investigations showed: haemoglobin 10.8 g/dl, white blood-cells 3-7xl0"/l, platelets 4xlO9/1, A.N.F. negative. Marrow aspirate was compatible with idiopathic thrombocytopenic purpura, and the patient was treated by splenectomy after unsuccessful treatment with high-dose prednisolone and azathioprine. The platelet-count remained normal for 4 years without drug therapy until relapse (platelets 9x10/1) in April, 1974, which was treated with further prednisolone, azathioprine, and corticotrophin. Arthropathy developed in May, 1975, together with soft-tissue swelling of the hands and Raynaud’s phenomenon. This was followed by malaise, fever, pericarditis, and pleural effusions. These features, together with positive A.N.F., L.E. cells, and anti-D.N.A.-antibody titre of 34 units/ml, formed the basis for a diagnosis of S.L.E. She remained fairly well for 2 years on azathioprine and steroids until September, 1977, when bilateral axillary lymphadenopathy was noted, associated with a relapse of the arthropathy and Raynaud’s phenomenon. A lymph-node biopsy in December, 1977, showed A
DETAILS OF PATIENTS WITH S.L.E. FOLLOWED BY LYMPHOMA
* present series. t alive at stated survival. to=firm clinical diagnosis ofs.L.B. c.L.L.=chronic lymphocytic leukxmia.
c.T.=cytotoxic therapy. N.H.L.=non-Hodgkin’s lymphoma. R.T.=radiotherapy.
755
Hodgkin’s disease of mixed cellularity, and mediastinal node enlargement was found on X-ray. Clinical staging was ns, and treatment with mantle radiotherapy was given, but she died suddenly at home 3 months later with presumptive evidence of overwhelming infection. Necropsy was not done. Case D A
28-year-old
ment
woman
presented
in
September, 1976, with
of sharp retrosternal pain aggravated by moveand associated with dyspnoea, palpitations, muscular
sudden
onset
aches, arthralgia, dysphagia, Raynaud’s phenomenon, fever, and sweating. Further inquiry elicited a 6-month history of malaise, weight-loss, and secondary amenorrhrea. On examination she
was
tachypnoea.
pyrexial (39°C) with sinus tachycardia and was 56 mm/h, and .c.G. showed s.T. elevan, aVF, V4-6’ Serum-immunoglobulins were nor-
E.S.R.
tion in leads i, mal, and blood-cultures, throat swab, Paul Bunnell test, A.N.F.,
cells, and antistreptolysin-0 titre were all negative. A diagnosis of pericarditis of presumed viral origin was made, and her condition improved then relapsed 5 days later. A widespread purpuric rash and loud pleuropericardial friction were present, and small cervical and axillary nodes were palpable. Hemoglobin had fallen to 9.9 g/dl, but the platelet and leucocyte counts were normal. A fixed high titre of antibody to Coxsackie B4 virus and an eightfold rise in the titre of anti-parainfluenza-virus antibody were observed. Skin biopsy showed a non-specific vasculitis. Symptoms were controlled with 40 mg prednisolone daily, but the lymphadenopathy progressed, and in November, 1976, a large axillary node showing the features of Hodgkin’s disease of mixed cell type was excised. Gallium-67 scanning, bone-marrow trephine, laparotomy, and splenectomy showed no other evidence of disease, and the extent was classified as stage UB. Telecobalt therapy was given to the supradiaphragmatic lymph-node areas, and there has been no clinical recurrence of the Hodgkin’s disease to date. Over the past 16 months she has been well despite an antiD.N.A.-antibody titre of 35 units/ml. L.E.
Discussion The clinical distinction between such
an
ill-defined
entity as s.L.E. and the rheumatic manifestations of malignant disease can be difficult, and in lymphomas this difficulty is compounded by their histological and serological similarities to S.L.E.l The 4 cases previously reported in which both diseases were diagnosed simultaneously4-6 and the 2 cases in which the lymphoma preceded S.L.E. by 2 and 4 years respectively46 all had evidence of extensive lymphomatous involvement, and the systemic symptoms could perhaps be explained by chronic tumour-derived antigenxmia giving rise to immune-complex and antinuclear-antibody formation. Although many patients would not have been investigated further once malignant disease was diagnosed, the lack of other reported cases is surprising. The label "systemic manifestation of malignant disease" may too often have been regarded as a diagnosis rather than as a stimulus to further thought on the pathophysiology of cancer. As has been proved with ectopically produced hormones, an interesting syndrome may later give rise to a useful marker of malignancy. All 12 patients in whom s.L.E. preceded lymphoma (see accompanying table) were women. The mean age at first
36 years, and at to 41 years. Lymphoma diagnosed at mean age 46. S.L.E. preceded the development of lymphoma by 2 months to 12 years. 4 cases were Hodgkin’s disease, and 8 were classified as non-Hodgkin’s lymphoma. There is much eviS.L.E.
symptom was
was
dence that the common factor underlying the association could be immunodeficiency. Patients with primary immunodeficiency disorders have an incidence of malignancy 10 000 times greater than expected,8 and a high proportion of these tumours are lymphomas. Delayed hypersensitivity and T and B cell function are impaired in S.L.E.,9 and genetic lesions located in the major histocompatibility complex adjacent to the postulated immune-response genes produce a disease similar to S.L.E.I0 NZB/BL mice spontaneously acquire an s.L.E.-like disease with glomerulonephritis, A.N.F., and L.E. cells, and they have a high incidence of lymphomas.11 Current concepts favour suppressor-T-cell dysfunction as the primary lesion in s.L.E.,12 13 predisposing to abnormal B-cell proliferation in response to an extrinsic antigen or autoantigen. Most non-Hodgkin’s lymphomas are thought to be of B-cell origin. A role for virus infection either as an initiator of the antigenic stimulation or as an opportunistic or latent infection causing malignant transformation of the primed lymphoid cells has been suggested. 12 Virus-like particles have been seen in s.L.E. lesions,14 and raised EpsteinBarr-virus titres have been recorded in S.L.E.15 as well as in Hodgkin’s disease and other lymphomas.16 A murine leuksemia virus produces an s.L.E.-like disease and lymphoma in neonatal mice.17 The immunosuppressive effect of the drugs used to treat the S.L.E. is another factor to be considered, but the evidence implicating azathioprine in the development of tumours is inconclusive,18 19 and the drug was used in only a minority of the patients with S.L.E. and lymphoma so far described. The widespread use of steroids in other conditions without lymphoid tumours being reported makes a causal relationship unlikely. S.L.E. is not a rare disease, and it is surprising that lymphomas are not more often reported if this is indeed a true association. The relation of S.L.E. to the subsequent development of lymphoma may be regarded as facilitation of the neoplastic process by the autoimmune disorder, however the former is initiated. It is even possible that chronic autoimmune and lymphoreticular neoplasms are all manifestations of one basic underlying pathological process-perhaps virus infection in a genetically susceptible host. Benign lymphadenopathy in autoimmune disease, immunoblastic lymphadenopathy, and lymphoma could then be regarded as forming a spectrum of diseases with a common oetiology. 20 21 We thank Dr D. S. Short and Dr R. A. Main for their management of patients A, B, and D. ’
Requests of Medicine,
help
in the
for
reprints should be addressed to J. A. G., Department University of Aberdeen, Foresterhill, Aberdeen AB9 2ZD. REFERENCES
1. 2.
Calabro, J. J. Arthritis Rheum. 1967, 10, 553. Razis, D. V., Diamond, H. D., Craver, L. F. Am. J.
med. Sci.
1959, 238,
327. 3. Talal, N., Bunim, J. J. Am. J. Med. 1964, 36, 529. 4. Miller, D. G. Am. J. intern. Med 1967, 66, 507 5. Howqua, J., Mackay, I. R. Blood, 1963, 22, 191. 6. Cammarata, R. J., Rodman, G. P., Jensen, W. N. Archs intern. Med.
1963, 111, 330. 7. Canoso, J. J., Cohen, A. A. Arthritis Rheum. 1974, 17, 383. 8. Gatti, R.A., Good, R.A. Cancer, 1971, 28, 89 9. Schneider, J., Chin. W., Friou, G. J., Cooper, S. M., Harding, B., Hill, R. L., Quismorio, F. P. Clin. exp. Immun. 1975, 20, 187. 10 Hauptmann, G., Grosshaus, E., Held, E. Annls Derm. Syph 1974, 101, 479.
756 ENZYMATIC BASIS OF TYPICAL X-LINKED
ICHTHYOSIS LARRY J. SHAPIRO ROBERTA WEISS MELODIE M. BUXMAN JACLYN VIDGOFF ROBERT L. DIMOND Division of Medical Genetics, Department of Pediatrics, U.C.L.A. School of Medicine-Harbor General Hospital, Torrance, California; and Department of Dermatology and Division of Medical Genetics, University of Oregon, Health Science Centre, Portland, Oregon, U.S.A.
JAMES A. ROLLER St. John’s Hospital for Diseases
R. S. WELLS
of the Skin, London
Steroid sulphatase activity was determined in cultured fibroblasts from 25 individuals with X-linked ichthyosis from four countries. All those with X-linked disease had markedly reduced enzyme levels compared with controls and patients with other types of ichthyosis. X-linked ichthyosis seems to be the result of a common mutation affecting the expression of steroid-sulphatase activity.
Summary
some other cases of X-linked ichthyosis, we undertook the present collaborative study and found that steroid-sulphatase deficiency appears to be the cause of many, and perhaps all, cases of X-linked ichthyosis in families from all over the world.
for
Patients and Methods Patients with various types of ichthyosis were recruited from several centres. Skin-biopsy specimens were obtained and cultured fibroblasts were grown as described elsewhere.s Control fibroblast lines were obtained from patients undergoing diagnostic skin biopsy for other reasons. Each patient was examined by an experienced dermatologist; family history was obtained, and their disease was classified on the basis of clinical, histological, and genetic criteria. Biopsy specimens from some patients were prepared for electron microscopy and examined as previously described.6 The samples were coded and sent to Torrance, California, for measurement of steroid-sulphatase activity. Assays were conducted without knowledge of
the dermatological diagnosis. Confluent fibroblast cultures at early passage, were harvested from T-75 flasks. Cells were washed and suspended in 0.05 mol/I "tris"-HCl buffer containing 10 mg/dl sodium CHOLESTEROL-SULPHATASE ACTIVITY IN NORMAL AND ABNORMAL
Introduction
ICHTHYOSIS is a descriptive term for the clinical findings in several genetic and sporadically occurring skin diseases. Although several rarer forms of ichthyosis have been associated with complex syndromes, lamellar ichthyosis, ichthyosis vulgaris, and X-linked ichthyosis are not uncommon disorders. Investigations of normal and abnormal keratinisation in an attempt to clarify the pathogenesis of these conditions have not met with much success. Furthermore, clinical differentiation between autosomal dominant ichthyosis vulgaris, autosomal recessive lamellar ichthyosis, and X-linked ichthyosis has been dependent upon physical distribution, size and colour of scales, histological appearance of and family history.23 Overlap between groups makes accurate diagnosis and genetic counselling difficult. When studying two families with steroid-sulphatase deficiency, we noted that individuals who had this inborn error of metabolism had a dermatosis clinically and genetically similar to X-linked ichthyosis.4 To assess the possibility that this enzymopathy might be responsible
biopsy specimens,
11. 12. 13. 14.
Mellors, R. C. Blood, 1966, 27, 435. Schwartz, R. S. Lancet, 1972, i, 1266.
Steinberg, A. D. Arthritis Rheum. 1974, 17, 11. Grausz, H., Earley, L. E., Stephens, B. G. New Engl. J. Med. 1970, 283,
506. 15. Evans, A. S., Niederman, J. C., Rothfield, N. F. Arthritis Rheum. 1971, 14, 160. 16. Epstein, M. A., Achong, B. A. A. Rev. Microbiol. 1973, 27, 413. 17. Crocker, B. P., Del Villano, B. C., Jensen, F. C., Lerner, R. A., Dixon, F. J.J. exp. Med. 1974, 140, 1028. 18. Hoover, R., Fraumeni, J. F. Lancet, 1973, ii, 55. 19. Casey, T. P. Clin. exp. Immun. 1968, 3, 305. 20. Lukes, R. J., Tindle, B. H. New Engl. J. Med. 1975, 292, 1. 21. Fizzera, G., Moran, E.M., Rappaport, H. Am. J. Med. 1975, 59, 803. 22. Nilsen, L. B., Missal, M. E., Condemi, J. J. Cancer, 1967, 20, 1930. 23. Smith, C. K., Cassidy, J.T., Bale, G.G. Am. J. Med. 1970, 48, 113. 24. Andreev, V. C., Zlathov, N. B. Br. J. Derm. 1968, 80, 503. 25. Lipsmeyer, E. A. Arthritis. Rheum. 1972, 15, 183. 26. Walden, P. A. M., Phibaliths, P. E., Joekes, A. M., Bagshawe, K. D. Clin.
Nephrol. 1977, 8, 317.
SKIN FIBROBLASTS
