FAMILIAL α-LIPOPROTEIN DEFICIENCY (TANGIER DISEASE) WITH NEUROLOGICAL ABNORMALITIES

1341

latter not carrying the risk of homologous serum jaundice. A further possibility is to include the essential aminoacids in the dialysate in a concentration equal to that in the plasma, as has been suggested by Young and Parsons (1966) in haemodialysis, or to include aminoacids in the dialysing fluid in a concentration equal to that found in the dialysate as proposed in haemodialysis by Giordano et al. (1966). Should this be taken into consideration, aminoacids could be added in amounts equal to the mean loss indicated in table n. Of course, addition of aminoacids to the dialysing fluid would cover only loss of aminoacids and none or little of the loss of protein, which should always be replaced by one of the above-mentioned methods. We would stress that the need for protein-and aminoacid replacement is particularly important in repeated peritoneal dialysis, much more so than in repeated hxmodialysis because of the combined protein and aminoacid loss in peritoneal dialysis. The relation of increasing aminoacid loss to increasing dialysate volume may be simply an expression of a constant drain from an aminoacid pool which is repeatedly and continually replenished from the labile proteins and tissue aminoacids. Alternatively it may be caused by increasing chemical irritation of the peritoneum, but this seems unlikely because it would be expected to lead to a greater protein loss with increasing duration of dialysis. This did not happen in our series. The problem could be settled with certainty by measuring aminoacid loss in individual exchanges throughout a dialysis rather than the

dialysate pool. This work represents the fruits of an international cooperative effort. The patients were in Manchester while the laboratory in which the extremely complicated analyses were carried out was in Naples, 1500 miles away. We thank the physicians who referred the patients to us, and Prof. D. A. K. Black and Prof. F. Magrassi for reading the manuscript. Part of this work was done under U.S. Public Health Service grant no. HE.05773-06 to one of us (C. G.) Requests for reprints should be addressed to G. M. B., Department of Medicine, Royal Infirmary, Manchester 13. REFERENCES

Berlyne, G. M., Hewitt, V., Jones, J. H., Nilwarangkur, S., Ralston, A. J. (1964) Proc. europ. Dial. Transplant. Ass. 1, 177. Jones, J. H., Hewitt, V., Nilwarangkur, S. (1964) Lancet, i, 738. Lee, H. A., Ralston, A. J., Woolcock, J. A. (1966) ibid. ii, 75. Giordano, C., Esposito, R., de Pascale, C., de Santo, N. G. (1966) Proc. Int. Congr. Nephrol. Washington (in the press). Moore, S., Spackman, D. H., Stein, W. H. (1958) Analyt. Chem. 30, 1185. —

—

Rosen, H., Meroney, W. H., Levenson, S. M. (1958) Clin. Sci. 17, 653. Young, G. A., Parsons, F. M. (1966) ibid. 31, 299.

" ... In the days when physicians had more authority in the community and few specific remedies, they realised that the art of healing transcended the writing of a prescription, a lesson that may be forgotten amid the modern welter of drugs. The

bottle of coloured water, standard material for humour, fell into disrepute because it could be used as a substitute for adequate diagnosis, but it was at least harmless.... Although the placebo effect has been recognised by scientific measurements, the placebo itself, however respectable its quantitated benefits, remains a disreputable remedy; it deserves a better fate. New drugs are like sports cars, exciting in their performance but difficult to control. Surgeons are more familiar than physicians with the drama of therapy; it is for the physician to ensure that the giving of any drug is considered as seriously as a surgical operation. This is the only way of curbing the alarming spread of iatrogenic disorders. Poetry, it is said, is born of emotion recollected in tranquillity. Unfortunately, it cannot be said that the average prescription is written after a period of recollection during which knowledge and judgment fill the writer’s mind. Prescribing throughout the world is a very idiosyncratic activity, born too often of speed, prejudice and defective information."-Editorial, 71 R. Coll. Physns Lond. April, 1967, p. 219.

FAMILIAL &agr;-LIPOPROTEIN DEFICIENCY

(TANGIER DISEASE) WITH NEUROLOGICAL ABNORMALITIES R. S. KOCEN RESIDENT MEDICAL

M.B. Leeds, M.R.C.P. OFFICER, NATIONAL HOSPITAL

FOR NERVOUS DISEASES

JUNE K. LLOYD M.D. Brist., M.R.C.P. SENIOR

LECTURER,

DEPARTMENT OF CHILD HEALTH

P. T. LASCELLES Lond., M.C.Path.

M.D.

SENIOR

DEPARTMENT OF CHEMICAL

LECTURER, PATHOLOGY, INSTITUTE

OF NEUROLOGY

AUDREY S. FOSBROOKE M.Sc. Birm., B.Sc. LECTURER, DEPARTMENT

Southampton OF CHILD HEALTH

DENIS WILLIAMS C.B.E., M.D., D.Sc. Manc., F.R.C.P. PHYSICIAN, NATIONAL HOSPITAL FOR NERVOUS DISEASES

From the National Hospital for Nervous Diseases, Queen Square, London W.C.1, and the Institute of Neurology and Institute of Child Health, University of London

patient with &agr;-lipoprotein deficiency presented with widespread dissociated loss of pain and temperature sensation and progressive focal muscle wasting and weakness. Electrical and histological investigations revealed disordered function and structure of the peripheral nerves. The typical pharyngeal appearSummary

A

present, and cholesterol ester was demonstrated in the sternal marrow and rectal mucosa. The small amount of &agr;-lipoprotein present contained an excessive proportion of triglyceride. An increased proportion of triglyceride was also present in &bgr;-lipoprotein. Studies of the serumlipoproteins in relatives confirmed the familial nature of the defect. Introduction FAMILIAL (x-lipoprotein deficiency was first described by Fredrickson et al. (1961) in a five-year-old boy and his six-year-old sister, and was named Tangier disease after the Chesapeake Bay island home of these children. A further three pairs of siblings from unrelated families with the disease have since been reported (Hoffman and Fredrickson 1965, Fredrickson 1966, Engel et al. unpublished) and the disorder has been shown to be inherited as an autosomal recessive (Fredrickson et al. 1964). The clinical manifestations include enlarged, yellow-orange tonsils or pharyngeal lymph follicles, present in all patients; and hepatosplenomegaly, lymphadenopathy, and corneal infiltration in some patients. Investigations have shown almost complete absence of a-lipoprotein from the serum with reduced cholesterol and increased triglyceride concentrations. Storage of cholesterol ester has been demonstrated in many tissues, particularly in the reticuloendothelial system. In 4 of the patients, the diagnosis was made during childhood and tonsillar enlargement was the presenting feature. In 2 adolescent siblings a relapsing peripheral neuropathy was present (Engel et al. unpublished). A forty-two-year-old man presented with hypersplenism; his brother, who was subsequently found to have the disease, had had angina for five years before his sudden death at the age of forty-eight years, probably from myocardial infarction. In the remaining patients, the disease has run an apparently benign ance was

course.

We describe here

a

further

example of this rare disorder

1342 in a

adult who presented with type not previously reported. an

neurological symptoms of

TABLE I-FASTING SERUM-LIPIDS AND LIPOPROTEINS IN THE PATIENT

Case-report patient, a thirty-seven-year-old Royal Air Force corporal, was admitted to the National Hospital for Nervous Diseases in July, 1966, at the request of Air Commodore P. J. O’Connor, with a ten-year history of having sustained a number of painless burns on his arms, and of having painlessly The

bitten the inside of his mouth. For several years he had been unable to close his eyes fully, and for about three years had noted slowly progressive weakness and wasting of his hands. Two years before his admission he had been found to have a small goitre; and investigations elsewhere disclosed a serumcholesterol level of 50 mg. per 100 ml. with normal results in radioactive iodine thyroid function tests. His neurological disorder was considered at that time to be due to syringomyelia; his cerebrospinal fluid on routine examination and a myelogram were normal, and he underwent radiotherapy (1000r) to the cervical spinal cord. He had no other symptoms, and his past

the exception of the distal parts of the legs, knees, and parts of hands and fingers (fig. 1). At the junction of the normal and abnormal areas there was gross delay in the appreciation of pain. Light touch, joint position, and vibration sense were normal, but the two-point discrimination threshold in the fingers and feet was raised. The histamine flare was present though diminished in the anxsthetic areas, but was normal elsewhere. The response to the Valsalva manoeuvre appeared normal. The peripheral nerves were not thickened on

palpation. Investigations The finding

of gross turbidity of the fasting serum with total cholesterol level of only 50 mg. per 100 ml. led to more detailed studies of the serum-lipids and lipoproteins (table I, figs. 2 and 3). a

Patient with shows distribution of temperature sensation.

Fig. 1-Shaded

history

was

area

impairment of pain

uneventful. His tonsils had been removed

at

Tangier

and

disease

strip stained for lipid the

age of four years.

On examination he was of normal physique and intelligence. His skin was scarred at the sites of previous injury to his arms and at the corners of his mouth. The left lobe of the thyroid gland was slightly enlarged but there was no clinical evidence of thyroid dysfunction. The pharynx showed a number of raised yellowish-orange plaques 5-10 mm. in diameter in the tonsillar fossae and on the posterior pharyngeal wall. A firm spleen was palpable 3 cm. below the left costal margin. The liver was not palpable, and there was no lymphadenopathy. Sigmoidoscopy (Dr. W. G. Reeves) revealed several small dark-red nodules 1-2 mm. in diameter throughout the mucosa, which was examined up to a distance of 15 cm. There were no ocular abnormalities, and, in particular, slit-lamp examination (Mr. P. J. Clover), dark adaptation, electroretinography, and electroculography were all normal. Trigeminal motor function was normal, and the corneal reflexes were brisk, but pain sensation was severely impaired and temperature sensation showed some impairment over the whole trigeminal territory. The periorbital muscles were slightly wasted and attempted eye closure was strikingly weakened, though other facial movements were relatively preserved. Wasting and weakness of the muscles of the hands were more pronounced on the left side, and there was some wasting of the distal part of the left forearm. Biceps, supinator, and finger jerks were normal, triceps and knee jerks were diminished, and ankle jerks were absent. Upper abdominal reflexes were present and lower ones absent. Plantar reflexes were flexor. Sensory examination disclosed severe impairment of pain and temperature sensation over the body and limbs with

strip stained For

protein

Normal control strip stained

for lipid

n. Fig. 2-Paper-electrophoretic pattern.

Patient with disease

Tangier

Normal control

/3-lipoprotein

precipitin line

oc-tipoprotein

precipitin line

Fig. 3-Immunoelectrophoresis: trough contains polyvalent antihuman antiserum ; precipitin lines stained with Sudan black.

1343 Total cholesterol was estimated according to the method of Brown (1961), triglyceride according to the method of Freeman (1964), and total phospholipids (lipid phosphorus x 25) according to the method of Bartlett (1959). The individual phospholipids were quantitatively measured after separation by thin-layer chromatography. Analysis of the fatty-acid composition of whole serum-triglyceride and cholesterol esters by gas-liquid chromatography (Dr. I. Tamir) showed a normal distribution of the major fatty acids; 3, 7, 11, 15-tetramethylhexadecanoic acid was not found (Prof. J. N. Cumings).

median nerve).

Sensory-

action potentials from the digital nerves in the fingers (Gilliatt and Sears 1958) and the lateral popliteal nerve action potential (Gilliatt et al. 1961) were absent. A biopsy specimen was taken from the superficial cutaneous branch of the left radial nerve just above the wrist.

Serum-lipoproteins were separated by paper electrophoresis (Salt and Wolff 1957) and by ultracentrifugation in a salinedensity gradient (Cornwell et al. 1961). Before ultracentrifugation, chylomicra were removed by centrifugation of the serum Light-microscopy for thirty minutes at 10,000 x g. On immunoelectrophoresis showed great increase in 4-Family tree : HDL high(Grabar and Williams 1955) using polyvalent antiserum the endoneurial collagen Figdensity lipoprotein (a-lipoprotein) and extensive loss of (Pasteur Institute, Paris) no a-lipoprotein could be detected. cholesterol concentrations (mg. per 100 ml.). Harmatological investigations showed: haemoglobin 14-8 g. myelin sheaths and Mean normal values for children, axons. Cells containing per 100 ml.; white-blood-cells 11,500 per c.mm. with normal 64 ± 17; adult males, 65 8; and differential count; platelets 135,000 per c.mm.; red-cell Scharlach R-positive morphology normal; erythrocyte-sedimentation rate 13 mm. in material were present in adult females, 88 ± 12. one hour; osmotic fragility normal. Sternal aspiration showed close relation to nerveThere was no evidence of amyloid material (Dr. an active marrow containing a large number of foam cells which fibres. stained with osmic acid and Scharlach R and gave a positive W. G. P. Mair, Dr. P. K. Thomas). A rectal biopsy specimen Schultz reaction for cholesterol esters. The periodic-acid/Schiff showed the presence of many cells with foamy cytoplasm and small nuclei lying in the mucosa and under the muscularis reaction for aldehyde groupings was negative. The red-cell and white-cell series, and megakaryocytes were normal (Dr. mucosa. These foam cells stained with Scharlach R; and the D. Donaldson). Pascal fat (mean excretion of 3-4 g. per day) Schultz reaction was positive. Amyloid material was not and xylose absorption were normal. The uptake of T -3 resin demonstrated (Dr. W. G. P. Mair). was normal. Thyroid cytoplasmic antibodies were demonFamily Studies strated by immunofluorescence, and the complement-fixation We were able to examine both parents, both siblings, the test was positive at a titre of 1/4. The tanned-red-cellpatient’s wife, and both his children. The family comes from hxmagglutination test for thyroglobulin antibodies was nega- the Bristol area, and there is no history of consanguinity. =

Immunofluorescent tests for antinuclear factors and gastric parietal cell antibodies were negative (Dr. D. Doniach, Middlesex Hospital Medical School). Serum sodium, potassium, calcium, inorganic phosphorus, acid phosphatase, folic acid, vitamin B12, iron, phosphocreatine kinase, uric acid, oral glucose tolerance, and liver-function tests, including bromsulpthalein excretion and prothrombin-time were normal. Total serum-protein was 7-0 g. per 100 ml. (albumin 3-8 g. per 100 ml.) and the immunoglobulin IgM was raised (255 mg. per 100 ml.) (Dr. J. R. Hobbs). The Wasserman reaction was negative in blood and cerebrospinal fluid. The cerebrospinal fluid contained no cells, 35 mg. per 100 ml. protein, and had a normal total phospholipid content (19-2 (j<.g. per 100 ml.) (Prof. J. N. Cumings). Proteinuria (1-0 g. per 24 hours), unaffected by posture, was present. No Bence-Jones protein was detected. There were no cells or casts, urinary aminoacids tive.

were normal, and there was no glycosuria. Blood-urea, creatinine-clearance, and water-concentration test were normal. X-rays revealed the presence of small, well-corticated, cystlike areas adjacent to the proximal interphalangeal joints of the index, middle, and ring fingers of the right hand, with a similar

but smaller and less well-corticated area in the left index finger. The tip of the tuft of the right ring finger showed absorption with a linear margin (Dr. R. Blend). An electroencephalogram and an electrocardiogram were normal. Electromyography (Dr. R. G. Willison) showed chronic partial denervation in the small muscles of the hands, with slowing of the motor conduction velocity in the fastest fibres to the affected muscles (down to 33 m. per sec. in the TABLE II-FASTING SERUM-LIPIDS

(mg.

per 100

ml.)

IN RELATIVES OF

THE PATIENT

Figures

in

parentheses indicate normal

ranges

(Fredrickson 1966)

Clinical examination of the relatives showed none of the abnormalities described in Tangier disease; the father has bilateral Dupuytren’s contractures, the brother has dextrocardia, and the sister had infrequent epileptic attacks during adolescence. The results of the serum-lipid studies are summarised in table 11 and fig. 4.

Discussion

The classical features of Tangier disease, the unique appearance of the tonsillar remnants and pharyngeal nodes, the presence of cholesterol ester in the bonemarrow and rectal mucosa, and the gross depletion of a-lipoprotein in the serum, were all present in our patient. The finding of reduced amounts of cx.-lipoprotein in the serum of some (though not all) of the presumed heterozygotes confirms the familial nature of the defect. In addition new features were found, both in the clinical manifestations and in the lipoprotein pattern. The concentrations of cholesterol, phospholipids, and triglyceride in the serum of our patient are similar to those previously reported in Tangier disease (Fredrickson 1966) and the finding of a low cholesterol concentration with high fasting serum-triglycerides appears to be virtually diagnostic for this condition. A reduction in the proportion of sphingomyelin compared to phosphatidyl choline in the serum has also been reported in the other cases. Although (x-lipoprotein was grossly reduced in our patient, and could not be detected by paper or immunoelectrophoresis, the amount present, as determined by ultracentrifugal separation, appears to be more than in the previously described cases. The difference may be accounted for, however, by differences in technique; in Fredrickson’s series (1966) 1-21 plasma fraction contains 15-25 mg. per 100 ml. of phospholipid

1344

bound to protein (Phillips 1959) and may contain 3-7 mg. per 100 ml. of cholesterol (Jones and Ways 1967). A further difference is in the method of ultracentrifugation; in our density-gradient method there is always the possibility that the high-density lipoprotein (alpha) fraction may be contaminated with low-density lipoprotein (beta) material. This can probably be discounted in our patient, since immunoelectrophoresis of the high-density fraction failed to reveal any &bgr;-lipoprotein. These considerations, together with the finding that accurate quantification of high-density lipoprotein by ultracentrifugal isolation is affected by changes in the lipoprotein during ultracentrifugation (Levy and Fredrickson 1965), probably indicate that there is no significant difference in respect of the amount of (x-lipoprotein present in our patient and the other patients with Tangier disease. We were unable to obtain an antiserum to (x-lipoprotein which was not contaminated with p-lipoprotein, and thus could not measure the amount present by immunochemical means with the Ouchterlony technique. Abnormalities of the P-lipoproteins were similar to those already described (Fredrickson 1966). The amount of lipoprotein of density 1-019-1-063 was considerably depleted, and that of density < 1-019 was increased; in both these fractions the ratio of cholesterol to phospholipid was decreased. These abnormalities are clearly visible on paper electrophoresis (fig. 2). The major band is broad and has the advanced mobility of pre-&bgr;-lipoprotein; this band represents the material floating at density < 1-019 (Pantelakis et al. 1964). No separate band can be seen in the position of &bgr;-lipoprotein (corresponding to density 1-019-1-063) probably because its amount is so small. Levy et al. (1966) have shown that both a-lipoprotein and p-lipoprotein are necessary for the formation of pre-&bgr;-lipoprotein and were unable to demonstrate pre(3-lipoprotein in their patients with Tangier disease, even when the very low density lipoproteins were further raised by the ingestion of high-carbohydrate diets. The small amount of a-lipoprotein present in Tangier disease " (ex T "), the protein moiety of which has been shown to differ immunochemically from normal ot-lipoprotein (Levy and Fredrickson 1966) may be sufficient to impart advanced mobility to P-lipoprotein in our patient. Estimation of triglyceride in the individual lipoprotein fractions has not been reported in the other cases. In all the fractions isolated in the ultracentrifuge, the amount of triglyceride was strikingly increased. Thus in the highdensity fraction, 51 % of the lipid present was triglyceride, in the low-density fraction 1-063-1-019, 59% of lipid was triglyceride, and in the fraction < 1-019, triglyceride comprised 72% of lipid. The values for healthy persons in these fractions are about 15%, 15%, and 50 %, respectively. One of the functions of normal oc-lipoprotein would therefore seem to be concerned with the lipid composition of all the lipoproteins, since, in its absence, both the ratio of cholesterol to phospholipid and the ratio of triglyceride " to other lipids is altered. Possibly the oc T " apoprotein cannot support the lipid composition of normal ot-lipoprotein, and thus secondarily affects lipid interchanges between the other lipoproteins. Comparisons between the a-lipoprotein values in the relatives of this patient and previously reported cases are subject to the same reservations in respect of differences in methodology already discussed. The amounts of cholesterol in the high-density fraction of the patient’s brother (II2) and younger daughter (III2) are abnormally

low by any standard, and enable the heterozygote state to be identified with fair certainty. Of the remaining presumed heterozygotes, the values for high-density lipoprotein cholesterol in the parents (Ii and 12) are lower than the mean normal values for adult males and females in our laboratory; we believe that they probably indicate the heterozygote abnormality. The entirely normal value in the elder daughter (IIIi) cannot at present be explained. A smaller proportion of females than males with " abnormally low " high-density lipoprotein values has been noted in other kindreds, and pronounced lability of this lipoprotein has also been found in some women (Fredrickson 1966). Clinical evidence of tissue-lipid storage was absent in our family as in the other families, but the presence of hypertriglyceridsemia in the fasting state in the brother (II2) may be associated with the premature development of atherosclerosis in the heterozygote (Fredrickson 1966). The neurological abnormalities which were the presenting feature in our patient have not been described in any of the patients previously reported. Their unusual pattern can be explained by a disorder of peripheral nerves, which is confirmed by the severe electrical and histological abnormalities found. Against the diagnosis of syringomyelia is the distribution of the motor and sensory deficit and the absence of any other evidence of spinal cord disease. Dissociated loss of pain and temperature sensation has been described in the early stages of the neuropathy of primary amyloidosis by Chambers et al. (1958) and by Andrade (1952), some of whose patients were initially diagnosed as having " lumbosacral syringomyelia " ; abnormalities of serum-lipoproteins have been reported in this disorder by Rukavina et al. (1956) but were unlike those found in our patient. Schwartz et al. (1963) and Sobrevilla et al. (1964) reported pathological changes both in the central nervous system and in the The relatively peripheral nerves in
hypercholesterolaemia, widespread cutaneous xanthomata, and a mild sensory neuropathy. The neurological abnormality in our patient may be due to cholesterol storage in the peripheral nerves interfering with normal nerve conduction, although the possibility of a disturbance of the lipid structure of neurones and Schwann cells be ruled out. Proteinuria has not yet been reported in other patients. Gross depletion of high-density lipoprotein has been described in severe renal failure and it has been suggested that renal regulation of this lipoprotein may occur (Lewis et al. 1966). In our patient, renal-function tests gave normal results, but renal biopsy was not carried out, and we therefore cannot say whether there was accumulation of cholesterol ester in renal tissue. The significance of the small goitre is uncertain. Perhaps the greatest importance of this finding in our patient was that it led to the determination of the serumcholesterol level and thus initiated the more detailed serum-lipid studies upon which the diagnosis was based. cannot

We are grateful to Miss D. Walker and Mr. D. Roberts for technical assistance; and to the Medical Research Council and the

1345 Research Board of the Hospital for Sick Children and the Institute of Child Health for financial support. Requests for reprints should be addressed to R. S. K.

Joint

REFERENCES

Andrade, C. (1952) Brain, 75, 408. Bartlett, G. R. (1959) J. Biochem. 234, 466. Brown, W. J. (1961) Aust. J. exp. Biol. 39, 223. Chambers, R. A., Medd, W. E., Spencer, H. (1958) Q. Jl Med. 27, 207. Cornwell, D. G., Kruger, F. A., Hamwi, G. J., Brown, J. B. (1961) Am. J. clin. Nutr. 9, 24. Engel, W. K., Dorman, J., Levy, R. I., Fredrickson, D. S. Unpublished. Fredrickson, D. S. (1966) in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson); p. 486. New York. Altrocchi, P. H., Avioli, L. V., Goodman, D. S., Goodman, H. C. (1961) Ann. intern. Med. 55, 1016. Young, O. M., Shiratori, T., Briggs, N. (1964) J. clin. Invest. 43, 228. Freeman, N. K. (1964) J. lipid Res. 5, 236. Gilliatt, R. W., Goodman, H. V., Willison, R. G. (1961) J. Neurol. Neurosurg. Psychiat. 24, 305. Sears, T. A. (1958) ibid. 21, 109 Grabar, P., Williams, C. A. (1955) Biochim. Biophys. Acta. 17, 67. Hoffman, H. N., Fredrickson, D. S. (1965) Am. J. Med. 39, 582. Jones, J. W., Ways, P. (1967) J. clin. Invest. (in the press). Lewis, L. A., Zuehlke, V., Nakamoto, S., Kolff, W. J., Page, I. H. (1966) New Engl. J. Med. 275, 1097. Levy, R. I., Fredrickson, D. S. (1965) J. clin. Invest. 44, 426. (1966) Circulation, 34, suppl. III, 156. Lees, R. S., Fredrickson, D. S. (1966) J. clin. Invest. 45, 63. Pantelakis, S. N., Fosbrooke, A. S., Lloyd, J. K., Wolff, O. H. (1964) Diabetes, 13, 153. Phillips, G. B. (1959) Proc. Soc. exp. Biol. Med. 100, 19. Rukavina, J. G., Block, W. D., Jackson, C. D., Falls, H. F., Carey, J. H., Curtis, A. C. (1956) Medicine, Baltimore, 35, 239. Salt, H. B., Wolff, O. H. (1957) Arch. Dis. Childh. 32, 404. Schwartz, J. F., Rowland, L. P., Eder, H., Marks, P. A., Osserman, E. F., Hirschberg, E., Anderson, H. (1963) Arch. Neurol. 8, 438. Sobrevilla, L. A., Goodman, M. L., Kane, C. A. (1964) Am. J. Med. 37, 821. Thomas, P. K., Walker, J. G. (1965) Brain, 88, 1079. —

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ŒSTROGEN TREATMENT OF RECURRENT APHTHOUS MOUTH ULCERS P. M. F. BISHOP D.M. Oxon., F.R.C.P. ENDOCRINOLOGIST, GUY’S HOSPITAL AND CHELSEA FOR WOMEN, LONDON

HOSPITAL

P. W. R. HARRIS MEDICAL

M.B. Cantab., M.R.C.P. REGISTRAR, GUY’S HOSPITAL, LONDON S.E.1

J. A. P. TRAFFORD M.B. Lond., M.R.C.P. PHYSICIAN, ROYAL SUSSEX COUNTY HOSPITAL,

development of single or multiple erosive lesions in the oral mucosa, surrounded by an area of oedema and hyperxmia, and usually varying in size from 2 to 10 mm. In some cases the ulcers may appear at any time or may be present continuously, but in other patients the episodes of ulceration are periodic, and in women characteristically occur

premenstrually.

aetiology The

cause of recurrent aphthous ulceration of the mouth has been positively established although numerous agents have been suggested as possible aetiological factors; these include herpes simplex and other viruses, Bacillus crassus, Toxoplasma gondii, allergy and hypersensitivity to foods, and genetic influences. A pleomorphic from of an a-hxmolytic streptococcus has been incriminated by Graykowski et al. (1966). Autoimmune factors have been suggested by Lehner (1964), who found antibodies against buccal mucosa in 75 % of patients with aphthous ulcers and in 10%of patients with non-aphthous ulcerating mouth lesions. Whatever may be the precise cause, if any, of recurrent aphthous ulceration there is no doubt that factors such as dental trauma, chemical irritants, and mental stress may aggravate or precipitate the condition, and in women outbreaks may occur in relation to the menstrual never

cycle. In their series of 335 patients with recurrent aphthous ulceration Sircus et al. (1957) reported that nearly 40% of the female patients had crops of ulcers at intervals of less than eight weeks and usually of less than one month, whereas in males the intervals were very much longer. In 43 of the 45 patients considered by Strauss (1947) all the outbreaks started during the sixteen days preceding the onset of menstruation. In an analysis of twelve-month diaries of 120 young adult female students with aphthous ulceration, Ship et al. (1961) noted peak activity of the disease in the seven days preceding menstruation and during the menstrual period itself. It therefore seems that in some patients an endocrine factor may be concerned in precipitating recurrences of the ulcers, and this is further supported by the association of buccal ulcers with similar ulcers in the vagina ’and vulva; Sircus et al. (1957), for instance, reported periodic involvement of the vagina and vulva in 12 of 80 female patients with recurrent buccal ulceration. Furthermore, several workers have observed that buccal ulcers disappear or show remission during pregnancy only to recur in the postpartum period (Ziserman 1934, Sircus et al. 1957, Ship et al. 1962).

Treatment BRIGHTON

Many agents have been used in the treatment of recurrent Department of Endocrinology, Guy’s Hospital, aphthous ulceration and, as may be expected in a condition the xtiology of which is unknown, have met with little success. In a double-blind trial Sircus et al. (1957) found that folic acid, The ætiology of recurrent aphthous ulceraSummary nicotinamide, riboflavine, a vitamin-B mixture, small doses of tion of the mouth is uncertain, but there is evidence suggesting that there is an endocrine factor in cortisone by mouth, and local radiotherapy were of no significant therapeutic value. Combined aneurine-hydrochloride and recurrences, which are not prevented by any treatment folic-acid therapy induced healing in half the cases reported by hitherto described. Since œstrogen produces hyperDurocher (1966), but the ulcers quickly recurred. Fraserkeratinisation and hyperplasia of oral epithelium we gave Moodie (1960) obtained temporary healing of the ulcers in this hormone to 43 female patients with recurrent aphthous some patients with y-globulin, but this agent proved no more ulceration who were referred to our endocrine clinic. effective than a placebo in preventing recurrences. It has been There was a good response to œstrogen treatment in 30 of suggested that there may be a psychosomatic element in the 33 patients in whom the ulcers were related to the menaetiology of the condtion, but hypnosis was found to be valueless by Chalmers and Sircus (1964). strual cycle, and in 5 of 10 patients without this association. Various forms of topical therapy may induce healing of the ulcers in some patients but are generally unsatisfactory, since Introduction the reponse to treatment is unpredictable and recurrences are RECURRENT aphthous ulceration of the mouth is a not prevented. The local application of tetracycline or chlortecommon and distressing condition. According to Sircus tracycline is probably the most effective (Sircus et al. 1957, et al. (1957), the disease probably affects 1 person in every Sagar and Faulkner 1965, Graykowski et al. 1966). Hydro5 in this country at some period of their lives, the incidence cortisone hemisuccinate, prepared in a lactose base and being higher in females than in males; in more than 50% allowed to dissolve slowly in the mouth, has proved moderately of cases the ulcers first develop between the ages of ten successful in healing aphthous ulcers in the acute phase (Cooke and thirty years. The condition is characterised by the and Armitage 1960, Truelove and Morris-Owen 1958) but From the

London

BB2