1975, British Journal of Radiology, 48, 374-376
Radiosensitivity in ataxia-telangiectasia By P. N. Cunliffe,* J . R. Mann, A . H. Cameron, and K. D. Roberts The Children's Hospital, Ladywood Middleway, Birmingham B16 8ET and H. W. C. Ward The Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH (Received June, 1974)
had developed anorexia, weight loss and weakness of four months duration. He was small (height: 111 cm, weight: 17 kg). There was ataxia of upper and lower limbs and his speech was slurred. The eyes showed nystagmus on lateral gaze and oculo-motor apraxia (halting, irregular conjugate gaze). Telangiectatic vessels were seen on the bulbar conjunctivae and ears (Fig. 1). The clinical diagnosis of ataxia-telangiectasia was supported by characteristic chromosome changes with a high incidence of gaps, breaks and rearrangements in lymphocyte and fibroblast cultures. These will be fully reported elsewhere (Harnden and Oxford, 1974). There was also evidence of immuno-incompetence. Serum IgA and IgG levels were low (IgA 60 mg/100 ml., normal 60—220 mg/100 ml.; IgG 360 mg/100 ml., normal 600-1500 mg/ 100 ml.). Lymphocyte transformation in response to both phytohaemagglutinin and poke weed mitogen was diminished. Chest X-ray examination (Fig. 2) revealed a large opacity in the upper lobe of the right lung. Infection and tumour were considered. Other investigations included: haemoglobin 11 -6 g/100 ml., total white cell count, 19,500/mm3, (80 per cent neutrophils, 15 per cent lymphocytes). Skeletal survey, bone marrow and urinary catecholamine excretion were all normal. At thoracotomy a tumour was found in the right upper lobe surrounding the main bronchus. A right radical pneumonectomy was performed and enlarged hilar lymph nodes were removed. The tumour measured 6 x 5 x 4 cm, and was well circumscribed but not encapsulated. Histology (719.73) revealed a malignant lymphoma. The tumour extended up the bronchus to the plane of resection but the lymph nodes removed showed no evidence of malignancy. Pneumonectomy was followed by radiotherapy. This was given by anterior and posterior parallel opposed 10x8 cm fields with 230 kV X-rays (HVL = 2 mm Cu). Treatment was given on five days each week and the daily incident dose of 200 rads to each field gave a mid-plane dose of approximately 200 rads. After 2,000 rads dysphagia was noted and there was erythema over both radiation fields. Symptoms worsened and treatment was stopped at 3,000 rads. Prednisolone (2 mg/kg per day) reduced the symptoms and skin erythema but when after five days dosage was halved they promptly returned. Resumption of the original dose was ineffective. His condition slowly deteriorated with increasing dysphagia and weakness, and he died three weeks later. The skin sloughed from the irradiated areas of his chest. Our patient was the third child of unrelated healthy parents. An older sister, who died aged five years in 1964 of recurrent pulmonary infection in another hospital, may also have had ataxia-telangiectasia; an older brother is healthy.
Ataxia-telangiectasia is a syndrome of autosomal recessive inheritance characterized by cerebellar ataxia and oculocutaneous telangiectasia (Boder and Sedgwick, 1958; Karpati et ah, 1965). The ataxia, which is progressive, is usually first noticed when the child starts to walk. The telangiectasia, unusual before the age of five, is seen over the bulbar conjunctivae and variously over the ears, nose, cheeks, palate, sternum, antecubital fossae and dorsae of the extremities. Although the basic karyotype is normal there are characteristic chromosomal changes with gaps, breaks, rearrangements, fragments and ring formations (Harnden, 1974). Similar chromosomal instability is also found in Bloom's and Fanconi's syndromes. Immunological deficiency is found in the majority of cases and this may be of either cellular or humoral immunity or both (Peterson, Cooper and Good, 1966). This predisposes to infections especially of the sinobronchial tree. There is also an increased incidence of malignancy, usually of the reticuloendothelial system (Kersey, Spector and Good, 1973). This may be a consequence of the inherent tendency towards cellular mutation in conjunction with the decreased immunological surveillance of immunodeficiency. Each, in other conditions, is associated with an increased incidence of neoplasia. Prognosis is poor because of pulmonary infection and malignancy. Most die in the first decade. Those surviving may develop dementia and chorea. It has been recorded twice before that patients with ataxia-telangiectasia may be sensitive to irradiation (Gotoff, Amirokri and Liebner, 1967; Morgan, Holcomb and Morrissey, 1968). We have ourselves recently observed this distressing complication and feel that further emphasis is needed if it is to be avoided in the future. Case history A seven-year-old boy, under the care of a local hospital for two years because of recurrent respiratory tract infection,
*Present address: Blacktown District Hospital, Blacktown, Sydney, Australia. Requests for reprints should be addressed to Dr. J. R. Mann.
Although it is not known why these patients are radiosensitive, it is interesting that the chromosomal changes of ataxia-telangiectasia are similar in
Radiosensitivity in ataxia-telangiectasia
FIG. 1. Telangiectasia of the bulbar conjunctiva and ear.
many respects to those of irradiation damage in previously normal individuals. From this it may be hypothesized that cells which are liable to spontaneous chromosomal damage of a particular type, may be unusually sensitive to a stimulus which tends to cause change in the same directions. It may be significant that irradiation in vitro of lymphocytes from patients with ataxia-telangiectasia has been reported to produce more chromosomal breaks than in control cells from normal children (Higurashi and Conen, 1973). Radiosensitivity might also be anticipated because of its well described association with light sensitivity, a feature of ataxiatelangiectasia. Of the two cases of radiosensitivity previously described in ataxia-telangiectasia, the first (Gotoff et ah, 1967) developed palatal lymphosarcoma aged FIG.
Chest X-ray showing a large area of opacity in the right upper zone, with elevation of the lesser fissure.
48, No. 569 P. N. Cunliffe, J. R. Mann, A. H. Cameron and K. D. Roberts
10£ years. 3,000 rads were administered to the tumour site resulting in severe dermatitis and deep tissue necrosis with death eight months later. The second (Morgan et al., 1968) with mediastinal Hodgkin's disease in a child aged seven years more closely resembled our case. After two weeks of radiotherapy dysphagia was noted and after 34 days and 2,750 rads, radiation was stopped. The skin became pigmented and desquamated. Severe oesophagitis occurred and the patient died two weeks later of "respiratory embarrassment". In view of these reports and the severe consequences of radiotherapy in our patient we consider that this form of treatment should, whenever possible, be avoided in patients with ataxia-telangiectasia. The suffering that may result is likely to outweigh the possible benefits especially in view of the poor prognosis of the underlying condition. Unfortunately, in patients in whom radiosensitivity is anticipated, sensitivity might also be expected to radiomimetic drugs. Actinomycin D is probably also contraindicated because it is known to enhance radiation reactions. A further disadvantage of chemotherapy is the danger of further suppressing the already defective immune system, thus possibly decreasing tumour resistance as well as increasing problems with infection. We would therefore suggest that if tumour treatment is considered warranted, cytotoxic drugs, other than alkylating agents and Actinomycin D, should be used in small dosage to avoid undue suppression of the immune system. Should radiotherapy still be decided upon, a low dose should be given (e.g. 2,000 rads) in small fractions and irradiation should be stopped at the first sign of a sensitivity reaction. Bloom's and Fanconi's syndromes, which have features in common with ataxia-telangiectasia, also
predispose to malignancy. Although there is no evidence to date that they also show radiosensitivity, this would seem possible as the chromosomes show similar aberrations to those of ataxia-telangiectasia and are also reported to be sensitive to irradiation in vitro (Higurashi and Conen, 1973). Also Bloom's syndrome, but interestingly not Fanconi's syndrome, is associated with light sensitivity. We suggest, however, that if patients with either syndrome are given radiotherapy or radiomimetic drugs, it should be with full awareness of possible sensitivity. ACKNOWLEDGMENT
We thank the late Dr. A. G. V. Aldridge for referring the patient to us and are grateful to Professor D. G. Harnden for the chromosome investigations and advice in preparing the paper, Dr. R. Astley for his radiological services and Dr. R. A. Thompson for the immunological studies. REFERENCES BODER, E., and SEDGWICK, R. P., 1958. Ataxia telangiec-
tasia. Pediatrics, 21, 526-554. GOTOFF, S. P., AMIRMOKRI, E., and LIEBNER, E. J., 1967.
Ataxia telangiectasia. American Journal of Diseases of Children, 114, 617-625. HARNDEN, D. G., 1974. In Chromosomes in Cancer, Ed. J.
German. (Wiley and Co., New York). HARNDEN, D. G., and OXFORD, J., 1974. Personal com-
munication. HIGURASHI, M., and CONEN, P. E., 1973. In Vitro chromoso-
mal radiosensitivity in Chromosomal Breakage Syndromes, Cancer, 32, 380-383. KARPATI, G., EISEN, A. H., ANDERMANN, ¥., BACAL, H. L.,
and ROBB, P., 1965. Ataxia telangiectasia. American Journal of Diseases of Children, 110, 51—63. KERSEY, J. H., SPECTOR, B. D., and GOOD, R. A., 1973.
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