Normal cellular radiosensitivity in an adult Fanconi anaemia patient with marked clinical radiosensitivity

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Abstract

Background: Fanconi anaemia is a rare disease associated with cellular sensitivity to chemicals (e.g. mitomycin C and diepoxybutane); variable but mild cellular radiosensitivity has also been reported.

Materials and methods: A 32-year-old patient with Fanconi anaemia and tonsillar carcinoma, treated by radiotherapy, was found to exhibit profound clinical radiosensitivity. Confluent, ulcerating oropharyngeal mucositis developed after a conventionally fractionated dose of 34 Gy and healing was incomplete by 2 months after cessation of therapy.

Results: Cellular radiosensitivity assays and RPLD studies from this patient did not suggest any major detectable radiosensitivity.

Conclusion: There is a discrepancy between the observed clinical radiosensitivity and the usual ‘predictive’ radiosensitivity assays in this patient with Fanconi anaemia.

Introduction

Fanconi anaemia (FA) is a rare autosomal recessive disorder characterised by severe aplastic anaemia, multiple congenital abnormalities and cancer susceptibility. T-lymphocytes or cultured cell lines from FA patients have been reported to display variable levels of radiosensitivity which may relate to the complementation group [9], [13], [14]. In the large comparative study of Deschavanne and Fertil [11], [12], such radiosensitivity was modest — fibroblasts from FA patients demonstrating moderate radiosensitivity comparable with that of ataxia telangiectasia (A-T) heterozygotes, Li Fraumeni syndrome fibroblasts and Down's syndrome fibroblasts. The opportunity to evaluate the response of FA patients to radiotherapy rarely arises as the disease is often fatal, precluding the necessity for radiotherapy treatment. However, one such case recently presented to us and the clinical and cellular radiobiological studies are reported here.

A 32-year-old pipe-smoking female from Saudi Arabia presented in the UK with a 10-month history of dysphagia. Her medical history showed that she had been diagnosed as having secondary amenorrhoea 3 years earlier for which hormone replacement therapy had been prescribed. She had been investigated 2 years earlier for anaemia but no specific diagnosis had been made. A cataract operation on one eye had taken place 1 year earlier.

Clinical examination revealed that she was of short stature with mild scaly eruption of her palms and the extensor surfaces of her legs. She had small hyperpigmented macular lesions on her anterior chest wall but the rest of her clinical examination was unremarkable. Oral examination revealed an ulcerating left tonsillar mass, biopsy of which revealed a moderately differentiated squamous carcinoma. Staging tests for metastatic disease were negative and she was referred for radiotherapy.

Initial blood investigations showed a macrocytic anaemia with a haemoglobin of 10 g/dl and a mean corpuscular volume (MCV) of 115 fmol. The patient was planned for radiotherapy on the tonsil and haematological investigations were initiated.

Using 6 MV photons, a prescription of 60 Gy in 30 daily fractions was planned using parallel opposed portals. The patient was noted to have an unusually brisk mucosal reaction at 24 Gy. When she had received 34 Gy, her treatment was discontinued, as she developed a severe radiation reaction with profound mucositis and ulceration of the hard palate and tonsil. The reaction was complicated by an episode of septicaemia and she was hospitalised for antibiotic therapy and total parenteral nutrition as she could swallow nothing — not even her own saliva. A deep necrotic ulcer developed in the tonsillar fossa where the tumour had been. Confluent ulcerating oropharyngeal mucositis involving all the regions in the primary radiation portals caused continuing complete dysphagia. In the third week following cessation of radiotherapy, the patient first became able to swallow saliva and sips of water and the mucositis settled over the next 6–7 weeks of in-patient care, leaving a persisting necrotic ulcer in the left tonsillar fossa bed and a very fragile mucosa in the primary radiation beam regions. By 2 months after the cessation of radiotherapy, the patient could swallow a very soft diet eaten at a very slow pace.

During radiotherapy, the patient's haemoglobin fell to 7.4 g/dl with an MCV of 117 fmol. Her white blood count was 2.6×109 l−1 and platelets 89×109 l−1. She had occasional blasts on the peripheral film. The bone marrow was a dry tap and the trephine showed hypocellularity with evidence of dysplasia.

Section snippets

Cell culture and radiosensitivity analysis

1BR3 and 425BR are untransformed fibroblasts established from a normal patient and the patient described here, respectively. AT1BR and AT5BI are untransformed fibroblasts derived from A-T patients. FaIBI is an untransformed fibroblast from another FA patient. Cells were cultured in minimal essential medium (MEM) supplemented with 15% foetal calf serum, penicillin and streptomycin as described previously [3]. Survival to γ-rays or mitomycin C (MMC) was carried out as described previously [3].

Results

A positive diagnosis of FA was made using the diepoxybutane (DEB) test on the patient's lymphocytes (Table 1). A fibroblast cell line (designated 425BR) established from a skin biopsy of the patient showed extreme sensitivity to the cross-linking agent, MMC, consistent with the diagnosis of FA (Fig. 1). To identify the complementation group, MMC activated G2 accumulation was examined following the introduction of cDNAs for FA-A, -C and -G by retroviral transfection. Elevated accumulation of

Discussion

FA is frequently grouped with cancer-prone syndromes such as A-T, Bloom's syndrome, and xeroderma pigmentosum. Collectively, these have been called the chromosome breakage syndromes since they are associated with chromosomal instability. Patients with FA have multiple congenital abnormalities, including growth retardation, abnormalities of the skin, with either hyperpigmentation or café au lait spots, upper extremity deformities, cardiac, genitourinary or central nervous system problems [1]. Of

Acknowledgements

The PAJ laboratory is supported by grants from the UKCCCR Radiation Research Programme, by the Human Frontiers Science Programme and by the Leukaemia Research Fund. We also thank Dr V. Favaudon of the Curie Institut for analysis of the survival data.

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