INTRODUCTION

Rothmund-Thomson syndrome (RTS [MIM #268400]) is a rare and severe au­tosomal recessive genodermatosis. It was first reported in 1868 in a patient with cataract and progressive poikilo­derma by the German opthalmologist Rothmund and subsequently by the British dermatologist, Thomson with the current eponym introduced in 1957 (Taylor 1957). RTS is diagnosed clinically and the main features include proportio­nate dwarfism, premature ageing, skin hyperpigmentation appearing within the first semester of life and longlife persist­ing, poikiloderma, telangiectasia, brittle hair sometimes progressing to total alo­pecia, dystrophic nails, juvenile cataract, photosensitivity and congenital skeletal defects as hypoplasia or absence of the radii and thumbs. There is a higher than expected incidence of cutaneous and non-cutaneous malignancies particularly osteosarcoma (Vennos et al. 1992, Wang et al. 2001). Several RTS patients have been described to have two malignancies including osteosarcoma and lymphoma (Wang et al. 2001).

Mutations in helicase RECQ4 gene are responsible for a subset of cases of RTS. The RECQ4 gene structure is unusual because it contains many small introns <100bp. Wang et al. (2002) described a proband with RTS who had a novel 11-bp intronic deletion and showed that this mutation results in a 66-bp intron too small for proper slicing. Constraint on intron size may represent a general mu­tational mechanism in RTS (Wang et al. 2002). This patient and his non-identical twin sister both had a homozygous muta­tion of the RECQ4 gene which is respon­sible for the severe phenotype asso­ciated with RTS (Balraj et al. 2002). The twin sister developed osteosarcoma of the left humerus at the age of 15. She received chemotherapy and underwent limb salvage surgery. However, she de­veloped metastases in her lungs and succumbed to the disease.

Response to radiotherapy in RTS pa­tients has been variable. An abnormal DNA repair mechanism in some RTS patients predisposes them to malignancy and influence the tolerance of radiothe­rapy. We are aware of three previous reports of patients with RTS developing squamous cell carcinoma (SCC) of the tongue (Borg et al. 1998, Martin-Bertolin et al. 1998, Dahele et al. 2004). A patient was reported to develop increased radio­sensitivity and tissue intolerance to che­motherapy (Borg et al. 1998) while another patient was reported to tolerate radiotherapy without evidence of in­creased morbidity (Dahele et al. 2004). In this report, we describe a patient with a history of osteosarcoma who developed SCC of the base of the tongue. He un­derwent a course of radiotherapy for the SCC of the tongue.

CASE REPORT

The patient is a 27 year-old male, the first twin of a set of non-identical twins. The twins first presented with clinical features of RTS at the age of 10 months. Four generation pedigree showed a high de­gree of consanguinity, and the parents are first cousins. Molecular analysis showed a homozygous mutation in RECQ4 helicase: 2746-2756-delTGGGCTGAGGC in IVS8 which is responsible for the severe phenotype associated with RTS in both twins, while both parents and the grandmothers were heterozygous. These findings were re­ported previously by Balraj et al.(2002).

The patient developed multicentric os­teosarcoma of the left humerus and right upper tibia at the age of 14 years. The tumor in the right upper tibia was re­sected and allogenic bone grafting was performed. Subsequently, he received chemotherapy and later limb salvage surgery was performed for the tumor in the left humerus. However, he had to undergo an above knee amputation of the right leg as the site of the bone graft was infected with avascular necrosis and detachment of the proximal part of the bone graft. He did not receive radiothe­rapy during the treatment for osteosar­coma. He was disease-free for 10 years following therapy.

On follow-up he was noted to have right submandibular lymphadenopathy of 2.5cm x 2.0cm but defaulted referral for a biopsy. Three months later he was ad­mitted for enlarging right neck swelling associated with right tongue pain and difficulty in eating. There was a history of intermittent fever, lethargy, and loss of weight (height 141.5cm, weight dropped from 26.3kg to 25.1kg, BMI dropped from 13.2 to 12.6). Physical examination re­vealed a 3.0cm x 3.5cm ulcer at the right side of the posterior base of his tongue (Figure 1). Biopsy of the ulcer confirmed the presence of a well-differentiated SCC (Figure 2). It was staged as T2N2CM0 according to the 1998 American Joint Committee on Cancer (AJCC) staging system (American Joint Committee on Cancer, 1998).

Tumor excision was not performed in view of the extension of the tumor and his poor clinical condition. The patient was then advised for radiotherapy. In the first phase of radiotherapy the primary tumor and neck was treated to a total dose of 40 Gy in 20 fractions at 2.0 Gy per fraction. The patient developed se­vere mucositis requiring regular intraven­ous morphine, oral toilet and liquid nutri­tional supplement and the treatment schedule was interrupted. After introduc­tion of spinal cord shielding in the second phase of treatment, the primary tumor and neck was boosted with a further 26 Gy in 13 fractions. Subsequently the right neck was treated with a boost of 10 Gy in 5 fractions. The overall treatment time was extended to 63 days from a planned 42 days because of toxicity-related breaks and patient non-compliance. The tumor size reduced to approximately 0.5cm x 0.5cm at completion of radiothe­rapy. The patient developed severe mu­cositis with skin desquamation in the treated area (Figure 3) following treat­ment. Local site infection was success­fully treated with antibiotics. The toxicity symptoms subsided two months after com­pletion of radiotherapy. Unfortunately,  the tumor recurred and the patient died 16 months after diagnosis of SCC.

DISCUSSION

We believe that in our patient, the severe phenotype was responsible for the mul­tiple malignancies. In addition, being a chronic cigarette smoker increased his relative risk of SCC in the tongue. Can­cers of the head and neck show a strong association with alcohol consumption and smoking, partic­ularly cigarettes. This patient however did not have a history of alcoholism. The severe phenotype, chronic cigarette smoking, and previous chemotherapy for treatment of osteosar­coma had most likely played a role in the pathogenesis of the tongue cancer in this patient.

In addition, we found that our patient had a severe toxicity from radiotherapy. A similar finding was reported by Borg et al. (1998) in a patient with an advanced tu­mor who had greater than expected post­operative radiotherapy toxicity, and the dose per fraction as well as the total dose was reduced (from 1.8 to 1.65 Gy per fraction and total dose from 66.6 Gy to 58.55 Gy). The treatment time in this re­port was also extended from 45 to 71 days as a result of the toxicity. In contrast, Dahele et al. (2004) described a patient with SCC of the tongue who tolerated postoperative radiotherapy well, without evidence of increased early or late radia­tion morbidity. The patient received ra­diotherapy at a total dose of 50 Gy in 25 fractions over 5 weeks without undue tox­icity. Given the heterogeneity in the syn­drome, it is possible that patients’ sus­cep­tibility to radiation toxicity also varies. Re­ports on abnormal DNA repair after irradi­ation in RTS could explain for excess treatment toxicity in some pa­tients.

Recently, Hicks et al. (2007) reported that the clinical behaviour of patients with RTS and osteosarcoma is similar to pa­tients with sporadic osteosarcoma, and suggested that these patients should initially be treated with conventional doses of chemotherapy as prescribed by current protocols.However, five patients were reported to require chemotherapy dose modifications, most commonly due to mucositis from doxorubicin (Hicks et al. 2007). Therefore, careful clinical ob­servation is needed to monitor for en­hanced doxorubicin sensitivity in RTS patients. It is apparent that some RTS patients have abnormal DNA repair me­chanisms that could lead to increased toxicity to radiotherapy and chemothe­rapy. Therefore a complete screening for malignancies of RTS patients are impor­tant to identify those patients who are prone to develop cancer and are there­fore likely to experience increase treat­ment morbidities. The present case illu­strates the importance of regular follow-up of all RTS patients and screening those who are prone to develop cancer.