Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto,
1 Department of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo,
2 AGENE Research Institute, Kanagawa and
3 Department of Rheumatology, Tokyo Metropolitan Ohtsuka Hospital, Tokyo, Japan
SIR, Werner syndrome (WS) is an autosomal recessive disorder that causes premature ageing with an increased risk of malignant neoplasia, osteoporosis and, sometimes, joint osteoarthritis. The average life span is 47 yr [1] and the main causes of death are atherosclerotic complications and malignant tumours, such as thyroid cancer, malignant melanoma and a variety of sarcomas [1].
Previously, WS was diagnosed primarily by the clinical findings, but it is now possible to make a diagnosis based on both clinical and genetic methods as the disease-associated gene has been identified [2]. In this report, we describe the first case of WS characterized by three kinds of primary sarcomas, osteoarthritic changes in the joints, osteoporosis and a novel WRN mutation (mutation 20).
The patient was a 58-yr-old male office worker who had been suffering from severe joint pain caused by osteoarthritis. He had undergone thyroidectomy for an adenoma at 43 yr of age and bilateral cataract surgery at 44 yr. His parents were first cousins and he had eight brothers and sisters. No siblings or relatives showed signs and symptoms similar to those of the present case except the eldest brother and sister, who had thyroid cancer (surgery at 71 yr, pathology unknown) and breast cancer (operated on at 67 yr, pathology unknown) respectively.
The patient noticed an indolent tumour, 2 cm in diameter, on the posteromedial area of the right popliteal fossa at 43 yr of age. The patient underwent marginal resection of what was diagnosed histologically as a malignant peripheral nerve sheath tumour (Fig. 1A), followed by chemotherapy for 6 months and wide resection of the tumour with a free skin graft at 48 yr. The patient noticed a rapidly growing tumour (8x8 cm) in the proximal area of the left thigh at 50 yr. An incisional biopsy resulted in a diagnosis of malignant fibrous histiocytoma (Fig. 1B
). Wide resection of the tumour was performed at 49 yr. A skin ulcer was found on the lateral malleolus of the right foot at 54 yr and a painful ipsilateral chronic ulcer covering the calcaneal region was observed at 55 yr. Magnetic resonance imaging showed osteosclerosis of the calcaneus and calcification at the Achilles tendon insertion and plantar aponeurosis; T1- and T2-weighted images both showed low intensity. An incisional biopsy indicated a well-differentiated intramedullary osteosarcoma (Fig. 1C
), and below-the-knee amputation was performed at 55 yr The patient was symptom-free in September 2002 at 62 yr of age.
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A total of 194 cases of malignant tumours have been identified among the 1250 reported individuals with WS all over the world. Twenty-four cases of WS with multiple primary tumours have been reported so far, but only one case with more than two non-epithelial malignant tumours has been noted [1]. However, only three reports of cases with more than three tumours have been published, and none similar to the present case with three primary sarcomas [1]. Among non-epithelial tumours in WS, soft-tissue sarcoma, osteosarcoma [8], melanoma, meningioma and leukaemia are common. Combinations of thyroid cancer and various sarcomas, or of meningioma and various sarcomas, suggest some special form of carcinogenesis (carcinogenic risk) in WS. In such a rare case as that reported here, almost 15 yr have passed since the first operation for a tumour, and appropriate treatment for all three sarcomas has extended survival up to this point.
In 1992, WS was found to be caused by the mutation of WRN gene [2], which is located in the 8p1112 chromosomal region [9]. A total of 19 different mutations have been confirmed to date [10]. If a patient has a known mutation, such as mutations 1, 4 and 6, WS can be diagnosed by mutation analysis. If the patient does not have a known mutation, an immunological method is useful. Furthermore, subsequent genomic sequencing can identify a new mutation and help in the diagnosis of WS, as in the present case [10].
Notes
Correspondence to: Y. Nakamura, Department of Orthopaedic Surgery, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan. E-mail: yukion{at}hsp.md.shinshu-u.ac.jp
4Present address: Genome Center, Japanese Foundation for Cancer Research, Tokyo, Japan
References