Succinate Dehydrogenase Subunit B (SDHB) Gene Mutations In Paediatric Metastatic Paraganglioma: A Report Of Two Cases

Abstract

Background: Paragangliomas and pheochromocytomas are catecholamine-releasing neuroendocrine tumors that occur rarely in the paediatric population. Mutations in cancer susceptibility genes can be identified in up to 40% of paediatric cases. Germline mutations in the succinate dehydrogenase subunit B (SDHB) gene in particular, are associated with extra-adrenal paraganglioma with high rate of metastasis and young age at presentation. Methods: Patients with metastatic paraganglioma diagnosed below the age of 18 years were identified from the Hong Kong Paediatric Haematology and Oncology Study Group database. With informed consent, peripheral blood was obtained from the subjects for extraction of DNA, PCR and direct DNA sequencing of all the 8 exons and splice sites of the SDHB were performed to test for germline mutation. Results: Two patients were identified and recruited for testing. Patient 1 was a 12-year-old boy diagnosed with subhepatic paraganglioma. The patient underwent adjuvant chemotherapy (gemcitabine, docetaxol, avastin) followed by en-bloc tumour resection. At the age of 15, MIBG-avid metastatic lesions at the L3-4 vertebrae were detected in surveillance scan and subtotal spondylectomy was performed. Urine HVA/VMA were normal all along. Family history was unremarkable. Further immunohistochemistry demonstrated loss of SDHB staining in the tumour cells. Sequencing of the SDHB gene revealed a novel heterozygous mutation, c.415C>T (p.Leu139Phe) that was not present in 150 normal controls. Sequencing of SDHC, SDHD, and VHL genes showed wild-type sequence. Patient 2 was a 13 year-old girl with negative family history who suffered from subhepatic paraganglioma and right adrenal phaeochromocytoma with metastasis to the right scapula and skull bone. Debulking surgery was performed for the abdominal primaries and curettage to the right shoulder metastasis. Three courses of 131-I-MIBG therapy were given with response. The patient subsequently developed left adrenal phaeochromocytoma and was treated surgically. Nevertheless, she relapsed at the age of 22 with metastasis at the intraabdominal nodes as well as lumbar vertebrae and was then managed with palliation. Sequencing of the SDHB gene confirmed the presence of a known pathogenic heterozygous mutation, c.572G>A (p.Cys191Tyr).