6390

SDHB

IP|PGL4|SDH|SDH1|SDH2|SDHIP;succinate dehydrogenase complex, subunit B, iron sulfur (Ip);SDHB;succinate dehydrogenase complex, subunit B, iron sulfur (Ip)

iron-sulfur subunit of complex II|succinate dehydrogenase [ubiquinone] iron-sulfur subunit, mitochondrial

1p36.1-p35

protein-coding

Extraadrenal pheochromocytomas and paragangliomas are rare entities within the pediatric population. We report the presentation of three synchronous extra-adrenal abdominal paragangliomas in an adolescent boy who carries a germline mutation in the succinate dehydrogenase B (SDHB) gene. Loss of heterozygosity of this allele was demonstrated by direct sequencing of DNA from two of his tumors, confirming loss of tumor suppressor function in the pathogenesis of these paragangliomas.

Organ of Zuckerkandl paragangliomas (PGLs) are rare neuroendocrine tumors that are derived from chromaffin cells located around the origin of the inferior mesenteric artery extending to the level of the aortic bifurcation. mutations inthe genes encoding succinate dehydrogenase subunits (SDH) B, C, and D (SDHx) have been associated with PGLs, but their contribution to PGLs of the organ of Zuckerkandl PGLs is not known. We aimed to describe the clinical presentation ofpatients with PGLs of the organ of Zuckerkandl and investigate the prevalence ofSDHx mutations and other genetic defects among them. The clinical characteristics of 14 patients with PGL of the organ of Zuckerkandl were analyzed retrospectively; their DNA was tested for SDHx mutations and deletions. Eleven out of 14 (79%) patients with PGLs of the organ of Zuckerkandl were found to have mutations in the SDHB (9) or SDHD (2) genes; one patient was found to have the Carney-Stratakis syndrome (CSS), and his PGL was discovered during surgery for gastrointestinal stromal tumor. Our results show that SDHx mutations are prevalent in pediatric and adult PGLs of the organ of Zuckerkandl. Patients withPGLs of the organ of Zuckerkandl should be screened for SDHx mutations and the CSS; in addition, asymptomatic carriers of an SDHx mutation among the relatives of affected patients may benefit from tumor screening for early PGL detection.

Paragangliomas are extradadrenal neuroendocrine tumors, recently associated withgene mutations in the succinate dehydrogenase complex (SDH). These mutations arethought to be responsible for the familial paraganglioma syndrome. Average age of tumor diagnosis for SDH mutation carriers is about 30 years of age, but patientsyounger than 10 years have been reported. We present the case of a 13 year-old boy with abdominal paraganglioma, whose mother also had a history of thoracic paraganglioma diagnosed at 14 years of age. Both were found to carry a mutation in exon 4 of the SDHB gene, heterozygous for c.418G>T, p.Val140Phe sequence. Compared to the other SDH subtypes, SDHB associated tumors have been found to bemuch more aggressive. This has led to current recommendations that tumor screening of asymptomatic SDHB carriers should start as early as 10 years of age. An even earlier initiation seems warranted for the identified carriers in this family.

PURPOSE: To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation beganin childhood or adolescence. PATIENTS AND METHODS: From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the NationalInstitutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients werefound to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. RESULTS: Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHBmutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. CONCLUSION: The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

Studies on gastrointestinal stromal tumors (GISTs) in young patients are limiteddue to their rarity, and none have been conducted in Asian populations. GISTs from patients under the age of 30 were retrospectively reviewed and were analyzed for clinicopathologic features, immunohistochemistry for SDHB (succinate dehydrogenase subunit B), and mutations for exon 9, 11, 13, and 17 of KIT gene and exon 12, 14, and 18 of PDGFRA gene. We found two pediatric (<18 years old) and 20 young adult (18-30 years old) GIST cases. pediatric GISTs occurred in twogirls, both as solitary masses with epithelioid histology in the stomach. Both GISTs were wild type for KIT and PDGFRA genes, were negative for SDHB, and therewas no recurrence during follow-up. Of the 20 GISTs in young adults, 12 (60%) were from extra-gastric locations (six duodenum, five jejunum, and one esophagus), and 16 (80%) showed a spindle cell morphology. mutations of KIT or PDGFRA genes were identified in 14 (78%) of the 18 cases. One patient with multiple gastric GISTs with perigastric lymph node metastases at presentation developed multiple distant metastases and died of the disease 7.3 years after diagnosis. Of the 19 R0-resected young adult patients, one patient with small intestinal GIST harboring KIT exon 11 deletion mutation developed recurrence andshowed partial responses for imatinib. In summary, compared with pediatric GIST cases, young adult GISTs are heterogeneous and share the characteristics of bothpediatric and adult GISTs. When a mesenchymal tumor is clinically suspected in the small intestine of young adults, a GIST should be included in the differential diagnoses. Further mutation studies and extensive treatments are recommended for these cases.#CI- (c) 2013 APMIS. Published by John Wiley & Sons Ltd.