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Jcem1279.Pdf JCEM ONLINE Brief Report—Endocrine Research Germline Mutations of the TMEM127 Gene in Patients with Paraganglioma of Head and Neck and Extraadrenal Abdominal Sites Hartmut P. H. Neumann, Maren Sullivan, Aurelia Winter, Angelica Malinoc, Michael M. Hoffmann, Carsten C. Boedeker, Hartmut Bertz, Martin K. Walz, Lars C. Moeller, Kurt W. Schmid, and Charis Eng Downloaded from https://academic.oup.com/jcem/article/96/8/E1279/2833767 by guest on 27 September 2021 Department of Nephrology and General Medicine (H.P.H.N., M.S., A.W., A.M.) and Divisions of Clinical Chemistry (M.M.H.), Otolaryngology (C.C.B.), and Hematology and Oncology (H.B.), University Medical Center, Albert-Ludwigs-University, D-79106 Freiburg, Germany; Department of Visceral Surgery (M.K.W.), Kliniken Essen Mitte, D-45276 Essen, Germany; Departments of Endocrinology (L.C.M.) and Pathology (K.W.S.), University of Duisburg-Essen, D-45141 Essen, Germany; and Genomic Medicine Institute (C.E.), Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195 Background: Hereditary pheochromocytoma is associated with germline mutations of a set of susceptibility genes to which the TMEM127 gene has recently been added. Patients with TMEM127 mutations have been thus far exclusively identified with adrenal tumors. Patients and Methods: A population-based series of 48 consecutive individuals from the European- American Pheochromocytoma Paraganglioma Registry with multiple paraganglial tumors and, of these, one extraadrenal paraganglial tumor were selected for this study. They all had normal results when screened for germline mutations of the genes RET, VHL, SDHB, SDHC, and SDHD. Germline mutation analysis of the TMEM127 gene included a search for intragenic mutations and large rearrangements. Results: Of the 48 eligible patients with extraadrenal paraganglial tumors, two (4.2%) were found to have TMEM127 mutations. One patient had multiple head and neck paraganglioma and one retroperitoneal extraadrenal and adrenal tumor. Conclusion: TMEM127 germline mutations confer risks of extraadrenal paraganglial tumors in addi- tion to the documented adrenal pheochromocytoma. Thus, surveillance for extraadrenal and adrenal paraganglial tumors is likely warranted in TMEM127 mutation carriers, although the true prevalence should be evaluated in patients with extraadrenal paraganglial tumors. (J Clin Endocrinol Metab 96: E1279–E1282, 2011) he family of susceptibility genes for hereditary pheo- sia syndromes are, in historical order, neurofibromato- T chromocytomas and paragangliomas is growing sis type 1, multiple endocrine neoplasia type 2, von Hip- and has implications for generalists and multiple spe- pel-Lindau disease, paraganglioma syndrome types 1, 2, cialties because of their protean location, symptomatol- 3, and 4, and furthermore, a distinct disorder exclusively ogy, and presentation. Patients with hereditary pheo- associated with adrenal pheochromocytoma (1). The re- chromocytoma or paraganglioma may either have a spective susceptibility genes are NF1, RET, VHL, SDHD, complex neoplasia syndrome or have tumors of the sdh5/SDHAF2, SDHC, SDHB, and TMEM127 (2–4). Be- paraganglial system as the only condition. The neopla- cause of clinical outcome studies of these genes, except for ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-0114 Received January 13, 2011. Accepted April 26, 2011. First Published Online May 25, 2011 J Clin Endocrinol Metab, August 2011, 96(8):E1279–E1282 jcem.endojournals.org E1279 E1280 Neumann et al. TMEM127 Mutations in Paragangliomas J Clin Endocrinol Metab, August 2011, 96(8):E1279–E1282 the most recent SDHAF2 and TMEM127, specific gene- Board-approved questionnaire for enrollment as experimental informed clinical surveillance can be performed. The most controls. recently identified gene is TMEM127 (4). The phenotype DNA variants of missense type were regarded as pathogenic mutations, if they do not occur in the controls. In addition, of mutation carriers has recently been described by Yao et pathogenicity was supported by in silico analysis tools Mutation al. (1). Of 990 probands, 20 (2%) patients have been iden- Taster (6), PolyPhen (7), and SNAP (8), which predict possible tified with germline TMEM127 mutations. All mutation impact of single amino acid substitutions on protein structure carriers in that study were found to exclusively carry ad- and function. renal paraganglial tumors, i.e. pheochromocytomas. Ex- traadrenal paraganglial tumors were not reported. If this held true, then finding a TMEM127 mutation would sug- Results gest only adrenal surveillance. Here, we sought to deter- Downloaded from https://academic.oup.com/jcem/article/96/8/E1279/2833767 by guest on 27 September 2021 We analyzed for intragenic germline mutations of the mine whether extraadrenal paraganglial tumors were a TMEM127 gene in 48 unrelated registrants selected for part of the phenotypic spectrum of germline TMEM127 two or more paraganglial tumors, of which at least one mutation carriers. must have been outside the adrenal glands. Of the 48 pa- tients, 24 had tumors of the head and neck. Of these 24, 22 had head and neck tumors only, whereas one patient Subjects and Methods also had a thoracic and a retroperitoneal extraadrenal tu- Research participants mor, and one patient had bilateral adrenal tumors. Of the The research participants were a nested series from the pop- remaining 24 patients, all had retroperitoneal extraadre- ulation-based European-American Pheochromocytoma-Para- nal tumors, with four exclusively in this location. In ad- ganglioma Registry (5). All registrations are based on a uniform dition, 20 of these 24 also had tumors in the adrenals, and questionnaire that includes capture of demographic data such as among the 20 with adrenal involvement, six had bilateral age, gender, and place of residence as well as clinical data such disease and the remaining 14, unilateral. Of the six pa- as biochemical data regarding catecholamines and metaneph- tients with bilateral adrenal disease, two also had thoracic rines, imaging data from magnetic resonance or computerized tomography and scintigraphic procedures as well as number and involvement. Pelvic tumors did not occur. Age at diagnosis location of the tumors and their biological behavior as benign or was 11–75 (median 40) years, and male to female ratio malignant disease. Criteria for malignancy were lymph node or was 1:2.5. A family history of paraganglial tumors was distant (extraparaganglial) metastases. present in three of the 48 patients. Of the 48 patients, 35 For purposes of this study, only unrelated symptomatic pa- are German, four Polish, three French, two each Swiss and tients, who were mutation and deletion negative for RET, VHL, Greek, and one each Spanish and Finnish. SDHB, SDHC, SDHD, and NF1, were included. Other inclusion criteria include having at least two paraganglial tumors, at least Among the 48 eligible patients, two patients (4.2%) one of which must be an extraadrenal paraganglial tumor. An were found to have germline TMEM127 mutations, both important exclusion criterion was that none of these research of missense type (Table 1). These two patients were mu- participants should also be included in the cohort described by tation negative for SDHAF2/SDHA. None of the 100 con- Yao et al. (1). A nested series of 48 unrelated individuals within trols showed these two missense mutations, and in silico the registry met eligibility criteria. This sample size is powered (P Ͼ 0.8) to detect even a 6% prevalence of TMEM127 muta- tion-positive cases. All subjects signed informed consent in accordance with our TABLE 1. Demographic and clinical information for the respective institutions’ Human Subjects Protection Committee/ TMEM127 mutation-positive individuals Ethical Committee. Variable Case I Case II Mutation analysis of TMEM127 Age at diagnosis (yr) 34 51 Gender Female Female Genomic DNA was extracted from EDTA-anticoagulated pe- Tumor number 2 6 ripheral white blood cells from each subject using standard pro- Tumor location CBT, CBT 4 adrenal left cedures. The gene TMEM127 was analyzed for intragenic mu- 1 adrenal right tations and large deletions and rearrangements. Mutation 1 extraadrenal screening was performed by denaturing HPLC (WAVE system, retroperitoneal model 3500 HT; Transgenomic, Glasgow, UK) followed by se- Malignant No No quencing (ABI 3130) for patients who showed abnormal dena- Family history Negative Negative turing HPLC chromatograms. Deletion/rearrangement analysis Other neoplasias Acute myeloid was performed using multiplex ligation-dependent probe am- leukemia TMEM127 mutation c.325 T3 c.553 G3 plification. Genomic DNA was extracted from 100 ancestry- C (p.S109P) A (p.G185R) matched population-based controls who were healthy anony- mous blood donors or who filled in an Institutional Review CBT, Carotid body tumor. J Clin Endocrinol Metab, August 2011, 96(8):E1279–E1282 jcem.endojournals.org E1281 analyses support the pathogenicity of these mutations. In if indeed TMEM127 mutations confer only risk for adre- addition, we observed the DNA variant TMEM127 c.621 nal pheochromocytomas, then surveillance can be lim- G3A (p.A207A) in 29% of the probands and 8% of the ited to the adrenals. However, in our study of a popu- controls. lation-based series with extraadrenal paraganglial The two mutation-positive females were aged 34 and tumors, we identified two unrelated individuals
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