Virchows Arch DOI 10.1007/s00428-015-1755-2
CASE REPORT
Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association Karen Gomez Hernandez 1 & Shereen Ezzat 1 & Chantal F. Morel 1,2 & Carol Swallow 3 & Mirek Otremba 2 & Brendan C. Dickson 4 & Sylvia L. Asa 5 & Ozgur Mete 5
Received: 24 January 2015 / Revised: 21 February 2015 / Accepted: 9 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-
* Prof. Ozgur Mete [email protected] 1
Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
2
Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
3
Division of General Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
4
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
5
Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada
related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype. Keywords Paraganglioma . Pheochromocytoma . Renal cell carcinoma . TMEM127 . VHL . SDH
Introduction As the field of genetics in pheochromocytoma and paraganglioma (PHEO/PGL) continues to evolve, the most recent data suggest that up to 40 % of these neoplasms are associated with germline genetic alterations in at least 15 susceptibility genes (succinate dehydrogenase subunit A (SDHA), succinate dehydrogenase subunit B (SDHB), SDHC, SDHD, SDHAF2, NF-1, RET, MAX, TMEM127, Von HippelLindau (VHL), HIF2a/EPAS1, PHD2/EGLN1, KIF1Bbeta, PHD1, and FH) [1–11]. Rare MEN1 patients have also been reported to develop PHEO/PGL [12, 13]; however, these observations require further validations to determine the role of MEN1 gene alterations in the pathogenesis of PHEO/PGL. Similar to the field of PHEO/PGLs, our understanding of hereditary renal cell carcinoma (RCC) has evolved over the past decade, and germline mutations in at least 12 genes (VHL, TSC1, TSC2, BAP1, SDHB, SDHC, SDHD, HRPT2/CDC73, FH, BHD/FCLN, MET, and TMEM127) have been defined in this spectrum [4, 14–16]. Among these genes, germline mutations in VHL, SHDB, SDHC, and SDHD genes have been detected in individuals with PHEO/PGL in which synchronous or metachronous RCCs have also been described [4,
Virchows Arch
15–17]. Morphologically, VHL-related PHEO/PGLs often present with a thick fibrovascular capsule, myxoidhyalinized stroma, and clear cell change [3, 4, 10]. SDHxrelated tumors are often detected when loss of SDHB immunoexpression is identified in an apparently sporadic neoplasm and confirmed with genetic testing [1, 3, 18, 19]. Most recently, both FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial forms of RCC but not in association with PHEO/PGL [14, 16]. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC associated with a novel germline mutation in the TMEM127 gene.
Clinical history A 47-year-old woman who was 10-week pregnant underwent a cardiac MRI for evaluation of polymorphic ventricular tachycardia that was diagnosed before she had decided to terminate her pregnancy. The heart did not have any structural abnormalities, but she was incidentally found to have a left adrenal and a left renal cystic mass and was referred to the Endocrine Oncology clinic for further evaluation. In retrospect, she had experienced symptoms of catecholamine excess for approximately 8 years; she had a history of intermittent anxiety, palpitations, headaches, and pallor that would last 5–15 min. Her blood pressure was never checked during any of those episodes, but she was not known to be hypertensive. Interestingly, she had been diagnosed with stress-induced cardiomyopathy, i.e., “Takotsubo cardiomyopathy” in light of two previous episodes of severe left-sided heart failure in the setting of acute coronary syndrome, typical wall motion abnormalities, and normal coronary angiographies. She had been prescribed PRN nitroglycerine and amlodipine 2.5 mg daily. Her past medical history was also significant for preeclampsia and subclinical hyperthyroidism due to a functioning 1.6-cm thyroid nodule. Her family history was negative for PHEO/PGL-, RCC-, and VHL-related tumors. She had three sons, and the youngest had been diagnosed with Dravet syndrome due to a de novo mutation in the SCN1A gene. On physical examination, she was normotensive with a heart rate of 68 bpm. She did not have any abnormal orthostatic changes. Exploration of her skin revealed multiple ephelides in her face including mucosae (upper and lower lips). Biochemical assessment confirmed catecholamine excess of a predominantly adrenergic phenotype: urinary total metanephrines = 19.5 μmol/day (
CASE REPORT
Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association Karen Gomez Hernandez 1 & Shereen Ezzat 1 & Chantal F. Morel 1,2 & Carol Swallow 3 & Mirek Otremba 2 & Brendan C. Dickson 4 & Sylvia L. Asa 5 & Ozgur Mete 5
Received: 24 January 2015 / Revised: 21 February 2015 / Accepted: 9 March 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Germline mutations in Von Hippel-Lindau (VHL), succinate dehydrogenase subunit B (SDHB), SDHC, and SDHD have been detected in individuals with synchronous or metachronous pheochromocytoma/paraganglioma (PHEO/PGL) and renal cell carcinoma (RCC). Most recently, FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial RCC. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC driven by a novel germline mutation in the TMEM127 gene. Morphologically, both the PHEOs and multilocular RCC were indistinguishable from those associated with VHL disease. However, at the biochemical level, the predominant adrenergic catecholamine profile distinguishes this presentation from SDH- and VHL-
* Prof. Ozgur Mete [email protected] 1
Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
2
Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
3
Division of General Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
4
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
5
Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada
related PHEOs. This case justifies the prioritization of genetic testing for germline TMEM127 in individuals with RCC and PHEO with a predominantly adrenergic phenotype. Keywords Paraganglioma . Pheochromocytoma . Renal cell carcinoma . TMEM127 . VHL . SDH
Introduction As the field of genetics in pheochromocytoma and paraganglioma (PHEO/PGL) continues to evolve, the most recent data suggest that up to 40 % of these neoplasms are associated with germline genetic alterations in at least 15 susceptibility genes (succinate dehydrogenase subunit A (SDHA), succinate dehydrogenase subunit B (SDHB), SDHC, SDHD, SDHAF2, NF-1, RET, MAX, TMEM127, Von HippelLindau (VHL), HIF2a/EPAS1, PHD2/EGLN1, KIF1Bbeta, PHD1, and FH) [1–11]. Rare MEN1 patients have also been reported to develop PHEO/PGL [12, 13]; however, these observations require further validations to determine the role of MEN1 gene alterations in the pathogenesis of PHEO/PGL. Similar to the field of PHEO/PGLs, our understanding of hereditary renal cell carcinoma (RCC) has evolved over the past decade, and germline mutations in at least 12 genes (VHL, TSC1, TSC2, BAP1, SDHB, SDHC, SDHD, HRPT2/CDC73, FH, BHD/FCLN, MET, and TMEM127) have been defined in this spectrum [4, 14–16]. Among these genes, germline mutations in VHL, SHDB, SDHC, and SDHD genes have been detected in individuals with PHEO/PGL in which synchronous or metachronous RCCs have also been described [4,
Virchows Arch
15–17]. Morphologically, VHL-related PHEO/PGLs often present with a thick fibrovascular capsule, myxoidhyalinized stroma, and clear cell change [3, 4, 10]. SDHxrelated tumors are often detected when loss of SDHB immunoexpression is identified in an apparently sporadic neoplasm and confirmed with genetic testing [1, 3, 18, 19]. Most recently, both FH and TMEM127 germline mutations, which are known to cause familial PHEO/PGL, have also been identified in familial forms of RCC but not in association with PHEO/PGL [14, 16]. We report the first case of an individual with both a PHEO and a multilocular clear cell RCC associated with a novel germline mutation in the TMEM127 gene.
Clinical history A 47-year-old woman who was 10-week pregnant underwent a cardiac MRI for evaluation of polymorphic ventricular tachycardia that was diagnosed before she had decided to terminate her pregnancy. The heart did not have any structural abnormalities, but she was incidentally found to have a left adrenal and a left renal cystic mass and was referred to the Endocrine Oncology clinic for further evaluation. In retrospect, she had experienced symptoms of catecholamine excess for approximately 8 years; she had a history of intermittent anxiety, palpitations, headaches, and pallor that would last 5–15 min. Her blood pressure was never checked during any of those episodes, but she was not known to be hypertensive. Interestingly, she had been diagnosed with stress-induced cardiomyopathy, i.e., “Takotsubo cardiomyopathy” in light of two previous episodes of severe left-sided heart failure in the setting of acute coronary syndrome, typical wall motion abnormalities, and normal coronary angiographies. She had been prescribed PRN nitroglycerine and amlodipine 2.5 mg daily. Her past medical history was also significant for preeclampsia and subclinical hyperthyroidism due to a functioning 1.6-cm thyroid nodule. Her family history was negative for PHEO/PGL-, RCC-, and VHL-related tumors. She had three sons, and the youngest had been diagnosed with Dravet syndrome due to a de novo mutation in the SCN1A gene. On physical examination, she was normotensive with a heart rate of 68 bpm. She did not have any abnormal orthostatic changes. Exploration of her skin revealed multiple ephelides in her face including mucosae (upper and lower lips). Biochemical assessment confirmed catecholamine excess of a predominantly adrenergic phenotype: urinary total metanephrines = 19.5 μmol/day (
