CASE REPORT
Jonathan Irish, MD, FRCSC, Section Editor
Hereditary paraganglioma-pheochromocytoma syndromes associated with SDHD and RET mutations Joseph Do Woong Choi, MBBS, B Sc (Adv),1* Katherine M. Tucker, MBBS, FRACP,2 Tack Tsiew Lee, BMBS, FRACS,1 Guan C. Chong, B Med Sc, MBBS, FRACS, FRCS (C), FRCS (E)1 1
Academic Unit of Surgery, Australian National University Medical School, The Canberra Hospital, Canberra, Australian Capital Territory, Australia, 2Hereditary Cancer Service, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Accepted 20 December 2013 Published online 20 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23598
ABSTRACT: Background. Hereditary paraganglioma-pheochromocytoma syndromes (PGL/PCC) are rare tumors arising from neuroendocrine cells. Methods and Results. The proband, a 59-year-old white man and his 42-year-old elder son had a medical history of bilateral carotid body PGL and both presented for treatment of abdominal PGLs. His 36-year-old daughter had excision of recurrent malignant carotid body PGL and vertebral metastasis. His 33-year-old youngest son presented for excision of a unilateral carotid body PGL. All 4 members had succinate dehydrogenase subunit D (SDHD) mutations, whereas the proband and youngest son also had concurrent rearranged during transfection (RET) mutation.
INTRODUCTION Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are rare autosomal dominant cancers characterized by PGLs: neuroendocrine tumors originating from neural crest chromaffin tissues along the paravertebral axis from base of skull to the pelvis and PCC: PGLs confined to the adrenal medulla.1 They mainly affect adults in the fourth or fifth decade of life, and have no sex predilection.2 Sympathetic PGL/PCC typically hypersecrete catecholamines and arise from the sympathetic ganglia from adrenal medulla or along the paravertebral axis from the neck to the pelvis, whereas parasympathetic PGL/PCC arise in the head and neck region and middle mediastinum and 95% are nonsecretory.3 Hereditary PGL/PCC are associated with constitutional mutation on susceptibility genes identified to date (succinate dehydrogenase subunit D [SDHD], succinate dehydrogenase subunit B [SDHB], C, A, succinate dehydrogenase complex assembly factor 2, transmembrane protein 127, and MYC-associated factor X), or genes involved in classic syndromes, such as multiple endocrine neoplasia (MEN) type 2 (rearranged during
*Corresponding author: J. D. W. Choi, Academic Unit of Surgery, Australian National University Medical School, The Canberra Hospital, Canberra, Australian Capital Territory, Australia, 2601. E-mail: [email protected] Contract grant sponsor: This work received intramural support from the Australian National University Medical School and Australian Capital Territory Government Health Directorate.
Conclusion. This is the first report of PGL/PCC with SDHD and RET mutations. The role of the RET gene as a modifier remains speculative. Additionally, the family pedigree suggests maternal inheritance of disease from the probands’ paternal grandmother. Clinicians should refer PGL/ PCC families for mutation analysis as well as being alert to changes in C 2014 Wiley Periodicals, Inc. Head Neck the classification of mutations. V 36: E99–E102, 2014
KEY WORDS: paraganglioma, pheochromocytoma, hereditary, succinate dehydrogenase subunit D (SDHD) mutation, rearranged during transfection (RET) mutation
transfection [RET]),4 von Hippel–Lindau disease or neurofibromatosis type 1.5–7 In this study, the authors present 4 cases from a family who presented for management of multifocal and malignant PGL/PCC, all with SDHD and 2 with concurrent RET mutations.
CASE REPORT Patient 1 The index case, a 59-year-old white man was referred to us after discovery of a solitary focus in the para-aortic region on CT. He was investigated for increasing renal impairment. His symptoms consisted of occasional palpitations and worsening hypertension. Bilateral carotid body and right jugulotympanic PGL were treated at age 44. He gave a history of multiple PGL in at least 5 and possibly 7 relatives, including 2 sisters and his 3 children. His paternal aunt and paternal grandmother were reported to be similarly affected (Figure 1). There was no personal or family history suggestive of one of the syndromes associated with PGL or PCC. His physical examination was unremarkable. Plasma normetadrenaline was elevated (1260 pmol/L; reference range T (p.Tyr791Phe) mutation was found, however, 5 years of annual investigations, including thyroid ultrasound, annual calcitonin, calcium, parathyroid hormone, plasma metanephrine, and normetanephrine levels have been normal. He attends yearly follow-up for recurrence/metastasis and for new foci of PGL/PCC.
Patient 2 Patient #1’s 42-year-old eldest son was referred to us after unremitting hypertension, headaches, migraines, and elevated 24-hour urinary noradrenaline (922 nmol/day; reference range, 45–680 nmol/day). Previous treatment of a glomus tumor at 30 years of age and bilateral carotid body PGL at 38 years of age was noted. Other than hypertension at 149/93 (sitting), his physical examination was unremarkable. Further investigations revealed elevated plasma normetadrenaline (2070 pmol/L) and chromogranin A (33 U/L), with normal urinary adrenaline, plasma metadrenaline, and thyroid function tests. MRI revealed no recurrence of head and neck PGL, but a mass in the left para-aortic region at the level of origin of the inferior mesenteric artery at L3 was noted. PET/CT scan confirmed a metabolically active lesion, consistent with a PGL. Phenoxybenzamine was prescribed before removal at laparotomy. As in patient #1, there was no macroscopic E100
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The 36-year-old daughter of patient #1 was referred to us because of a left neck mass, and a sclerotic mass in the T7 vertebra. Left and right carotid body PGL had been removed at ages 13 and 28. Physical examination revealed a palpable cylindrical mass on the left carotid, which was tender to palpation. The contralateral neck, breast examination, spine examination, and blood pressure were unremarkable. Urinary and plasma metabolites, dopamine, and calcium were normal. An MRI of the head and neck revealed a mass at the left carotid bifurcation measuring 20 3 40 mm, with no lymphadenopathy or skull base involvement. CT and Tc99m whole body bone scan demonstrated a 15 mm sclerotic solitary focus within the posterior aspect of the T7 vertebral body, which confirmed PGL on bone biopsy. MIBG was unremarkable. In view of the patient’s findings, a recurrence of a malignant PGL was strongly suspected. She was treated at a medical center elsewhere for resection of a 20- 3 40-mm recurrent left carotid PGL. Surgery was complicated by unilateral X and XII nerve palsy, because of dense fibrosis and nerve adherence to the tumor capsule. Additionally, excision of the T7 vertebral body, insertion of hardware, implantation of bone graft, and radiotherapy were performed to control spinal metastasis. Her postoperative course was essentially uneventful. The SDHDc.287289delCTA mutation was identified but not the RETc.2372A>T mutation. She undergoes regular followup visits to monitor for recurrence/metastasis.
Patient 4 The youngest son (aged 33) presented for routine follow-up after excision of a right carotid body PGL at age 22. Physical examination was unremarkable. Urinary and plasma metabolites and calcium were normal. Regional bone scan of the head, neck, and upper thoracic spine were unremarkable. MRI confirmed the presence of a 2-cm left carotid body tumor. Surgical excision was recommended given his strong family history. At surgical removal, referred elsewhere, a likely PGL was found medial to the left carotid bifurcation with no macroscopic tumor invasion into the surrounding tissues. Pathology confirmed a carotid PGL. His surgery and postoperative progress were uneventful. He was identified as having the same SDHD and the RET mutation as his father.
DISCUSSION PGL/PCC represents the same syndrome, subcategorized only by different sites of presentation. Approximately 10% of patients with PGL/PCC have a significant family history and 30% are associated with susceptibility genes to date.5,6 Of these, succinate dehydrogenase subunit A, SDHB, succinate dehydrogenase subunit C, and SDHD genes encode for 4 subunit proteins of succinate dehydrogenase (SDH) subunits A, B, C, and D. SDH
HEREDITARY
catalyzes oxidation of succinate to fumarate in the Krebs cycle and provides electrons to the mitochondrial electron transport chain, and it is proposed that mutation leads to stabilization and activation of hypoxia-inducible factor a, which in turn causes cellular proliferation.5,8 SDHD mutations (familial PGL type 1) are associated predominantly with multifocal head and neck, but also thoracic and abdominal PGLs.3 In contrast, SDHB mutations (familial PGL type 4), are more likely to be extra-adrenal, abdominal, and develop malignant disease.3 Our patients presented with primarily head and neck PGL, and 2 patients had abdominal PGL/PCC, which is typical of SDHD mutations; however, 1 patient presented with metastasis, found in only 3% of SDHD families, in contrast to SDHB mutations in which the rate is 13% to 23%.6 The RET gene is located on chromosome 10, and its protein, a transmembrane receptor of the tyrosine kinase family, is expressed in cell lineages derived from neural crest cells. It is involved in cell proliferation, migration, differentiation, and survival.9 Mutations in this gene are associated with MEN 2 and familial medullary thyroid cancer. Five percent to 10% of patients with PCC have RET mutation,9 so consideration of this as a compound heterozygote was plausible. However, there is controversy in the literature about the pathogenicity of this mutation.10 Although this was initially called a mutation (and is still called a lower penetrance mutation in the Medullary Thyroid Guidelines of the American Thyroid Association),11 there is growing evidence that it is not a mutation with high penetrance.12 This RETc2372A>T (p.Tyr791Phe) found in the study, raises the issue of when a previously reported mutation is truly pathogenic. Plon et al13 discusses a clinical classification of mutations into 5 classes: (1) not pathogenic or of low clinical significance; (2) possibly benign; (3) unknown; (4) possibly pathogenic; and (5) definitely pathogenic (in which the calculated Baysean probability of pathogenicity are 0.99, respectively). The authors highlight the clinical conundrum that clinicians face in this situation. Although the proband may develop a medullary thyroid cancer, the fact that this is really a class 3 variant now and not a pathogenic mutation raises complex issues. We decided to monitor and not proceed to thyroidectomy as recommended in the American Thyroid Guidelines, as in the most recent overview of MEN 2, this mutation was excluded.12 After consultation with the patients, we monitor them as if it is a mutation, but calcitonin stimulation testing was considered too invasive. To date, no biochemical or ultrasound abnormalities have been detected over a 5-year period. Another interesting finding is the high penetrance and expression of PGL/PCC. Although the family’s severe phenotype may be due to SDHD alone, the RET variant could be acting as a modifier gene. What and if the RET mutation is a modifier in this family remains speculative. An unusual finding is the report of the probands’ paternal grandmother having had a glomus tumor and his paternal aunt (Figure 1). Mutations in SDHD demonstrate parent-of-origin effects and almost exclusively cause disease only when the mutation is inherited from the father, which suggests the existence of genomic imprinting.1,14 In this situation, although each
PARAGANGLIOMA-PHEOCHROMOCYTOMA SYNDROMES
offspring has a 50% chance of inheriting the disease causing mutation, the high risk of developing PGL/PCC is only if it was paternally inherited. However, if his paternal aunt truly had a glomus tumor, she must have inherited it from her mother. Rare maternal inheritance of PGL/PCC has been reported in other studies14 and it is proposed that this is due to methylation of the seventh CTCF binding site, located upstream of the maternally expressed tumor suppressor gene H19 mapped to 11p15, suggesting a gain of imprinting.14 Investigations of PGL/PCC include measuring secreted catecholamine and its metabolites. Plasma metanephrines are recommended to be the best initial test in all hereditary PGL syndromes, as they are more sensitive (99%) but less specific (89%) than urine metabolites (sensitivity, 77%; specificity, 93%).15 Biopsy is contraindicated because of the risk of precipitating a hypertensive crisis, hemorrhage, and tumor cell seeding.1 Recommended first imaging modality is MRI owing to superior tissue characterization, absence of radiation, and visualizing adjacent vascular structures. CT has a sensitivity of 90% for detecting PGLs, but the specificity of CT and MRI may be as low as 50%.15 The specificity is increased to 95% to 100% by using MIBG, and a PET scan is more useful as it has greater sensitivity compared to an MIBG.15 Management involves multidisciplinary input from physicians and surgeons. The definite treatment of benign PGL/PCC is via complete resection after alpha and beta adrenergic blockade.16 For malignant disease, aggressive treatment involving primary surgical excision, regional lymphadenectomy, 131I-MIBG, chemotherapy (cyclophosphamide, vincristine, doxorubicin, dacarbazine), or external beam radiation therapy may be indicated.17,18 Close, lifelong follow-up is necessary for all family members for recurrence and metastasis, as well as new primary PGL/PCCs. In addition, in patients 1 and 4, close monitoring for medullary thyroid cancer and hyperparathyroidism is necessary until the variant is formally reclassified. This includes yearly plasma metanephrine/normetanephrine and/or 24-hour urinary fractionated metanephrine/catecholamine,19 MRI of the skull base and neck every 1 to 2 years, and 3–4 yearly whole body MRI.1 The role of regular 131I MIBG to detect PGL/PCC metastasis with mutation carriers is controversial because of the cumulative radiation dose.1 The surgeon plays an important role in facilitating referral for mutation analysis, usually before 10 years of age, unless the family had early onset cases.
CONCLUSIONS The case series outlines the clinical outcomes of a family affected with PGL/PCC associated with SDHD and RET mutations, and how the surgeons’ role in follow-up and referral for mutation analysis is critical. It is possible that many genes may interact to produce high phenotypic expression in the offspring. Additionally, the family history of the probands’ paternal grandmother and paternal aunt both being affected raises the possibility that the maternal imprinting did not occur in this case. Finally, there was an emphasis on the importance of genetic testing and family screening to offspring and first degree relatives for PGL/PCC. HEAD & NECK—DOI 10.1002/HED
OCTOBER 2014
E101
CHOI ET AL.
Acknowledgments The authors thank the patients and the family for consent to publish their health data.
REFERENCES 1. Kirmani S, Young WF. Hereditary paraganglioma-pheochromocytoma syndromes. In: Pagon RA, Bird TD, Dolan CR, et al, editors. Gene reviews [Internet]. Seattle, WA: University of Washington; 2012. 2. Lin WC, Wang HY, Chang CW, Lin JL, Tsai CH. Retroperitoneal paraganglioma manifesting as paralytic ileus: a case report. J Med Case Rep 2012; 6:158. 3. da Silva ME, Carvalho MJ, Rodrigues AP, et al. Rare vertebral metastasis in the case of hereditary paraganglioma. Hered Cancer Clin Pract 2012;10: 12. 4. Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary carcinoma of the thyroid gland. Cancer 1975;35:695–704. 5. Burnichon N, Abermil N, Buffet A, Favier J, Gimenez–Roqueplo AP. The genetics of paragangliomas. Eur Ann Otorhinolaryngol Head Neck Dis 2012;129:315–318. 6. van Hulsteijn LT, Dekkers OM, Hes FJ, Smit JW, Corssmit EP. Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. J Med Genet 2012;49:768–776. 7. Opocher G, Schiavi F. Genetics of pheochromocytomas and paragangliomas. Best Pract Res Clin Endocrinol Metab 2010;24:943–956. 8. Kapoor N, Pai R, Ebenazer A, et al. Familial carotid body tumors in patients with SDHD mutations: a case series. Endocr Pract 2012;18:e106– e110.
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9. Galan SR, Kann PH. Genetics and molecular pathogenesis of pheochromocytoma and paraganglioma. Clin Endocrinol (Oxf) 2013;78:165–175. 10. Erlic Z, Hoffman MM, Sullivan M, et al. Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel–Lindau syndrome. J Clin Endocrinol Metab 2010;95:308–313. 11. American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565–612. 12. Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med 2011;13:755–764. 13. Plon SE, Eccles DM, Easton D, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 2008;29:1282–1291. 14. Pigny P, Vincent A, Cardot Bauters C, et al. Paraganglioma after maternal transmission of a succinate dehydrogenase gene mutation. J Clin Endocrinol Metab 2008;93:1609–1615. 15. Donahue J, Sahani D, Tso L, Cusack JC Jr. Extra-adrenal pheochromocytoma involving the organ of Zuckerkandl. Surgery 2008;143:830–832. 16. Erdogan BA, Bora F, Altin G, Paksoy M. Our experience with carotid body paragangliomas. Prague Med Rep 2012;113:262–270. 17. Moskovic DJ, Smolarz JR, Stanley D, et al. Malignant head and neck paragangliomas: is there an optimal treatment strategy? Head Neck Oncol 2010;2:23. 18. Fishbein L, Bonner L, Torigian DA, et al. External beam radiation therapy (ERBT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG. Horm Metab Res 2012;44:405–410. 19. Remine WH, Chong GC, Van Heerden JA, Sheps SG, Harrison EG Jr. Current management of pheochromocytoma. Ann Surg 1974;179:740–748.
Jonathan Irish, MD, FRCSC, Section Editor
Hereditary paraganglioma-pheochromocytoma syndromes associated with SDHD and RET mutations Joseph Do Woong Choi, MBBS, B Sc (Adv),1* Katherine M. Tucker, MBBS, FRACP,2 Tack Tsiew Lee, BMBS, FRACS,1 Guan C. Chong, B Med Sc, MBBS, FRACS, FRCS (C), FRCS (E)1 1
Academic Unit of Surgery, Australian National University Medical School, The Canberra Hospital, Canberra, Australian Capital Territory, Australia, 2Hereditary Cancer Service, Prince of Wales Hospital, Randwick, New South Wales, Australia.
Accepted 20 December 2013 Published online 20 March 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.23598
ABSTRACT: Background. Hereditary paraganglioma-pheochromocytoma syndromes (PGL/PCC) are rare tumors arising from neuroendocrine cells. Methods and Results. The proband, a 59-year-old white man and his 42-year-old elder son had a medical history of bilateral carotid body PGL and both presented for treatment of abdominal PGLs. His 36-year-old daughter had excision of recurrent malignant carotid body PGL and vertebral metastasis. His 33-year-old youngest son presented for excision of a unilateral carotid body PGL. All 4 members had succinate dehydrogenase subunit D (SDHD) mutations, whereas the proband and youngest son also had concurrent rearranged during transfection (RET) mutation.
INTRODUCTION Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are rare autosomal dominant cancers characterized by PGLs: neuroendocrine tumors originating from neural crest chromaffin tissues along the paravertebral axis from base of skull to the pelvis and PCC: PGLs confined to the adrenal medulla.1 They mainly affect adults in the fourth or fifth decade of life, and have no sex predilection.2 Sympathetic PGL/PCC typically hypersecrete catecholamines and arise from the sympathetic ganglia from adrenal medulla or along the paravertebral axis from the neck to the pelvis, whereas parasympathetic PGL/PCC arise in the head and neck region and middle mediastinum and 95% are nonsecretory.3 Hereditary PGL/PCC are associated with constitutional mutation on susceptibility genes identified to date (succinate dehydrogenase subunit D [SDHD], succinate dehydrogenase subunit B [SDHB], C, A, succinate dehydrogenase complex assembly factor 2, transmembrane protein 127, and MYC-associated factor X), or genes involved in classic syndromes, such as multiple endocrine neoplasia (MEN) type 2 (rearranged during
*Corresponding author: J. D. W. Choi, Academic Unit of Surgery, Australian National University Medical School, The Canberra Hospital, Canberra, Australian Capital Territory, Australia, 2601. E-mail: [email protected] Contract grant sponsor: This work received intramural support from the Australian National University Medical School and Australian Capital Territory Government Health Directorate.
Conclusion. This is the first report of PGL/PCC with SDHD and RET mutations. The role of the RET gene as a modifier remains speculative. Additionally, the family pedigree suggests maternal inheritance of disease from the probands’ paternal grandmother. Clinicians should refer PGL/ PCC families for mutation analysis as well as being alert to changes in C 2014 Wiley Periodicals, Inc. Head Neck the classification of mutations. V 36: E99–E102, 2014
KEY WORDS: paraganglioma, pheochromocytoma, hereditary, succinate dehydrogenase subunit D (SDHD) mutation, rearranged during transfection (RET) mutation
transfection [RET]),4 von Hippel–Lindau disease or neurofibromatosis type 1.5–7 In this study, the authors present 4 cases from a family who presented for management of multifocal and malignant PGL/PCC, all with SDHD and 2 with concurrent RET mutations.
CASE REPORT Patient 1 The index case, a 59-year-old white man was referred to us after discovery of a solitary focus in the para-aortic region on CT. He was investigated for increasing renal impairment. His symptoms consisted of occasional palpitations and worsening hypertension. Bilateral carotid body and right jugulotympanic PGL were treated at age 44. He gave a history of multiple PGL in at least 5 and possibly 7 relatives, including 2 sisters and his 3 children. His paternal aunt and paternal grandmother were reported to be similarly affected (Figure 1). There was no personal or family history suggestive of one of the syndromes associated with PGL or PCC. His physical examination was unremarkable. Plasma normetadrenaline was elevated (1260 pmol/L; reference range T (p.Tyr791Phe) mutation was found, however, 5 years of annual investigations, including thyroid ultrasound, annual calcitonin, calcium, parathyroid hormone, plasma metanephrine, and normetanephrine levels have been normal. He attends yearly follow-up for recurrence/metastasis and for new foci of PGL/PCC.
Patient 2 Patient #1’s 42-year-old eldest son was referred to us after unremitting hypertension, headaches, migraines, and elevated 24-hour urinary noradrenaline (922 nmol/day; reference range, 45–680 nmol/day). Previous treatment of a glomus tumor at 30 years of age and bilateral carotid body PGL at 38 years of age was noted. Other than hypertension at 149/93 (sitting), his physical examination was unremarkable. Further investigations revealed elevated plasma normetadrenaline (2070 pmol/L) and chromogranin A (33 U/L), with normal urinary adrenaline, plasma metadrenaline, and thyroid function tests. MRI revealed no recurrence of head and neck PGL, but a mass in the left para-aortic region at the level of origin of the inferior mesenteric artery at L3 was noted. PET/CT scan confirmed a metabolically active lesion, consistent with a PGL. Phenoxybenzamine was prescribed before removal at laparotomy. As in patient #1, there was no macroscopic E100
HEAD & NECK—DOI 10.1002/HED
OCTOBER 2014
The 36-year-old daughter of patient #1 was referred to us because of a left neck mass, and a sclerotic mass in the T7 vertebra. Left and right carotid body PGL had been removed at ages 13 and 28. Physical examination revealed a palpable cylindrical mass on the left carotid, which was tender to palpation. The contralateral neck, breast examination, spine examination, and blood pressure were unremarkable. Urinary and plasma metabolites, dopamine, and calcium were normal. An MRI of the head and neck revealed a mass at the left carotid bifurcation measuring 20 3 40 mm, with no lymphadenopathy or skull base involvement. CT and Tc99m whole body bone scan demonstrated a 15 mm sclerotic solitary focus within the posterior aspect of the T7 vertebral body, which confirmed PGL on bone biopsy. MIBG was unremarkable. In view of the patient’s findings, a recurrence of a malignant PGL was strongly suspected. She was treated at a medical center elsewhere for resection of a 20- 3 40-mm recurrent left carotid PGL. Surgery was complicated by unilateral X and XII nerve palsy, because of dense fibrosis and nerve adherence to the tumor capsule. Additionally, excision of the T7 vertebral body, insertion of hardware, implantation of bone graft, and radiotherapy were performed to control spinal metastasis. Her postoperative course was essentially uneventful. The SDHDc.287289delCTA mutation was identified but not the RETc.2372A>T mutation. She undergoes regular followup visits to monitor for recurrence/metastasis.
Patient 4 The youngest son (aged 33) presented for routine follow-up after excision of a right carotid body PGL at age 22. Physical examination was unremarkable. Urinary and plasma metabolites and calcium were normal. Regional bone scan of the head, neck, and upper thoracic spine were unremarkable. MRI confirmed the presence of a 2-cm left carotid body tumor. Surgical excision was recommended given his strong family history. At surgical removal, referred elsewhere, a likely PGL was found medial to the left carotid bifurcation with no macroscopic tumor invasion into the surrounding tissues. Pathology confirmed a carotid PGL. His surgery and postoperative progress were uneventful. He was identified as having the same SDHD and the RET mutation as his father.
DISCUSSION PGL/PCC represents the same syndrome, subcategorized only by different sites of presentation. Approximately 10% of patients with PGL/PCC have a significant family history and 30% are associated with susceptibility genes to date.5,6 Of these, succinate dehydrogenase subunit A, SDHB, succinate dehydrogenase subunit C, and SDHD genes encode for 4 subunit proteins of succinate dehydrogenase (SDH) subunits A, B, C, and D. SDH
HEREDITARY
catalyzes oxidation of succinate to fumarate in the Krebs cycle and provides electrons to the mitochondrial electron transport chain, and it is proposed that mutation leads to stabilization and activation of hypoxia-inducible factor a, which in turn causes cellular proliferation.5,8 SDHD mutations (familial PGL type 1) are associated predominantly with multifocal head and neck, but also thoracic and abdominal PGLs.3 In contrast, SDHB mutations (familial PGL type 4), are more likely to be extra-adrenal, abdominal, and develop malignant disease.3 Our patients presented with primarily head and neck PGL, and 2 patients had abdominal PGL/PCC, which is typical of SDHD mutations; however, 1 patient presented with metastasis, found in only 3% of SDHD families, in contrast to SDHB mutations in which the rate is 13% to 23%.6 The RET gene is located on chromosome 10, and its protein, a transmembrane receptor of the tyrosine kinase family, is expressed in cell lineages derived from neural crest cells. It is involved in cell proliferation, migration, differentiation, and survival.9 Mutations in this gene are associated with MEN 2 and familial medullary thyroid cancer. Five percent to 10% of patients with PCC have RET mutation,9 so consideration of this as a compound heterozygote was plausible. However, there is controversy in the literature about the pathogenicity of this mutation.10 Although this was initially called a mutation (and is still called a lower penetrance mutation in the Medullary Thyroid Guidelines of the American Thyroid Association),11 there is growing evidence that it is not a mutation with high penetrance.12 This RETc2372A>T (p.Tyr791Phe) found in the study, raises the issue of when a previously reported mutation is truly pathogenic. Plon et al13 discusses a clinical classification of mutations into 5 classes: (1) not pathogenic or of low clinical significance; (2) possibly benign; (3) unknown; (4) possibly pathogenic; and (5) definitely pathogenic (in which the calculated Baysean probability of pathogenicity are 0.99, respectively). The authors highlight the clinical conundrum that clinicians face in this situation. Although the proband may develop a medullary thyroid cancer, the fact that this is really a class 3 variant now and not a pathogenic mutation raises complex issues. We decided to monitor and not proceed to thyroidectomy as recommended in the American Thyroid Guidelines, as in the most recent overview of MEN 2, this mutation was excluded.12 After consultation with the patients, we monitor them as if it is a mutation, but calcitonin stimulation testing was considered too invasive. To date, no biochemical or ultrasound abnormalities have been detected over a 5-year period. Another interesting finding is the high penetrance and expression of PGL/PCC. Although the family’s severe phenotype may be due to SDHD alone, the RET variant could be acting as a modifier gene. What and if the RET mutation is a modifier in this family remains speculative. An unusual finding is the report of the probands’ paternal grandmother having had a glomus tumor and his paternal aunt (Figure 1). Mutations in SDHD demonstrate parent-of-origin effects and almost exclusively cause disease only when the mutation is inherited from the father, which suggests the existence of genomic imprinting.1,14 In this situation, although each
PARAGANGLIOMA-PHEOCHROMOCYTOMA SYNDROMES
offspring has a 50% chance of inheriting the disease causing mutation, the high risk of developing PGL/PCC is only if it was paternally inherited. However, if his paternal aunt truly had a glomus tumor, she must have inherited it from her mother. Rare maternal inheritance of PGL/PCC has been reported in other studies14 and it is proposed that this is due to methylation of the seventh CTCF binding site, located upstream of the maternally expressed tumor suppressor gene H19 mapped to 11p15, suggesting a gain of imprinting.14 Investigations of PGL/PCC include measuring secreted catecholamine and its metabolites. Plasma metanephrines are recommended to be the best initial test in all hereditary PGL syndromes, as they are more sensitive (99%) but less specific (89%) than urine metabolites (sensitivity, 77%; specificity, 93%).15 Biopsy is contraindicated because of the risk of precipitating a hypertensive crisis, hemorrhage, and tumor cell seeding.1 Recommended first imaging modality is MRI owing to superior tissue characterization, absence of radiation, and visualizing adjacent vascular structures. CT has a sensitivity of 90% for detecting PGLs, but the specificity of CT and MRI may be as low as 50%.15 The specificity is increased to 95% to 100% by using MIBG, and a PET scan is more useful as it has greater sensitivity compared to an MIBG.15 Management involves multidisciplinary input from physicians and surgeons. The definite treatment of benign PGL/PCC is via complete resection after alpha and beta adrenergic blockade.16 For malignant disease, aggressive treatment involving primary surgical excision, regional lymphadenectomy, 131I-MIBG, chemotherapy (cyclophosphamide, vincristine, doxorubicin, dacarbazine), or external beam radiation therapy may be indicated.17,18 Close, lifelong follow-up is necessary for all family members for recurrence and metastasis, as well as new primary PGL/PCCs. In addition, in patients 1 and 4, close monitoring for medullary thyroid cancer and hyperparathyroidism is necessary until the variant is formally reclassified. This includes yearly plasma metanephrine/normetanephrine and/or 24-hour urinary fractionated metanephrine/catecholamine,19 MRI of the skull base and neck every 1 to 2 years, and 3–4 yearly whole body MRI.1 The role of regular 131I MIBG to detect PGL/PCC metastasis with mutation carriers is controversial because of the cumulative radiation dose.1 The surgeon plays an important role in facilitating referral for mutation analysis, usually before 10 years of age, unless the family had early onset cases.
CONCLUSIONS The case series outlines the clinical outcomes of a family affected with PGL/PCC associated with SDHD and RET mutations, and how the surgeons’ role in follow-up and referral for mutation analysis is critical. It is possible that many genes may interact to produce high phenotypic expression in the offspring. Additionally, the family history of the probands’ paternal grandmother and paternal aunt both being affected raises the possibility that the maternal imprinting did not occur in this case. Finally, there was an emphasis on the importance of genetic testing and family screening to offspring and first degree relatives for PGL/PCC. HEAD & NECK—DOI 10.1002/HED
OCTOBER 2014
E101
CHOI ET AL.
Acknowledgments The authors thank the patients and the family for consent to publish their health data.
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