Genetics of pheochromocytoma and paraganglioma: New developments

Since 2000, several new susceptibility genes for hereditary pheochromocytoma or paraganglioma have been discovered. The aim of this review is to highlight how these discoveries have improved our knowledge on the mode of inheritance of these tumors and also on their molecular pathogenesis. Concerning this specific point, we will show that the different key players of tumorigenesis can converge on two pathways, the first being the hypoxia/angiogenesis pathway and the second being the control of neural crest cell development pathway. Finally, practical issues are considered; for us, it would be preferable to apply easy-to-identify clinical predictors to preselect patients eligible for molecular testing in order to improve the efficiency of these high-cost tests.     

SDH-related pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma are rare tumors of adrenals as well as the sympathetic and parasympathetic paraganglia. Clinical presentation of these tumors depends on localization, secretory profile and malignant potential. Four distinct syndromes – PGL1–4 – are related to mutations in the succinate dehydrogenase gene – mitochondrial complex involved in electron transfer and Krebs cycle. Here we describe etiology, genetics, as well as clinical aspects of SDH-related tumors. We also describe recent discoveries in HIF-related pathway of tumorigenesis and mutations in new SDH-related genes that have improved our understanding of this disease.     

Extra-adrenal pheochromocytoma (paraganglioma).

The authors describe the case of a 19-year-old female patient with an abdominal paraaortic extra-adrenal pheochromocytoma (paraganglioma), presenting arterial hypertension. The predominant catecholamine produced by the tumor was norepinephrine (4110 pg/ml; normal < 450 pg/ml). 131I metaiodobenzylguanidine (131I-MIBG), computed tomography and magnetic resonance imaging allowed location and characterization of the tumor. Histologically the tumor (weight = 34.2 g; 5.8 x 4 x 3 cm) was a typical pheochromocytoma.     

Concurrent bilateral pheochromocytoma and thoracic paraganglioma during pregnancy

Although hypertension occurring during pregnancies is not uncommon and its prognosis is generally excellent, some of its unusual causes can lead to catastrophic consequences, especially in undiagnosed cases. Here, we report a pregnant woman who presented with hypertension in her early pregnancy. It was subsequently found to be caused by bilateral pheochromocytoma. After removal of both tumors, catecholamine levels unexpectedly and unexplainably remained elevated. At 23 weeks of gestation, the fetus was found dead in utero. After the fetal death, additional studies were performed and revealed a thoracic paraganglioma. To our knowledge, this is the first report of a case of three catecholamine-producing tumors occurring concurrently during a pregnancy. Genetic analysis helped identify this unprecedented condition; the patient harbored a heterozygous missense mutation c.482G>A in exon 3 of the VHL gene, indicating von Hippel-Lindau syndrome. Physicians who care for hypertensive pregnant patients should be aware of this condition as its diagnosis would probably lead to a better outcome.     

A functioning intrapericardial paraganglioma (pheochromocytoma)

A patient with a functioning intrapericardial paraganglioma (pheochromocytoma) that was located at the root of the aorta overlying the right coronary artery and adherent to the right ventricular wall is reported. The tumour was successfully removed under total cardiopulmonary bypass without inducing cardiac arrest.     

A functioning intrapericardial paraganglioma (pheochromocytoma).

A patient with a functioning intrapericardial paraganglioma (pheochromocytoma) that was located at the root of the aorta overlying the right coronary artery and adherent to the right ventricular wall is reported. The tumour was successfully removed under total cardiopulmonary bypass without inducing cardiac arrest.     

Posterior mediastinal paraganglioma with bilateral adrenal pheochromocytoma

Paraganglioma and adrenal pheochromocytoma are tumors of common origin arising from chromaffin cells. However, it is extremely rare to find mediastinal paraganglioma simultaneously with bilateral adrenal pheochromocytoma. We report a 53-year-old man who was diagnosed with posterior mediastinal paraganglioma and bilateral adrenal pheochromocytoma and who underwent successful excision of the posterior mediastinal mass and bilateral total adrenalectomy.     

Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes

CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.     

Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first‐degree relatives (and second‐degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy‐catecholamines and bi‐annual rapid whole‐body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre‐symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow‐up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.     

Precision medicine in pheochromocytoma and paraganglioma: current and future concepts

Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics‐based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro‐mitogenic and anti‐apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome‐related tumours. Genotype‐tailored treatment options, follow‐up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large‐scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.     

嗜铬细胞瘤的诊断及其发病机制研究

嗜铬细胞瘤是来源于肾上腺髓质和肾上腺外嗜铬组织的分泌儿茶酚胺的肿瘤,是内分泌性高血压的重要原因,可导致心、脑、肾血管系统的严重并发症。其在高血压人群中的患病率约为1.9%,早期发现及正确诊断、治疗嗜铬细胞瘤患者具有重要的意义。应高度重视嗜铬细胞瘤发病机制及治疗的研究。     

Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma

Pheochromocytomas (PCCs) are rare tumors that arise from chromaffin tissue in the adrenal medulla, but can also occur in the abdomen outside the adrenals and are then called sympathetic paragangliomas (sPGLs). According to the literature, between 15 and 25% of apparently sporadic adrenal PCC and sPGL are caused by germline mutations in RET, von Hippel-Lindau disease (VHL), succinate dehydrogenase subunit B (SDHB), or subunit D SDHD. However, few studies have addressed the mutationfrequency of these candidate genes in selected subgroups of PCC andsPGL, such as bilateral adrenal PCC or extra-adrenal sPGL, and none have looked at somatic mutations by analyzing tumor tissue. Therefore, we have investigated the occurrence of germline and somatic mutations in RET, VHL, SDHB, and SDHD in comparatively large series of bilateral adrenal PCC (n = 33 patients) and sPGL (n = 26 patients), with the aim of determining the mutation frequency of each of these genes and to establish a genetic testing algorithm. Twenty-one RET, two VHL germline, and one SDHD mutations were found in the patients with bilateral adrenal PCC. In sPGL, one novel SDHB germline and one novel SDHB somatic mutation were observed. In addition, two SDHD germline mutations were found. We conclude that germline RET mutations are predominantly found in bilateral PCC, and that somatic and germline SDHB and SDHD mutations usually occur in sPGL, which has practical consequences for genetic testing algorithms. We suggest that sequential mutation analysis should be directed first at RET, followed by VHL and SDHD for patients with bilateral adrenal PCC at diagnosis, and at SDHB and SDHD for patients with sPGL.     

Genetics and pathogenesis of small-vessel vasculitis

Small-vessel vasculitides are uncommon autoimmune diseases characterised by inflammation and necrosis of arterioles, capillaries and venules, frequently described as various (previously eponymous) clinical syndromes. Some are associated with vessel wall immune complex deposition, whereas others are pauci-immune but paradoxically often associated with circulating anti-neutrophil cytoplasmic antibodies (ANCA). Most is known about the pathogenesis of the pauci-immune ANCA-associated syndromes, which are gradually becoming better understood with regard to their genetic predisposition and the critical pathways mediating disease initiation, as well as their particular phenotypic features. Through better understanding of key cellular and molecular players, we have been able to develop novel biomarkers and treatment strategies, which should translate to improved diagnostics, treatment protocols and, ultimately, better patient outcomes. These conditions are treatable but not yet curable, although it is clear that patients may follow different disease courses, which for some include restoration of their pre-morbid immune status.     

Exercise-induced nausea and vomiting: another sign and symptom of pheochromocytoma and paraganglioma

A cohort of nine patients, mostly young adults, presented with a new sign/symptom of pheochromocytoma/paraganglioma: exercise-induced nausea and vomiting. The aims of this article are to introduce this sign/symptom and offer a possible hypothesis for the observation. Following a 2000 report from a paraganglioma patient experiencing exercise-induced nausea and vomiting, we began asking patients about instances of nausea and vomiting with exercise. A total of nine patients, 4.4% of our pheochromocytoma/paraganglioma population, presented with reports of exercise-induced nausea and vomiting, initially with moderate-to-intense levels of exercise, at the first presentation of their disease. All of these patients reported a cessation of exercise-induced nausea and vomiting following the removal of their primary tumor. Two patients with metastatic disease to the lungs reported a recurrence of exercise-induced nausea and vomiting. The majority of patients studied were young adults with mean onset age of 19.4?years (range of 9-51?years) and the mean age of diagnosis being 24.1?years (range of 11-53?years). Exercise-induced nausea and vomiting should be considered a sign/symptom of pheochromocytoma/paraganglioma and should be addressed in the clinical evaluation of these patients, especially in young adults. Whether exercise-induced elevated catecholamine levels could account for the induced nausea and vomiting via activation of adrenergic receptors in the area postrema remains to be established.     

Mitochondrial function and content in pheochromocytoma/paraganglioma of succinate dehydrogenase mutation carriers

To date, the consequences of succinate dehydrogenase (SDH) impairment on overall mitochondrial functions are still obscure. In this study, we evaluated SDH activity and expression and mitochondrial homeostasis in 57 tissue samples of pheochromocytoma (PHEO)/paraganglioma (PGL) obtained from patients genotyped for PHEO/PGL susceptibility genes. The resulted SDH activity and content always decreased in SDH-mutated tumors, in one out of two MAX-mutated patients and in four patients resulted wild type (wt) at genetic screening. All these four wt patients were further screened for large deletions in SDH genes, TMEM127 and MAX and resulted wt but two had somatic SDHD mutations. The RT-PCR in the MAX-mutated sample suggests that the decrease in SDH depends on complex instability and not on a reduced SDHB expression. SDH mutations neither alter citrate synthase (CS) activity nor the content of voltage-dependent anion channel (VDAC) while the expression of the mitochondrial complex IV (cytochrome c oxidase (COX)) was found extremely variable in all (mutated and wt) samples suggesting an impairment of mitochondrial cristae in these tumors. In conclusion, tumors from patients with germ line SDH mutations invariably show decreased enzymatic activity and content, but an SDH impairment may also depend on SDH somatic mutations or, seemingly, on MAX mutations. The impaired SDH activity in the two wt tissues suggests mutations in other still unknown susceptibility genes. Finally, the extreme variability in COX expression levels is yet to be explained and this strongly suggests to evaluate other mitochondrial features to better understand the mitochondrial role in the pathogenesis of these tumors.     

嗜铬细胞瘤/副节瘤患者心血管表现的临床分析

目的探究嗜铬细胞瘤/副节瘤(PH/PGL)患者中心血管异常的发生率、表现形式、临床转归与其发生机制。方法入选2010年10月至2013年4月期间就诊于北京协和医院的78例PH/PGL患者,记录患者临床症状、血压、心率、心肌酶、心力衰竭标记物、心电图、超声心动图表现及24 h尿儿茶酚胺水平,并进行分析。结果 (1)78例患者中,66例(84.6%)有高血压,3例(3.8%)病程中有低血压病史。45例(57.7%)存在心脏损害,包括急性左心功能不全3例(3.8%),心肌酶与心电图ST-T段动态变化6例(7.7%),左心室射血分数下降6例(7.7%),其中5例随访恢复正常,心律失常30例(38.5%),左心室肥厚25例(32.1%)。(2)以有无左心室肥厚将高血压PH/PGL患者分为两组,两组高血压病程、表现为持续与阵发性血压升高比例、血压水平差异无统计学意义,肥厚组24 h尿去甲肾上腺素[435(61⁷66)μg/24 h比110(35766)μg/24 h比110(35²42)μg/24 h,U=320,P<0.01]、肾上腺素[3.51(3.01242)μg/24 h,U=320,P<0.01]、肾上腺素[3.51(3.01⁴.53)μg/24 h比2.88(2.324.53)μg/24 h比2.88(2.32³.89)μg/24 h,U=337,P=0.02]显著高于无肥厚组。结论PH/PGL可引起多种心血管损害,少数出现左心室射血分数下降,大多可逆。