Paraganglioma Patients Research Articles

Low penetrance of paraganglioma and pheochromocytoma in an extended kindred with a germline SDHB exon 3 deletion.

In the Netherlands, the majority of hereditary paragangliomas (PGL) is caused by SDHD, SDHB and SDHAF2 mutations. Founder mutations in SDHD are particularly prevalent, but several SDHB founder mutations have also been described. Here, we describe an extended PGL family with a Dutch founder mutation in SDHB, c.201-4429_287-933del. The proband presented with apparently sporadic head and neck paraganglioma at advanced age. Subsequently, evaluation of the family identified several unaffected mutation carriers, asymptomatic and symptomatic PGL patients, and patients presenting with early-onset malignant pheochromocytoma. The calculated penetrance of the SDHB mutation in this kindred is lower than the risk suggested for SDHB mutations in the literature. This may represent a characteristic of this particular SDHB mutation, but may also be a reflection of the inclusion of relatively large numbers of asymptomatic mutation carriers in this family and adequate statistical correction for ascertainment bias. The low penetrance of SDHB mutations may obscure the hereditary nature of SDHB-linked disease and is important in the counseling of SDHB-linked patients. Risk estimates should preferably be based on the specific mutation involved.

The Challenges of Treating Paraganglioma Patients with (177)Lu-DOTATATE PRRT: Catecholamine Crises, Tumor Lysis Syndrome and the Need for Modification of Treatment Protocols.

A high percentage of paragangliomas express somatostatin receptors that can be utilized for targeted radioisotope therapy. The aim of this study was to describe and discuss the challenges of treating these tumors with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) radioisotope therapy using established protocols. Three paraganglioma patients were treated with 4-5 cycles of (177)Lu-DOTATATE and were evaluated for side effects and response to therapy. Two of the three patients developed severe adverse reactions following their first (177)Lu-DOTATATE treatment. One patient developed a catecholamine crisis and tumor lysis syndrome within hours of treatment, requiring intensive care unit (ICU) support, and another developed a catecholamine crisis 3days after treatment, requiring hospitalization. The treatment protocols at our institution were subsequently modified by increasing the radioisotope infusion time from 15 to 30min, as recommended in the literature, to 2-4h and by reducing the administered dose of (177)Lu-DOTATATE. Subsequent (177)Lu-DOTATATE treatments utilizing the modified protocols were well tolerated, and response to therapy was achieved in all three patients, resulting in significantly improved quality of life. (177)Lu-DOTATATE is an exciting new therapeutic option in the management of paragangliomas; however, current treatment protocols described in the literature may need to be modified by lengthening the infusion time and/or lowering the initial treatment dose to prevent or reduce the severity of adverse reactions.

Instability of succinate dehydrogenase in SDHD polymorphism connects reactive oxygen species production to nuclear and mitochondrial genomic mutations in yeast.

Mitochondrial succinate dehydrogenase (SDH) is an essential complex of the electron transport chain and tricarboxylic acid cycle. Mutations in the human SDH subunit D frequently lead to paraganglioma (PGL), but the mechanistic consequences of the majority of SDHD polymorphisms have yet to be unraveled. In addition to the originally discovered yeast SDHD subunit Sdh4, a conserved homolog, Shh4, has recently been identified in budding yeast. To assess the pathogenic significance of SDHD mutations in PGL patients, we performed functional studies in yeast. SDHD protein expression was reduced in SDHD-related carotid body tumor tissues. A BLAST search of SDHD to the yeast protein database revealed a novel protein, Shh4, that may have a function similar to human SDHD and yeast Sdh4. The missense SDHD mutations identified in PGL patients were created in Sdh4 and Shh4, and, surprisingly, a severe respiratory incompetence and reduced expression of the mutant protein was observed in the sdh4Δ strain expressing shh4. Although shh4Δ cells showed no respiratory-deficient phenotypes, deletion of SHH4 in sdh4Δ cells further abolished mitochondrial function. Remarkably, sdh4Δ shh4Δ strains exhibited increased reactive oxygen species (ROS) production, nuclear DNA instability, mtDNA mutability, and decreased chronological lifespan. SDHD mutations are associated with protein and nuclear and mitochondrial genomic instability and increase ROS production in our yeast model. These findings reinforce our understanding of the mechanisms underlying PGL tumorigenesis and point to the yeast Shh4 as a good model to investigate the possible pathogenic relevance of SDHD in PGL polymorphisms.

Integrative Genetic Characterization and Phenotype Correlations in Pheochromocytoma and Paraganglioma Tumours

BackgroundAbout 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results.AimThe purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours.MethodsA total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray.ResultsPathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases.ConclusionSomatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients.

Pediatric Endocrine Surgery: A 20-Year Experience at the Mayo Clinic

Surgically managed endocrinopathies are rare in children. Most surgeons have limited experience in this field. Herein we report our operative experience with pediatric patients, performed over two decades by high-volume endocrine surgeons. The study was conducted at the Mayo Clinic (a tertiary referral center). Patients were <19 years old and underwent an endocrine operation (1993-2012). Demographics, surgical procedure, diagnoses, morbidity, and mortality were retrospectively reviewed. A total of 241 primary cases included 177 thyroid procedures, 13 neck dissections, 24 parathyroidectomies, 14 adrenalectomies, 7 paragangliomas, and 6 pancreatic procedures. Average age of patients was 14.2 years. There were 133 total thyroidectomies and 40 hemithyroidectomies. Fifty-three cases underwent a central or lateral neck dissection. Six-month follow-up was available for 98 total thyroidectomy patients. There were four cases of permanent hypoparathyroidism (4%) and no permanent recurrent laryngeal nerve (RLN) paralyses. Sequelae of neck dissections included temporary RLN neurapraxia and Horner's syndrome. Parathyroidectomy was performed on 24 patients: 20 with primary hyperparathyroidism (HPT), three with tertiary HPT, and one with familial hypocalciuric hypocalcemia. Three patients (16%) had recurrent HPT, all with multiglandular disease. One patient had temporary RLN neurapraxia. We performed seven bilateral and seven unilateral adrenalectomies; eight were laparoscopic. Indications included pheochromocytoma, Cushing's syndrome, adrenocortical carcinoma, congenital adrenal hyperplasia, and ganglioneuroma. One death was due to adrenocortical carcinoma. Five paraganglioma patients had succinate dehydrogenase subunit B mutations, and one recurred. Six patients with insulinoma underwent enucleation (n = 5) or distal pancreatectomy (n = 1). A single postoperative abscess was managed nonoperatively. Pediatric endocrine procedures are uncommon but can be safely performed with complication rates comparable to those of the adult population. It is imperative that these operations be performed by high-volume surgeons.

A founder SDHB mutation in Portuguese paraganglioma patients

This work was supported by Fundacao para a Ciencia e Tecnologia (Program Ciencia 2007 to V Maximo, Program Ciencia 2008 to J Lima, grant numbers SFRH/BPD/64233/2009 to Pedro Soares, PIC/IC/83037/2007 to V Maximo, and PTDC/CS-ANT/113832/2009 to T Rito). Further funding by Portuguese Foundation for Science and Technology by the project ‘Microenvironment, metabolism and cancer’ partially supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte) under the Quadro de Referencia Estrategico Nacional (QREN) and through the Fundo Europeu de Desenvolvimento Regional (FEDER).

Avoiding and Nonexpressing: Coping Styles of Patients With Paragangliomas

Paraganglioma (PGL) patients and succinate dehydrogenase (SDH) gene mutation carriers at risk for PGLs have a decreased quality of life (QoL). QoL may be affected by the strategy an individual uses when dealing with a stressful situation, ie, specific coping styles. Understanding the various approaches to coping may allow the development of targeted interventions to improve patient QoL. The objective of the study was to assess coping styles in PGL patients and SDH mutation carriers. This was a cross-sectional study. The study was conducted at a tertiary referral center. Coping styles were assessed using the Utrecht Coping List. The results from the study cohort were compared with a control group and data derived from the literature. Potential differences in coping styles between the various SDH mutation carriers and PGL patients without an SDH mutation were explored. Of the 174 patients who responded, 122 were SDHD, 25 SDHB, and 2 SDHC mutation carriers. An additional 25 patients lacked an SDH mutation. They recruited 100 peers as controls. Compared with the general population, the study cohort was more avoidant of problems (P < .001) and reported less expression of emotion (P < .01). Compared with patients with other conditions, they sought more social support (P < .001). There were no significant differences in coping styles between the various categories of mutation carriers or PGL patients lacking a mutation. Coping styles of PGL patients and SDH mutation carriers differ from those of control and reference groups and include an avoidant coping style and a lack of emotional expression.

Paraganglioma of the Carotid Body: Treatment Strategy and SDH-gene Mutations

The aim of the present study was to review treatment results in patients with paraganglioma (PGL) of the neck presenting as carotid body tumour, long-term follow-up and relevance of genetic testing for succinate dehydrogenase (SDH)-gene mutations. Retrospective analysis of prospectively collected data and prospective genetic analysis. Over a 25-year period (1987-2011) 50 patients were operated for 63 PGLs of the neck. Pre-, intra- and postoperative findings were analysed. Sanger sequencing was performed for genetic testing of SDH-gene mutations (SDH B, SDHC and SDHD). Fifty patients underwent resection of 63 PGLs (62 benign, one malignant) without mortality. Eight patients underwent preoperative embolisation. Vascular surgical procedures were required in 15 operations (15/63 = 23.8%). Nerve lesions occurred after 13 operations (13/63 = 20.6%) and were associated with large tumours. A total of 44 patients are alive after a mean follow-up of 9.8 years. In 40 patients 17 SDH-gene mutations were detected (17/40 = 42.5%): 14 SDHD mutations, two SDHB mutations and one rare SDHC mutation. Surgery for PGL is recommended. All PGL patients should be screened for SDH mutations because it impacts the individual follow-up strategy. Whereas all PGL patients require annual ultrasound control, mutation carriers and family members with proven mutations should in addition be regularly examined by magnetic resonance imaging (MRI) of head, neck, thorax, abdomen and pelvis.

Quality of life is decreased in patients with paragangliomas

Germline mutations in succinate dehydrogenase (SDH) genes predispose carriers for developing paragangliomas, and studies on their quality of life (QoL) are scarce. The objectives of this study were to assess QoL in patients with paragangliomas (PGL), to evaluate long-term QoL, and to explore potential differences in QoL between SDH mutation carriers and paraganglioma patients without an SDH mutation. Cross-sectional, case-control study. Tertiary referral center. ONE HUNDRED AND SEVENTY FOUR PARAGANGLIOMA PATIENTS WERE INCLUDED: 25 SDHB, two SDHC, and 122 SDHD mutation carriers and 25 patients without an SDH mutation. They provided 100 peers as control persons. Furthermore, patients were compared with age-adjusted reference populations. QOL WAS ASSESSED USING THREE VALIDATED HEALTH-RELATED QOL QUESTIONNAIRES: the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Index 20, and the Short Form 36. Patients reported a significantly impaired QoL compared with their own controls, mainly on fatigue and physical condition subscales. Compared with age-adjusted literature values, patients had significantly impaired scores on physical, psychological, and social subscales. A decreased QoL was mainly related to paraganglioma-associated complaints. There was no difference in QoL between the various SDH mutation carriers or paraganglioma patients without an SDH mutation. QoL in asymptomatic mutation carriers, i.e. without manifest disease, did not differ from QoL of the general population. Long-term results in 41 patients showed no alteration in QoL besides a reduced level of activity. QoL is decreased in paraganglioma patients but stable when measured over time.

Sorafenib in the treatment of metastatic paraganglioma: A case report.

e13523 Background: Paragangliomas (extra-adrenal pheochromocytomas) are rare chromaffin cell tumors that can often be cured by resection. Excess release of catecholamines is characteristic for paragangliomas. Paragangliomas are mostly benign if diagnosed and treated early. Overall 0–36% of paraganglioma patients develop metastatic disease, depending on the type of tumor. Methods: We present a case of a 43-year-old woman who admitted to our department with a history of episodic headaches, diaphoresis and weakness. Hypertension and tachycardia were diagnosed. She had elevated plasma catecholamine levels and a right paraaortic mass (9x9.5cm) was visualized on CT. The mass was excised and the diagnosis of paraganglioma was confirmed. In postoperative follow-up the patient's blood pressure and catecholamine levels were normalized. After twenty months follow up, local recurrence and metastases were detected in thorax, abdomen, and skeletal system. Plasma catecholamine levels were high. Results: Chemotherapy with CVD (adriamycine (7mg/m2), dacarbazine (400mg/m2), cyclophosphamide (500mg/m2), vincristine (1.4mg/m2) on day 1 and 2, repeated every 21 days; were administered and no improvement was observed in PET-CT following a treatment of three cycles. Sorafenib (800mg/m2/day) was applied for three-months. Finally the patient’s plasma catecholamine levels and metastatic lesions regressed. Conclusions: Treatment options of metastatic paragangliomas (MP) are removal by excision or ablation, chemotherapy, or targeted pharmaceuticals. Benefits of CVD chemotherapy for MP appears to be short-term and do not include an increase in patient survival. As targeted therapy, treatment of MP with everolimus or imatinib were attempted with no significant benefit, and thus are not recommended. However partial response was reported with Sunitinib some cases. We used sorafenib as another multiple TKI and detected complete response. So far, sorafenib has not been applied in the treatment of MP in literature. Sorafenib can be preferred in the treatment of MP. Therefore, more comprehensive clinical trials are needed.

Diagnostic performance of 18F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis

The aim of this study was to systematically review and conduct a meta-analysis of published data about the diagnostic performance of (18)F-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) in patients with paraganglioma (PG). A comprehensive computer literature search of studies published through 30 June 2011 regarding (18)F-DOPA PET or PET/computed tomography (PET/CT) in patients with PG was performed in PubMed/MEDLINE, Embase and Scopus databases. Pooled sensitivity and specificity of (18)F-DOPA PET or PET/CT in patients with PG on a per patient- and on a per lesion-based analysis were calculated. The area under the receiver-operating characteristic (ROC) curve was calculated to measure the accuracy of (18)F-DOPA PET or PET/CT in patients with PG. Furthermore, a sub-analysis taking into account the different genetic mutations in PG patients was also performed. Eleven studies comprising 275 patients with suspected PG were included in this meta-analysis. The pooled sensitivity of (18)F-DOPA PET and PET/CT in detecting PG was 91% [95% confidence interval (CI) 87-94%] on a per patient-based analysis and 79% (95% CI 76-81%) on a per lesion-based analysis. The pooled specificity of (18)F-DOPA PET and PET/CT in detecting PG was 95% (95% CI 86-99%) on a per patient-based analysis and 95% (95% CI 84-99%) on a per lesion-based analysis. The area under the ROC curve was 0.95 on a per patient- and 0.94 on a per lesion-based analysis. Heterogeneity between the studies about sensitivity of (18)F-DOPA PET or PET/CT was found. A significant increase in sensitivity of (18)F-DOPA PET or PET/CT was observed when a sub-analysis excluding patients with succinate dehydrogenase subunit B (SDHB) gene mutations was performed. In patients with suspected PG (18)F-DOPA PET or PET/CT demonstrated high sensitivity and specificity. (18)F-DOPA PET or PET/CT are accurate methods in this setting. Nevertheless, possible sources of false-negative results should be kept in mind. Furthermore, SDHB gene mutations could influence (18)F-DOPA PET or PET/CT diagnostic performance.

Comparison of clinical and imaging features in succinate dehydrogenase-positive versus sporadic paragangliomas

Limited data exist concerning the clinical and imaging features that distinguish sporadic from familial paragangliomas (PGLs). Clinical, genetic (succinate dehydrogenase [SDHB] vs no SDHx), and imaging (computed tomography [CT], magnetic resonance imaging, (18)F-fluoro-deoxy-glucose positron emission tomography [(18)F-FDG-PET]) features obtained during a decade in 124 PGL patients were studied. Data were analyzed by Fisher's exact test or Wilcoxon rank-sum test. Mean age at diagnosis was younger in the SDHB-positive (SDHB+) group compared with the sporadic (no SDHx) group (28 vs 39 years, respectively, P < .001). Rate of supradiaphragmatic neoplasms were greater in the SDHB+ group (16.7 vs 4.7%, P = .11). Metastasis rates were greater in the SDHB+ group (78.9 vs 48.3%, P < .001), as was the existence of metastases or multiple PGLs at presentation (38.5 vs 16.7%, P < .05). Tumor volumes >250 mL were exclusively observed in SDHB+ patients (P < .05). On CT, SDHB+ tumors were more enhanced (P < .05). On (18)F-FDG-PET, SDHB+ tumors' had greater mean standard uptake values (12.3 vs 8.0, P < .05). Clinically young age, large tumor volume, greater rate of metastatic and multifocal PGLs, greater SUV values on (18)F-FDG-PET, and increased CT enhancement are observed in SDHB+ PGLs. These findings may warrant genetic screening. Because SDHB+ patients demonstrate more supradiaphragmatic lesions, whole-body imaging may be of particular value in these patients.

Mutations in SDHD are the major determinants of the clinical characteristics of Dutch head and neck paraganglioma patients

Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands. We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center. The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate. The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands.

Normal Life Expectancy for Paraganglioma Patients: A 50-Year-Old Cohort Revisited

The objective of this study was to assess the long-term survival of patients with a paraganglioma of the head and neck compared with the survival of the general Dutch population. This historic cohort study was conducted using nationwide historical data of paraganglioma patients. We retrieved a cohort of 86 patients diagnosed with a paraganglioma of the head and neck between 1945 and 1960 in the Netherlands. Dates of death were retrieved from the national bureau of genealogy. Survival after diagnosis was compared with age and sex adjusted survival in the general population, by means of Wilcoxon signed rank test and Kaplan-Meier actuarial survival curves. Although surgery had more complications in the studied era than today and the death of five patients with carotid body tumors caused immediate excess mortality, the survival of the followed cohort was not significantly reduced if compared with the general population. Paragangliomas of the head and neck do not reduce life expectancy.

Is the c.3G&gt;C mutation in the succinate dehydrogenase subunit D (SDHD) gene due to a founder effect in Chinese head and neck paraganglioma patients?

Three Chinese patients with head and neck paragangliomas have been reported to carry the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene. In addition, in our hospital, two further patients were identified who have the same mutation. It is unclear whether the c.3G>C mutation in Chinese patients is a recurrent mutation or if it is due to a founder effect. We conducted haplotype analysis on these patients to answer this question. Individual case-control study. Germ-line mutations were confirmed in the patients and their families examined in this study using direct sequencing. We also constructed and analyzed haplotypes in four Chinese families. Genotype frequencies were compared to the control group. Three of four families shared the same haplotype, which rarely occurred in the control group. The last family shared a very short area on the physical map with the other three families. There is a founder effect in Chinese head and neck paraganglioma patients carrying the SDHD c.3G>C mutation.

A non-catecholamine-producing sympathetic paraganglioma of the spermatic cord: the importance of performing candidate gene mutation analysis

BackgroundCatecholamine-producing tumours are called pheochromocytomas when they are located in the adrenal gland and sympathetic paragangliomas when they are located elsewhere in the abdomen. Rarely these tumours do not produce catecholamines and even more rarely they arise in the spermatic cord. Over the past decade, systematic mutation analysis of apparently sporadic cases of pheochromocytomas and paragangliomas has elucidated the frequent presence of germ line mutations in one of five candidate genes, including RET, VHL, SDHB, SDHC, and SDHD.Clinical history and methodsWe describe a 45-year-old man with a non catecholamine-producing paraganglioma of the spermatic cord. We performed SDHB immunohistochemistry and performed mutation analysis of the SDHB, SDHC, and SDHD genes.ResultsThere was no staining of tumour cells with SDHB immunohistochemistry, indicative of an SDH mutation. Mutation analysis demonstrated a germ line SDHD mutation (p.Val147Met).ConclusionsSystematic mutation analysis is required in paraganglioma patients for the detection of germ line mutations. This should be preceded by SDHB immunohistochemistry to limit the number of genes to be tested.

Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management.

Background: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11–29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation. Methods: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution. Results: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age ≤50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular. Conclusions: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.

Relevance of Germline Mutation Screening in Both Familial and Sporadic Head and Neck Paraganglioma for Early Diagnosis and Clinical Management

Background: Head and neck paraganglioma (PGL) are benign tumors that can cause important direct or surgery induced morbidity. Almost all familial and 11–29% of sporadic PGL are caused by inactivating germline mutations in succinate dehydrogenase (SDH) genes. Our aim was to screen for such mutations and to evaluate clinical parameters as predictors of germline mutation.Methods: Seventy-four PGL patients were analyzed for germline mutations and large deletions in SDH genes, VHL and RET. Results were correlated to clinical characteristics including gender, age, tumor localization and multifocality. The surgical approach was evaluated in terms of tumor origin, sequelae and subsequent evolution.Results: Mutations in SDHB and SDHD were identified in equal proportion in 13/13 (100%) of familial and in 15/61 (25%) of sporadic cases. Familiarity, age ≤50 years and male gender were predictors of any germline mutation, while multifocality and carotid/vagal localization were indicative of SDHD mutation in particular.Conclusions: In contrast to other series, this cohort of Spanish patients showed many SDHB mutations. Sporadic cases with germline mutation are frequent and underline the importance of mutational screening of all PGL patients, allowing the identification of relatives at risk and the early diagnosis of the disease, reducing or avoiding morbidity.

Mutation analysis of the SDHB and SDHD genes in pheochromocytomas and paragangliomas: identification of a novel nonsense mutation (Q168X) in the SDHB gene

Pheochromocytoma (PCC) and paraganglioma (PGL) are tumors of the autonomic nervous system. The former is a tumor that occurs in only adrenal glands, and the latter can be found in the head and neck or in the thorax and abdomen. In PCC and PGL, genetic mutations account for approximately 30% of functional (secrete catecholamines) and nonfunctional cases. In addition to RET, VHL and NF-1, genes encoding succinate dehydrogenase complex subunit B (SDHB), subunit C (SDHC), and subunit D (SDHD) are recognized as susceptibility genes for PCC and PGL. Recently, PCC and PGL caused by genetic mutations of SDHB, SDHC and SDHD were established as hereditary pheochromocytoma paraganglioma syndrome (HPPS). Approximately 15% of all PCCs and PGLs are recognized as HPPS. Among these three susceptibility genes, SDHB and SDHD are known to be strongly related to HPPS. The aim of this study was to analyze SDHB and SDHD mutations in PCC and PGL patients. Among 18 patients, we identified a novel heterozygous nonsense mutation at codon 168 resulting in a CAG (glutamine) to TAG (stop) substitution (Q168X) in the SDHB gene in a patient diagnosed with solitary sporadic PGL. A number of studies have reported that SDHB mutation-associated disease demonstrates a higher rate of malignancy. However, all seven patients diagnosed with malignancy in this study did not have genetic mutation of SDHB and only one patient with no malignant sign had genetic mutation of SDHB. Further accumulation of cases is necessary to confirm the association between SDHB mutation and malignant potential.

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out