Familial Paraganglioma Research Articles

Modeling dioxygenase enzyme kinetics in familial paraganglioma.

ABSTRACTHypoxia inducible factors (HIFs) play vital roles in cellular maintenance of oxygen homeostasis. These transcription factors are responsible for the expression of genes involved in angiogenesis, metabolism, and cell proliferation. Here, we generate a detailed mathematical model for the enzyme kinetics of α-ketoglutarate-dependent HIF prolyl 4-hydroxylase domain (PHD) dioxygenases to simulate our in vitro data showing synergistic PHD inhibition by succinate and hypoxia in experimental models of succinate dehydrogenase loss, which phenocopy familial paraganglioma. Our mathematical model confirms the inhibitory synergy of succinate and hypoxia under physiologically-relevant conditions. In agreement with our experimental data, the model predicts that HIF1α is not stabilized under atmospheric oxygen concentrations, as observed. Further, the model confirms that addition of α-ketoglutarate can reverse PHD inhibition by succinate and hypoxia in SDH-deficient cells.

Discrepancy between radiologic and pathologic measuraments in pancreatic neuroendocrine tumors: A retrospective study on 199 patients

While the vast majority of pancreatic neuroendocrine tumours (pNETs) are sporadic, the recognition of an inherited pNET represents an evolving clinical responsibility of practising pathologists in the era of personalized medicine. The initially well-defined inherited pNET syndromes includes multiple endocrine neoplasia type 1 (MEN-1), von Hippel Lindau disease (VHL), neurofibromatosis type 1 (NF) and tuberous sclerosis (TS). Over the past decade, the spectrum of inherited pNETs has been expanded by the inclusion of new presentations such as multiple endocrine neoplasia type 4 (MEN-4), glucagon cell adenomatosis (Mahvash disease) along with germline mutations in DNA repair genes (MUTYH, BRCA2, and CHEK2) in a subset of seemingly sporadic looking pNETs as well as isolated case reports of succinate dehydrogenase deficient (SDH)- and mismatch repair deficient-pNETs occurring in the setting of SDH-related familial paraganglioma syndrome and Lynch syndrome, respectively. The findings have pointed out that the spectrum of inherited pNETs is indeed larger than what most physicians generally anticipate, likely reaching a rate greater than 15% of the overall presentations. From a morphological perspective, the identification of multifocal pNET should prompt the attention of pathologists to the possibility of an underlying genetic susceptibility. Since not all inherited pNETs manifest with multifocal disease, careful morphological assessment of the tumour and the non-tumorous pancreas, and application of immunohistochemical biomarkers are essential in the prediction of inherited pNETs. In order to facilitate the recognition of inherited pNETs, this review is aimed to provide a practical overview of pancreatic endocrine manifestations of MEN-1, MEN-4, VHL, NF-1, TS and glucagon cell adenomatosis.

Oxygen concentration controls epigenetic effects in models of familial paraganglioma.

Familial paraganglioma (PGL) is a rare neuroendocrine cancer associated with defects in the genes encoding the subunits of succinate dehydrogenase (SDH), a tricarboxylic acid (TCA) cycle enzyme. For unknown reasons, a higher prevalence of PGL has been reported for humans living at higher altitude, with increased disease aggressiveness and morbidity. In this study, we evaluate the effects of oxygen on epigenetic changes due to succinate accumulation in three SDH loss cell culture models. We test the hypothesis that the mechanism of α-ketoglutarate (α-KG)-dependent dioxygenase enzymes explains the inhibitory synergy of hypoxia and succinate accumulation. We confirm that SDH loss leads to profound succinate accumulation. We further show that hypoxia and succinate accumulation synergistically inhibit α-KG-dependent dioxygenases leading to increased stabilization of transcription factor HIF1α, HIF2α, and hypermethylation of histones and DNA. Increasing oxygen suppresses succinate inhibition of α-KG-dependent dioxygenases. This result provides a possible explanation for the association between hypoxia and PGL, and suggests hyperoxia as a potential novel therapy.

Recent advances in management of phaeochromocytoma

Pheochromocytoma (PCC) and paraganglioma (PGL) are the neuroendocrine tumours that arise in adrenal medulla or extra adrenal sympathetic and parasympathetic paraganglia. Paraganglia are small organs that mainly consist of neuroendocrine cells derived from the embryonic neural crest that have the ability to synthesize and secrete catecholamines. Sympathetic PGLs are usually located in the chest, abdomen, or pelvis while parasympathetic PGLs are distributed along parasympathetic nerves in the head, neck, and upper mediastinum, also referred to as head and neck PGL (HNP). PCC/PGLs can be either functional (sympathetic) or non-functional (parasympathetic) based on catecholamine synthesis and secretion. In children diagnosed with hypertension, up to 1.7% have a catecholamine-secreting neoplasm. The majority of these tumours in childhood are PCC/PGLs. Incidence rates of PCC/PGLs are estimated at 0.3 cases per million per year or less. Approximately 10 –20% of these cases are diagnosed during childhood. Approximately half of the apparently sporadic PCC/PGLs that present in patients younger than 18 years are due to an identifiable germline mutation and this increases up to 70% in children less than 10 years of age. Hereditary tumor syndromes associated with PCC include Von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia 2 (MEN-2), the familial PGL syndromes and rarely, neurofibromatosis (NF) type 1. Recently, many other genes are found to be involved in pathogenesis of PCC/PGLs. Hereditary PCC/PGLs are often multifocal and, in the case of PCC, frequently bilateral. Children usually present becauseof symptomatic catecholamine hypersecretion or, less often, due to tumor mass effects (e.g. pain), or as an incidental radiographic finding, or because of family screening. At present, the diagnostic test of choice is the measurement of fractionated plasma and/or urine metanephrines (metanephrines and normetanephrines). A four-fold increase above the reference range is associated with an almost 100% probability of the presence of a catecholamine-secreting tumor. 123I-metaiodobenzylguanidine(MIBG) is a highly specific test that can confirm the catecholamine-secreting nature of a tumor, localize tumors not seen with cross-sectional imaging, and identify other sites of disease as well as metastasis. Because MIBG testingis not 100% sensitive, particularly in some genetic mutations, recently other functional scans have been studied in the evaluation of PCC/PGL: 18F fluorodihydroxyphenylalanine (DOPA) positron emission tomography (PET), 18F fluorodopamine (FDA) PET,18F fluorodeoxyglucose (FDG) PET. Surgical resection is the mainstay in the treatment of PCC/PGLs. It should be done after adequate alfa and beta adrenergic blockade to minimize the hemodynamic fluctuation during surgery. Laparoscopic adrenalectomy is the preferred procedure for most PCC. Laparotomy should be considered in patients with large PCC and/or a concern for underlying malignancy based upon the clinical presentation or radiographic appearance of the tumor. In the setting of bilateral PCC, cortical-sparing procedures should be considered for the adrenal with the least tumor bulk. The cortical-sparing approach is particularly attractive in young children and children at risk for noncompliance with lifelong glucocorticoid and mineralocorticoid replacement. The surgical approach for removal of a PGL depends upon the location of the tumor but in selected cases can also be performed laparoscopically. Patients with unresectable malignant tumors or distant metastatic disease can usually be treated symptomatically with adrenergic blockade. Radiation therapy or radiofrequency ablation can help with symptomatic metastatic disease, and IV bisphosphonates can be considered bony metastases, particularly in patients with bone pain or lesions that increase the risk of pathological fracture. Systemic treatment modalities are only palliative in nature and include 123I-MIBG therapy, peptide receptor radiotherapy (PRRT) and chemotherapy. PCC/PGLs can have unpredictable behavior and metastasize late in the clinical course. In addition, children in particular are at risk for the development of metachronous tumors. This makes long-term follow-up mandatory in children with PCC/PGL.

Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.

Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported. We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages. No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx-deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex. The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation.

Succinate Dehydrogenase Loss in Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics.

It is counterintuitive that metabolic defects reducing ATP production can cause, rather than protect from, cancer. Yet this is precisely the case for familial paraganglioma, a form of neuroendocrine malignancy caused by loss of succinate dehydrogenase in the tricarboxylic acid cycle. Here we review biochemical, genetic, and epigenetic considerations in succinate dehydrogenase loss and present leading models and mysteries associated with this fascinating and important tumor.

Dexmedetomidine for anaesthetic management of phaeochromocytoma in a child with von Hippel-Lindau type 2 syndrome.

Phaeochromocytoma is a rare neoplasm in the paediatric population with fewer than 20% of diagnosed cases.[1] We describe the use of dexmedetomidine infusion for successful management of an 11-year-old male child with von Hippel-Lindau type 2 syndrome (VHL), who underwent bilateral adrenalectomy for phaeochromocytoma.

Clinical management of paragangliomas.

Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs)) and extraadrenal (sympathetic paraganglioma (sPGLs)) locations or parasympathetic tissue of the head and neck paragangliomas (HNPGLs). As HNPGLs are usually benign and most tumors grow slowly, a wait-and-scan policy is often advised. However, their location in the close proximity to cranial nerves and vasculature may result in considerable morbidity due to compression or infiltration of the adjacent structures, necessitating balanced decisions between a wait-and-see policy and active treatment. The main treatment options for HNPGL are surgery and radiotherapy. In contrast to HNPGLs, the majority of sPGL/PCCs produces catecholamines, in advanced cases resulting in typical symptoms and signs such as palpitations, headache, diaphoresis, and hypertension. The state-of-the-art diagnosis and localization of sPGL/PCCs are based on measurement of plasma and/or 24-h urinary excretion of (fractionated) metanephrines and methoxytyramine (MT). sPGL/PCCs can subsequently be localized by anatomical (computed tomography and/or magnetic resonance imaging) and functional imaging studies (123I-metaiodobenzylguanidine-scintigraphy, 111In-pentetreotide scintigraphy, or positron emission tomography with radiolabeled dopamine or dihydroxyphenylalanine). Although most PGL/PCCs are benign, factors such as genetic background, tumor size, tumor location, and high MT levels are associated with higher rates of metastatic disease. Surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. PGL/PCCs have a strong genetic background, with at least one-third of all cases linked with germline mutations in 11 susceptibility genes. As genetic testing becomes more widely available, the diagnosis of PGL/PCCs will be made earlier due to routine screening of at-risk patients. Early detection of a familial PGL allows early detection of potentially malignant PGLs and early surgical treatment, reducing the complication rates of this operation.

Novel germline SDHD mutation in a patient with recurrent familial carotid body tumor and concomitant pheochromocytoma

Recent advances in genetics revealed that 25% to 30% of head and neck paragangliomas (PGLs) are inherited tumors associated with germline mutation, mainly in the succinate dehydrogenase (SDH) gene. DNA was isolated from whole blood and polymerase chain reaction (PCR) products were sequenced with an ABI3730 × 1 Genetic Analyzer. A 30-year-old Korean woman underwent resection of a carotid PGL. Fourteen years later, she was readmitted for a cervical mass. (18) F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT revealed a hot spot in the adrenal gland, besides the carotid mass. Surgical pathology confirmed recurrence of the carotid PGL and a concomitant pheochromocytoma. Genetic analysis revealed SDHD c.119del T (p.I40TfsX46) mutation. One daughter has been identified as a carrier. We found a novel SDHD mutation from a Korean family that shows similar clinical features to those in other SDHD mutations, mostly from Western countries. Further studies are needed to determine whether similar genotype-phenotype correlations exist in the Asian patients with familial PGLs.

Counseling patients with succinate dehydrogenase subunit defects: genetics, preventive guidelines, and dealing with uncertainty.

The discovery that mutations in the succinate dehydrogenase (SDH) complex subunit (SDHA, B/C/D/AF2) genes predispose patients to the development of tumors has led to the identification of a large population of patients and relatives at risk for developing malignancies. The most frequent conditions associated with these mutations are the familial paraganglioma syndromes. Other tumors that are frequently associated with SDH mutations (SDHx) are gastrointestinal stromal tumors and renal cell carcinomas. A number of other rare associations have also been described. SDHx mutations are often clinically silent and metastatic, but they may also be aggressive in their presentation. The penetrance of these mutations is beginning to be understood, and the characteristics of the phenotype are being elucidated. However, the inability to accurately predict the appearance, nature, and location of tumors as well as their tendency to recur or metastasize pose challenges to those who counsel and manage patients with SDHx mutations. In this work, we present our approach for counseling these families in the context of the current uncertainties, while striving to maintain patient autonomy.

Familial paraganglioma of head and neck

Paragangliomas are tumors originated from non-chromaffin paranganglia cells derived from the neural crest. These highly vascular tumors are located in the region which extends from skull base to arcus aorta. Head and neck paragangliomas have rare occurence constituting 0.012% of all the body tumors and 0.6% of head and neck tumors. Head and neck paragangliomas occur in sporadic and familial forms. The ratio of familial head and neck paragangliomas is about 10%. Familial form has a characteristic of autosomal dominant inheritance. In this article, four cases having first and second degree of affinity that we followed for paraganglioma diagnosis are presented.

Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management

Paragangliomas are rare, slow-growing tumors that frequently arise in the head and neck, with the carotid bodies and temporal bone of the skull base being the most common sites. These neoplasms are histologically similar to pheochromocytomas that form in the adrenal medulla and are divided into sympathetic and parasympathetic subtypes based on functionality. Skull base and head and neck region paragangliomas (SHN-PGs) are almost always derived from parasympathetic tissue and rarely secrete catecholamines. However, they can cause significant morbidity by mass effect on various cranial nerves and major blood vessels. While surgery for SHN-PG can be curative, postoperative deficits and recurrences make these lesions challenging to manage. Multiple familial syndromes predisposing individuals to development of paragangliomas have been identified, all involving mutations in the succinate dehydrogenase complex of mitochondria. Mutations in this enzyme lead to a state of "pseudohypoxia" that upregulates various angiogenic, survival, and proliferation factors. Moreover, familial paraganglioma syndromes are among the rare inherited diseases in which genomic imprinting occurs. Recent advances in gene arrays and transcriptome/exome sequencing have identified an alternate mutation in sporadic SHN-PG, which regulates proto-oncogenic pathways independent of pseudohypoxia-induced factors. Collectively these findings demonstrate that paragangliomas of the skull base and head and neck region have a distinct genetic signature from sympathetic-based paragangliomas occurring below the neck, such as pheochromocytomas. Paragangliomas serve as a unique model of primarily surgically treated neoplasms whose future will be altered by the elucidation of their genomic complexities. In this review, the authors present an analysis of the molecular genetics of SHN-PG and provide future directions in patient care and the development of novel therapies.

Dandy-Walker Malformation, Papillary Thyroid Carcinoma, and SDHD-Associated Paraganglioma Syndrome

A 43-year-old female presented to a local hospital with the recent onset of intermittent dizziness suggestive of intermittent rotatory vertigo, but no abnormal findings on examination. Magnetic resonance imaging of the brain demonstrated a large cerebrospinal fluid collection in the posterior fossa, incomplete fusion of the posterior elements of the cerebellum and vermis, and dilatation of the third and lateral ventricles, indicative of a significant Dandy-Walker malformation (Figures 1 and 2). The patient reported a history of papillary thyroid carcinoma diagnosed at 16 years of age and an abdominal paraganglioma diagnosed at the age of 28 in the immediate postoperative period after a cesarean section. Her 2 samples of 24-hour urinary normetanephrine was 10 578 and 19 409 nmol/24 h (normal, 600); the tumor was 4-cm in maximum diameter, I-MIBG positive, and at the level of the lower pole of the right kidney. It was successfully removed. There were no cutaneousfeaturessuggestingahereditarysyndrome.Family history revealed two daughters who had both undergone craniofacial surgery. Genetic analysis demonstrated a pathogenic germline succinate dehydrogenase (SDH) type D mutation (c.60_ 63delGCTT). Further investigation revealed bilateral head and neck paragangliomas at the left jugular foramen and on the right just above the carotid bifurcation; these are currently being considered for therapy. The asymptomatic Dandy-Walker malformation in our patient is an uncommon finding, and few cases have been diagnosed in adults (1). SDHx mutations cause familial paraganglioma syndromes but have also been related to other neoplasias such as renal and pituitary tumors (2) and thyroid cancer (3). It seems probable that SDH may be involved in central nervous system organogenesis as well as acting as a tumor suppressor.

The management of head-and-neck paragangliomas

Paragangliomas (PGLs) are tumours originating from neural crest-derived cells situated in the region of the autonomic nervous system ganglia. Head-and-neck PGLs (HNPGLs) originate from the sympathetic and parasympathetic paraganglia, most frequently from the carotid bodies and jugular, tympanic and vagal paraganglia, and are usually non-catecholamine secreting. Familial PGLs are considered to be rare, but recently genetic syndromes including multiple PGLs and/or phaeochromocytomas have been more thoroughly characterised. Nowadays, genetic screening for the genes frequently implicated in both familial and sporadic cases is routinely being recommended. HNPGLs are mostly benign, generally slow-growing tumours. Continuous growth leads to the involvement of adjacent neurovascular structures with increased morbidity rates and treatment-related complications. Optimal management mostly depends on tumour location, local involvement of neurovascular structures, estimated malignancy risk, patient age and general health. Surgery is the only treatment option offering the chance of cure but with significant morbidity rates, so a more conservative approach is usually considered, especially in the more difficult cases. Radiotherapy (fractionated or stereotactic radiosurgery) leads to tumour growth arrest and symptomatic improvement in the short term in many cases, but the long-term consequences are unclear. Early detection is essential in order to increase the chance of cure with a lower morbidity rate. The constant improvement in diagnostic imaging, surgical and radiation techniques has led to a safer management of these tumours, but there are still many therapeutic challenges, and no treatment algorithm has been agreed upon until now. The management of HNPGLs requires a multidisciplinary effort addressing the genetic, surgical, radiotherapeutic, oncological, neurological and endocrinological implications. Further progress in the understanding of their pathogenesis will lead to more effective screening and earlier diagnosis, both critical to successful treatment.

Renal cancer in von Hippel–Lindau disease and related syndromes

Sporadic and hereditary forms of renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease and the familial paraganglioma syndromes are closely related in terms of their clinical, molecular, and genetic aspects. Most RCCs occur sporadically and the heritable fraction of RCC is estimated to be just 2-4%. An understanding of the molecular genetic basis, the disease-specific and gene-specific biology and the clinical characteristics of these cancer syndromes is of utmost importance for effective genetic diagnosis and appropriate treatment. In addition, such insight will improve our understanding of sporadic RCCs. To date, 10 different heritable RCC syndromes have been described. VHL syndrome is the oldest known hereditary RCC syndrome. Similar to VHL disease, phaeochromocytoma is a major manifestation of the paraganglioma syndromes types 1, 3 and 4 in which RCCs have been reported. These syndromes are therefore regarded as VHL-related disorders and are included in this Review. Multifocal tumours, bilateral occurrence, a young age at diagnosis and/or family history are clinical red flags suggestive of hereditary disease and should trigger referral for genetic and molecular analysis. The identification of an underlying genetic alteration enables gene-specific risk assessment and opens up the possibility of a tailored follow-up strategy and specific surveillance protocols as the basis of effective preventive medicine. The important goals of preventive medicine are to increase the life expectancy of affected patients and to improve their quality of life. The study of seemingly rare hereditary syndromes and their susceptibility genes has consistently revealed clues regarding the aetiology and pathogenesis of these diseases, and can aid diagnosis and the development of therapeutics for patients affected by much more common sporadic counterparts.

Overexpression of the insulin‐like growth factor 1 receptor (IGF‐1R) is associated with malignancy in familial pheochromocytomas and paragangliomas

Pheochromocytomas and paragangliomas (pheo/pgl) are neuroendocrine tumours derived from chromaffin cells. Although mostly benign, up to 26% of pheo/pgl will undergo malignant transformation. Reliable histological signs to differentiate benign pheo/pgl from malignant tumours are currently lacking. Increased IGF-1R expression has been shown during progression to metastatic phenotypes of several types of cancer. To analyse the distribution and expression of the IGF-1R in pheo/pgl of different genetic origin and degree of malignancy. We studied the expression of the IGF-1R protein by immunohistochemistry, in 40 primary tumours from patients with pheo/pgl from different genetic aetiology (11 of 29 metastatic/nonmetastatic diseases). We found a strong association between increased expression of IGF-1R and malignant behaviour regardless of the age at diagnosis and the genetic aetiology. IGF-1R labelling was mostly weak in primary tumours from patients with nonmetastatic pheo/pgl. Conversely, intense IGF-1R labelling was predominant in cases of pheo/pgl with confirmed metastatic disease. The risk of metastases was 11·7 times higher if tumour IGF-1R labelling was intense independently of age at diagnosis. The probability of remaining free of metastases was higher in patients with pheo/pgl scored weak for IGF-1R at 60months and more than twofold higher at 120months of follow-up than in patients with intense IGF-1R labelling in their primary tumours. Our results strongly suggest that IGF-1R is associated with malignancy in familial pheo/pgl and that IGF-1R expression in the primary tumour might be a useful tool to detect those patients harbouring pheo/pgl who have an increased risk of metastasis.

Familial malignant paraganglioma is long-term stabilized with the tyrosine-kinase inhibitor sunitinib

Familial malignant paraganglioma is long-term stabilized with the tyrosine-kinase inhibitor sunitinib

High-throughput screening for growth inhibitors using a yeast model of familial paraganglioma.

Classical tumor suppressor genes block neoplasia by regulating cell growth and death. A remarkable puzzle is therefore presented by familial paraganglioma (PGL), a neuroendocrine cancer where the tumor suppressor genes encode subunits of succinate dehydrogenase (SDH), an enzyme of the tricarboxylic acid (TCA) cycle of central metabolism. Loss of SDH initiates PGL through mechanisms that remain unclear. Could this metabolic defect provide a novel opportunity for chemotherapy of PGL? We report the results of high throughput screening to identify compounds differentially toxic to SDH mutant cells using a powerful S. cerevisiae (yeast) model of PGL. Screening more than 200,000 compounds identifies 12 compounds that are differentially toxic to SDH-mutant yeast. Interestingly, two of the agents, dequalinium and tetraethylthiuram disulfide (disulfiram), are anti-malarials with the latter reported to be a glycolysis inhibitor. We show that four of the additional hits are potent inhibitors of yeast alcohol dehydrogenase. Because alcohol dehydrogenase regenerates NAD+ in glycolytic cells that lack TCA cycle function, this result raises the possibility that lactate dehydrogenase, which plays the equivalent role in human cells, might be a target of interest for PGL therapy. We confirm that human cells deficient in SDH are differentially sensitive to a lactate dehydrogenase inhibitor.

Síndrome de paraganglioma familiar: expresividad clínica y relevancia de una nueva mutación en SDHB

Background and objectiveAdvances in molecular biology have discovered new genes involved in the development of familial paraganglioma syndrome (PGL) including those encoding mitochondrial succinate dehydrogenase complex (SDH). We describe the diagnosis, clinical expression and genetic counselling in a family diagnosed of PGL due to a new SDHB mutation. Patients and methodGenetic study by PCR-direct sequencing SDHB gene and biochemical determination in blood/urine fractionated catecholamine 24h, metanephrines and conventional (computed tomography/magnetic resonance imaging) and functional imaging (123I-MIBG) in all members of a family diagnosed of PGL. ResultDNA sequencing showed a non-described SDHB heterozygous mutation (c.287-3C>G intron3/exon4) in 5 of the subjects (71%). The estimated penetrance of the mutation's carriers was 40%, with a mean age of 35 years at diagnosis. All patients with active illness required surgical treatment after imaging and laboratory confirmation. ConclusionsWe describe the pathogenicity, diagnostic algorithm, genetic counselling and clinical expression of a new SDHB mutation (c.287-3C>G) in a family diagnosed of PGL.

Diagnostic yield of EUS-FNA in pancreatic neuro-endocrine tumours (PNET) – solid versus cystic PNETs – 9 year experience from a tertiary centre

While the vast majority of pancreatic neuroendocrine tumours (pNETs) are sporadic, the recognition of an inherited pNET represents an evolving clinical responsibility of practising pathologists in the era of personalized medicine. The initially well-defined inherited pNET syndromes includes multiple endocrine neoplasia type 1 (MEN-1), von Hippel Lindau disease (VHL), neurofibromatosis type 1 (NF) and tuberous sclerosis (TS). Over the past decade, the spectrum of inherited pNETs has been expanded by the inclusion of new presentations such as multiple endocrine neoplasia type 4 (MEN-4), glucagon cell adenomatosis (Mahvash disease) along with germline mutations in DNA repair genes (MUTYH, BRCA2, and CHEK2) in a subset of seemingly sporadic looking pNETs as well as isolated case reports of succinate dehydrogenase deficient (SDH)- and mismatch repair deficient-pNETs occurring in the setting of SDH-related familial paraganglioma syndrome and Lynch syndrome, respectively. The findings have pointed out that the spectrum of inherited pNETs is indeed larger than what most physicians generally anticipate, likely reaching a rate greater than 15% of the overall presentations. From a morphological perspective, the identification of multifocal pNET should prompt the attention of pathologists to the possibility of an underlying genetic susceptibility. Since not all inherited pNETs manifest with multifocal disease, careful morphological assessment of the tumour and the non-tumorous pancreas, and application of immunohistochemical biomarkers are essential in the prediction of inherited pNETs. In order to facilitate the recognition of inherited pNETs, this review is aimed to provide a practical overview of pancreatic endocrine manifestations of MEN-1, MEN-4, VHL, NF-1, TS and glucagon cell adenomatosis.