Approach to the paediatric patient with suspected pheochromocytoma or paraganglioma versus neuroblastoma.

Catecholamine producing tumours of childhood include neuroblastic tumours, phaeochromocytoma and paraganglioma (PPGL). PPGL and neuroblastic tumours can arise in similar anatomical locations and clinical presentations can overlap resulting in diagnostic challenges. Distinguishing between these tumour types is critical as management and long-term surveillance strategies differ depending on the diagnosis. Herein we describe two clinical cases and illustrate key considerations in the diagnostic work up of a neuroblastoma versus PPGL for patients presenting with adrenal, pelvic, and retroperitoneal masses in childhood.

Anesthetic management of a dog undergoing unilateral adrenalectomy for phaeochromocytoma excision using a partial intravenous anesthetic protocol.

Background: The anesthetic management of adrenalectomies for phaeochromocytoma excision, a catecholamine-secreting tumor, is challenging due to the potential for fatal complications following severe hemodynamic variations, including hypertensive crisis following tumor manipulation or sympathetic stimulation, but also severe hypotension and volume depletion post resection. Case Description: An 11 kg, 15-year-old male neutered Jack Russel Terrier, with mitral valve disease stage B2, was referred for adrenalectomy for phaeochromocytoma resection. The patient was administered per os prazosin 0.11 mg/kg twice a day and amlodipine 0.125 mg/kg once a day for preoperative stabilization. On the day of surgery, the dog received maropitant 1 mg/kg intravenously (IV) and was premedicated with 0.2 mg/kg methadone IV. Anesthesia was induced with alfaxalone 1 mg/kg IV and midazolam 0.2 mg/kg IV and maintained with partial intravenous anesthesia using sevoflurane in 70% oxygen and constant rate infusions of dexmedetomidine 0.5 µg/kg/hour and maropitant 100 µg/kg/hour. After induction of anesthesia, the dog was mechanically ventilated, and a transversus abdominal plane block was performed with ropivacaine 0.2%. The dog remained remarkably stable with a single, self-limiting, hypertension episode recorded intraoperatively. Postoperative rescue analgesia consisted of methadone and ketamine. The dog was discharged 48 hours after surgery, but persistent hypertension was reported at suture removal. Conclusion: The use of a low-dose dexmedetomidine CRI, a maropitant CRI, and a transversus abdominal plane block provided stable perioperative hemodynamic conditions for phaeochromocytoma excision in a dog.

Characterisation of an Adult Zebrafish Model for SDHB-Associated Phaeochromocytomas and Paragangliomas.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from chromaffin cells. Pathogenic variants in the gene succinate dehydrogenase subunit B (SDHB) are associated with malignancy and poor prognosis. When metastases arise, limited treatment options are available. The pathomechanism of SDHB-associated PPGL remains largely unknown, and the lack of suitable models hinders therapy development. Germline heterozygous SDHB pathogenic variants predispose to developing PPGLs with a life-long penetrance of around 50%. To mimic the human disease phenotype, we characterised adult heterozygous sdhb mutant zebrafish as a potential model to study SDHB-related PPGLs. Adult sdhb mutant zebrafish did not develop an obvious tumour phenotype and were anatomically and histologically like their wild-type siblings. However, sdhb mutants showed significantly increased succinate levels, a major hallmark of SDHB-related PPGLs. While basal activity was increased during day periods in mutants, mitochondrial complex activity and catecholamine metabolite levels were not significantly different. In conclusion, we characterised an adult in vivo zebrafish model, genetically resembling human carriers. Adult heterozygous sdhb mutants mimicked their human counterparts, showing systemic elevation of succinate levels despite the absence of a tumour phenotype. This model forms a promising basis for developing a full tumour phenotype and gaining knowledge of the pathomechanism behind SDHB-related PPGLs.

Adrenal washout CT in patients with no history of cancer: a waste of time?

PURPOSE: To validate the diagnostic performance of adrenal washout CT in patients without known malignancy in a Western Australian population. METHODS: A radiology information system (RIS) search for CT reports containing "adrenal" and "washout" across six networked metropolitan public hospitals between January 2005 and November 2021. Homogenous nodules ≥ 1 cm, ≥ 10 HU without a suspected functional component in patients without a history of malignancy were included. Reported absolute and relative washout percentages were recorded and re-measured from unenhanced, 60-s portal venous and 15-min delayed phase imaging and compared to either histopathological or CT follow up for growth (≥ 12 months) reference standards. RESULTS: 2653 studies were screened with 191 meeting inclusion criteria. 105 nodules underwent washout CT and then had either histopathological (12 patients) or CT follow up (93 patients) reference standards available. Reported absolute washout (aWO) estimated sensitivity and specificity for malignant/indeterminate nodules was low at 33% (95% CI 25-43%) and 77% (95% CI 68-84%) respectively. Reported relative washout (rWO) sensitivity and specificity were 56% (95% CI 46-65%) and 69% (95% CI 60-77%) respectively. Negative predictive values for both aWO and rWO were reassuring at 92% (95% CI 86-96%) and 94% (95%CI 88-97%). CONCLUSION: Our study validates a recent report suggesting that adrenal washout has poor sensitivity for and consequent limited utility to exclude malignancy in patients with no cancer history. However, patients with incidental adrenal nodules < 4 cm in size with benign washout can be reassured by the high negative predictive value and worked up to exclude functional adenoma and re-imaged in a year to confirm no growth.

Surgery for phaeochromocytomas and paragangliomas: Current practice in the United Kingdom.

INTRODUCTION: There is wide variability in the perioperative management of phaeochromocytoma and paraganglioma (PPGL) in different centres. This study aimed to summarise the management of PPGLs as reported in the United Kingdom Registry for Endocrine and Thyroid Surgery (UKRETS) database and to determine current perioperative management of PPGLs by surveying UK clinicians. METHODS: Data recorded on UKRETS from 2005 to 2021 were subjected to descriptive analyses. British Association of Endocrine and Thyroid Surgeons members were invited to participate in an open survey relating to the perioperative management of patients with PPGLs. RESULTS: A total of 2,007 operations for PPGL from 49 participating centres were included. The median annual workload in each centre was four cases. Operations were performed predominantly laparoscopically (69%). The median length of stay (4 days) was the same in groups of surgeons stratified by volume. The survey had 29 respondents from 22 centres across the UK, and a formal protocol for perioperative management exists in 48% of the centres. Phenoxybenzamine (72%) was preferred for alpha-blockade. The practice of admitting patients for optimisation from 1 to 7 days before the day of surgery was common (62%). Central venous pressure and blood glucose monitoring were mentioned as routine intraoperative adjuncts by 72% of the responders. CONCLUSIONS: There is significant variation in the workload and perioperative management of PPGLs in the UK. This is potentially detrimental to patient outcomes and a consensus document might be beneficial to harmonise practice across the UK.

A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide.

BACKGROUND: Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes. RESULTS: Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1. CONCLUSIONS: Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.

Primary perioperative haemodynamic effects of ß-receptor blockade in patients with catecholamine-secreting tumours.

Introduction: Guidelines for the treatment of catecholamine-producing tumours strictly recommend starting ß-receptor blocking medication only after α-receptor blockade has been established. This recommendation is supported only by non-surgical case reports. However, in clinical practice ß-receptor blockade is often started before the diagnosis of a phaeochromocytoma is made. As we routinely treat patients with catecholamine-producing tumours without α-receptor blockade, our aim was to evaluate haemodynamic changes in such patients with and without ß-receptor blockade. Methods: Perioperative blood pressure was assessed prospectively for all patients. The primary outcome was the highest pre-, intra-, and postoperative systolic blood pressure in patients with or without a ß-receptor blockade. Secondary outcomes were the incidence of intraoperative systolic blood pressure peaks >250 mm Hg and hypotensive episodes. Subsequently, a propensity score matching (PSM) analysis was performed. Results: Out of 584 phaeochromocytoma and paraganglioma resections, 383 operations were performed without α-receptor blockade (including 84 with ß-receptor blockade). Before operation and intraoperatively, patients with ß-receptor blockade presented with higher systolic blood pressure (155 [25] and 207 [62] mm Hg) than patients without ß-receptor blockade (147 [24] and 183 [52] mm Hg; P=0.006 and P=0.001, respectively). Intraoperatively, patients with ß-receptor blockade demonstrated a higher incidence of hypotensive episodes (25% without vs 41% with ß-blockade; P<0.001). After propensity score matching no difference between the groups could be confirmed. Conclusion: Overall, patients with isolated ß-receptor blockade developed higher blood pressure before operation and intraoperatively. After propensity score matching a difference could no longer be detected. Overall, ß-receptor blockade seems to be more a sign for severe disease than a risk factor for haemodynamic instability.

Adrenocorticotropic hormone-secreting phaeochromocytoma as a cause of treatment-resistant hypertension and recurrent pulmonary emboli.

We report an unusual case of a patient presenting with Cushing's syndrome caused by a phaeochromocytoma secreting adrenocorticotropic hormone (ACTH). The patient had a history of treatment-resistant hypertension, secondary amenorrhoea and tendency towards hypokalaemia. She had multiple signs of Cushing's syndrome, such as swelling, bruising, abdominal striae and proximal myopathy. Hypokalaemia is more common in patients with ectopic ACTH-secretion than other causes of Cushing's syndrome. Computed tomography, adrenal vein sampling and biochemistry could confirm an ACTH-secreting phaeochromocytoma. It is important to consider that hypersecretion of more than one hormone may exist in a unilateral adrenal adenoma. This patient also presented with recurrent pulmonary emboli, and there is an increased risk of venous thromboembolism in patients with ACTH-secreting phaeochromocytoma. Anticoagulation should be considered for as long as the disease is active. We demonstrate that unilateral adrenalectomy can be curative in patients with ACTH-secreting phaeochromocytoma.

A Laboratory Medicine Perspective on the Investigation of Phaeochromocytoma and Paraganglioma.

Phaeochromocytomas (PC) and sympathetic paragangliomas (PGL) are potentially malignant tumours arising from the adrenal medulla (PC) or elsewhere in the sympathetic nervous system (PGL). These tumours usually secrete catecholamines and are associated with significant morbidity and mortality, so accurate and timely diagnosis is essential. The initial diagnosis of phaeochromocytoma/paraganglioma (PPGL) is often dependent on biochemical testing. There is a range of pre-analytical, analytical and post-analytical factors influencing the analytical and diagnostic performance of biochemical tests for PPGL. Pre-analytical factors include patient preparation, sample handling and choice of test. Analytical factors include choice of methodology and the potential for analytical interference from medications and other compounds. Important factors in the post-analytical phase include provision of appropriate reference ranges, an understanding of the potential effects of various medications on metanephrine concentrations in urine and plasma and a consideration of PPGL prevalence in the patient population being tested. This article reviews these pre-analytical, analytical and post-analytical factors that must be understood in order to provide effective laboratory services for biochemical testing in the diagnosis of PPGL.

Paediatric phaeochromocytoma and paraganglioma: A clinical update.

Paediatric phaeochromocytomas and paragangliomas (PPGLs), though rare tumours, are associated with significant disability and death in the most vulnerable of patients early in their lives. However, unlike cryptogenic and insidious disease states, the clinical presentation of paediatric patients with PPGLs can be rather overt, allowing early diagnosis, granted that salient findings are recognized. Additionally, with prompt and effective intervention, prognosis is favourable if timely intervention is implemented. For this reason, this review focuses on four exemplary paediatric cases, succinctly emphasizing the now state-of-the-art concepts in paediatric PPGL management.

Phaeochromocytoma associated with cardiomyopathy and leukocytoclastic vasculitis in a dog.

Phaeochromocytomas are rare tumours of the adrenal medulla that can be associated with various presentations. Many of the better characterized clinical signs, including weakness, tachycardia and tachypnoea, are attributable to excessive and unregulated catecholamine secretion from functional tumours. In addition to catecholamine-induced cardiomyopathy and vasospasm, the invasive nature of phaeochromocytomas can lead to occlusion of the caudal vena cava contributing to systemic cardiovascular compromise. In humans, leukocytoclastic vasculitis is a rarely reported manifestation of catecholamine excess associated with phaeochromocytomas. We now describe a dog that had an invasive unilateral phaeochromocytoma with histological evidence of myocardial damage, consistent with catecholamine-induced cardiomyopathy, and leukocytoclastic vasculitis of small vessels in a range of tissues. We conclude that catecholamine excess may have played a role in the pathogenesis of vasculitis in this case. To the best of our knowledge, this is the first documented association between phaeochromocytoma and leukocytoclastic vasculitis in a non-human species.

Surgical management and outcomes of spinal metastasis of malignant adrenal tumor: A retrospective study of six cases and literature review.

Purpose: Spinal metastasis of malignant adrenal tumor (SMMAT) is an extremely rare and poorly understood malignant tumor originating from the adrenal gland. The objective of this study is to elucidate the clinical characteristics and discuss surgical management and outcomes of SMMAT. Methods: Included in this study were six SMMAT patients who received surgical treatment in our center between February 2013 and May 2022. Their clinical data and outcomes were retrospectively analyzed to gain a better understanding of SMMAT. In addition, ten cases from the literature focusing on SMMAT were also reviewed. Results: Surgery was performed successfully, and the associated symptoms were relieved significantly in all patients postoperatively. The mean follow-up duration was 26.2 (range 3-55) months. Two patients died of tumor recurrence 12 and 48 months after operation respectively. The other four patients were alive at the last follow-up. Conclusions: The prognosis of SMMAT is usually poor. Preoperative embolization and early surgical radical resection can offer satisfactory clinical outcomes. The patient's health status, preoperative neurological function, tumor location and the resection mode are potential prognostic factors of SMMAT.

Distortion in transmission of pathogenic SDHB- and SDHD-mutated alleles from parent to offspring.

Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs's cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew's Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

Risk factors for postoperative hypotension after adrenalectomy for phaeochromocytoma: derivation of the PACS risk score.

BACKGROUND: Due to the risk of postoperative hypotension (PH), invasive monitoring is recommended for patients who undergo adrenalectomy for phaeochromocytoma. Due to high costs and limited availability of intensive care, our aim was to identify patients at low risk of PH who may not require invasive monitoring. METHODS: Data for patients who underwent adrenalectomy for phaeochromocytoma between 2012 and 2020 were retrospectively collected by nine UK centres, including patient demographics, intraoperative and postoperative haemodynamic parameters. Independent risk factors for PH were analysed and used to develop a clinical risk score. RESULTS: PH developed in 118 of 430 (27.4%) patients. On univariable analysis, female sex (p = 0.007), tumour size (p < 0.001), preoperative catecholamine level (p < 0.001), open surgery (p < 0.001) and epidural analgesia (p = 0.006) were identified as risk factors for PH. On multivariable analysis, female sex (OR 1.85, CI95%, 1.09-3.13, p = 0.02), preoperative catecholamine level (OR: 3.11, CI95%, 1.74-5.55, p < 0.001), open surgery (OR: 3.31, CI95%, 1.57-6.97, p = 0.002) and preoperative mean arterial blood pressure (OR: 0.59, CI95%, 0.48-1.02, p = 0.08) were independently associated with PH, and were incorporated into a clinical risk score (AUROC 0.69, C-statistic 0.69). The risk of PH was 25% and 68% in low and high risk patients, respectively. CONCLUSION: The derived risk score allows stratification of patients at risk of postoperative hypotension after adrenalectomy for phaeochromocytoma. Postoperatively, low risk patients may be managed on a surgical ward, whilst high risk patients should undergo invasive monitoring.

[18F] MFBG PET imaging: biodistribution, pharmacokinetics, and comparison with [123I] MIBG in neural crest tumour patients.

PURPOSE: Despite its limitations, [123I]MIBG scintigraphy has been the standard for human norepinephrine transporter (hNET) imaging for several decades. Recently, [18F]MFBG has emerged as a promising PET alternative. This prospective trial aimed to evaluate safety, biodistribution, tumour lesion pharmacokinetics, and lesion targeting of [18F]MFBG and perform a head-to-head comparison with [123I]MIBG in neural crest tumour patients. METHODS: Six neural crest tumour patients (4 phaeochromocytoma, 1 paraganglioma, 1 neuroblastoma) with a recent routine clinical [123I]MIBG scintigraphy (interval: - 37-75 days) were included. Adult patients (n = 5) underwent a 30-min dynamic PET, followed by 3 whole-body PET/CT scans at 60, 120, and 180 min after injection of 4 MBq/kg [18F]MFBG. One minor participant underwent a single whole-body PET/CT at 60 min after administration of 2 MBq/kg [18F]MFBG. Normal organ uptake (SUVmean) and lesion uptake (SUVmax; tumour-to-background ratio (TBR)) were measured. Regional distribution volumes (VT) were estimated using a Logan graphical analysis in up to 6 lesions per patient. A lesion-by-lesion analysis was performed to compare detection ratios (DR), i.e. fraction of detected lesions, between [18F]MFBG and [123I]MIBG. RESULTS: [18F]MFBG was safe and well tolerated. Its biodistribution was overall similar to that of [123I]MIBG, with prominent uptake in the salivary glands, liver, left ventricle wall and adrenals, and mainly urinary excretion. In the phaeochromocytoma subgroup, the median VT was 37.4 mL/cm3 (range: 18.0-144.8) with an excellent correlation between VT and SUVmean at all 3 time points (R2: 0.92-0.94). Mean lesion SUVmax and TBR at 1 h after injection were 19.3 ± 10.7 and 23.6 ± 8.4, respectively. All lesions detected with [123I]MIBG were also observed with [18F]MFBG. The mean DR with [123I]MIBG was significantly lower than with [18F]MFBG (61.0% ± 26.7% vs. 99.8% ± 0.5% at 1 h; p = 0.043). CONCLUSION: [18F]MFBG is a promising hNET imaging agent with favourable imaging characteristics and improved lesion targeting compared with [123I]MIBG scintigraphy. TRIAL REGISTRATION: Clinicaltrials.gov : NCT04258592 (Registered: 06 February 2020), EudraCT: 2019-003872-37A.

High rates of the SDHB p.Arg46Gln pathogenic variant predisposes New Zealand Maori to phaeochromocytoma/paraganglioma.

BACKGROUND: Phaeochromocytomas (PCC) and paragangliomas (PGL; together PPGL) are rare tumours of the adrenal medulla or extra-adrenal paraganglia. They may secrete catecholamines with significant cardiovascular effects. Management of PPGL is predominantly surgical, despite the anaesthetic risks related to potential haemodynamic instability. Meticulous pre-treatment and intra-operative management are required to improve cardiovascular outcomes. AIMS: There are limited local data regarding the incidence of PPGL and the clinical characteristics of individuals diagnosed with these tumours in New Zealand. We undertook a retrospective study investigating the local practice and patient characteristics with an additional focus on intra-operative haemodynamic stability and post-operative outcomes. METHODS: Electronic patient records were searched for individuals with a diagnosis of PPGL. Clinical records and electronic databases were interrogated for pre-operative, intra-operative and post-operative data points. Particular attention was paid to rates and types of germline mutations, intra-operative haemodynamic stability and post-operative renal and cardiovascular outcomes. RESULTS: We identified 49 individuals with PPGL, of whom 34 were from the local area. This gave a local incidence of PPGL of around five cases per million people per year. Maori were significantly over-represented in our cohort, with this being in part due to high rates of the SDHB R46Q mutation. Over 95% of our cohort met pre-specified pre-operative blood pressure parameters. Intra-operative monitoring revealed a tendency to hypotension, but this did not translate into adverse post-operative outcomes, which were infrequent. CONCLUSIONS: Maori were over-represented due to high rates of germline SDHB R46Q mutations. There were few post-operative adverse outcomes in this contemporary cohort.

Adrenal nodules for the non-specialist: What to look out for and when to refer.

Almost all medical specialities utilise cross-sectional imaging of the abdomen to evaluate many different medical conditions. This ever-increasing use of cross-sectional imaging has led to a dramatic increase in the detection rate of adrenal nodules. Following appropriate biochemical and radiological evaluation, the vast majority of these are shown to be benign adrenal adenomas. A small minority are diagnosed with a functional or malignant lesion that may result in significant morbidity and mortality requiring specialist management.

Hydroxocobalamin to treat refractory vasoplegia following phaeochromocytoma resection in a child.

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours that often secrete catecholamines, which can cause dramatic swings in blood pressure and end-organ damage. During surgical resection of these tumours, antihypertensive drug infusions are often required, but after resection patients may become vasoplegic, in part due to cessation of catecholamine secretion by the tumour in the context of pre-operative α1 adrenoceptor antagonism. Numerous medications have been used to treat vasoplegia in this setting, including noradrenaline, vasopressin and, more recently, angiotensin II. We report the case of a patient who experienced vasoplegia after phaeochromocytoma resection which was refractory to vasopressin and angiotensin II infusions but was successfully treated with high dose hydroxocobalamin.

Bladder Paraganglioma Presenting as Post-Micturition Syncope.

A 22-year-old woman presented with a 12-year history of intensifying paroxysms of anxiety, palpitations and recurrent syncope following micturition. The patient was referred to endocrinology upon discovery of hypertension. An extended family history revealed metastatic phaeochromocytoma and paraganglioma in two grand-uncles. Clinical examination revealed hypertension, with a mean 24-hour ambulatory blood pressure of 150/100 mmHg. Supine plasma normetanephrines were markedly elevated with a raised 3-methoxytyramine, while plasma metanephrines were normal. Computed tomography identified a 4.4 cm mass at the right inferolateral margin of the bladder wall. Scintigraphic imaging confirmed unifocal bladder lesion uptake with no additional metastatic lesions. Following pre-operative alpha blockade, the patient underwent a partial cystectomy. Histology confirmed a paraganglioma, and SDHB staining was lost in neoplastic cells consistent with an SDHB-related paraganglioma. Plasma normetanephrine, 3-methoxytyramine and blood pressure returned to normal postoperatively. Genetic screening identified a germline heterozygous SDHB gene variant c.723C>G. Bladder paragangliomas are a rare but important differential to consider when investigating post-micturition syncope. An extended family history should be sought and suspicion for a genetic cause should be raised, especially when the condition presents at a young age. This is the first reported case describing phaeochromocytoma or paraganglioma with the SDHB gene variant c.723C>G. LEARNING POINTS: Bladder paragangliomas are a rare neuroendocrine tumour which should be considered when assessing patients with haematuria and hypertension, headache, palpitations, sweating and facial pallor with micturition.This case highlights the importance of a thorough clinical history with an extended family history and examination in the setting of micturition syncope, which can rarely occur with bladder paraganglioma.Young age at presentation, a family history of phaeochromocytoma and paraganglioma (PPGL), unusual paraganglioma location, mutifocality and aggressive disease should raise the suspicion for a genetic predisposition to PPGL.

Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours.

Pituitary neuroendocrine tumours (PitNETs) associated with paragangliomas or phaeochromocytomas are rare. SDHx variants are estimated to be associated with 0.3-1.8% of PitNETs. Only a few case reports have documented the association with MAX variants. Prolactinomas are the most common PitNETs occurring in patients with SDHx variants, followed by somatotrophinomas, clinically non-functioning tumours and corticotrophinomas. One pituitary carcinoma has been described. SDHC, SDHB and SDHA mutations are inherited in an autosomal dominant fashion and tumorigenesis seems to adhere to Knudson's two-hit hypothesis. SDHD and SDHAF2 mutations most commonly have paternal inheritance. Immunohistochemistry for SDHB or MAX and loss of heterozygosity analysis can support the assessment of pathogenicity of the variants. Metabolomics is promising in the diagnosis of SDHx-related disease. Future research should aim to further clarify the role of SDHx and MAX variants or other genes in the molecular pathogenesis of PitNETs, including pseudohypoxic and kinase signalling pathways along with elucidating epigenetic mechanisms to predict tumour behaviour.