Pheochromocytoma Syndrome Research Articles

Hereditary Paraganglioma Pheochromocytoma Syndrome (HPPS) Presenting as Resistant Hypertension in Patients with ESKD: A Rare Presentation

Hereditary Paraganglioma Pheochromocytoma Syndrome (HPPS) Presenting as Resistant Hypertension in Patients with ESKD: A Rare Presentation

Abstract 13830: Pheochromocytoma in a Patient With Tetralogy of Fallot and Chromosome 17p12 Duplication

Description of Case: A 22-year-old male with Tetralogy of Fallot (TOF) status post transannular patch repair, hypothyroidism, and known partial duplication of chromosome 17p12 concerning for Charcot-Marie-Tooth disease (CMT), presented to his cardiologist with exertional angina and dyspnea, difficulty gaining weight, and diaphoresis. Cardiac MRI demonstrated moderate to severe pulmonic regurgitation with regurgitation fraction of 35% and RV end-diastolic volume index of 150 cc/m 2 . He was referred for pulmonic valve replacement surgery. While awaiting surgical evaluation, he presented to an ER with new hypertension with blood pressure to 240/140 and tachycardia to 107. A CT scan demonstrated a 4.3 x 5.0 x 4.4 cm mass in the right adrenal gland. On admission he was started on phenoxybenzamine and carvedilol. Workup revealed elevated catecholamines and metanephrines ( Table ). He underwent surgical adrenalectomy without complications. Immunohistochemical staining was consistent with pheochromocytoma. Post-procedurally, he was normotensive off medications. He was seen in clinic three weeks after surgery with significant improvement in symptoms. Discussion: We report on a novel genetic association of chromosome 17p12 duplication and pheochromocytoma. The region transcribes peripheral myelin protein-22, which has associations with CMT. Overlap has been demonstrated in other CMT-associated mutations and pheochromocytoma syndromes (e.g. kinesin family member 1B). In congenital heart disease, risk for pheochromocytoma is felt to be driven by hypoxia causing catecholamine secretion, adrenal hyperplasia, and eventual neoplasia. Further study is needed to characterize genetic associations between pheochromocytoma, neuropathy, and congenital heart disease. This patient’s presentation is a lesson in maintaining a high index of suspicion for pheochromocytoma in congenital heart disease, especially with associated genetic syndromes.

Hereditary renal tumor syndromes.

Kidney tumors may develop in association with hereditary tumor syndromes. The clinical presentation of these disorders is various, and in some cases, the renal tumor is the first manifestation of the syndrome. Thus, pathologists need to be aware of the gross and histological signs that may suggest the possibility of a tumor syndrome. In this paper, we summarize and illustrate the characteristics of kidney tumors, genetic background along with the extrarenal manifestations in the following diseases: Von Hippel-Lindau syndrome, hereditary papillary renal cell carcinoma syndrome, hereditary leiomyomatosis and renal cell carcinoma syndrome, Birt-Hogg-Dubé syndrome, tuberous sclerosis, hereditary paraganglioma and pheochromocytoma syndrome, and inherited BAP1 tumor syndrome. At the end of the manuscript, we discuss the tumor syndromes with increased risk of Wilms tumors. Such patients require a holistic approach and multidisciplinary care. Our work aims to make those involved in the diagnosis and treatment of kidney tumors aware of these rare diseases that require life-long surveillance. Orv Hetil. 2023; 164(10): 363-375.

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

ПОЧЕЧНО-КЛЕТОЧНАЯ КАРЦИНОМА С ДЕФИЦИТОМ СУКЦИНАТДЕГИДРОГЕНАЗЫ В У РЕБЕНКА 15 ЛЕТ С СИНДРОМОМ НАСЛЕДСТВЕННОЙ ФЕОХРОМОЦИТОМЫ И ПАРАГАНГЛИОМЫ 4-го ТИПА

Succinate dehydrogenase-deficient renal cell carcinoma (SDH-deficient RCC) is histological variant of RCC recently recognized and included in the classification of renal tumors. SDH-deficient RCC constitutes only 0,02–0,5% of all RCC. The main role in the development of this malignant neoplasm (MN) belongs to mutations in the genes of succinate dehydrogenase (SDHx). The article presents a clinical case report of SDH-deficient RCC in the 15-year-old child. RCC developed as a consequence of the syndrome of hereditary pheochromocytoma and paraganglioma type 4. A literature review describes the histological and molecular genetic characteristics of SDH-deficient RCC, the clinical picture, approaches to therapy and monitoring of patients, as well as indications for genetic testing of patients and their relatives to identify cancer predisposition syndromes.

Experience Completing Population Screening for Variants Associated With Endocrine Tumor Syndromes in a Large, Healthcare-Based Cohort

Hereditary endocrine tumor syndromes (ETS) including Multiple Endocrine Neoplasia Types 1 and 2 (MEN1 and MEN2), von Hippel-Lindau (VHL), and Hereditary Paraganglioma and Pheochromocytoma syndromes (PGL/PCC) have a collective prevalence of 1 in 8500. In current practice, patients’ personal and family histories are used to determine whether genetic testing for ETS is warranted. Population genetic screening for other actionable conditions implies that current practice can be enhanced to identify individuals with genetic variants and that identification of such individuals can lead to improvements in risk management and early-onset diagnoses. It is unknown whether such benefits occur when screening for ETS risk. We report on the rate of syndrome-related features and post-disclosure risk management in patients informed of a pathogenic/likely pathogenic (P/LP) variant in a gene associated with an ETS through the MyCode Community Health Initiative (MyCode).MyCode is a biobank of individuals from a health system who consent to health-related research and return of clinically actionable results. Exome sequences are analyzed for P/LP variants in actionable genes, confirmed by a clinical laboratory, and disclosed to participants and their providers. All participants are offered follow-up with a genetics provider post-disclosure. Here, we focus on participants that received a P/LP variant in MEN1, RET, VHL, or an SDHx gene from June 2016-October 2019. From May-July 2020 we performed dual, manual review of participants’ electronic health records to assess personal and family histories, risk management behaviors, and post-disclosure diagnoses of endocrine neoplasms.Of 87,493 participants with available exome data, P/LP variants in genes of interest were identified in and disclosed to 80 participants (65% female, 99% self-reported White race, 99% self-reported non-Hispanic ethnicity, median age 57 years at results disclosure, median time since disclosure 2 years). Eighty-one percent of participants (n=65) did not have a prior diagnosis of an ETS and were included in additional analyses. Five participants (8%) had a personal history of syndrome-related features; 16 (25%) had a positive family history. Only seven (11%) met existing clinical testing criteria pre-disclosure. Post-disclosure, 37 (57%) completed at least one recommended risk management behavior; 11 of these (17%) were diagnosed with a syndrome-related neoplasm (e.g., medullary thyroid cancer).Results of population screening in a healthcare cohort suggest genetic variants associated with ETS risk are more common than previously reported (1 in 1094). Though additional studies on clinical utility are needed, these results suggest that screening healthcare populations for genetic risk can enable detection of individuals at risk for ETS, lead to uptake of risk management, and facilitate relevant clinical diagnoses.

A Case of Carney Triad Complicated by Renal Cell Carcinoma and a Germline SDHA Pathogenic Variant

Background: Carney triad is a rare multiple-neoplasia syndrome presenting as an association of paragangliomas (PGL), gastrointestinal stromal tumors (GIST), and pulmonary chondromas (CHO). Succinate dehydrogenase deficiency has been associated with several neoplasias, including Carney triad, renal cell carcinoma (RCC) and those associated with hereditary PGL/ pheochromocytoma (PHEO) syndromes. Clinical Case: A 57-year-old male diagnosed with hypertension at age 49, presented with a gradual increase in blood pressure over a period of 12 months. For seven years following his diagnosis of hypertension, the patient experienced episodic increases in blood pressure, to a systolic pressure greater than 180 mmHg associated with a tight band sensation around his forehead lasting half a day. Abdominal computed tomography (CT) revealed a left adrenal adenoma, a 5.1 cm para-aortic mass, and a right renal superior pole lesion measuring 2.5 cm, which was suspicious for a carcinoma. 123I-metaiodobenzylguanidine (123I-MIBG) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scans were performed, which suggested the para-aortic mass to be consistent with a PGL. Additionally, 18F-FDG uptake was noted in the gastroesophageal region and was suspicious for a GIST. The left adrenal mass was not associated with 123I-MIBG or 18F-FDG activity. Chest CT demonstrated a right middle lobe lung lesion suggestive of a CHO, although no biopsy was performed. A diagnosis of Carney triad was made. The patient underwent surgical resection of the PGL and GIST, as well as a partial right nephrectomy. The PGL and GIST were positive for SDHA and negative for SDHB by immunohistochemical (IHC) staining. Pathology from the renal lesion was consistent with a 2.3 cm conventional clear cell renal carcinoma, with positive staining for SDHA and SDHB by IHC. The patient was found to harbor a germline heterozygous pathogenic variant (c.91 C>T, p.R31X) in SDHA which has been previously reported and results in loss of function of SDHA. SHDC hypermethylation was not detected in the PGL, GIST, or RCC. Additionally, DNA sequencing of the RCC did not indicate loss of heterozygosity at the variant region of interest. Although the SDHA disease-causing variant is responsible for the patients Carney triad phenotype, it is unclear if this variant is causative of the RCC. Conclusion: This is a novel presentation of a germline inactivating SDHA pathogenic variant in a patient with Carney triad complicated by RCC. However, an SDHA disease-causing variant was previously reported in a patient with comorbid GIST and RCC. This case provides further support to the increasing evidence that SDHx pathogenic variants may predispose patients to develop renal neoplasms.

A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant.

SummarySuccinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.Learning points The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.

Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore

BackgroundHereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients.MethodsWe describe the clinical characteristics and genetic testing outcomes of patients with suspected hereditary PGL/PCC who were referred to a tertiary cancer genetics clinic in Singapore.ResultsAmong 2196 patients with suspected hereditary cancer syndrome evaluated at the cancer genetics clinic from 2000 to 2019, 13/2196 (0.6%) patients fulfilled clinical suspicion for hereditary PGL/PCC syndrome. After genetic counselling, 10 patients underwent multi-gene next generation sequencing and deletion/duplication analysis, including SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127. Seven of 10 patients (70%) were identified to carry pathogenic variants, including 3 unrelated Chinese patients with head and neck PGL who carried the same SDHD: c.3G > C (p.Met1Ile) variant that was previously reported to be a possible founder variant in Chinese, and 3 patients with urogenital PGL and 1 patient with retroperitoneal PGL who carried different SDHB variants. Variant carriers were younger, more likely to present with multiple tumours, or have family history of paraganglioma or pheochromocytoma, than non- variant carriers.ConclusionHereditary PGL/PCC accounts for only 0.6% of patients seen in an adult cancer genetics clinic in Asia. SDHD and SDHB genes remain the most important causative genes of hereditary PGL/PCC in Asia even when patients are tested with multi-gene NGS panel.

Tumor detection rates in screening of individuals with SDHx-related hereditary paraganglioma–pheochromocytoma syndrome

PurposeMinimal data exist regarding the efficacy of screening protocols for individuals with SDHx germline pathogenic variants with hereditary paraganglioma–pheochromocytoma syndrome. This study aimed to evaluate the SDHx-related tumor detection rate in individuals undergoing clinical screening protocols. MethodsA multicenter retrospective longitudinal observational study was conducted. Individuals with germline SDHx pathogenic variants underwent clinical whole-body imaging and biochemical testing. ResultsTwo hundred sixty-three individuals with SDHx germline pathogenic variants completed 491 imaging screens. Individuals with SDHB germline pathogenic variants were most common (n=188/263, 72%), followed by SDHD (n=35/263, 13%) and SDHC (n=28/263, 11%). SDHx-related tumors were found in 17% (n=45/263) of the cohort. Most SDHx-related tumors were identified on baseline imaging screen (n=39/46, 85%). Individuals with SDHD pathogenic variants had the highest tumor detection rate (n=14/35, 40%). Of imaging screens identifying SDHx-related paraganglioma/pheochromocytoma, 29% (n=12/41) had negative biochemical testing. Secondary actionable findings were identified in 15% (n=75/491) of imaging screens. ConclusionCurrent SDHx screening protocols are effective at identifying SDHx-related tumors. Tumor detection rates vary by SDHx gene and screening has the potential to uncover actionable secondary findings. Imaging is an essential part of the screening process as biochemical testing alone does not detect all disease.

MON-195 Genetic Analysis and Clinical Characteristics of Hereditary Paraganglioma and Pheochromocytoma Syndrome in Korean Population

Pheochromocytoma (PCC) and paragangliomas (PGL), rare neuroendocrine tumor originating from the chromaffin cells together referred as PPGL, are acknowledged to be more than 40% hereditary, related to germline mutations of susceptibility gene. With the advancement of genetic analysis technique, including next-generation sequencing (NGS), there has been attempts to classify PPGL into molecular clusters - Pseudohypoxic, Wnt signaling, and Kinase signaling PPGL. With NGS being applied to clinical setting only recently in Korea, we aimed to review the result of genetic analysis, including NGS, and investigate its association with clinical characteristics in Korean PPGL patients. We reviewed medical records of patients with PPGL in Severance hospital enrolled between January of 2006 to October of 2019. We gathered clinical phenotype by reviewing medical records of the patients who underwent targeted NGS from March of 2017 to October of 2019 using Severance hospital’s endocrine panel or who had known germline mutations of related genes. Family gene analysis was recommended for family members of patients with significant gene mutations. Among 78 patients with PPGL, 58 patients underwent targeted NGS results or had prediagnosed mutations. Thirty-three patients (62.1%) had clinically significant germline mutation. In patients with hereditary PPGL, there were higher likelihood of family history and presence of other tumors. There were significant differences in the type of PPGLs, percentage of family history, metastasis rate and the presence of other tumors among 3 molecular clusters - pseudohypoxic TCA cycle-related, pseudohypoxic VHL/EPAS1-related and kinase-signaling group. Twenty-seven different germline mutations from 11 genes (SDHB, RET, VHL, EPAS1, NF1, KIF1B, MAX, SDHA, SDHC, SDHD, and TMEM127) were found, SDHB mutation being the most common. Four of them were novel mutations; EPAS1 c.1250G>A (p.Gly417Glu), NF1 c.6215delA (p.His2072LeufsTer10), NF1 c.6777del (p.Gly2260fs), and SDHC exon 2-6 duplication. In conclusion, we report the prevalence of germline mutations in Korean PPGL patients, and the rate of hereditary PPGL is estimated to be as high as 62.1%. NGS is a good and accessible tool for genetic analysis in patients with PPGLs, and further research on molecular classification will lead to precision medicine.

SAT-186 Metastatic Paraganglioma Secondary to SDHB Gene Mutation: A Case Report and Review of New Therapies

Background: Paragangliomas (PGL) are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, majority of which are benign. 0-36% of PGL patients can develop metastatic disease, depending on the genetic mutation. We present a case of a patient with metastatic PGL due to an SDHB gene mutation. We then summarize published and ongoing trials of therapies for metastatic pheochromocytoma/PGL. Clinical Case: A 54 years old male presented to the Emergency Department with severe left lower quadrant pain. He additionally reported recent episodes of headaches and uncontrolled hypertension, as well as an approximate weight loss of 50 pounds in the preceding two years.A CT abdomen and pelvis demonstrated an 8 cm left peri-aortic retroperitoneal mass, along with a 2 cm solitary hepatic lesion concerning for metastatic disease. Normetanephrine levels were elevated at 1210 pg/mL (normal 0-145 pg/mL). Endoscope-guided biopsy of the retroperitoneal mass demonstrated findings consistent with a PGL.The patient was referred to a genetic counsellor where he underwent PGLNext testing. He tested positive for a c.418G>T mutation in the SDHB gene, consistent with a diagnosis of hereditary paraganglioma - pheochromocytoma (PGL-Pheo) syndrome.Patient was planned for surgical debulking of his PGL, and was treated pre-operatively with Phenoxybenzamine, followed by B-blockers. He underwent resection of the retroperitoneal mass and wedge resection of the hepatic mass. Surgical pathology revealed a 10.5 cm extra adrenal PGL and a 2 cm metastatic PGL involving the liver with negative margins of resection.Patient did well in the post-operative period, and was discharged with plans to repeat plasma metanephrines in 6-8 weeks. The patient was referred to the National Cancer Institute (NCI) for enrollment in a clinical trial using Lu-177-DOTATATE. Conclusion: Though rare, pheochromocytomas (pheo) and PGL can be lethal if not diagnosed and managed appropriately. As of 2019, at least 19 genes have been identified that predispose to familial pheochromocytoma/PGL. Importantly, PGL that are associated with SDHB, the mutation our patient had, are more likely to appear in the abdomen (rather than the head and neck), are usually secretory (most commonly norepinephrine) and are more likely to become metastatic (21-79%).Patients with metastatic pheo/PGL require complex care in specialized centers by a multidisciplinary team of specialists. Patients with advanced or non-resectable metastatic pheo/PGL should preferably be offered a referral to NCI or an NCI designated cancer center for enrollment in a clinical trial of targeted therapies.

Preimplantation genetic diagnosis for a single gene mutation for succinate dehydrogenase subunit B (the genetic basis for malignant paraganglioma) with successful pregnancy

Purpose: To report the first successful case of the birth of normal baby using preimplantation diagnosis for hereditary paraganglioma (PGL) followed by embryo transfer and to emphasize the importance of using mild follicle stimulating hormone (FSH) stimulation for IVF in women with diminished oocyte reserve. Materials and Methods: The female partner had a baseline serum FSH of 16.5 mIU/mL and the male partner had the malignant hereditary form of the PGL - pheochromocytoma (PGL/PCC) syndrome related to a mutation of the nuclear mitochondrial enzyme, succinate-dehydrogenase enzyme (specifically the B subunit) (SDHB). He was suffering from the malignant transformation of these neuroendocrine tumors. Before his death, he wanted to enjoy for a short time a baby with his own genes but feared passing the SDHB autosomal gene mutation to their child. Results: Eight blastomeres from eight embryos biopsied on day 3 were tested for SDHB gene by polymerase chain reaction. These eight metaphase II oocytes were obtained following mild FSH stimulation (150 units from day 3). Intracytoplasmic sperm injection (ICSI) was performed using the frozen/thawed sperm of this 35-year-old male suffering from a malignant pheochromocytoma. Five of the eight embryos were found to have mutations of the SDHB gene. Two embryos with normal SDHB were transferred and one resulted in a healthy baby. Genetic testing of the baby confirmed the absence of the SDHB mutation. Discussion: The successful pregnancy supports, but does not prove, the importance of using mild FSH stimulation in the presence of diminished oocyte reserve to inhibit the iatrogenic development of a much higher percentage of embryos with aneuploidy.

OR29-4 Pregnancy Outcomes in Women with Pheochromocytoma and Paraganglioma: An International Multi-Center Study

Background: Unrecognized or newly diagnosed pheochromocytoma (PHEO) or paraganglioma (PGL) during pregnancy may lead to adverse maternal and fetal outcomes. Recommendations for the management of women with PHEO or PGL (PPGL) during pregnancy are limited by the scarcity of published literature. Objective: To describe the presentation, management and outcomes of women with active PPGL during pregnancy and to identify predictors of unfavorable maternal and fetal outcomes. Methods: international retrospective multi-center study, 1968-2018. Results: Seventy-nine women with active PPGL had 89 pregnancies at a median age of 28 yrs (range, 16-46). At the time of pregnancy, 37 (42%) women had unilateral PHEO, 11 (12%) bilateral PHEO, 26 (29%) PGL, 8 (9)% multifocal disease and 7 (8%) metastatic PPGL. Of 51 patients evaluated for a predisposing mutation, 38 were positive (12 SDHB, 11 VHL, 8 RET, 7 other). Median tumor size was 6 cm (range, 1.9-29). Of 74 patients with available data on function, 65 (88%) had functioning PPGL. Of 89 pregnancies, only 13 (15%) patients had a known PPGL prior to pregnancy (8 with known metastases), while in 42 (47%) pregnancies, PPGL was diagnosed during pregnancy at a median gestation of 16 weeks (range, 2-38) and during 34 (38%) pregnancies, PPGL remained unrecognized until postpartum, diagnosed at a median of 9 weeks (range, 0-78) after delivery. PPGL surgery was performed in 72 women: 14 intrapartum at median gestation week 16 (range, 13-26) and 58 postpartum at a median of 36 weeks (range, 0-270) after pregnancy. Of 41 pregnancies with antepartum diagnosis of PHEO not treated with surgery, 25 (61%) were managed with medical therapy and 15 (39%) were closely monitored. Delivery was by C-section in 39 (44%) pregnancies (38 healthy babies, one death delivered at 22 weeks) and vaginal in 35 (39%) with no adverse maternal or fetal outcomes. Elective abortion was pursued in 5 (6%) pregnancies. Intrauterine fetal demise occurred in 6 (7%) pregnancies at a median of 21 weeks gestation (range, 11-28), all in women with unrecognized functioning PPGL. Adverse maternal outcomes occurred in 3 (3%) pregnancies, all in unrecognized functioning PPGL resulting in 1 death (at gestation week 38) and 2 severe cardiovascular complications (immediately postpartum). The most significant predictor of an unfavorable pregnancy outcome was postpartum diagnosis of PHEO, with an odds ratio of 16.6 (95% CI, 2-140, P=0.001), but not maternal age, tumor size, presence of metastases, antepartum surgery for PHEO, or known PHEO syndrome. Conclusion: The majority of pregnancies in women with active PPGL had excellent outcomes, even in women with metastatic or functional disease, especially when PPGL was diagnosed before or during pregnancy, allowing for appropriate management. However, unrecognized and untreated PPGL was associated with 16-fold higher risk of either maternal or fetal complications.

MON-377 Hereditary Paraganglioma Pheochromocytoma Syndrome in the Setting of End Stage Renal Disease

Pheochromocytomas and Paragangliomas represent rare catecholamine producing tumors of the adrenal gland or sympathetic/parasympathetic nervous system respectively. These can arise de novo or can result from genetically inherited mutations that predispose their origin. Overall these are rare tumors that can range from being asymptomatic to have symptoms related to excess catecholamines (including labile hypertension). While labile blood pressure is often associated with end stage renal disease (ESRD), pheochromocytoma/paragangliomas as cause of this are very rare with only 30 cases being reported in the literature. We report the case of a hereditary paraganglioma in a patient with ESRD. The patient is a 19 year old man with a history of ESRD secondary to hypoplastic kidneys and hypertension. He had initial presented to the hospital with shortness of breath in the setting of missing hemodialysis (HD). He received a session of HD in the emergency department without improvement and was placed on BIPAP. As part of his admission workup he had a CT of his chest which was negative for PE but did show a 5.3 by 3.5 by 4.7 cm left periaortic mass. Suspicion for possible paraganglioma was raised in the setting of difficult to control blood pressure along with his reported symptoms of palpitations and periodic sweats. Plasma metanephrines drawn after HD revealed an elevated normetanephrine of 28 nmol/L (<0.90 nmol/L) and plasma catecholamines were elevated with a norepinephrine of 17,928 pg/ml ( 70-750 pg/ml while supine or 200-1700 pg/ml while standing) and dopamine of 123 pg/ml (<30 pg/ml). He underwent metaiodobenzylguanidine (MIBG) scanning that showed abnormal radiotracer uptake in the left periaortic mass concerning for a paraganglioma. He was started on alpha-blockade and arrangements were made for surgery in several weeks time. While awaiting surgery genetic testing for hereditary paraganglioma pheochromocytoma syndrome returned positive for a variant mutation in SDHB. He underwent successful resection of his paraganglioma and was able to come off of his blood pressure medications. Postoperative testing showed normalization of his plasma metanephrines and catecholamines and arrangements were made for his siblings to undergo genetic testing. This case represents a relatively rare presentation of a paraganglioma in a patient with ESRD. The typical diagnostic workup for a paraganglioma can often not be pursued as 24 hour urine catecholamines can often not be collected as patients are often anuric/oliguric so plasma catecholamines must be pursued. Clinicians must be aware that those on HD can naturally have elevated catecholamines as a result of sympathetic nervous system activation from fluid shifting. Studies have shown that these values never exceed more than 3 times the upper limit of normal as a result of HD and values beyond that should raise suspicion for a paraganglioma or pheochromocytoma.

Pancreatic and Adrenal Disorders

Critically ill patients who lack preexisting endocrine diagnoses may still develop endocrine dysfunction, as exhibited by critical illness-related corticosteroid insufficiency and glycemic abnormalities. Glycemic control remains an important issue in critically ill patients, as hyperglycemia, hypoglycemia, and glucose variability are all independently associated with increased mortality. Hyperglycemia is a common manifestation of critical illness that may result from an acute response to stress and injury or may reflect preexisting diabetes mellitus. Hypoglycemia most commonly occurs as a result of treatment of hyperglycemia but may also be due to other causes such as sepsis and decreased nutritional intake. Hypoglycemia and other glycemic emergencies such as diabetic ketoacidosis and a hyperosmolar hyperglycemic state must be quickly recognized and treated. This review provides a general overview of diabetes mellitus, glycemic targets in the critically ill, glycemic emergencies, adrenal gland disorders, pheochromocytoma, and carcinoid syndrome. This review contains 1 figures, 4 tables, and 43 references. Keywords: adrenal crisis, carcinoid syndrome, critical illness-related corticosteroid insufficiency, Cushing syndrome, diabetes mellitus, diabetic ketoacidosis, glycemic goals, hyperosmolar hyperglycemic state, hypoglycemia, pheochromocytoma

Update of Pheochromocytoma Syndromes: Genetics, Biochemical Evaluation, and Imaging.

Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare commonly benign neuroendocrine tumors that share pathology features and clinical behavior in many cases. While PCCs are chromaffin-derived tumors that arise within the adrenal medulla, PGLs are neural-crest-derived tumors that originate at the extraadrenal paraganglia. Pheochromocytoma-paraganglioma (PPGL) syndromes are rapidly evolving entities in endocrinology and oncology. Discoveries over the last decade have significantly improved our understanding of the disease. These include the finding of new hereditary forms of PPGL and their associated susceptibility genes. Additionally, the availability of new functional imaging tools and advances in targeted radionuclide therapy have improved diagnostic accuracy and provided us with new therapeutic options. In this review article, we present the most recent advances in this field and provide an update of the biochemical classification that further reflects our understanding of the disease.

A novel succinate dehydrogenase subunit B germline variant associated with head and neck paraganglioma in a Dutch kindred: A family-based study.

In the Netherlands, the majority of hereditary head and neck paragangliomas (HNPGL) are caused by germline variants in the succinate dehydrogenase genes (SDHD, SDHB, SDHAF2). Here, we evaluate a four-generation family linked to a novel SDHB gene variant with the manifestation of a HNPGL. A family-based study. The VU University Medical Center (VUmc) Amsterdam, a tertiary clinic for Otolaryngology and Head and Neck Surgery. The index patients presented with an embryonic rhabdomyosarcoma and a non-Hodgkin lymphoma. Array-based comparative genomic hybridisation (aCGH) analysis and multiplex ligation-dependent probe amplification (MLPA) revealed a novel deletion of exon 1-3 in the SDHB gene, suspected to predispose to paraganglioma (PGL)/pheochromocytoma (PHEO) syndrome type 4. Subsequently, genetic counselling and DNA testing were offered to all family members at risk. Individuals that tested positive for this novel SDHB gene variant were counselled and additional clinical evaluation was offered for the identification of HNPGL and/or PHEO. The DNA of 18 family members was tested, resulting in the identification of 10 carriers of the exon 1-3 deletion in the SDHB gene. One carrier was diagnosed with a carotid body PGL and serum catecholamine excess, which was surgically excised. Negative SDHB immunostaining of the carotid body tumour confirmed that it was caused by the SDHB variant. The remaining 9 carriers showed no evidence of PGL/PHEO. Deletion of exon 1-3 in the SDHB gene is a novel germline variant associated with the formation of hereditary HNPGL.

Multimodality Radionuclide Imaging in a Patient With Hereditary Paraganglioma-Pheochromocytoma Syndrome

Hereditary paraganglioma (PGL)-pheochromocytoma (PCC) syndrome is a genetic disorder caused by a mutation of the tumor suppressor gene SDHD that results in a predisposition for head and neck PGLs and PCCs. We present a case of a 33-year-old woman where F-FDG PET/CT showed areas of increased uptake in both the adrenal and cervical regions, consistent with PCCs and PGLs, respectively. Further imaging revealed that PCCs were I-MIBG avid, whereas the PGLs were In-octreotide avid. This demonstrates the varying sensitivities of different imaging modalities in regard to neuroendocrine tumors and the potential for treatment using multiple targeted therapies.

Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood.

Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors. Clin Cancer Res; 23(12); e68-e75. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.