Family History Of Pheochromocytoma Research Articles

FRI270 A Rare Case Of Giant Benign Pheochromocytoma

Abstract Disclosure: M.S. Hossain: None. B. Gautam: None. K. Mandal: None. H. Liao: None. D.S. Rosenthal: None. S.C. Kumar: None. Background: Pheochromocytomas are Catecholamine-secreting tumors that arise from the adrenal medulla. These tumors are rare however giant pheochromocytomas (>7 cm) are even rarer entities, which are thought to be more aggressive and malignant. Here we present a case of incidentally found giant but benign pheochromocytoma. Case Report: A 40-year-old female with no PMH presented to the hospital with fever & cough for 1 month which was associated with weight loss (10lb). Patient was started on antibiotics and CT revealed right-sided adrenal incidentaloma while searching for sources of infection. CT & MRI abdomen were done for better characterization, showed a round circumscribed right adrenal mass measuring 11.3 x 11.4 x 12.8 cm. Mass had irregular central necrosis, peripheral enhancement & neovascularization. Patient denied headache, sweating & palpitation; no personal or family history of pheochromocytoma. On physical examination BP: 103/70, HR: 98, Temp: 98F, BMI:25.9, unremarkable for cushingoid features, virilization & hirsutism. Hormonal workup showed elevated free normetanephrine 185 (<148pg/ml) & chromogranin A 801 (<311ng/ml), but normal free metanephrine <25 (<57pg/ml) & total metanephrines 185 (<205pg/ml). 24hr Urine study: elevated total metanephrines 1661 (182-739mcg/24h) & normetanephrine 1482 (88-649mcg/24h) but normal metanephrine 179(58-203mcg/24h), urine volume 2360ml/24h, urine creatinine 0.87(0.50-2.15g/24h). Patient Cortisol, ACTH, Aldosterone, Renin activity, DHEA-S, Androstenedione was normal. Patient was started on alpha-blockers. Patient underwent successful right-sided adrenalectomy & nephrectomy with IVC resection. Pathology reported pheochromocytoma stage II T2Nx, Ki 67 <5%. No vascular and extracapsular invasion & no mitosis. Post operative outpatient follow up showed elevated plasma free normetanephrine 199(<148pg/ml) & normal free metanephrine <25 (<57pg/ml) & total metanephrine 199 (<205pg/ml). 24hr urine study: normal metanephrine 61 (58-203mcg/24h), Normetanephrine 268 (88-649mcg/24h) & total metanephrines 329 (182-739mcg/24h). Patient was advised for Ga68 DOTATE/PET scan, genetic counseling & lifelong follow-up with endocrinology for surveillance. Discussion: Pheochromocytoma symptoms may vary regardless of tumor size. Giant pheochromocytoma may not have high secretory potential due to central necrosis resulting in reduced chromaffin cells or catecholamines that are restricted to capsular mass which may release into the bloodstream intraoperatively1. Therefore, initiating alpha-blockers before surgery in these cases may prevent perioperative complications.1. Minei S, Yamashita H, Koh H, Satoh T, Kobayashi S, Furuhata M, et al. Giant cystic pheochromocytoma A case report. Hinyokika Kiyo. 2001;47:561-3. Presentation: Friday, June 16, 2023

FRI368 Thyroid Paraganglioma: A Rare Manifestation Of Paraganglioma Syndrome Associated With SDHD Mutation

Abstract Disclosure: K. Samuel: None. C. McMullen: None. C. Veloski: None. S. Kushchayev: None. J.E. Hallanger-Johnson: None. J. Hernandez Prera: None. J. Muzaffar: None. G.Q. Yang: None. V. Tarasova: None. Background: Thyroid paragangliomas (TP) are exceptionally rare, representing 0.5% of all paragangliomas (PGL) with total of less than 70 cases reported to date. We report a case of a TP presenting with an indeterminate thyroid nodule, as a first manifestation of multifocal head and neck PGL, associated with succinate dehydrogenase complex subunit D (SDHD) mutation. Clinical case: A 59-year female was initially seen at the tertiary referral center for an indeterminate thyroid nodule discovered incidentally on neck ultrasound (US) ordered for evaluation of a palpable posterior left neck mass. Neck/thyroid US showed multiple nonspecific bilateral lymph nodes measuring up to 1.2 cm and a 1.7 cm right interpolar markedly hypoechoic and hypervascular solid thyroid nodule (TR5). Clinically, the patient did not have symptoms related to the thyroid nodules or lymph nodes in the neck. Thyroid function tests were within normal range. An US-guided FNA biopsy was nondiagnostic. Core biopsy was suspicious for papillary thyroid carcinoma (hypercellular thyroid parenchyma with some follicular cells with nuclear irregularity, grooves, and hyperchromasia). Pathology slides review at the tertiary center showed nondiagnostic sample (Bethesda I) on cytopathology and neuroendocrine neoplasm consistent with PGL on core biopsy (immunohistochemical stains showed tumor cells positive for synaptophysin, chromogranin and GATA3. TTF1, TG, calcitonin, CEA and AE1/3 negative). US of the neck/thyroid 4 months later showed stable disease. Calcitonin and 24-h urinary catecholamines, metanephrines were within normal limits. There was no family history of pheochromocytoma or PGL. Genetic testing showed germline SDHD mutation (p.P81L(c.242c>5). 68Ga-DOTATATE PET/CT revealed multifocal areas of increased somatostatin receptor expression from the skull base to the left thoracic inlet, which included right and left skull base lesions, left neck level IIA lymph node, right and left level III lymph nodes, right thyroid lobe lesion, and left prevascular superior mediastinal lesion. An MRI of the brain and neck with and without contrast showed 1.7 cm right jugular, 0.6 cm right carotid, and 0.6 cm left vagal PGL, 1.3 cm right thyroid nodule, left level II 1.1x.6 cm lymphadenopathy, and 0.4 cm left superior mediastinal nodule. A CT of the neck w/contrast showed multiple areas likely representing bilateral carotid body tumors, left vagal PGL, right glomus jugular, and thyroid PGL stable over 6 months. MIBG nuclear medicine scan revealed no radiotracer accumulation in the lesions. EBRT therapy is planned to the skull base lesion. Conclusions: TP should be considered in the differential diagnosis of hypervascular thyroid nodules in patients with SDH-related pheochromocytoma-PGL syndromes. This case illustrates the importance of experienced multidisciplinary team evaluation and management of complex and rare PRG cases. Presentation: Friday, June 16, 2023

Tumor-to-tumor metastasis of colon cancer metastasizing to a pancreatic neuroendocrine tumor associated with von Hippel-Lindau disease: a case report

Von Hippel-Lindau disease (VHL) is frequently associated with pancreatic neuroendocrine tumors (PNETs). Here, we report a case of tumor-to-tumor metastasis in a VHL patient in whom colon cancer metastasized to the interior of a PNET. A 65-year-old man had undergone bilateral adrenalectomy for pheochromocytomas in both adrenal glands in his 50 s. Genetic screening was performed considering his family history of pheochromocytoma, and he was diagnosed with VHL. PNET was detected, for which the patient was regularly monitored by follow-up imaging. One year ago, the patient underwent right hemicolectomy to remove a tumor in the ascending colon (pT3N0M0, pStage IIA). He was admitted to our department for detailed examination because the pancreatic tumor had grown, and thus, pancreaticoduodenectomy was performed. Diagnostic imaging and histological findings indicated tumor-to-tumor metastasis, in which the patient’s previous colon cancer had metastasized to and proliferated within the PNET. Colon cancer metastasizing to a PNET is extraordinarily rare and has never been reported in the literature. Thus, practitioners should be vigilant for tumor-to-tumor metastasis when performing imaging surveillance of PNETs.

Pheochromocytoma: A Clinicopathologic and Molecular Study of 390 Cases From a Single Center.

Pheochromocytomas are rare neuroendocrine tumors arising from chromaffin cells in the adrenal medulla. They may occur sporadically or in the context of hereditary syndromes. All pheochromocytomas are considered to have malignant potential (defined as risk of metastasis, not local invasion). The use of grading systems with incorporated clinical and histopathologic parameters can help but not definitively predict the metastatic potential of pheochromocytomas. The recent discovery of susceptibility genes provided new insights into the pathogenesis and introduced additional approaches to estimate the metastatic risk of pheochromocytoma. However, the prevalence of these genetic signatures in pheochromocytomas has yet to be fully addressed. Therefore, in the present study, we retrospectively reviewed cases of pheochromocytoma from 1980 to 2018 in the archives of our institution. Three hundred ninety cases were identified, and their clinicopathologic characteristics and genetic statuses were analyzed. About 25% of the cases had metastases, which were more common in older patients (median, 49 y) than in younger ones. Univariate and multivariate analyses revealed that older age, Hispanic ethnicity, metastasis, and large primary tumor size were markedly associated with poor overall survival. In contrast, family history of pheochromocytoma, lack of symptoms, and bilateral adrenal involvement were associated with better survival. About 37% of the pheochromocytomas were associated with inherited syndromes. About 52% of tested patients had pathogenic mutations of pheochromocytoma susceptibility genes. Of these, succinate dehydrogenase B gene mutation had the strongest association with metastasis. These data support that genetic testing should be offered to all patients with pheochromocytoma.

Hereditary pheochromocytoma/paraganglioma syndrome with a novel mutation in the succinate dehydrogenase subunit B gene in a Japanese family: two\xa0case reports

BackgroundPheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B.Case presentationA 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father’s paraganglioma tissues. In silico analysis predicted the mutation as “disease causing.” She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery.ConclusionsWe detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.

Inflammatory Myofibroblastic Adrenal Tumor: An Extreme Rare Cause of Adrenal Incidentaloma

Introduction: An inflammatory myofibroblastic tumor (IMT) is considered a complex disease with a suggested neoplastic nature. It has a variable histological and clinical presentation. Up to now, the exact etiology is still unknown. Various sites such as the lungs (first site described in 1939), the heart, the gastrointestinal tract, and the genitourinary tract have been reported in the literature. The adrenal glands are considered an extremely rare location with no recurrence reported after surgical management. Up to our knowledge, only 9 cases have been described in the literature. The age of presentation was variable (from newborn to 57 years old). Case Report: A 70 years old female with a past medical history of well-controlled diabetes type 2, and hypertension presented with a progressively increasing chronic right flank pain for the past couple of months, associated with 10 lb weight loss. Workup was done and an incidental right adrenal mass was found on CT scan. The mass was 3.2cm x 3.3 cm partially necrotic with adjacent stranding abutting the right adrenal gland and the liver. The opposite gland was normal and there was no evidence of any other mass lesion in the abdomen. MRI adrenal showed 3.2x2.5x3.6 cm solid heterogeneous mass in the right adrenal gland (Hypointense on T1 and T2 weighted images. She had no sign or symptoms suggestive of Cushing and/or pheochromocytoma. Her hypertension was well controlled on lisinopril 10 mg. Hormonal workup was within normal range except for a mild elevation of DHEAS. Given the size of the mass, the worrisome radiological characteristics, and a family history of pheochromocytoma in her daughter, surgical options were discussed with the patient. Subsequently, the patient underwent the right robotic adrenalectomy. The postoperative course was uneventful. Pathology revealed a 6.5x6x 5 cm IMT of the adrenal. The CT scan done 6 months postoperatively didn’t show any recurrence. Discussion: and conclusion: Adrenal IMTs are extremely rare but they should be considered in the differential diagnosis of adrenal masses. Follow-up is warranted since its behavior still remains uncertain. More cases are needed to unmask the true biological behavior and pathogenesis of adrenal IMTs.

Case report: a synonymous VHL mutation (c.414A\u2009>\u2009G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing

Backgroundvon Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood.Case presentationWe report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband’s children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level.ConclusionsOur study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.

Pheochromocytoma complicated by cyanotic congenital heart disease: a case report

.Coincidental cyanotic congenital heart disease and pheochromocytoma is uncommon, although some cases have been reported. We describe a girl aged 15 yr and 11 mo with pheochromocytoma and tricuspid atresia treated by performing the Fontan surgery. The patient did not have any specific symptoms of syndrome related to pheochromoytoma or a family history of pheochromocytoma. During cardiac catheterization, her blood pressure increased markedly, and an α-blocker was administered. Catecholamine hypersecretion was observed in the blood and urine, and abdominal computed tomography revealed a tumor in the right adrenal gland. Scintigraphy showed marked accumulation of 123I-metaiodobenzylguanidine in the tumor, which led to a diagnosis of pheochromocytoma. We did not detect any germline mutations in the RET, VHL, SDHB, SDHD, TMEM127, or MAX genes. This patient had experienced mild systemic hypoxia since birth, which may have contributed to the development of pheochromocytoma.

Pheochromocytoma: A Mimicry of ACS

There are diseases which at times presents in such a way as to mimic for an acute coronary syndrome event. Pheochromocytoma is one of those disorders. Episodic or transient hypertension is one of its cardinal features. Presence of palpitation, diaphoresis and headache along with hypertension alarms for Pheochromocytoma. However, accompanying of these symptoms with a family history of Pheochromocytoma or syndromic presentation of MEN 2A, MEN 2B, VHL or Neurofirbomatosis, further increases the likelihood. Therefore, should be screened with a more sensitive test like plasma levels for catecholamine and metanephrine. Scanning techniques should be carried out to localize the tumor and to look for malignancy. Once localized, the only curative therapy is surgical resection of the tumor.n.

Multiple endocrine neoplasia type 2A

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant inherited cancer syndrome that expresses nonendocrine and endocrine tumors. Here, we describe a 42-year-old man with an initial presentation of low back pain and hypertension. Clinical assessments revealed pheochromocytoma, medullary thyroid carcinoma with bone metastasis, and parathyroid hyperplasia. MEN 2A was diagnosed, and a family history of pheochromocytoma was traced. Surgical resection of the pheochromocytoma of the adrenal gland resulted in a cure of the patient’s hypertension. He received systemic chemotherapy with the “MAID” regimen (mesna, doxorubicin, ifosfamide, and dacarbazine) over three cycles of 3 weeks each, and showed a partial response.

Persistent Hiccups—An Unusual Presentation of Bilateral Pheochromocytoma without Syndromic Association: A Case Report

Pheochromocytoma is a rare catecholamine-producing tumor arising from chromaffin tissue in the adrenal medulla, occurring in less than 0.2 percent of patients with hypertension. The mean age at diagnosis is about 40 years. Pheochromocytomas are commonly inherited as features of multiple endocrine neoplasia type 2 or several other pheochromocytoma-associated syndromes and have variable clinical presentation. Among the presenting symptoms, episodes of palpitations, headaches, and profuse sweating are typical and constitute a classic triad. We report a case of a 17-year-old male patient with rare bilateral pheochromocytoma presenting with persistent hiccups for 4 months and blurring of vision for 1 week, later followed by hypertensive crisis. There was neither family history of pheochromocytoma nor any classic symptoms. Patient was diagnosed with bilateral pheochromocytoma without any syndromic association. But still this patient needs to be followed for future development of medullary carcinoma of thyroid because it could be an initial presentation of MEN 2A/2B/VHL syndromes. Our paper highlights the importance of maintaining a high level of suspicion for persistent hiccups and careful clinical screening for hypertension even in absence of associated syndromes of pheochromocytoma and classical symptoms to achieve prompt diagnosis and to avoid improper management.

Comparison of plasma metanephrines measured by a commercial immunoassay and urinary catecholamines in the diagnosis of pheochromocytoma

Background: The diagnosis of pheochromocytomas requires consideration among patients suffering from hypertension, unexplained spells, incidental adrenal masses, or a family history of pheochromocytoma. Accordingly, the diagnosis requires a biochemical test with high sensitivity and specificity. Aim: To compare plasma free metanephrines as measured by a commercial immunoassay and the 24-hour urinary excretion of catecholamines. Method: Plasma free metanephrines were measured in 185 patients suspected of pheochromocytoma. Concomitant measurements of urinary catecholamines were performed in 115 patients. Based on clinical findings, imaging and biochemistry 11 cases were found; 9 were diagnosed with pheochromocytoma, one patient with paraganglioma and one patient with ganglioneuroma. Results: All patients with pheochromocytoma/paraganglioma had abnormally elevated concentrations of either plasma metanephrine or normetanephrine. The patient with ganglioneuroma had normal plasma metanephrine levels, corresponding to a sensitivity of 91%. In two patients where pheochromocytoma was excluded, plasma metanephrin or normetanephrine was above the reference level, corresponding to a specificity of 99%. Urinary catecholamines were determined in 10 of 11 patients with a positive diagnosis, and all 10 showed elevated levels of either urinary epinephrine or norepinephrine, including the patient with ganglioneuroma (equivalent to a sensitivity of 100%). Seven patients, in whom pheochromocytoma was excluded, had elevated urinary catecholamines (equivalent to a specificity of 94%). Conclusion: Measurement of plasma free metanephrines by immunoassay appears to be a useful diagnostic test in patients suspected of pheochromocytoma, with a high specificity as compared with urinary catecholamines. The latter may result in fewer false-positive findings, an outcome which may be particularly troublesome.

Retrocardiac Catecholamine-Producing Paraganglioma

Paragangliomas (PGLs) represent about 20% of catecholamine-producing tumors (1). As reported by Erickson et al. (2), they are mostly found in the head and neck, whereas the retrocardial location represents an unusual finding (3–5). A 41-yr-old woman came to our attention because of hypertensive crises associated with headache, sweating, and tachycardia. Pheochromocytoma was suspected on the basis of elevated 24-h urinary normetanephrines of 3,418 g/d, normal value (n.v.) 90–445 (18,662 nmol/d, n.v. 491–2,430) and norepinephrines of 828 g/d, n.v. 12–86 (4,893 nmol/d, n.v. 71–507). With the integrated use of various radiological and nuclear medicine techniques, a 46-mm retrocardial PGL was diagnosed (Figs. 1 and 2). The patient did not have a family history of pheochromocytoma. Genetic testing excluded RET and SDHx subunit (SDHB, SDHC, and SDHD) mutations. After adequate treatment with doxazosin, cardiac surgery was performed in extracorporeal circulation. The surgical approach was through a median sternotomy. The aorta and the pulmonary artery were divided to access the tumor, which was posterior to the left atrium. Macroscopically, the tumor was encapsulated, and there was a plane of cleavage with the surrounding structures. Complete resection was achieved. Histology confirmed a PGL (chromogranin A and synaptophysin positive at immunohistochemistry; Ki 67, 2%). After surgery, the patient was treated with copious hydration, whereas antihypertensive therapy was withdrawn. Blood pressure was maintained in the normal-low range, and no hypertensive crises were documented. Biochemical evaluations performed 3 months after surgery confirmed the remission of the disease: normetanephrines were 112 g/d, n.v. 90 – 445 (611 nmol/d, n.v. 491-2430), and norepinephrines were 20 g/d, n.v. 12– 86 (118 nmol/d, n.v. 71–507).

Prevalence of hereditary GIST susceptibility in adults with GIST.

10043 Background: GIST is the most common mesenchymal tumor of the GI tract, associated with somatic gain-of-function mutations in KIT and less often, PDGFRA. Families with inherited mutations in KIT/PDGFRA have autosomal dominant transmission of GIST predisposition. Germline mutations of the succinate dehydrogenase complex (SDH) may underlie kindreds with GIST and paraganglioma, particularly in GISTS of the pediatric/wild-type histology. We are conducting a multicenter study to ascertain the prevalence of hereditary GIST. Methods: Individuals ≥ age 18 years with confirmed GIST are recruited through sarcoma specialty clinics at the Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute, or a web recruitment tool. Participants are stratified to high- and low-hereditary risk groups based on questionnaire and family history review. Germline analysis of KIT and PDGFRA is ongoing at Oregon Health & Science University on specimens from all high-risk subjects; SDHX analysis is in process for a subset. Results: Thus far we have enrolled 512 participants. Specimens from 92 high-risk and 41 low-risk subjects have been analyzed to date. Eight mutations were found in KIT, zero in PDGFRA. In-frame deletion of KIT D579 was found in 5 families, two of which report a common ancestor, and W557R, K642E, and K509I were identified each in one family. Two of these families, one segregating D579del and the second W557R, were reported previously by other groups, and one, K642E, was reported in the course of this study. Germline analysis of KIT exons 8, 9, 11, 13, 17 and PDGFRA 12, 14, 18 is negative in four families. KIT mutations were identified only in individuals with family history of GIST in relatives. Two individuals with SDHB mutations, identified by other investigators in the course of this study, are included. Germline analysis of the SDH family of genes in five individuals with pediatric/wild-type GIST and/or family history of pheochromocytoma or paraganglioma is in progress. Conclusions: The hereditary form of GIST constitutes a small fraction of all GISTs. Individuals with GIST and without a family history of GIST in other relatives are unlikely to carry inherited susceptibility linked to the KIT or PDGFRA protooncogenes.

A Large Pheochromocytoma With Invasion of Multiple Local Organs

A Large Pheochromocytoma With Invasion of Multiple Local Organs

A novel mutation of the Succinate Dehydrogenase B Gene in a Korean Family with Pheochromocytoma

Pheochromocytoma is a tumor that originates from the adrenal cortex and sympathetic chains. Most pheochromocytomas are sporadic, whereas others occur as hereditary syndromes. Familial pheochromocytoma has been frequently found in association with various mutations in genes of the succinate dehydrogenase family. A 21-year-old Korean male presented with recurrent chest tightness, severe headache, and hypertension. He was diagnosed as pheochromocytoma based on a 24-hour urine test, abdominal computed tomography, and (131)I-MIBG scintigraphy. Genomic DNA was extracted from the patient's whole blood. Primers covering all the coding regions and flanking introns of succinate dehydrogenase (SDH) B, C and D genes were designed and synthesized, and a DNA sequence analysis was performed using the polymerase chain reaction. Direct sequencing of the SDHB gene revealed a deletion of nucleotide 757 (thymidine) in exon 7. This thymidine deletion caused a shift in the reading frame that created a downstream stop codon and a truncated product (p.Cys253ValfsX5). Although the patient had no family history of pheochromocytoma, his father had the same mutation. We report a novel SDHB gene mutation from a Korean family with pheochromocytoma. This is the first report of pheochromocytoma with a confirmed SDHB germline mutation in Korea.

Commentary on Germline SDHB mutations and familial renal cell carcinoma

Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2), and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings (1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, (2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and (3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.

Cyclic Rapid Fluctuation of Hypertension and Hypotension in Pheochromocytoma

Cyclic Rapid Fluctuation of Hypertension and Hypotension in Pheochromocytoma

Germline SDHB Mutations and Familial Renal Cell Carcinoma

Familial renal cell carcinoma (RCC) is a heterogeneous disorder that is most commonly caused by germline mutations in the VHL, MET, and FLCN genes or by constitutional chromosome 3 translocations. However, for many patients with familial RCC, the genetic basis of the disease is undefined. We investigated whether germline mutations in fumarate hydratase (FH) or succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD) were associated with RCC susceptibility in 68 patients with no clinical evidence of an RCC susceptibility syndrome. No mutations in FH, SDHC, or SDHD were identified in probands, but 3 of the 68 (4.4%) probands had a germline SDHB mutation. Patients with a germline SDHB mutation presented with familial RCC (n = 1) or bilateral RCC (n = 2) and no personal or family history of pheochromocytoma or head and neck paraganglioma. Age at diagnosis of RCC in SDHB mutation carriers ranged from 24 to 73 years. These findings 1) demonstrate that patients with suspected inherited RCC should be examined for germline SDHB mutations, 2) suggest that all identified SDHB mutation carriers should be offered surveillance for RCC, and 3) provide a further link between familial RCC and activation of hypoxic-gene response pathways.

Clinical Characteristics of Pheochromocytoma Patients With Germline Mutations in SDHD

We examined the value of SDHD mutation screening in patients presenting with apparently sporadic and familial pheochromocytoma for the identification of SDHD-related pheochromocytomas. This retrospective study involved 126 patients with adrenal or extra-adrenal pheochromocytomas, including 24 patients with a family history of multiple endocrine neoplasia 2, von Hippel-Lindau disease, neurofibromatosis type 1, or paraganglioma (PGL). Conformation-dependent gel electrophoresis and sequence determination analysis of germline and tumor DNA were used to identify SDHD alterations. The clinical and molecular characteristics of sporadic and hereditary tumors were compared. We reviewed the literature and compared our results with those from previously published studies. Pathogenic germline SDHD mutations were identified in three patients: two (2.0%) of the 102 apparently sporadic pheochromocytoma patients and one patient with a family history of PGL. These patients presented with multifocal disease (two of three multifocal patients) or with a single adrenal tumor (one of 82 patients). In the literature, mutations are mostly found in patients </= 35 years of age or presenting with multifocal or extra-adrenal disease. All patients with an SDHD mutation developed extra-adrenal tumors (pheochromocytomas or PGLs) at presentation or during follow-up. SDHD gene mutations in patients presenting with apparently sporadic adrenal pheochromocytoma are rare. We recommend SDHD mutation screening for patients presenting with a family history of pheochromocytoma or PGL, multiple tumors, isolated adrenal or extra-adrenal pheochromocytomas, and age </= 35 years. Analysis of SDHD can also help to distinguish synchronous primary tumors from abdominal metastases.