Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.

Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3' UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.

Pheochromocytoma/Paraganglioma Syndrome Type 1 Presenting with Atypical Symptoms and a Novel Pathogenic Variant in the SDHD Gene: A Case Report.

This case report presents a 10-year-old patient diagnosed with pheochromocytoma/paraganglioma syndrome type 1 (PPGL1), underlined by a novel heterozygous pathogenic variant (c.154_161del, p.ser52Profster14) in the SDHD gene. Initially, the patient manifested symptoms unusual for pheochromocytoma, including polyuria and polydipsia; however, further diagnostic investigations revealed a pheochromocytoma (PCC) tumor in the adrenal gland. Subsequently, whole exome sequencing (WES) test identified a pathogenic frameshift variant in the SDHD gene, strongly suggestive of PPGL1. This study highlights the importance of considering atypical symptoms in diagnosing rare pediatric pheochromocytoma/paraganglioma tumors and underscores the value of genetic testing in identifying underlying genetic causes, thereby facilitating personalized management of the condition.

Overview of recent guidelines and consensus statements on initial screening and management of phaeochromocytoma and paraganglioma in SDHx pathogenic variant carriers and patients.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a strong genetic predisposition, involving over 20 genes and with germline pathogenic variants identified in 40 % of cases. The succinate dehydrogenase (SDHx) genes are the most commonly implicated in hereditary PPGLs, accounting for 20 % of cases, and present unique diagnostic and treatment challenges due to their potential for multiple, recurrent, and aggressive manifestations, often necessitating lifelong follow-up. Over the past two decades, advances in biochemical and imaging assessments, management, and follow-up protocols have significantly improved care for both adult and paediatric patients. These advances include next-generation sequencing, new biochemical tests, cluster-specific functional imaging, and improved surgical and radiotherapy techniques, such as stereotactic surgery and peptide receptor radionuclide therapy (PRRT). International consensus guidelines have been developed to standardise the management of patients with SDHx pathogenic variants, emphasising multidisciplinary approaches and frequent tumour board discussions. These guidelines, summarised below, cover recommendations for initial genetic testing, tumour screening, follow-up care, and management of patients and asymptomatic carriers.

Thyroid Paraganglioma: A Rare Manifestation of Paraganglioma Syndrome Associated With Pathogenic Variant in SDHD.

Evaluation of an incidentally discovered indeterminate thyroid nodule (TN) in a previously healthy 59-year female led to diagnosis of thyroid paraganglioma (TPGL) and subsequently hereditary succinate dehydrogenase complex subunit D (SDHD)-related multifocal head and neck paragangliomas (PGLs). An ultrasound-guided fine needle aspiration (FNA) biopsy of the 1.7-cm TN was nondiagnostic and core biopsy was suspicious for papillary thyroid carcinoma. Pathology slides reviewed at tertiary center showed neuroendocrine neoplasm consistent with PGL. Her 24-hour urinary catecholamines and metanephrines were normal. Given the diagnosis of TPGL, genetic testing was recommended, which identified a pathogenic variant in SDHD (c.242C > T(p.P81L). Gallium-68-DOTATATE PET/CT revealed multifocal areas of increased somatostatin receptor expression from the skull base to thoracic inlet. Magnetic resonance imaging of the brain/neck showed multiple PGLs (right jugular, carotid, thyroid, left vagal, left level II, and superior mediastinal), all measured up to 1.7 cm. The right jugular PGL was treated with external beam radiation therapy of 3000 cGy. All PGLs remained stable and asymptomatic at 22-month follow-up imaging. TPGL should be considered in the differential diagnosis of a hypervascular TN in patients with SDHx-related pheochromocytoma-PGL syndromes and when such lesions with indeterminate cytology are encountered in patients with no known history of SDHx-mutation or syndrome.

Paraganglioma of the Right Recurrent Laryngeal Nerve Presenting as a Thyroid Nodule.

Paragangliomas are abnormal growth cells of neuroectodermal origin that arise from the autonomic nervous system. Head and neck paragangliomas are rare, commonly benign and often have a hereditary origin. Head and neck paragangliomas most commonly arise in the carotid bodies, vagus and glossopharyngeal nerves, and the sympathetic chain. However, we present a case of a paraganglioma arising from the recurrent laryngeal nerve, a phenomenon that has been reported only three times before in the literature. The patient is a 49-year-old female with a past medical history of bilateral carotid body paragangliomas and Hashimoto's disease. She has a family history of paragangliomas in her father and distant relatives and carries a pathogenic variation in the succinate-dehydrogenate subunit D (SDHD) gene, which was first identified through the original linkage studies involving her family. She presented with a mild swelling sensation in her neck. A thyroid ultrasound revealed a right lobe nodule measuring 3.3 x 2.2 x 2.1 cm. Fine needle aspiration of the nodule revealed an atypia of undetermined significance with a risk of malignancy judged as 50%. A total thyroidectomy was performed due to concern for malignancy. During the operation, the thyroid was nodular and hypervascular. At the right thyroid lobe, there was a pearlescent tubular structure approximately 4-5 mm in size. This was stimulated via intraoperative nerve monitoring and was consistent with being a part of the right recurrent laryngeal nerve. Pathology of the tubular structure revealed a 2.8 cm paraganglioma of the right recurrent laryngeal nerve. An incidental 0.1 cm papillary thyroid microcarcinoma within the left thyroid lobe was also noted. Our patient presented with a history of paragangliomas at a very young age and bilaterality, features that are highly characteristic of hereditary disease. Through the original linkage studies involving her family, her father was recognized as being an obligate carrier at risk of bearing occult paragangliomas. Imaging showed that he carried three paragangliomas. Identification of the familial SDHD syndrome as well as SDHD testing has now become widely available. Recognizing hereditary paraganglioma and other cancer susceptibility syndromes can help foster more knowledge on the subject and improve clinical outcomes. More attention should be put on the presentation of paragangliomas in an atypical location, such as in our case.

Consanguineous couple with SDHD gene mutations: Diagnosis, treatment, and implications of family genetic testing.

The newly published clinical consensus guideline on the management of PGL/PCC is helpful for decision-making for diagnostics and treatment. Still, the treatment of patients with SDHD gene mutations requires an individual approach and those patients belong to multiprofessional teams. It is often assumed that spouses are genetically unrelated. However, the genetic relationships between spouses should always be examined empathetically and impartially.

Outcomes of systemic treatment according to germline mutational status in patients with metastatic pheochromocytoma and paraganglioma.

INTRODUCTION: Metastatic disease affects approximately 15% to 17% of patients with pheochromocytomas and paragangliomas (PPGLs). Unfortunately, treatment options for metastatic PPGLs are limited and rely on small, nonrandomized clinical trials. The impact of germline mutation status on systemic treatment outcomes remains unclear. To address these gaps, we retrospectively evaluated treatment outcomes in patients with PPGL. PATIENTS AND METHODS: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. RESULTS: The median age of the patients was 49. Germline mutations were revealed in nine patients (39.1%) out of 23 who underwent germline testing, with SDHB mutation being the most frequent in 5 patients. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy was administered to 18 patients, with an objective response rate (ORR) of 22% and a disease control rate (DCR) of 67%. The median progression-free survival (PFS) was 7.9 and the median overall survival (OS) was 36.2 months. Sunitinib was given to 6 patients, which had an ORR of 33%, a DCR of 83%, and a median PFS of 14.6 months. Notably, patients with SDHB/SDHD mutation (4 patients and one patient, respectively) who received CVD treatment had a significantly better OS than those without (median OS 94.0 months vs. 13.7 months, P = .01). CONCLUSION: Our study reveals that CVD and sunitinib are effective treatments for metastatic PPGLs. The results are consistent with previous studies and patients with SDHB and SDHD mutations may benefit most from CVD treatment.

High incidence of occult familial SDHD cases amongst Czech patients with head and neck paragangliomas.

Introduction: Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors, which are mostly benign in nature. Amongst all genes, Succinate Dehydrogenase Subunit D (SDHD) is the most commonly mutated in familial HNPGLs. In about 30% of HNPGLs, germline mutations in SDHD can also occur in the absence of positive family history, thus giving rise to "occult familial" cases. Our aim was to evaluate the pattern of SDHD germline mutations in Czech patients with HNPGLs. Materials and methods: We analyzed a total of 105 patients with HNPGLs from the Otorhinolaryngology departments of 2 tertiary centers between 2006 - 2021. All underwent complex diagnostic work-up and were also consented for genetic analysis. Results: Eighty patients aged 13-76 years were included; around 60% with multiple PGLs were males. Carotid body tumor was the most frequently diagnosed tumor. Germline SDHD mutation was found in only 12% of the Czech patients; approximately 78% of those harboring the mutation had negative family history. The mutation traits had higher affiliation for multiple tumors with nearly 70% patients of ≤ 40 years of age. Conclusion: An SDHD mutation variant was shared amongst unrelated patients but no founder-effect was established. Our findings confirmed that the pattern of SDHD mutation distribution amongst HNPGLs in Czech Republic differs from most studies worldwide.

Single-cell transcriptome sequencing reveals tumor heterogeneity in family neuroblastoma.

Neuroblastoma(NB) is the most common extracranial solid tumor in childhood, and it is now believed that some patients with NB have an underlying genetic susceptibility, which may be one of the reasons for the multiplicity of NB patients within a family line. Even within the same family, the samples show great variation and can present as ganglioneuroblastoma or even benign ganglioneuroma. The genomics of NB is still unclear and more in-depth studies are needed to reveal its key components. We first performed single-cell RNA sequencing(sc-RNAseq) analysis on clinical specimens of two family neuroblastoma(FNB) and four sporadic NB cases. A complete transcriptional profile of FNB was constructed from 18,394 cells from FNB, and we found that SDHD may be genetically associated with FNB and identified a prognostic related CAF subtype in FNB: Fib-4. Single-cell flux estimation analysis (scFEA) results showed that malignant cells were associated with arginine spermine, oxaloacetate and hypoxanthine, and that malignant cells metabolize lactate at lower levels than T cells. Our study provides new resources and ideas for the development of the genomics of family NB, and the mechanisms of cell-to-cell interactions and communication and the metabolic landscape will provide new therapeutic targets.

A case report of an intracardiac paraganglioma attached to the left main coronary artery in a patient with a succinate dehydrogenase complex subunit D mutation.

Background: Cardiac paragangliomas are extremely rare neuroendocrine tumours derived from neural crest cells that represent <2% of all paragangliomas. Approximately 35-40% of all paragangliomas are associated with inherited syndromes such as mutation in the succinate dehydrogenase (SDH) enzyme. Case summary: A 44-year-old male with an SDH complex subunit D (SDHD) mutation was diagnosed with an intracardiac paraganglioma attached to the left main coronary artery. Multimodality imaging, including gallium dotatate positron emission tomography computed tomography, cardiac magnetic resonance imaging, and coronary computed tomography angiography (CCTA) confirmed the suspected intracardiac paraganglioma. During follow-up with a CCTA, the mass showed growth, and surgical removal was recommended to anticipate on the risk of compression of the left main coronary artery. Prior to surgery, coronary angiography was performed, which showed no coronary calcifications. The highly vascularized paraganglioma was visible near the left main and proximal left anterior descending artery. The intracardiac paraganglioma was successfully removed through a median sternotomy with cardiopulmonary bypass, without any complications. The post-operative course was uneventful, and histological examination confirmed the diagnosis of a paraganglioma. Discussion: Intracardiac paragangliomas in the vicinity of the left main coronary artery are rare, and surgical removal may be challenging. Therefore, screening and the use of multiple imaging modalities in patients with SDHD mutations prior to surgery is of major importance.

Germline genetic variants in pheochromocytoma/paraganglioma: single-center experience.

Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%), SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.

Genotype-phenotype associations in paragangliomas of the temporal bone in a multi-ethnic cohort.

BACKGROUND: Temporal bone paragangliomas are rare tumours with variable presentation that can be hereditary. Identification of clinical and genetic factors of aggressive tumour behaviour is important. OBJECTIVE: To determine the underlying genetic mutations and genotype/phenotype correlations in a multi-ethnic population of South Florida with sporadic temporal bone paragangliomas. METHODS: In a cohort of glomus tympanicum (GT) and glomus jugulare (GJ) cases, we assessed the frequency of pathogenic single nucleotide variants, insertions, deletions, and duplications in coding exons of genes that have been associated with paragangliomas (SDHB, SDHC, SDHD, SDHA, SDHAF2, RET, NF1, VHL, TMEM127, and MAX). RESULTS: None of the 12 GT cases had mutations. Among 13 GJ cases, we identified four mutation carriers (31%); two in SDHC, one in SDHB, and one in SDHD. All patients with pathogenic mutations were of Hispanic ethnicity, presented at a younger age (mean 27.5 versus 52.11 years), and with more advanced disease when compared to mutation-negative GJ cases.Conclusions and Significance: Mutations in the SDH genes are found in 31% of sporadic GJ. SDH-associated GJ had advanced disease and a 50% risk of metastasis. Our data supports emerging recommendations for genetic screening in all populations with GJ tumours as the genetic status informs management.

Reduced Risk of Corporal Tumors in Patients With Head and Neck Paragangliomas With p.Pro81Leu Mutations.

OBJECTIVE: Patients with head and neck paragangliomas who are positive for the SDHD p.Pro81Leu (P81L) mutation are thought to have a distinct phenotype from other SDHx mutations, but few studies have focused on this mutation. The objective of this study was to determine the hazard of developing a second primary, metastatic, or recurrent paraganglioma in SDHx patients with or without P81L. STUDY DESIGN: Retrospective chart review of 60 patients with head and neck paragangliomas and genetic testing, followed for a median of 9 years. SETTING: Single academic medical center. METHODS: Univariable Cox proportional hazards regression evaluated second primary and recurrent paragangliomas in patients with SDHD P81L, SDHx non-P81L, and nonhereditary paraganglioma. RESULTS: This series comprised 31 patients without SDHx, 14 with SDHD P81L, and 15 with other SDHx mutations. At a median 9 years of follow-up, corporal (not head and neck) second primary paragangliomas occurred in 31% of patients with SDHx non-P81L mutations, compared with 0% and 4% of patients with SDHD P81L and without SDHx mutations, respectively. Second corporal paragangliomas were more likely in patients with SDHx non-P81L mutations than in those without a mutation (hazard ratio = 5.461, 95% confidence interval: 0.596-50.030, p = .13). CONCLUSION: This is the first study to report a lower likelihood of corporal tumors for patients with head and neck paragangliomas with SDH mutations positive for P81L. Larger studies are needed to determine if head and neck paraganglioma patients with P81L qualify for less intensive imaging surveillance to screen for second primary paragangliomas outside the head and neck.

Back to Biochemistry: Evaluation for and Prognostic Significance of SDH Mutations in Paragangliomas and Pheochromocytomas.

There is increasing recognition of the high prevalence of hereditary predisposition syndromes in patients diagnosed with paraganglioma/pheochromocytoma. It is widely acknowledged that germline pathogenic alterations of the succinate dehydrogenase complex genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) contribute to the pathogenesis of most of these tumors. Herein, we have provided an update on the biology and diagnosis of succinate dehydrogenase-deficient paraganglioma/pheochromocytoma, including the molecular biology of the succinate dehydrogenase complex, mechanisms and consequences of inactivation of this complex, the prevalence of pathogenic alterations, and patterns of inheritance.

Combined left thoracoscopic and median sternotomy approach to resect aortopulmonary mediastinal paraganglioma following feeding artery embolization: a case report.

BACKGROUND: Aortopulmonary mediastinal paragangliomas are rare. Complete resection of the tumor is desirable regardless of tumor size in view of the risk of sudden death induced by adjacent organ compression and poor prognosis after partial resection or untreated observation. Due to the hypervascularity of the tumor, the risk of intraoperative bleeding is significant, and cardiopulmonary bypass is often required for complete resection. CASE PRESENTATION: The patient was diagnosed as having bilateral carotid body tumors and supposedly an aortic body tumor at the age of 43 and eventually underwent resections of bilateral carotid body tumors at the age of 52. The pathology of the carotid body tumors was compatible with paraganglioma on both sides. A familial succinate dehydrogenase subunit D mutation was subsequently identified. Five years later, a contrast-enhanced computed tomography scan showed an enlarged tumor of 45 mm in size in the aortopulmonary mediastinum. Based on the previously known genetic mutation, the tumor was thought to be a paraganglioma. After confirming with an endocrinologist that the aortic body tumor was non-functional, radiologists performed preoperative embolization of the feeding vessels. Subsequently, a surgical team consisting of thoracic and cardiovascular surgeons resected the aortic body tumor using a video-assisted small left thoracotomy approach combined with a median sternotomy approach. The procedure was completed without cardiopulmonary bypass or blood transfusion. The patient was discharged home on postoperative day 9 uneventfully. CONCLUSIONS: After conduction of preceding interventional embolization of multiple feeding vessels, we employed a video-assisted thoracoscopic surgical approach to dissect the aspects of the tumor adjacent to the esophagus, descending thoracic aorta, and left pulmonary artery, followed by a median sternotomy approach to dissect the other aspects of the tumor adjacent to the ascending aorta, aortic arch, right pulmonary artery, and trachea. There have been no reports on scheduled preoperative embolization of feeding vessels to an aortopulmonary mediastinal paraganglioma. Multidisciplinary approach was effective for complete resection of this challenging rare mediastinal tumor.

A Four-Generational Report on Hereditary Head and Neck Paraganglioma.

Background This article investigates the inheritance, penetrance, clinical presentation, and therapeutic outcomes of hereditary head and neck paragangliomas (HNPGLs) by offering a four-generational report of an 18-member family affected by this rare condition. Methodology Information was compiled by examination of patients and a review of medical records and correspondence (retrospective case series). Results Six members of the 18-member family were diagnosed with HNPGL between 2002 and 2018. A known pathogenic point mutation in subunit D of the succinyl dehydrogenase complex (SDHD, c.317G>T, p.Gly106Val) was responsible for the tumor phenotype. The mutation could be revealed in seven family members, three diseased adults, one healthy adult, and three healthy children, out of the nine who consented to gene testing. The median age at diagnosis was 33.5 years (range: 22-50 years). Five of the eight primary tumors were glomus caroticum, two were glomus jugulare, and one was a glomus vagale tumor. The therapeutic approaches were multimodal and included embolization therapy, surgery, radiation, and watchful waiting. Follow-up was reported for five of the six patients (mean follow-up of 34.8 months after primary therapy); three showed no disease progression or recurrence. Conclusions This study exemplifies the autosomal dominant, parent-of-origin-dependent inheritance and the high disease penetrance in hereditary paraganglioma-pheochromocytoma syndromes. Six out of a total of eight adult descendants (75%) of the original SDHD mutation carrier developed tumors, and the morbidity associated with the disease as well as its therapy was especially high in late-diagnosed, advanced cases. This substantiates the necessity for early radiologic surveillance and genetic testing.

Identification of Putative SDHI Target Site Mutations in the SDHB, SDHC, and SDHD Subunits of the Grape Powdery Mildew Pathogen Erysiphe necator.

Succinate dehydrogenase inhibitors (SDHIs) are fungicides used in control of numerous fungal plant pathogens, including Erysiphe necator, the causal agent of grapevine powdery mildew (GPM). Here, the sdhb, sdhc, and sdhd genes of E. necator were screened for mutations that may be associated with SDHI resistance. GPM samples were collected from 2017 to 2020 from the U.S. states of California, Oregon, Washington, and Michigan, and the Canadian province of British Columbia. Forty-five polymorphisms were identified in the three sdh genes, 17 of which caused missense mutations. Of these, the SDHC-p.I244V substitution was shown in this study to reduce sensitivity of E. necator to boscalid and fluopyram, whereas the SDHC-p.G25R substitution did not affect SDHI sensitivity. Of the other 15 missense mutations, the SDHC-p.H242R substitution was shown in previous studies to reduce sensitivity of E. necator toward boscalid, whereas the equivalents of the SDHB-p.H242L, SDHC-p.A83V, and SDHD-p.I71F substitutions were shown to reduce sensitivity to SDHIs in other fungi. Generally, only a single amino acid substitution was present in the SDHB, SDHC, or SDHD subunit of E. necator isolates, but missense mutations putatively associated with SDHI resistance were widely distributed in the sampled areas and increased in frequency over time. Finally, isolates that had decreased sensitivity to boscalid or fluopyram were identified but with no or only the SDHC-p.G25R amino acid substitution present in SDHB, SDHC, and SDHD subunits. This suggests that target site mutations probably are not the only mechanism conferring resistance to SDHIs in E. necator.

The SDHD:p.H102R Variant Is Frequent in Russian Patients with Head and Neck Paragangliomas and Associated with Loss of 11p15.5 Region and Hypermethylation of H19-DMR.

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in SDHx genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the SDHD gene. We determined this variant in 34% of the SDHD mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of SDHD:p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found SDHD:p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the SDHD:p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs.

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

PURPOSE: The weight of the evidence to attach to observation of a novel rare missense variant in SDHB or SDHD in individuals with the rare neuroendocrine tumors, pheochromocytomas and paragangliomas (PCC/PGL), is uncertain. METHODS: We compared the frequency of SDHB and SDHD very rare missense variants (VRMVs) in 6328 and 5847 cases of PCC/PGL, respectively, with that of population controls to generate a pan-gene VRMV likelihood ratio (LR). Via windowing analysis, we measured regional enrichments of VRMVs to calculate the domain-specific VRMV-LR (DS-VRMV-LR). We also calculated subphenotypic LRs for variant pathogenicity for various clinical, histologic, and molecular features. RESULTS: We estimated the pan-gene VRMV-LR to be 76.2 (54.8-105.9) for SDHB and 14.8 (8.7-25.0) for SDHD. Clustering analysis revealed an SDHB enriched region (ɑɑ 177-260, P = .001) for which the DS-VRMV-LR was 127.2 (64.9-249.4) and an SDHD enriched region (ɑɑ 70-114, P = .000003) for which the DS-VRMV-LR was 33.9 (14.8-77.8). Subphenotypic LRs exceeded 6 for invasive disease (SDHB), head-and-neck disease (SDHD), multiple tumors (SDHD), family history of PCC/PGL, loss of SDHB staining on immunohistochemistry, and succinate-to-fumarate ratio >97 (SDHB, SDHD). CONCLUSION: Using methodology generalizable to other gene-phenotype dyads, the LRs relating to rarity and phenotypic specificity for a single observation in PCC/PGL of a SDHB/SDHD VRMV can afford substantial evidence toward pathogenicity.

Retroperitoneal Paraganglioma With Asymptomatic Follicular Lymphoma: A Case Report.

Paraganglioma (PGL) is a rare tumor originating from extra-adrenal paraganglionic chromaffin tissues, and most sympathetic PGLs have excessive catecholamine secretion. However, nonfunctional PGLs are sometimes found. Although malignant PGL is defined by metastasis to nonchromaffin tissues, it is difficult to predict malignancies due to the lack of reliable markers of potential malignancies. We report the case of a 69-year-old Japanese woman with an incidental retroperitoneal tumor and multiple enlarged mesenteric lymph nodes simultaneously. The patient had no subjective symptoms and there were no laboratory findings suggesting catecholamine hypersecretion. Both the retroperitoneal tumor and the enlarged mesenteric lymph nodes showed high accumulation of fluorodeoxyglucose (FDG), whereas metaiodobenzylguanidine (MIBG) was accumulated only at the retroperitoneal tumor. Although a retroperitoneal tumor was diagnosed as nonfunctional PGL by examination including MIBG scintigraphy, the cause of enlarged mesenteric lymph nodes could not be diagnosed by imaging and biochemical tests. As a result of retroperitoneal tumor resection and mesenteric lymph nodes sampling, histopathological examination revealed that a retroperitoneal tumor was PGL and enlarged mesenteric lymph nodes were follicular lymphoma. To reveal an underlying genetic factor, we performed whole exome sequencing of genomic DNA, and we identified 2 possible candidate variants in SDHD and DLST, but the pathogenicity of these variants remains uncertain in the present case. This rare case reinforces the importance of histopathological diagnosis of nonchromaffin tissue lesions in patients with PGL for the appropriate treatment strategy.