SDHB Associated Paraganglioma Syndrome in Africa – A Need for Greater Genetic Testing

Abstract A germline mutation is identified in almost 40% of Pheochromocytoma-Paraganglioma (PPGL) Syndromes. Genetic testing and counselling are essential for the management of index cases as well as pre-symptomatic identification and pre-emptive management of affected family members. Mutations in the genes encoding the mitochondrial enzyme succinate dehydrogenase (SDH) are well described in patients with hereditary PPGL. Amongst patients of African ancestry the prevalence, phenotype, germline mutation spectrum and penetrance of SDH mutations is poorly characterized. We describe a multifocal paraganglioma in a young African male with an underlying mis-sense SDHB mutation, with a history of three first-degree relatives who demised at young ages from suspected cardiovascular causes. The same SDHB mutation, Class V variant c.724C>A p.(Arg242Ser), was detected in one of his asymptomatic siblings. As there is limited data describing hereditary PPGL syndromes in Africa this report of an SDHB associated PPGL is a notable contribution to the literature in this growing field. Due to the noteworthy clinical implications of PPGL mutations, it highlights the existing need for broader genetic screening amongst African patients with PPGL despite the limited healthcare resources available in this region.

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A Unique Case of Metastatic, Functional, Hereditary Paraganglioma Associated With anSDHC Germline Mutation

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01302 ◽

2018 ◽

Vol 103 (8) ◽

pp. 2802-2806 ◽

Cited By ~ 3

Author(s):

Raquel Kristin S Ong ◽

Shahida K Flores ◽

Robert L Reddick ◽

Patricia L M Dahia ◽

Hassan Shawa

Keyword(s):

Germline Mutation ◽

External Beam Radiation ◽

Unique Case ◽

Beam Radiation ◽

Lumbar Vertebral Body ◽

Lytic Lesions ◽

Genes Encoding ◽

Paraganglioma Syndrome ◽

Bone Scans ◽

The Right

Abstract Context Mutations in genes encoding for the succinate dehydrogenase (SDH) complex are linked to hereditary paraganglioma syndromes. Paraganglioma syndrome 3 is associated with mutations inSDHC and typically manifests as benign, nonfunctional head and neck paragangliomas. Design We describe a case of a 51-year-old woman who initially presented with diarrhea and hypertension and was found to have a retroperitoneal mass, which was resected with a pathology consistent with paraganglioma. Five years later, her symptoms recurred, and she was found to have new retroperitoneal lymphadenopathy and lytic lesions in the first lumbar vertebral body and the right iliac crest, which were visualized on CT scan and octreoscan but not on iodine-123-meta-iodobenzylguanidine (123I-MIBG) and bone scans. She had significantly elevated 24-hour urine norepinephrine and dopamine. The patient received external beam radiation and a series of different antineoplastic agents. Her disease progressed, and she eventually expired within 2 years. Genetic testing revealed a heterozygousSDHC c.43C>T, p.Arg15X mutation, which was also detected in her daughter and her grandson, both of whom have no biochemical or imaging evidence of paraganglioma syndrome yet. Conclusion We report a unique case of functional, metastatic abdominal paraganglioma associated withSDHC germline mutation. Our case exemplifies thatSDHC germline mutation has variable penetrance, which may manifest with an aggressive biology that could be missed by a123I-MIBG scan.

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

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-020-00156-9 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Kay Reen Ting ◽

Pei Yi Ong ◽

Samuel Ow Guan Wei ◽

Rajeev Parameswaran ◽

Chin Meng Khoo ◽

...

Keyword(s):

Genetic Testing ◽

Cancer Genetics ◽

Chinese Patients ◽

Hereditary Cancer Syndrome ◽

Limited Data ◽

Cancer Syndrome ◽

Causative Gene ◽

Asian Patients ◽

Pathogenic Variants ◽

History Of

Abstract Background Hereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients. Methods We 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. Results Among 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. Conclusion Hereditary 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.

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An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

F1000Research ◽

10.12688/f1000research.15542.1 ◽

2018 ◽

Vol 7 ◽

pp. 1350 ◽

Cited By ~ 22

Author(s):

Lydie Da Costa ◽

Anupama Narla ◽

Narla Mohandas

Keyword(s):

Genetic Testing ◽

Congenital Malformations ◽

Ribosomal Proteins ◽

Ribosome Biogenesis ◽

Macrocytic Anemia ◽

Diamond Blackfan Anemia ◽

Biological Features ◽

Genes Encoding ◽

History Of ◽

Hypoplastic Anemia

Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

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Current Approach of Functioning Head and Neck Paragangliomas: Case Report of a Young Patient with Multiple Asynchronous Tumors

Case Reports in Endocrinology ◽

10.1155/2020/6827109 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Alejandro Terrones-Lozano ◽

Alan Hernández-Hernández ◽

Edgar Nathal Vera ◽

Gerardo Yoshiaki Guinto-Nishimura ◽

Jorge Luis Balderrama-Bañares ◽

...

Keyword(s):

Genetic Testing ◽

Head And Neck ◽

Germline Mutation ◽

Germline Mutations ◽

Current Approach ◽

Genetic Syndromes ◽

Pet Ct ◽

History Of ◽

Head And Neck Paragangliomas

Introduction. Pheochromocytomas (Pheo) and paragangliomas (PGL) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and from the extra-adrenal autonomic paraganglia, respectively. Only 1–3% of head and neck PGL (HNPGL) show elevated catecholamines, and at least 30% of Pheo and PGL (PCPG) are associated with genetic syndromes caused by germline mutations in tumor suppressor genes and proto-oncogenes. Clinical Case. A 33-year-old man with a past medical history of resection of an abdominal PGL at the age of eleven underwent a CT scan after a mild traumatic brain injury revealing an incidental brain tumor. The diagnosis of a functioning PGL was made, and further testing was undertaken with a PET-CT with 68Ga-DOTATATE, SPECT-CT 131-MIBG, and genetic testing. Discussion and Conclusion. The usual clinical presentation of functioning PCPG includes paroxistic hypertension, headache, and diaphoresis, sometimes with a suggestive family history in 30–40% of cases. Only 20% of PGL are located in head and neck, of which only 1–3% will show elevated catecholamines. Metastatic disease is present in up to 50% of cases, usually associated with a hereditary germline mutation. However, different phenotypes can be observed depending on such germline mutations. Genetic testing is important in patients with PCPG since 31% will present a germline mutation. In this particular patient, an SDHB gene mutation was revealed, which can drastically influence the follow-up plan and the genetic counsel offered. A multidisciplinary approach is mandatory for every patient presenting with PCPG.

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National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2017.73.6314 ◽

2017 ◽

Vol 35 (34) ◽

pp. 3800-3806 ◽

Cited By ~ 112

Author(s):

Christopher P. Childers ◽

Kimberly K. Childers ◽

Melinda Maggard-Gibbons ◽

James Macinko

Keyword(s):

Ovarian Cancer ◽

Genetic Testing ◽

Unmet Need ◽

Cancer Control ◽

The United States ◽

Eligibility Criteria ◽

Cross Sectional ◽

Age Of Diagnosis ◽

History Of ◽

Interview Survey

Purpose In the United States, 3.8 million women have a history of breast (BC) or ovarian cancer (OC). Up to 15% of cases are attributable to heritable mutations, which, if identified, provide critical knowledge for treatment and preventive care. It is unknown how many patients who are at high risk for these mutations have not been tested and how rates vary by risk criteria. Methods We used pooled cross-sectional data from three Cancer Control Modules (2005, 2010, 2015) of the National Health Interview Survey, a national in-person household interview survey. Eligible patients were adult females with a history of BC and/or OC meeting select 2017 National Comprehensive Cancer Network eligibility criteria on the basis of age of diagnosis and family history. Outcomes included the proportion of individuals reporting a history of discussing genetic testing with a health professional, being advised to undergo genetic testing, or undergoing genetic testing for BC or OC. Results Of 47,218 women, 2.7% had a BC history and 0.4% had an OC history. For BC, 35.6% met one or more select eligibility criteria; of those, 29.0% discussed, 20.2% were advised to undergo, and 15.3% underwent genetic testing. Testing rates for individual eligibility criteria ranged from 6.2% (relative with OC) to 18.2% (diagnosis ≤ 45 years of age). For OC, 15.1% discussed, 13.1% were advised to undergo, and 10.5% underwent testing. Using only four BC eligibility criteria and all patients with OC, an estimated 1.2 to 1.3 million individuals failed to receive testing. Conclusion Fewer than one in five individuals with a history of BC or OC meeting select National Cancer Comprehensive Network criteria have undergone genetic testing. Most have never discussed testing with a health care provider. Large national efforts are warranted to address this unmet need.

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

Journal of Medical Case Reports ◽

10.1186/s13256-021-02852-z ◽

2021 ◽

Vol 15 (1) ◽

Author(s):

Rei Hirose ◽

Yuya Tsurutani ◽

Chiho Sugisawa ◽

Kosuke Inoue ◽

Sachiko Suematsu ◽

...

Keyword(s):

Genetic Testing ◽

Succinate Dehydrogenase ◽

Novel Mutation ◽

Case Reports ◽

Site Mutation ◽

Japanese Family ◽

Paraganglioma Syndrome ◽

Succinate Dehydrogenase Subunit B ◽

Hereditary Pheochromocytoma ◽

Subunit B

Abstract Background Pheochromocytoma 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 presentation A 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. Conclusions We 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.

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R1352Q CACNA1A Variant in a Patient with Sporadic Hemiplegic Migraine, Ataxia, Seizures and Cerebral Oedema: A Case Report

Case Reports in Neurology ◽

10.1159/000512275 ◽

2021 ◽

pp. 123-130

Author(s):

Anker Stubberud ◽

Emer O’Connor ◽

Erling Tronvik ◽

Henry Houlden ◽

Manjit Matharu

Keyword(s):

Mental Retardation ◽

Case Report ◽

Genetic Testing ◽

Head Trauma ◽

Cerebral Oedema ◽

De Novo ◽

Minor Head Trauma ◽

Hemiplegic Migraine ◽

Wide Range ◽

History Of

Mutations in the CACNA1A gene show a wide range of neurological phenotypes including hemiplegic migraine, ataxia, mental retardation and epilepsy. In some cases, hemiplegic migraine attacks can be triggered by minor head trauma and culminate in encephalopathy and cerebral oedema. A 37-year-old male without a family history of complex migraine experienced hemiplegic migraine attacks from childhood. The attacks were usually triggered by minor head trauma, and on several occasions complicated with encephalopathy and cerebral oedema. Genetic testing of the proband and unaffected parents revealed a de novo heterozygous nucleotide missense mutation in exon 25 of the CACNA1A gene (c.4055G>A, p.R1352Q). The R1352Q CACNA1A variant shares the phenotype with other described CACNA1A mutations and highlights the interesting association of trauma as a precipitant for hemiplegic migraine. Subjects with early-onset sporadic hemiplegic migraine triggered by minor head injury or associated with seizures, ataxia or episodes of encephalopathy should be screened for mutations. These patients should also be advised to avoid activities that may result in head trauma, and anticonvulsants should be considered as prophylactic migraine therapy.

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Low Nucleotide Diversity in Chimpanzees and Bonobos

Genetics ◽

10.1093/genetics/164.4.1511 ◽

2003 ◽

Vol 164 (4) ◽

pp. 1511-1518 ◽

Cited By ~ 1

Author(s):

Ning Yu ◽

Michael I Jensen-Seaman ◽

Leona Chemnick ◽

Judith R Kidd ◽

Amos S Deinard ◽

...

Keyword(s):

Nucleotide Diversity ◽

Nuclear Dna ◽

Demographic History ◽

Nuclear Genome ◽

Limited Data ◽

Effective Population ◽

East Central ◽

Dna Diversity ◽

History Of ◽

Mtdna Diversity

Abstract Comparison of the levels of nucleotide diversity in humans and apes may provide much insight into the mechanisms of maintenance of DNA polymorphism and the demographic history of these organisms. In the past, abundant mitochondrial DNA (mtDNA) polymorphism data indicated that nucleotide diversity (π) is more than threefold higher in chimpanzees than in humans. Furthermore, it has recently been claimed, on the basis of limited data, that this is also true for nuclear DNA. In this study we sequenced 50 noncoding, nonrepetitive DNA segments randomly chosen from the nuclear genome in 9 bonobos and 17 chimpanzees. Surprisingly, the π value for bonobos is only 0.078%, even somewhat lower than that (0.088%) for humans for the same 50 segments. The π values are 0.092, 0.130, and 0.082% for East, Central, and West African chimpanzees, respectively, and 0.132% for all chimpanzees. These values are similar to or at most only 1.5 times higher than that for humans. The much larger difference in mtDNA diversity than in nuclear DNA diversity between humans and chimpanzees is puzzling. We speculate that it is due mainly to a reduction in effective population size (Ne) in the human lineage after the human-chimpanzee divergence, because a reduction in Ne has a stronger effect on mtDNA diversity than on nuclear DNA diversity.

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Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

International Journal of Molecular Sciences ◽

10.3390/ijms22094700 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4700

Author(s):

Michelle M. Monasky ◽

Emanuele Micaglio ◽

Giuseppe Ciconte ◽

Ilaria Rivolta ◽

Valeria Borrelli ◽

...

Keyword(s):

Genetic Testing ◽

Family History ◽

Risk Stratification ◽

Brugada Syndrome ◽

Electrophysiological Study ◽

Functional Characterization ◽

The Family ◽

Novel Variant ◽

History Of ◽

Scn5a Gene

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

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Estimating time to onset of swine influenza symptoms after initial novel A(H1N1v) viral infection

Epidemiology and Infection ◽

10.1017/s0950268810002566 ◽

2010 ◽

Vol 139 (9) ◽

pp. 1418-1424 ◽

Cited By ~ 8

Author(s):

B. D. M. TOM ◽

A. J. VAN HOEK ◽

R. PEBODY ◽

J. McMENAMIN ◽

C. ROBERTSON ◽

...

Keyword(s):

Incubation Time ◽

Time Distribution ◽

Age Groups ◽

Swine Influenza ◽

Interval Censoring ◽

Limited Data ◽

History Of ◽

Influenza Case ◽

Time To Onset

SUMMARYCharacterization of the incubation time from infection to onset is important for understanding the natural history of infectious diseases. Attempts to estimate the incubation time distribution for novel A(H1N1v) have been, up to now, based on limited data or peculiar samples. We characterized this distribution for a generic group of symptomatic cases using laboratory-confirmed swine influenza case-information. Estimates of the incubation distribution for the pandemic influenza were derived through parametric time-to-event analyses of data on onset of symptoms and exposure dates, accounting for interval censoring. We estimated a mean of about 1·6–1·7 days with a standard deviation of 2 days for the incubation time distribution in those who became symptomatic after infection with the A(H1N1v) virus strain. Separate analyses for the <15 years and ⩾15 years age groups showed a significant (P<0·02) difference with a longer mean incubation time in the older age group.

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