scholarly journals The phenotype of SDHB germline mutation carriers: a nationwide study

2017 ◽  
Vol 177 (2) ◽  
pp. 115-125 ◽  
Author(s):  
Nicolasine D Niemeijer ◽  
Johannes A Rijken ◽  
Karin Eijkelenkamp ◽  
Anouk N A van der Horst-Schrivers ◽  
Michiel N Kerstens ◽  
...  
Keyword(s):  
Head And Neck ◽  
Metastatic Disease ◽  
Germline Mutation ◽  
Descriptive Study ◽  
Germline Mutations ◽  
Nationwide Study ◽  
B Subunit ◽  
Mutation Carriers ◽  
Head And Neck Paragangliomas

Objective Succinate dehydrogenase B subunit (SDHB) gene germline mutations predispose to pheochromocytomas, sympathetic paragangliomas, head and neck paragangliomas and non-paraganglionic tumors (e.g. renal cell carcinoma, gastrointestinal stromal tumor and pituitary neoplasia). The aim of this study was to determine phenotypical characteristics of a large Dutch cohort of SDHB germline mutation carriers and assess differences in clinical phenotypes related to specific SDHB mutations. Design Retrospective descriptive study. Methods Retrospective descriptive study in seven academic centers. Results We included 194 SDHB mutation carriers consisting 65 (33.5%) index patients and 129 (66.5%) relatives. Mean age was 44.8 ± 16.0 years. Median duration of follow-up was 2.6 years (range: 0–36). Sixty persons (30.9%) carried the exon 3 deletion and 46 (23.7%) the c.423 + 1G > A mutation. Fifty-four mutation carriers (27.8%) had one or multiple head and neck paragangliomas, 4 (2.1%) had a pheochromocytoma and 26 (13.4%) had one or more sympathetic paragangliomas. Fifteen patients (7.7%) developed metastatic paraganglioma and 17 (8.8%) developed non-paraganglionic tumors. At study close, there were 111 (57.2%) unaffected mutation carriers. Statistical analyses showed no significant differences in the number and location of head and neck paragangliomas, sympathetic paragangliomas or pheochromocytomas, nor in the occurrence of metastatic disease or other tumors between carriers of the two founder SDHB mutations (exon 3 deletion vs c.423 + 1G > A). Conclusions In this nationwide study of disease-affected and unaffected SDHB mutation carriers, we observed a lower rate of metastatic disease and a relatively high number of head and neck paragangliomas compared with previously reported referral-based cohorts.

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

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.

scholarly journals Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations

BJS Open ◽  
2018 ◽  
Vol 2 (2) ◽  
pp. 62-69 ◽  
Author(s):  
J. A. Rijken ◽  
N. D. Niemeijer ◽  
C. R. Leemans ◽  
K. Eijkelenkamp ◽  
A. N. A. van der Horst-Schrivers ◽  
...  
Keyword(s):  
Head And Neck ◽  
Germline Mutations ◽  
Nationwide Study ◽  
Head And Neck Paragangliomas

scholarly journals Risk-adapted approach to prostate cancer screening

2018 ◽  
Vol 14 (2) ◽  
pp. 109-121 ◽  
Author(s):  
A. A. Kirichek ◽  
L. N. Lyubchenko ◽  
V. B. Matveev
Keyword(s):  
Prostate Cancer ◽  
Early Detection ◽  
Germline Mutation ◽  
Prostate Cancer Screening ◽  
Germline Mutations ◽  
Polygenic Inheritance ◽  
Psa Screening ◽  
Psa Testing ◽  
Mutation Carriers ◽  
Brca1 Brca2

Mass prostatic specific antigen (PSA) testing (population-based PSA screening) has remained controversial, nevertheless there are men cohorts likely to benefit from PSA screening. Heritable factors contribute to 60 % risk for developing familial prostate cancer. Despite the fact that its clinical application is challenging due to polygenic inheritance, advances in new generation sequencing technologies permit identifying highly penetrant germline mutations in genes BRCA1, BRCA2, CHEK2, HOXB13 and MMR associated with tremendous increase in risk of developing the prostate cancer. Several germline mutations are associated with clinically aggressiveness of disease and shortened survival. Targeted screening that is based on family history and genomic aberrations should be the next step towards the precision medicine. Men at elevated risk should been performed for early detection are those with familiar history of prostate cancer, or BRCA1, BRCA2, CHEK2, HOXB13 and MMR pathogenic germline mutation carriers, or first line relatives diagnosed with certain types of cancer. Systematic PSA testing in 1–2 years among germline mutation carriers men beginning at age 45 years would contribute to increase in early detection of localized prostate cancer resulting in more chance of curative treatment and improve survival rates

scholarly journals Tinnitus With Unexpected Spanish Roots: Head and Neck Paragangliomas Caused by SDHAF2 Mutation

2020 ◽  
Vol 4 (3) ◽  
Author(s):  
Laura Maria Roose ◽  
Niels J Rupp ◽  
Christof Röösli ◽  
Nadejda Valcheva ◽  
Achim Weber ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Head And Neck ◽  
Carotid Body ◽  
Loss Of Function ◽  
Negative Family History ◽  
Paraganglioma Syndrome ◽  
Plasma Free Metanephrines ◽  
The Right ◽  
Head And Neck Paragangliomas

Abstract It is estimated that up to 40% of all head and neck paragangliomas (HNPGL) have a hereditary background with the most common mutations being found in the succinate dehydrogenase (SDH) genes. SDHAF2 mutation leads to the rare paraganglioma syndrome 2. The authors present the case of a 15-year-old male patient with 2, non-secretory HNPGLs, presenting with left-sided, pulsatile tinnitus, and hearing loss. Imaging led to the suspicion of a jugulotympanic paraganglioma on the left, as well as a carotid body tumor on the right. After resection of the jugulotympanic tumor, histology confirmed the presence of a paraganglioma; immunohistochemistry furthermore suggested a loss of SDHB expression. Genetic testing revealed a rare germline, loss-of-function mutation in the SDHAF2 gene, previously described to cause hereditary paraganglioma syndrome 2. Twenty months after the first operation, the patient underwent a resection of the right carotid body paraganglioma. Plasma-free metanephrines/catecholamines always remained within the reference range; the patient is under regular follow-up, and his relatives will be screened. Our findings emphasize the relevance of genetic testing in patients with HNPGL, also with negative family history, especially when the patients present at a young age and with multiple lesions.

Effect of germline ATM mutations on clonal hematopoiesis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1509-1509
Author(s):  
Thomas Paul Slavin ◽  
Kar Wing Kevin Tsang ◽  
Jeffrey Longmate ◽  
Danielle Castillo ◽  
Josef Herzog ◽  
...  
Keyword(s):  
Germline Mutation ◽  
White Blood Cells ◽  
Germline Mutations ◽  
Lymphocytic Leukemia ◽  
Repair Gene ◽  
Clonal Hematopoiesis ◽  
Mutation Carriers ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Allele Fraction

1509 Background: Clonal hematopoiesis (CH) in myeloid related-genes is associated with development of primary and secondary leukemia and atherosclerotic disease, as well as, decreased overall survival. Identification of factors beyond age and cytotoxic exposures that predispose to CH may be useful to both recognize individuals at increased risk for CH and to better understand how CH develops. We have previously shown that germline mutations in the DNA repair gene ATM may predispose to CH. We hypothesized here that heterozygous ATM germline mutation carriers would have higher rates of CH in myeloid genes compared to controls. Methods: Germline DNA samples from 34 heterozygous ATM germline mutation carriers (cases) and 22 controls without ATM germline mutations were sequenced on an Illumina 2500 using a custom 79-gene-myeloid-CH-coding-exon-amplicon-based Qiaseq panel. Read depth averaged 130x. Pathogenic and likely pathogenic CH variants (PV) above an allele fraction of 2% were used for analyses. Cases and controls were compared using a rank-sum test. Results: Cases had a higher median age (56 years, range 30-82) than controls (48 years, range 5-72). Cases and controls were similar in solid tumor cancer history and known exposure to cancer cytotoxic therapy; 73.5% vs 86.4%, and 18.1 vs 20.6%, respectively. The number of CH PV was similarly associated with age in both cases and controls (cor = 0.31, p = 0.01). Cases displayed more CH PVs than controls (total 62 vs 3 PVs, median 2 PVs vs 0, p = 10-6). Of note, cases frequently had a concomitant second (n = 10; 29% of cases) or third (n = 4; 11.8% of cases) unique ATM CH PV, whereas no ATM CH PVs were seen in controls. Even after excluding ATM CH PVs, CH PVs were more frequent in cases (p = 0.00003). After ATM CH PVs, the most frequent CH PVs in cases were in NF1 (5 PVs), BCORL1 (4 PVs), and DMNT3A (4 PVs). Conclusions: Our study supports ATM as a strong predisposition locus for myeloid gene CH. CH in ATM germline mutation carriers frequently involved unique low allele fraction PVs in ATM, suggesting ATM germline PVs are driving production of likely bi-allelic ATM inactivation in white blood cells, or complete ATM loss. Complete ATM loss may be a nidus particularly for lymphocytic leukemia, as bi-allelic ATM inactivation is a frequent somatic finding.

Malignant Head and Neck Paragangliomas in SDHB Mutation Carriers

2007 ◽  
Vol 137 (1) ◽  
pp. 126-129 ◽  
Author(s):  
Carsten Christof Boedeker ◽  
Hartmut P. H. Neumann ◽  
Wolfgang Maier ◽  
Birke Bausch ◽  
Jörg Schipper ◽  
...  
Keyword(s):  
Head And Neck ◽  
Molecular Genetic ◽  
Gene Mutations ◽  
Distant Metastases ◽  
High Rate ◽  
Body Region ◽  
Sdhb Mutation ◽  
Sdhd Gene ◽  
Mutation Carriers ◽  
Head And Neck Paragangliomas

OBJECTIVE: Three of four paraganglioma syndromes (PGLs) have been characterized on a molecular genetic basis. PGL 1 is associated with mutations of the succinate dehydrogenase subunit D ( SDHD) gene, PGL 3 is caused by SDHC gene mutations, and PGL 4 is caused by SDHB gene mutations. The objective of this study was to investigate whether PGLs are associated with malignant head and neck paragangliomas (HNPs). STUDY DESIGN AND SETTING: Through November 2005, we screened 195 HNP patients for mutations of the genes SDHB, SDHC, and SDHD. RESULTS: We detected 5 SDHC, 13 SDHB, and 45 SDHD gene mutations. In seven SDHB mutation carriers, there were distant metastases. No signs of metastases were found in SDHC and SDHD patients. One patient with a sporadic HNP presented with locally metastatic disease. CONCLUSIONS: SDHB mutations are associated with a high rate of malignant HNPs. SIGNIFICANCE: In SDHB patients, a three-body region imaging and scintigraphy or DOPA-PET must be performed to exclude metastases.

scholarly journals Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients

2012 ◽  
Vol 19 (2) ◽  
pp. 149-155 ◽  
Author(s):  
Valentina Piccini ◽  
Elena Rapizzi ◽  
Alessandra Bacca ◽  
Giuseppe Di Trapani ◽  
Raffaele Pulli ◽  
...  
Keyword(s):  
Head And Neck ◽  
Clinical Laboratory ◽  
Germ Line ◽  
Strong Predictor ◽  
Missense Mutations ◽  
Mutation Carriers ◽  
Germ Line Mutations ◽  
Group A ◽  
Group B ◽  
Head And Neck Paragangliomas

Head and neck paragangliomas (HNPGLs) are neural crest-derived tumors. In comparison with paragangliomas located in the abdomen and the chest, which are generally catecholamine secreting (sPGLs) and sympathetic in origin, HNPGLs are, in fact, parasympathetic in origin and are generally nonsecreting. Overall, 79 consecutive patients with HNPGL were examined for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127 genes by PCR/sequencing. According to a detailed family history (FH) and clinical, laboratory (including metanephrines), and instrumental examinations, patients were divided into three groups: a) patients with a positive FH for HNPGL (index cases only), b) patients with a negative FH and multiple HNPGLs (synchronous or metachronous) or HNPGL associated with an sPGL, and c) patients with negative FH and single HNPGL. The ten patients in group a) proved to be SDHD mutation carriers. The 16 patients in group b) proved to be SDHD mutation carriers. Among the 53 patients in group c), ten presented with germ-line mutations (three SDHB, three SDHD, two VHL, and two SDHAF2). An sPGL was found at diagnosis or followed up in five patients (6.3%), all were SDHD mutation carriers. No SDHC, SDHA, MAX, and TMEM127 mutations were found. In SDHD mutation carriers, none of the patients affected by HNPGL associated with sPGL presented missense mutations. In conclusion, a positive FH or the presence of multiple HNPGLs is a strong predictor for germ-line mutations, which are also present in 18.8% of patients carefully classified as sporadic. The most frequently mutated gene so far is SDHD but others, including SDHB, SDHAF2, and VHL, may also be affected.

scholarly journals Increased prevalence of catecholamine excess and phaeochromocytomas in a well-defined Dutch population with SDHD-linked head and neck paragangliomas

2005 ◽  
Vol 152 (1) ◽  
pp. 87-94 ◽  
Author(s):  
W H van Houtum ◽  
E P M Corssmit ◽  
P B Douwes Dekker ◽  
J C Jansen ◽  
A G L van der Mey ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Head And Neck ◽  
Histopathological Examination ◽  
Positive Family History ◽  
Mibg Scintigraphy ◽  
Resonance Imaging ◽  
Catecholamine Excess ◽  
Head And Neck Paragangliomas

Objective: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas. Methods: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done. Results: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catechol-amine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases. Conclusions: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.

Identification of SDHA germline mutations in sporadic SDHA mutant gastrointestinal stromal tumors (GIST): The need of a genetic counselling.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11537-11537 ◽  
Author(s):  
Margherita Nannini ◽  
Milena Urbini ◽  
Valentina Indio ◽  
Angela Schipani ◽  
Bruno Vincenzi ◽  
...  
Keyword(s):  
Genetic Counselling ◽  
Germline Mutations ◽  
Gastric Gist ◽  
Missense Mutations ◽  
Mutation Carriers ◽  
Age Of Diagnosis ◽  
History Of ◽  
Sporadic Cases ◽  
Paraganglioma Syndrome

11537 Background: SDH- deficient GIST, as defined by the loss of expression of SDHB, account up to about 10% of all gastric GIST and generally affect younger population. Germline mutations in SDHB, SDHC, and SDHD occur in about 20–30% of SDH- deficient, that may be referred to a hereditary condition known as hereditary GIST-paraganglioma syndrome (Carney-Stratakis Syndrome), whereas germline SDHA mutations have been rarely described in apparently sporadic cases. Currently, even germline testing is recommended for SDH- deficient GIST, there are no clear guidelines for genetic counselling and follow-up of SDH x mutation carriers and relatives, especially for SDHA mutant GIST not yet linked to well-defined hereditary syndrome. The aim of this work was to study the SDHA gene in the normal DNA of patients with SDHA mutant GIST. Methods: Thirteen patients carrying SDHA-mutant GIST were studied (8F/5M). Median age of diagnosis was 45,9 years (range 25-74). All GIST were located in the stomach and 3 patients out 13 presented a metastatic disease. In all cases except one, the GIST was the only cancer presentation and no personal or familial history of cancer was revealed. All cases were negative for SDHB immunohistochemistry. Germline mutations were identified through Sanger sequencing of SDHA in the normal counterpart. Results: Germline mutations were identified in all patients for which normal counterpart was available: 4 cases harboured truncating mutations (S384X, R31X and W119X); 5 cases carried pathogenic missense mutations (G233V, R171H, R589Q, G257A and R600Q) and 2 cases had splice site alterations (c.457-3_457-1 delCAG and c.456+9 C > T). In 8 cases the tumor DNA showed the loss of the corresponding wild-type allele, while in the other 3 cases compound heterozygosity for an additional somatic mutation was detected (R589W, R451C,and R171C). In 2 patients, unfortunately, normal DNA was not available, however both tumours carried two mutational hits on SDHA (one with heterozygous G419R and E564K, and one with homozygous R585Q). Of note, 5 patients presented un-usaul SDHA related clinical characteristics as were not young adult ( > 50 years-old) or no multifocal GIST. Conclusions: We demonstrated that germline SDHA mutations are highly frequent in SDHA- deficient GIST. Therefore, although a clear syndrome has not been defined, genetic counselling and follow-up of SDHA mutation carriers and relatives should be clarified.

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