Germline FH Mutations Presenting With Pheochromocytoma

Clark, Graeme R.; Sciacovelli, Marco; Gaude, Edoardo; Walsh, Diana; Kirby, Gail; Simpson, Michael A.; Trembath, Richard C.; Berg, Jonathan; Woodward, Emma R.; Kinning, Esther; Morrison, Patrick J.; Frezza, Christian; Maher, Eamonn R.

doi:10.1210/jc.2014-1659

Cited by 151 publications

(134 citation statements)

References 19 publications

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“…15,16 Similar associations of these genes with high rates of malignant PCC/PGL have also been reported in children.…”

Section: 15supporting

confidence: 60%

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

Shah¹,

Sarathi²,

Mayilvaganan³

2016

World Journal of Endocrine Surgery

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Pheochromocytoma/paraganglioma (PPGL) have been reported to have germline mutations in more than 15 genes. PPGL diagnosed during childhood have the highest heritability (up to 80%). PPGL associated genes are classified into two clusters; cluster 1 (VHL, SDHx, EPAS1, PDH1, PDH2, FH, MDH2) and cluster 2 (RET, NF-1, TMEM127, MAX). Cluster 1 genes associated PPGL are norepinephrine secreting whereas cluster 2 genes associated PPGL are epinephrine secreting. In children with PPGL, VHL mutations are the most common followed by SDHB and SDHD. Bilateral PCC are frequent in patients with VHL mutations whereas extra-adrenal PGL are frequent in SDHx mutations. SDHB related PPGL are frequently malignant. Genetic testing should be performed in all children with PPGL and prioritization of genetic testing based on clinical characteristics (extra-paraganglial manifestations, location and number of PPGL, biochemical phenotype and metastasis) may be cost-effective.

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“…15,16 Similar associations of these genes with high rates of malignant PCC/PGL have also been reported in children.…”

Section: 15supporting

confidence: 60%

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

Shah¹,

Sarathi²,

Mayilvaganan³

2016

World Journal of Endocrine Surgery

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“…Pituitary adenomas were reported in patients with PPGLs in familial settings in which an SDH mutation was detected 84,85 . Germ line FH mutations have been described in patients with phaeochromocytomas and uterine leiomyomas 14,20,24 , and, in the past year histone gene mutations (H3F3A) were found in a new syndrome of multiple paragangliomas and giant cell tumour of bone, which implicates chromatin remodelling defects in PPGL tumorigenesis and susceptibility 14 .…”

Section: Discussionmentioning

confidence: 99%

“…All participants have adopted, and reported on, NGS-based technologies in their research and/or clinical practice [14][15][16][17][18][19][20][21][22][23][24][25][26] . Discussions took place via conference calls, e-mail communications and file exchanges and one plenary session (at the 14th ENS@T Scientific Meeting on November 20th, 2015, Munich, Germany).…”

Section: Methodsmentioning

confidence: 99%

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.

Funding Agencies|Cancer Prevention and Research Institute of Texas (CPRIT) [RP101202, RP57154]; Department of Defense [CDMRP W81XWH-12-1-0508]; Voelcker Fund; National Institutes of Health (NIH)s National Center for Research Resources; National Center for Advancing Translational Sciences [8UL1TR000149]; INSERM; French National Cancer Institute (INCA); Direction Generale de lOffre de Soins (DGOS); INCA [INCA-DGOS_8663]; European Union [633983]; Brazilian National Council for Scientific and Technological Development (CNPq); Cancer Research for PErsonalized Medicine (CARPEM); ERC Advanced Researcher Award

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“…Through both germline and somatic tumor testing of individuals with PGL, the prevalence of germline susceptibility genes altered in HNPGL is now ~30 to 40%, involving predominantly genes encoding subunits of succinate dehydrogenase ("SDHx" genes) [3,5]. In addition to SDHx, VHL, NF1 and RET, genes including MAX [6], TMEM127 [7] fumarate hydratase [8] and HIF2A [9] have now been associated with HNPGL in rare cases. The clinical implications of hereditary disease have led the Endocrine Society to recommend referring all patients diagnosed with PGL for clinical genetic testing regardless of site of origin or lack of familial events [10].…”

Section: Geneticsmentioning

confidence: 99%

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

Williams

Tischler

2017

Head and Neck Pathol

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Germline FH Mutations Presenting With Pheochromocytoma

Abstract: These findings 1) confirm that germline FH mutations may present, albeit rarely with PCC or PGL; and 2) extend the clinical phenotype associated with FH mutations to pediatric PCC.

Cited by 151 publications

References 19 publications

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

Genotype–phenotype Correlation in Children with Pheochromocytoma and Paraganglioma

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Paragangliomas

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