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Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1.

ABSTRACT: BACKGROUND:Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations. OBJECTIVE:Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations. MATERIALS & METHODS:The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours. CONCLUSIONS:This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype.

SUBMITTER: Leidenz FB

PROVIDER: S-EPMC6863626 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1.

Leidenz Franciele B FB Bastos-Rodrigues Luciana L Oliveira Marcelo M Mamede Marcelo M Sarquis Marta M Friedman Eitan E de Marco Luiz L

Genetics research 20150330

<h4>Background</h4>Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations.<h4>Objective</h4>Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations.<h4>Materials & methods</h4>The proband presented with large bilateral carotid body tumours and family ...[more]

PMID: 25819804

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Project description:BackgroundPhaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series.MethodsImmunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing.FindingsSDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively.InterpretationPhaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome.FundingThe Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network.

Dataset Information

Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1.

Publications

Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1.

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