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.

中文翻译：

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一个副神经节瘤综合征1型家庭的恶性表型和两个SDHD突变。

背景技术1型副神经节瘤综合征（PGL1）是一种罕见的常染色体显性综合症，与SDHD基因突变引起的多种，绝大多数为良性的嗜铬细胞瘤和副神经节瘤相关。目的临床上和分子上表征具有两个看似致病的SDHD种系突变的副神经节瘤恶性表型的家族。材料与方法该先证者在其五个兄弟姐妹中均患有双侧大的颈动脉体瘤和子宫颈肿块的家族史。所有家庭成员均接受临床检查，影像学研究（18F-FDG PET / CT）和相关基因的基因分型。先证者被诊断出患有局部晚期神经节旁瘤；他的高血压父亲，没有症状，患有局部晚期嗜铬细胞瘤，他的三个兄弟姐妹表现出多个头颈部肿块，证实是具有局部转移的神经节旁瘤。所有受影响的患者均在SDHD基因中携带了两个种系突变。先前报道的外显子1的无义突变（p.Trp5X）和外显子2的新的错义突变（p.Pro53Leu），通过计算机模拟分析具有很高的危害性。对于任何已分析的肿瘤，均未显示SDHD位点的等位基因缺失。结论这是一种罕见的恶性PGL1病例，在SDHD基因中似乎有双重致病性突变，这突显了这两个突变的存在与更具攻击性的表型有关的可能性。先前报道的外显子1的无义突变（p.Trp5X）和外显子2的新的错义突变（p.Pro53Leu），通过计算机模拟分析具有很高的危害性。对于任何已分析的肿瘤，均未显示SDHD位点的等位基因缺失。结论这是一种罕见的恶性PGL1病例，在SDHD基因中似乎有双重致病性突变，这突显了这两个突变的存在与更具攻击性的表型有关的可能性。先前报道的外显子1的无义突变（p.Trp5X）和外显子2的新的错义突变（p.Pro53Leu），通过计算机模拟分析具有很高的危害性。对于任何已分析的肿瘤，均未显示SDHD位点的等位基因缺失。结论这是一种罕见的恶性PGL1病例，在SDHD基因中似乎有双重致病性突变，这突显了这两个突变的存在与更具攻击性的表型有关的可能性。