Abstract
Simple SummaryPheochromocytoma/paraganglioma (PPGL) has been recognised as one of the most frequent inherited tumours with genetic heterogeneity based on studies in Caucasian populations. Early identification of germline variants is crucial for accurate treatment and follow-up in affected patients and relatives. However, there are only a few large cohort studies in Asia and none from the Japanese population. In this first comprehensive study of Japanese patients with PPGL, we found one in four PPGLs with apparently sporadic presentation harboured germline variant in any of the seven susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET). SDHB was the most frequently mutated gene and was strongly associated with metastatic PPGLs. Our findings emphasise the importance of genetic testing in determining appropriate treatment and follow-up strategies for patients and relatives.The high incidence of germline variants in pheochromocytoma and paraganglioma (PPGL) has been reported mainly in Europe, but not among Japanese populations in Asia. We aimed to study the prevalence of germline variants in Japanese PPGL patients and the genotype–phenotype correlation. We examined 370 PPGL probands, including 43 patients with family history and/or syndromic presentation and 327 patients with apparently sporadic (AS) presentation. Clinical data and blood samples were collected, and the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, VHL, and RET) were tested using Sanger sequencing. Overall, 120/370 (32.4%) patients had pathogenic or likely pathogenic variants, with 81/327 (24.8%) in AS presentation. SDHB was the most frequently mutated gene (57, 15.4%), followed by SDHD (27, 7.3%), and VHL (18, 4.9%). The incidence of metastatic PPGL was high in SDHB carriers (21/57, 36.8%). A few unique recurrent variants (SDHB c.137G>A and SDHB c.470delT) were detected in this Japanese cohort, highlighting ethnic differences. In summary, almost a quarter of patients with apparently sporadic PPGL in Japan harboured germline variants of the targeted genes. This study reinforces the recommendation in Western guidelines to perform genetic testing for PPGL and genotype-based clinical decision-making in the Japanese population.
Highlights
Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumours derived from the chromaffin cells in the adrenal medulla and autonomic nervous system ganglia, respectively
Applying the simple criterion of non-familial and nonsyndromic presentation as apparently sporadic (AS) presentation, we found a 24.8% frequency of germline variants in anyof the seven major susceptibility genes (MAX, SDHB, SDHC, SDHD, TMEM127, Von Hippel–Lindau (VHL), and RET)
Our study showed that SDHB was the most mutated gene (47.5% of patients with positive variant and 15.4% of all cases studied), followed by SDHD (22.5%, 7.3% of all)
Summary
Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumours derived from the chromaffin cells in the adrenal medulla and autonomic nervous system ganglia, respectively. PCC and PGL share a common pathological basis and genetic background and are collectively referred to as pheochromocytoma/paraganglioma (PPGL) [1,2]. Even in PPGL with apparently sporadic (AS) presentation (no familial/syndromic [FS] characteristics), pathogenic variants have been found with a frequency of 11–24% [11,12,13]. In this context, current guidelines recommend that germline genetic testing should be considered in all patients with PPGLs regardless of family history [2,14,15]. Identification of a predisposing germline variant enables risk assessment of distant metastases in probands and clinical surveillance of variant carriers in healthy relatives [1,2,9,16]
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