Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes

Abstract

Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre, we aimed to characterise the genotype-phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n = 59) diagnosed with a rare variant in SDHX during a 13-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and, therefore, useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, forming a basis for larger multi-centre follow up studies.

Keywords: PPGL; genotype; phenotype.

Figures

Figure 1

Flow chart of the study. CRH, corticotropin-releasing hormone; HNPGL, head and neck paraganglioma; ki-67, antigen associated with cellular proliferation; NSE, neuron-specific enolase; PASS, phaeochromocytoma of the adrenal gland scaled score; PCC, phaeochromocytoma; PGL, paraganglioma; PPGL, phaeochromocytoma and paraganglioma; SDHX, succinate dehydrogenase genetic variants; SS receptor, somatostatin receptor; VIP, vasoactive intestinal peptide.

Figure 2

Age at first tumour diagnosis (PPGL or RCC) in patients with class 4 and 5 variants of SDHA (n = 1), SDHB (n = 15), and SDHC (n = 3) genes (open circles depict non-metastatic tumours, stars show metastatic disease). None of the SDHD variants were class 4 or 5. AM1, SDHA family, male 1; B1F1 to B8F1, SDHB families 1, 3, 4–8; F, female; M, male; CF3 to CM2, SDHC families; RCC, renal call carcinoma; PPGL, phaeochromocytoma and paraganglioma; SDH, succinate dehydrogenase.