Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients

Abstract

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

Keywords: PCC/PGL; SDHB; SDHD; genotype–phenotype correlation.

Figure 1

Histopathological features of the tumors. (A, proband 1; B, proband 2; C, proband 3; stained with H&E ×200.)

Figure 2

Abdominal CT or MRI scans of the probands. (A and D) Coronal (A) and axial (D) CT images of the 5.1 × 3.4 cm retroperitoneal mass between the aorta and inferior vena cava in proband 1. (B and E) Coronal (B) and axial MRI (E) images of the 3 × 2 × 2 cm retroperitoneal para-aorta mass in proband 2. (C and F) Coronal (C) and axial (F) images of the 2.9 × 2.7 cm mass located at the bifurcation of the abdominal aorta in proband 3.

Figure 3

Gene sequencing reveals mutations in the SDHB and SDHD gene. (A) The mutation c.343C>T in proband 1. (B) The mutation c.541-2A>G in proband 2. (C) The mutation c.334_337delACTG in proband 3.

Figure 4

IHC staining for SDHB and SDHD in the tumor tissues. (A, B, C and D) IHC staining for SDHB in the GIST positive control tissue (A), in PCC/PGL tissue of proband 1 (B), 2 (C), and 3 (D). (E, F, G and H) IHC staining for SDHD in the tumor tissue of the sporadic PGL patient (used as positive control tissue, E), in PCC/PGL tissue of proband 1 (F), 2 (G), and 3 (H). Magnification ×200.