First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome

Abstract

Context: Molecular genetic research has so far resulted in the identification of 10 well-characterized susceptibility genes for hereditary pheochromocytoma (PHEO) or paraganglioma (PGL). Recently, a new syndrome characterized by multiple PGLs and somatostatinomas associated with congenital polycythemia due to somatic mutations in HIF2A has been reported.

Objective: The aim of the study was to define the genetic defect in a new case of bilateral PHEO and multiple PGLs associated with congenital polycythemia.

Patient: A female patient presented with neonatal polycythemia (treated by phlebotomies, 1 session approximately every 4 mo), mildly enlarged cerebral ventricles, and bilateral PHEO and multiple PGLs. There was no family history of any neuroendocrine tumor or polycythemia. Surgical removal of the tumors only temporarily normalized plasma erythropoietin (Epo) levels and discontinued phlebotomies. No germline mutations were initially detected in the SDHB, SDHC, SDHD, VHL, and PHD2 genes, known to be associated with polycythemia. The PHEOs presented with a typical noradrenergic biochemical phenotype.

Results: A heterozygous missense mutation (c.1589C>T) was identified in exon 12 of HIF2A, resulting in an alanine 530 substitution in the HIF-2α protein with valine (A530V). This somatic mutation was detected in the tissue from 1 PHEO and 1 PGL, with no HIF2A germline mutation found. This mutation led to stabilization of HIF-2α and hence a gain-of-function phenotype, as in previously published studies.

Conclusion: This case represents the first association of a somatic HIF2A gain-of-function mutation with PHEO and congenital polycythemia, and it alerts physicians to perform proper genetic screening in patients presenting with multiple norepinephrine-producing PHEOs and polycythemia. This report also extends the previous findings of a new syndrome of only multiple PGLs, somatostatinomas, and polycythemia to multiple PHEOs.

Figure 1.

Preoperative axial CT images showing bilateral adrenal PHEO (arrows).

Figure 2.

PGL of the aortic bifurcation. A, Sagittal T2-weighted MRI image showing a typical hyperintense tumor (arrow). B, ¹⁸F-FDOPA PET/CT: maximum intensity projection [MIP] image (left) and 3-dimensional tomographic sections with ¹⁸F-FDOPA PET/CT fusion images showing a highly avid lesion (arrow). C, Follow-up image using ¹⁸F-FDOPA PET/CT; note the absence of abnormal uptake.

Figure 3.

Electrophoretograms of the HIF2A mutations. Heterozygous c.1589C>T mutations in HIF2A were identified in PHEO and PGL by Sanger sequencing.

Figure 4.

Recurrent PGLs. A, ¹⁸F-FDOPA PET/CT (maximum intensity projection [MIP] image). B, Coronal ¹⁸F-FDOPA PET/CT image showing 2 suspected foci (arrows on attenuation-corrected image). C, 3-Dimensional tomographic acquisition centered over the upper retroperitoneum performed 30 minutes after furosemide injection, increasing diagnostic confidence (arrows on attenuation-corrected image). D and E, ¹⁸F-FDOPA PET/CT axial fusion images showing lesions adjacent to the surgical bed (see surgical clips), suggesting recurrent tumors.