Endocrine Abstracts

JOINT2052

Introduction: Pheochromocytomas and paragangliomas (PPGLs) have the highest heritability among endocrine tumors, with approximately 40% of patients carrying a germline mutation in one of about 20 related genes. Succinate dehydrogenase (SDH) complex gene mutations are a well-known cause of hereditary PPGLs. Interestingly, unlike other SDH subunit gene mutations, germline SDHD mutations exhibit a ‘parent-of-origin’ effect. Tumors typically develop only when the mutated allele is inherited paternally, consistent with maternal imprinting. However, rare cases of maternally inherited SDHD pathogenic variants causing disease have been reported, including our case.

Case Report: A 22-year-old man presented with a two-week history of right iliac fossa pain, which resolved spontaneously. He denied headaches or palpitations but reported generalized sweating. Hypertension was noted on examination. CT revealed an incidental finding of a 5.5 cm left adrenal mass. Notably, he had a strong family history of SDHD mutation, with all affected family members on the maternal side, primarily presenting with head and neck paragangliomas. Plasma metanephrines showed an elevated normetanephrine level of 5690 pmol/l (reference range <560 pmol/l), with normal metanephrine and 3-MT levels. A DOTATATE PET scan revealed an intensely avid left adrenal mass with no suspicious findings elsewhere, particularly in the head and neck region. He subsequently underwent a laparoscopic left adrenalectomy, and histology confirmed a 46 mm PPGL with clear margins, a GAPP score of 2 and negative SDHB staining. Genetic testing identified a heterozygous c.191_192delTC (Leu64Profs*4) mutation in the SDHD gene, along with a variant of uncertain significance in the PDGFRA gene. Upon reviewing his family’ genetic test results, it was confirmed that he carried the same SDHD mutation as his mother and maternal grandfather. Postoperatively, his plasma metanephrines normalized. We plan to request tumor gene expression analysis to confirm loss of heterozygosity, further establishing the pathogenicity of the mutation. Additionally, we intend to screen his father to rule out any potential paternal inheritance.

Conclusion: An international consensus on the role of surveillance for maternally inherited SDHD pathogenic variants has not yet been established. Given the rarity of such cases, it is important to discuss genetic testing with the patient and his first-degree relatives, as well as to consider ongoing surveillance for the patient himself.