Endocrine Abstracts

Pheochromocytoma is a rare neuroendocrine tumor; many cases are sporadic but 1/3 are familial or syndromic and associated with many susceptibility genes including germline mutations of the gene encoding succinate dehydrogenase (SDH) subunits. We describe the case of a 70-years-old woman with arterial hypertension poorly controlled by therapy in a patient with secondary progressive multiple sclerosis started at 25 years of age, associated with euthyroid autoimmune thyroiditis, hepatic angiomas, cholelithiasis and right adrenal inhomogeneous incidentaloma detected at abdomen CT, cm 4×3. Functional adrenal analysis detected elevated urinary normetanephrine; screening for MEN was negative. The patient underwent laparoscopic right adrenalectomy: histology confirmed the suspicion of pheochromocytoma with PASS score =4. Complete genetic testing for known loci associated to pheochromocytoma was performed. In detail, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, RET, TMEM127, MAX genes were analysed in order to detect point mutation or large rearrangement, respectively by Sanger sequencing and MLPA (Multiplex ligation-dependent probe amplification). Moreover, FH, SLC25A11 and MDH2 genes were investigated. Molecular analysis only identified a synonymous substitution in exon 12 of SDHA gene, c.1554A>G p.(Ser518=). The identified sequence variant affects a non-conserved nucleotide and does not alter the protein sequence. In silico splicing analysis does not predict consistent changes at the acceptor site 3 basepairs upstream, and this prediction was confirmed by the use of a minigene assay. The immunohistochemistry highlighted a positive staining for SDHA and the expression of the SDHA protein sustained the non-pathogenicity of the identified variant. Even if the SDHA c.1554A>G was not present in GnomAD exomes and genomes (v2.0.1), it appeared to be a ‘private’ variation, as no additional evidence of pathogenicity has been identified. Therefore, it has been classified as likely benign. After about three years the patient was normotensive, urinary metanephrines were in the normal range and multiple sclerosis was clinically stable.

In conclusion: - we reported a rare case of pheochromocytoma in a patient affected by multiple sclerosis;

- even if the PASS score suggested a potential biologically aggressive behaviour, after three years of follow up there are no evidences of metastasis or relapses;

- the extensive genetic analysis identified no pathogenic mutations, only a ‘private’ variation in SDHA gene without functional evidence of pathogenicity, classifying the pheochromocytoma as sporadic.