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A 62-year-old woman with no family history of hereditary diseases presented to the ER department in 2008 with the diagnosis of a subarachnoid hemorrhage that required urgent decompressive craniotomy. On February 2011, due to resistant hypertension, an abdominal CT scan was performed, revealing a left adrenal gland-dependent tumor of 70x86 mm, with additional increased normetanephrine levels in a 24-hour urine sample. Laparoscopic left adrenalectomy was performed on June 3, 2011, with a histological report of pheochromocytoma. It was also documented an elevation of iPTH (301 pg/ml) with corrected calcium of 11 mg/dL and phosphorus of 2.7 mg/dL. Parathyroidectomy was performed with the report of parathyroid adenoma. On January 2015, an abdominal CT scan was performed, revealing recurrence of the pheochromocytoma at the surgical site. A MIBG PET-CT confirmed the recurrence and detected a left retroperitoneal lesion close to the tail of the pancreas. Metastasectomy of the retroperitoneal lesions, distal pancreatectomy, and dissection of tumor adjacent to left kidney were performed with a histopathologic report of pheochromocytoma with nest pattern and extensive necrosis, negative margins, and three positive lymph nodes. During follow-up a significant increase of normetanephrine in 24-hour urine sample was documented (3 months after surgery). A Ga-DOTATOC PET-CT revealed the presence of hepatic metastases. In the 131-MIBG SPECT-CT performed one year later, a decreased height of C3 vertebral body with an abnormal concentration of the radiopharmaceutical in relation to secondary deposit was also found. On August 2017 the patient was treated with a therapeutic dose of 131-MIBG, achieving complete biochemical remission during 14 months of follow-up. On March 2018 an Invitae Multi-Cancer Panel reported the germline variant C. 416C > G (P. Ser139Cys) related to VHL without mutations in other pathogenic genes related to pheochromocytoma. VHL c.416C>G (at the cDNA level ) is a germline variant of Von Hipple Lindau (VHL) disease, also known as p.Ser139Cys (S139C) at the protein level. It results in the change of a Serine to a Cysteine (TCT>TGT), located in 3p25.3. This variant has been reported in population databases (rs587780732, ExAC 0.06%) and related to familiar erythrocytosis, monogenic diabetes (likely benign) and a type of autosomal recessive A1 deafness (uncertain significance); however, to our knowledge it has not been previously published in the literature as a pathogenic nor benign form of the VHL disease. It was also not observed in the NHLBI Exome Sequencing Project that included 6,500 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. Because of the lack of evidence to determine its role in disease, to date, it is considered a variant of uncertain significance. |
