An abdominal CT scan showed one slightly hyperdense solid focal lesion of 28x27 mm localized in the pancreatic tail and bilateral nephrolithiasis (see figure 1).

B)

Figure 1. CT scan of abdomen. A) Solid lesion located in pancreatic tail (red arrowhead). B) Left nephrolithiasis.

Surgery was attempted and intraoperative direct pancreatic ultrasound revealed a single homogeneous mass of 25x20 mm in the pancreatic tail. A distal pancreatectomy plus splenectomy due to bleeding of the splenic vessels was done. The microscopic study of the specimens showed multiple nodules. Some of them revealed positivity for insulin and some for glucagon. Immunohistochemical studies, revealed positivity for cytokeratin 8-18, synaptophysin, chromogranin, E-cadherin, and a Ki-67 proliferation index <1%. Beta-catenin was negative in the nuclei and positive in membranes and cytokeratin 7 was negative. Those findings were consistent with multifocal neuroendocrine tumors.

Approximately 36 hours after the surgery, the patient presented an episode of hypoglycemia of 39 mg/dL. For this reason, medical treatment with frequent feedings and diazoxide was continued. The patient presented post-surgical complications with a pancreatic fistula, ascites, bilateral pleural effusion and acute renal insufficiency. Once he was stabilized the patient was discharged with medical treatment. However, a subsequent hospitalization was required for persistent hypoglycemic symptoms. During the two-month follow up CT scans and an endoscopic US (EUS) were done. Since no residual neuroendocrine tumor could be demonstrated it was decided, in conjunction with the patient, to continue with medical management and not perform surgical reintervention due to the high morbidity and mortality it represented.

Genomic DNA sequence analysis and deletion/duplication testing from peripheral blood leukocytes was done in a clinical commercial laboratory as part of a patient initiative. Direct sequence analysis of MEN1revealed heterozygosity for a novel pathogenic 4-bp insertion: c.1224_1225insGTCC(p.Cys409Valfs*41)

Molecular analysis of the variant showed that while this is not anticipated to result in nonsense mediated mRNA decay, it is expected to disrupt the last 202 amino acids of the MEN1 protein which result in truncation of the protein and its Nuclear Localization Signal (NLS) domains (see figure 2). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with MEN1-related disease. ClinVar database contains an entry for this variant (Variation ID: 428066). Literature analysis showed that several different truncations located downstream of this variant (p.Arg516Profs*15, p.Arg516Glyfs*43 and p.Gln554*) have been determined to be pathogenic (Cardinal et al., 2005; Langer et al., 2001; Lemmens et al., 1997; Lemos & Thakker, 2008). This suggests that deletion of this region of the MEN1 protein is causative of the disease.