It's not a mystery, it's in the history: Multidisciplinary management of multiple endocrine neoplasia type 1

Abstract

The patient (ML) was followed at the Mayo Clinic in Rochester, Minnesota, from 2009 to 2012, at The University of Texas MD Anderson Cancer Center from 2013 to 2016, and at Intermountain Healthcare of Utah from 2017 onward. ML is a 41 year old male who, in August 2009 at the age of 30 years, presented to his internist with abdominal pain and hypercalcemia of 10.8 mg/dL (normal range, 8.9-10.1 mg/dL). He had facial angiofibromas and lipomas. Laboratory testing revealed an inappropriately normal intact parathyroid hormone (iPTH) level of 44 pg/mL (normal range, 15-65 pg/mL), a normal 25-hydroxy vitamin D3 level of 33 ng/mL (normal range, 25-80 ng/mL), and high-normal 24-hour urinary calcium of level 237 mg (normal range, 25-300 mg), which was concerning for primary hyperparathyroidism (PHPT). He reported a family history of nephrolithiasis, constipation, and metastatic thymic neuroendocrine tumor (NET) in his father and pituitary macroadenoma in his paternal uncle. He underwent germline genetic testing that found a heterozygous, pathogenic variant in the MEN1 gene, confirming a diagnosis of MEN1. In addition to PHPT, his fasting laboratory tests showed an elevated pancreatic polypeptide (PP) level of 1600 pg/mL (normal, ≤ 249 pg/mL) with normal gastrin, insulin, C-peptide, chromogranin A (CgA), prolactin, and insulin-like growth factor 1 (IGF-1) levels. Endoscopic ultrasound (EUS) in October 2009 identified 1.0 cm and 1.2 cm solid lesions in the head and tail of the pancreas, respectively, and multiple 2 mm to 3 mm hyperechoic lesions. Fine-needle aspiration (FNA) of the head of pancreas lesion was consistent with a well differentiated grade 1 (Ki-67 2%) pancreatic NET (pNET). In 2011, dual energy x-ray absorptiometry (DXA) demonstrated decreased bone mineral density for age at the lumbar spine (T-score, −2.9; Z-score, −2.7) and otherwise normal BMD. He underwent a subtotal parathyroidectomy and bilateral cervical thymectomy in November 2011. Subsequent serum calcium and iPTH levels have remained within normal limits. The patient's initial chest computed tomography (CT) in 2009 and subsequent images were without evidence of a thoracic NET. Pituitary magnetic resonance imaging (MRI) in 2009 was normal, but repeat MRI in 2012 identified a possible 2.3 mm pituitary microadenoma (Fig. 1) that has remained stable. Pituitary hormone levels have always been normal. The multifocal pNETs were followed with alternating EUS and abdominal MRI. By 2016, the pancreatic head NET had grown in size to 1.9 cm and, by July 2017, the same lesion had grown further to 3.0 cm (Fig. 2). He underwent a pylorus-preserving pancreaticoduodenectomy in August 2017. Pathology documented a 2.1 cm well differentiated grade 2 (Ki-67 4.7%) NET and innumerable microadenomas (pT2N0M0). His postoperative course was complicated by delayed gastric emptying. He is followed by yearly abdominal MRI, which shows stable lesions in the pancreatic remnant. The patient has 2 healthy children, both of whom underwent predictive genetic testing. His daughter was negative for the familial MEN1 variant, whereas predictive testing in his son at age 2 years was positive. His son undergoes annual clinical and laboratory assessment and is without MEN1 manifestations. At presentation, the patient was a young man diagnosed with PHPT, facial angiofibromas, and lipomas. Up to 15% of PHPT cases are caused by an underlying inherited predisposition (e.g., MEN1, MEN2, hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia).1 This is important to recognize because hereditary disease influences prognosis, surgical strategy, and the risk of other syndromic manifestations and has important implications for family members.2 The characteristics of this patient should prompt an evaluation for genetic causes of PHPT because the factors associated with hereditary PHPT are young age at diagnosis (<40 years), the presence of syndromic features/tumors, contributory family history, an