Late onset asymptomatic pancreatic neuroendocrine tumor – A case report on the phenotypic expansion for MEN1

Abstract

BackgroundMultiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome associated with several endocrine as well as non-endocrine tumors and is caused by mutations in the MEN1 gene. Primary hyperparathyroidism affects the majority of MEN1 individuals by age 50 years. Additionally, MEN1 mutations trigger familial isolated hyperparathyroidism. We describe a seemingly unaffected 76-year-old female who presented to our Genetics Clinic with a family history of primary hyperparathyroidism and the identification of a pathogenic MEN1 variant.Case PresentationThe patient was a 76 year-old woman who appeared to be unaffected. She had a family history of a known MEN1 pathogenic variant. Molecular testing for the known MEN1 mutation c.1A > G, as well as, biochemical testing, MRI of the brain and abdomen were all performed using standard methods. Molecular testing revealed our patient possessed the MEN1 pathogenic variant previously identified in her two offspring. Physical exam revealed red facial papules with onset in her seventies, involving her cheeks, nose and upper lip. Formerly, she was diagnosed with rosacea by a dermatologist and noted no improvement with treatment. Clinically, these lesions appeared to be facial angiofibromas. Brain MRI was normal. However, an MRI of her abdomen revealed a 1.5 cm lesion at the tail of the pancreas with normal adrenal glands. Glucagon was mildly elevated and pancreatic polypeptide was nearly seven times the upper limit of the normal range. The patient underwent spleen sparing distal pancreatectomy and subsequent pathology was consistent with a well-differentiated pancreatic neuroendocrine tumor (pNET).ConclusionsAge-related penetrance and variable expressivity are well documented in families with MEN1. It is thought that nearly all individuals with MEN1 manifest disease by age 40. We present a case of late-onset MEN1 in the absence of the most common feature, primary hyperparathyroidism, but with the presence of a pNET and cutaneous findings. This family expands the phenotype associated with the c.1A > G pathogenic variant and highlights the importance of providing comprehensive assessment of MEN1 mutation carriers in families that at first blush may appear to have isolated hyperparathyroidism.

Approach of Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome–Related Skin Tumors

“…In MEN1, the most frequent location is facial, mainly the upper lip, in contrast with tuberous sclerosis, where this location is spared [ 76 , 78 ]. Angiofibromas were the most frequent cutaneous tumor observed and were found in 18 studies according to our research [ 48 , 49 , 50 , 52 , 53 , 54 , 55 , 56 , 57 , 59 , 62 , 63 , 64 , 66 , 67 , 68 , 69 , 70 ]. Angiofibromas in MEN1 patients are reported with a frequency between 11% and 88% on studies of different sample size (varying from 145 to 5 patients) [ 48 , 49 , 69 ] ( Table 2 ).…”

“…As mentioned, Marini et al found that seven out of 37 patients with lipomas associated with MEN1 had lipomas as the first manifestation [ 69 ]. In addition, two case reports included individuals who developed cutaneous tumors 5, respective 20 years prior to the actual MEN1 diagnosis [ 59 , 67 ]. The presence of angiofibromas is more frequent in patients with MEN1 syndrome than seen in subjects with sporadic ZES, as proved by Asgharian et al In order to ensure an adequate screening and management of MEN1 syndrome, the differentiation between sporadic and syndromic pancreatic NETs and of other NETs with different sites is crucial, which is why dermatological screening could be a useful tool [ 53 ].…”

“…Overall, we identified 27 original studies involving clinical presentation of patients with MEN1 syndrome and cutaneous tumors [ 31 , 39 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. We also mentioned eight original studies involving the genetics of these types of skin tumors [ 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ].…”

“…Table 4 summarizes the genetic mutations of patients with MEN1 syndrome and the most frequent cutaneous tumors (angiofibroma, lipoma, collagenoma) [ 49 , 52 , 54 , 56 , 58 , 60 , 65 , 66 , 67 , 70 , 71 , 90 ].…”

The Genetics of Neuroendocrine Tumors: A Brief Overview

“…Normal function of this protein seems to inhibit transcription elongation. Lack of normal alpha HIF degradation produces over stimulation of blood vessel growth and tumor development [14][15][16][17].…”