Mahvash Disease: An Autosomal Recessive Hereditary Pancreatic Neuroendocrine Tumor Syndrome

Abstract

Mahvash disease is a rare autosomal recessive hereditary pancreatic neuroendocrine tumor syndrome characterized by inactivating mutations in the glucagon receptor, hyperglucagonemia without symptoms of the glucagonoma syndrome, pancreatic α-cell hyperplasia and pancreatic neuroendocrine tumors. In Mahvash disease, the lack of negative feedback from glucagon receptor signaling results in compensatory hyperplasia of pancreatic α-cells and secondary tumorigenesis. Over ten clinical cases consistent with Mahvash disease have been reported thus far, most of which have confirmed biallelic mutations in the glucagon receptor. Mahvash disease provides insight into glucagon signaling pathway regulation and pathogenesis of pancreatic neuroendocrine tumors.

Non-functioning pancreatic neuroendocrine tumors: Surgery or observation?

“…While most of PNETs occur sporadically, 10%-30% of them are associated with various inherited disorders including MEN1, Von Hippel-Lindau syndrome, neurofibromatosis 1, tuberous sclerosis, and Mahvash disease[ 14 , 15 ]. The majority of PNETS related to MEN1 and VHL syndromes are non-functioning tumors[ 1 ].…”

Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies

“…To date, 9 GCGR pathogenic alterations have been identified, all determining decreased or absent GCGR activity [121]. Mahvash disease is characterized by hyperglucagonemia without glucagonoma syndrome in association to coexisting histological features of diffuse alfa cell hyperplasia, dysplasia, micro-pancreatic neuroendocrine tumors (pNET), and gross pNET [120].…”

“…It presents full penetrance and affects both sexes with an average age at diagnosis ranging from 25 to 74 years [120]. Given the rarity of GCHN, its natural history has not been well defined yet [121]. Accumulating data suggest that pNETs in Mahvash disease appear to be slow-growing tumors, predominantly glucagonomas and clinically non-functioning [120].…”

“…In most cases, no recurrence of pNETs after surgery has been identified during a follow-up period of 2-13 years [120,[122][123][124][125]. So far, only one case of distant metastasis to the liver was reported by Tang et al [121,123]. Due to the limited clinical evidence on Mahvash disease, current management may be extrapolated by the guidelines used for the treatment of other inherited pNET syndromes such as MEN1 [120].…”

“…The role of pharmacological therapy warrants further research. The benefits of SSAs are difficult to assess, since they may improve hyperglucagonemia, but are associated with a major risk of hypoglycemia [121]. Moreover, also one case of recurrent liver failure was reported by Robbins et al after octreotide administration in a patient with Mahvash disease [126].…”