Homozygous pathogenic glucagon receptor gene (GCGR) mutations cause a syndrome with pancreatic glucagon cell hyperplasia and neoplasia (GCHN) and hyperglucagonaemia without a glucagonoma syndrome named Mahvash disease. The disease follows an autosomal recessive course and is an exceptionally rare hereditary pancreatic neuroendocrine tumour (panNET) syndrome, with only seven cases documented in the literature. The study aims to elucidate the genotype–phenotype correlation in Mahvash disease and panNET development. Clinical features, molecular profile, pancreatic pathology, and follow-up were studied in detail in six of the 11 family members. The patients’ medical records were reviewed up until November 2024. Eight family members were positive for the likely pathogenic GCGR c.455C>T (p.Ser152Phe) germline variant. Three of the family members were homozygous for the GCGR germline variant. Two homozygous patients showed GCHN in pancreatic resection samples, with one exhibiting lymphogenic and hepatic metastases. Three patients had a glucagon-positive tumour with distinct somatic mutations in the MEN1 gene. One family member, heterozygous for the GCGR variant, presented with three small panNET, with the one biopsied lesion showing glucagon immunoreactivity. We report the first study of a single family with multiple members presenting with GCNH caused by a novel germline GCGR variant. We are also presenting the first patient with liver metastases in GCHN and another patient with multiple small panNET heterozygous for the novel GCGR gene variant. Our observations highlight the malignant potential for GCHN and suggest that somatic MEN1 mutations may play a role in the development of glucagon-positive panNET from glucagon cell hyperplasia.
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