Glucagon cell hyperplasia and neoplasia (GCHN) is a rare pancreatic condition. Its autosomal recessive form, Mahvash disease, which is linked to homozygous glucagon receptor (GCGR) mutations, remains poorly characterised, with only seven prior cases reported. 

Kuiper et al. present the first detailed family study, uncovering new genotype–phenotype correlations, metastatic potential, and involvement of somatic MEN1 mutations. Their work identified a new GCGR germline variant across eight relatives. Three were homozygous and exhibited classic signs of Mahvash disease, including elevated glucagon levels, pancreatic hypertrophy and GCHN. Notably, one patient developed liver metastases – the first confirmed case in Mahvash disease. A heterozygous carrier showed formation of pancreatic neuroendocrine tumours (panNETs) without GCHN, challenging previous assumptions about the benign nature of heterozygosity. Molecular analysis revealed distinct somatic MEN1 mutations in multiple panNET samples, implicating MEN1 inactivation as a potential driver of tumour progression from hyperplastic α-cells, parallelling mechanisms in sporadic panNETs.

This elegant study expands our understanding of Mahvash disease, underscores the malignant potential of GCHN, and emphasises the value of genetic and molecular testing in familial panNET syndromes.

Read the full article in Endocrine-Related Cancer 32 e250087 https://doi.org/10.1530/ERC-25-0087