Challenging the recessive paradigm of Mahvash disease: heterozygous phenotypes from a novel splice-site variant

Mahvash disease is a rare autosomal recessive condition caused by biallelic inactivating variants in the GCGR gene, impairing glucagon signaling and leading to alpha-cell hyperplasia and pancreatic neuroendocrine tumors (PNETs). Fewer than 20 cases have been reported, and the clinical impact of heterozygous variants remains unclear. Case Presentation: We report a family with a novel GCGR splice-site variant (c.1176+1_1176+7delGTGCCCG). The index case, a 61-year-old woman, presented with extensive pancreatic cystic disease and was found to be homozygous for the variant. She developed well-differentiated PNETs and underwent total pancreatectomy. Her sister, also homozygous, had similar clinical features and surgical history. In contrast, the heterozygous brother and two sons showed mild biochemical changes, such as elevated glucagon levels and small pancreatic cysts, without overt disease. The two homozygous sisters required pancreatic surgery followed by insulin and enzyme replacement therapy, whereas heterozygous carriers are currently being managed with biochemical and imaging surveillance. This family's phenotype suggests a broader spectrum of GCGR-related disease. While homozygous individuals displayed classic Mahvash disease, heterozygotes exhibited subtle biochemical and structural pancreatic changes, indicating possible semidominant expression. These findings are consistent with emerging evidence that monoallelic receptor pathway mutations may produce mild or subclinical phenotypes. This case challenges the classical recessive model of Mahvash disease and highlights the potential for disease expression in heterozygous carriers. These findings suggest that heterozygosity is not entirely silent and underline the need to reconsider surveillance recommendations for GCGR heterozygotes.