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

TL;DR

A family with a new genetic variant in the GCGR gene shows that heterozygous carriers can have mild pancreatic changes, challenging the idea that Mahvash disease only affects homozygous individuals.

Contribution

This study reports a novel splice-site variant in GCGR and demonstrates that heterozygous carriers can exhibit subtle phenotypes, challenging the recessive model of Mahvash disease.

Findings

Homozygous individuals displayed classic Mahvash disease features, including pancreatic tumors and hyperplasia.

Heterozygous carriers showed mild biochemical and structural pancreatic changes without overt disease.

The findings suggest semidominant expression of GCGR-related disease and the need to reconsider surveillance for heterozygotes.

Abstract

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.

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