GCGR – GCGR-related Hyperglucagonemia (Mahvash Syndrome)

Glucagon receptor (GCGR; HGNC:4192) biallelic loss-of-function mutations underlie an autosomal recessive syndrome of marked hyperglucagonemia, pancreatic α-cell hyperplasia/neoplasia (GCHN) and predisposition to pancreatic neuroendocrine tumors, termed Mahvash syndrome (MONDO:0018582). This condition features early biochemical markers (e.g., hyperaminoacidemia) and often presents in adulthood with PNET and, rarely, PTH-independent hypercalcemia.

An adult case described a 47-year-old man with severe PTH-independent hypercalcemia (13.95 mg/dL) and metastatic α-cell neoplasia; genomic analysis revealed homozygous c.187G>A (p.Asp63Asn) (PMID:30032256). Prior work identified a homozygous c.256C>T (p.Pro86Ser) variant in a patient with isolated α-cell hyperplasia and hyperglucagonemia, demonstrating >90 % reduction in glucagon binding and cyclic AMP response in vitro (PMID:19657311).

A first pediatric case involved a 7-year-old girl with persistent hyperaminoacidemia, intermittent emesis and anorexia (HP:0002039); exome sequencing uncovered homozygous c.958_960del (p.Phe320del), and functional studies confirmed receptor inactivation (PMID:30294546).

A multi-generation pedigree study of 11 members identified eight carriers of a novel c.455C>T (p.Ser152Phe) variant, including three homozygotes who developed GCHN with lymphogenic and hepatic metastases; heterozygotes showed multiple small panNETs, indicating high penetrance in homozygotes and suggesting a modifier role for somatic MEN1 mutations (PMID:40424057).

The variant spectrum comprises three missense mutations (p.Pro86Ser, p.Asp63Asn, p.Ser152Phe) and one in-frame deletion (p.Phe320del), each abolishing receptor function. Recurrent p.Asp63Asn has been reported in independent cases and functional assays, solidifying its pathogenicity.

Mechanistically, GCGR loss-of-function leads to disrupted Gα_s signaling. In vitro cell-based assays of P86S and Asp63Asn confirm dramatically reduced ligand binding and cAMP production, while GcgrV369M knock-in and Gcgr–/– mouse models recapitulate hyperglucagonemia, α-cell hyperplasia and altered glucose homeostasis (PMID:32677665).

Collectively, biallelic GCGR mutations in seven reported probands across four families, segregation in a large pedigree, and concordant cellular and animal data define a Strong clinical validity. Genetic (Strong) and functional (Moderate) evidence support diagnostic molecular testing and longitudinal surveillance for PNET. Key take-home: GCGR genetic screening facilitates early recognition of Mahvash syndrome and guides timely tumor surveillance and management.

References

• The Journal of Clinical Endocrinology and Metabolism • 2018 • Hypercalcemia in Glucagon Cell Hyperplasia and Neoplasia (Mahvash Syndrome): A New Association. PMID:30032256
• Molecular Genetics and Metabolism Reports • 2018 • The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine. PMID:30294546
• Endocrine-Related Cancer • 2025 • Familial Mahvash disease with metastatic pancreatic NET and MEN1 mutations. PMID:40424057
• Pancreas • 2009 • Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. PMID:19657311
• The Biochemical Journal • 2020 • Characterization of a naturally occurring mutation V368M in the human glucagon receptor and its association with metabolic disorders. PMID:32677665

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