Familial Mahvash disease with metastatic pancreatic NET and MEN1 mutations

Area of Science:

• Endocrinology
• Genetics
• Oncology

Background:

• Mahvash disease, characterized by pancreatic glucagon cell hyperplasia and neoplasia (GCHN) and hyperglucagonaemia, results from homozygous pathogenic glucagon receptor gene (GCGR) mutations.
• It is an extremely rare autosomal recessive hereditary pancreatic neuroendocrine tumour (panNET) syndrome, with only seven cases previously reported.

Purpose of the Study:

• To investigate the genotype-phenotype correlation in Mahvash disease and the development of panNET.
• To characterize a novel GCGR germline variant within a single family exhibiting GCHN.

Main Methods:

• Detailed clinical, molecular, and pathological analysis of six family members from a single family.
• Review of medical records up to November 2024 to assess disease progression and outcomes.

Main Results:

• Eight family members carried the likely pathogenic GCGR c.455C>T (p.Ser152Phe) germline variant; three were homozygous.
• Two homozygous patients displayed GCHN, with one developing lymphogenic and hepatic metastases.
• Three patients had glucagon-positive tumours with somatic MEN1 mutations; one heterozygous family member had multiple small panNETs.

Conclusions:

• This study reports the first family with multiple GCHN cases due to a novel germline GCGR variant.
• It presents the first GCHN patient with liver metastases and a heterozygous patient with multiple small panNETs.
• Findings underscore the malignant potential of GCHN and suggest a role for somatic MEN1 mutations in glucagon-positive panNET development.