Glucagonoma With Necrolytic Migratory Erythema: Metabolic Profile and Detection of Biallelic Inactivation of DAXX Gene.

Abstract

Context:

Necrolytic migratory erythema (NME) occurs in approximately 70% of patients with glucagonoma syndrome. Excessive stimulation of metabolic pathways by hyperglucagonemia, which leads to hypoaminoacidemia, contributes to NME pathogenesis. However, the molecular pathogenesis of glucagonoma and relationships between metabolic abnormalities and clinical symptoms remain unclear.

Patient:

A 53-year-old woman was referred to our hospital with a generalized rash and weight loss. NME was diagnosed by histopathological examination of skin biopsy tissue. Laboratory tests revealed diabetes, hyperglucagonemia, marked insulin resistance, severe hypoaminoacidemia, ketosis, and anemia. Enhanced computed tomography scans detected a 29-mm pancreatic hypervascular tumor, which was eventually diagnosed as glucagonoma. Preoperative treatment with octreotide long-acting release reduced the glucagon level, improved the amino acid profile, and produced NME remission. Surgical tumor excision normalized the metabolic status and led to remission of symptoms, including NME.

Interventions:

Whole-exome sequencing (WES) and subsequent targeted capture sequencing, followed by Sanger sequencing and pyrosequencing, identified biallelic alteration of death-domain associated protein (DAXX) with a combination of loss of heterozygosity and frameshift mutations (c.553_554del:p.R185fs and c.1884dupC:p.C629fs) in the glucagonoma. Consistently, immunohistochemistry confirmed near-absence of DAXX staining in the tumor cells. Tumor expression of glucagon and somatostatin receptor subtype 2 and 3 messenger RNA was markedly upregulated.

Conclusions:

This is a report of glucagonoma with biallelic inactivation of DAXX determined by WES. The tumor manifested as glucagonoma syndrome with generalized NME. This case showed the relationship between hypoaminoacidemia and NME status. Further investigations are required to elucidate the underlying mechanisms of NME onset and glucagonoma tumorigenesis.

• Authors: Ai Tamura, Tatsuki Ogasawara, Yoichi Fujii, Hiyori Kaneko, Akitoshi Nakayama, Seiichiro Higuchi, Naoko Hashimoto, Yui Miyabayashi, Masanori Fujimoto, Eri Komai, Takashi Kono, Ikki Sakuma, Hidekazu Nagano, Sawako Suzuki, Hisashi Koide, Koutaro Yokote, Kozue Iseki, Rena Oguma, Hiroyuki Matsue, Hiroyuki Nojima, Kensuke Sugiura, Hideyuki Yoshitomi, Masayuki Ohtsuka, Bahityar Rahmutulla, Atsushi Kaneda, Naoko Inoshita, Seishi Ogawa, Tomoaki Tanaka
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 103 Issue 7 Pg. 2417-2423 (07 01 2018) ISSN: 1945-7197 [Electronic] United States
• PMID: 29688432 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Co-Repressor Proteins
• DAXX protein, human
• Molecular Chaperones
• Nuclear Proteins

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Alleles
• Co-Repressor Proteins
• Female
• Gene Silencing
• Glucagonoma (genetics)
• Humans
• Metabolome (genetics)
• Middle Aged
• Molecular Chaperones
• Necrolytic Migratory Erythema (genetics)
• Nuclear Proteins (genetics)
• Pancreatic Neoplasms (genetics)