期刊
MOLECULAR GENETICS AND METABOLISM REPORTS
卷 17, 期 -, 页码 46-52出版社
ELSEVIER
DOI: 10.1016/j.ymgmr.2018.09.006
关键词
Glucagon receptor; Newborn screening; GCGR mutation; Hyperaminoacidemia; Mahvash disease; Pancreatic alpha cell hyperplasia (ACH); Pancreatic neuroendocrine tumor (PNET)
资金
- Youth Innovation Promotion Association
- Natural Science Foundation of Shanghai, China [18ZR1447800]
- National Institutes of Health, United State [DK071662]
- Fudan-SIMM Joint Research Fund, China [FU-SIMM-20174003]
- SA-SIBS Scholarship Program
Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in adults with pancreatic a cell hyperplasia and PNETs. We describe a 7-year-old girl with persistent hyperaminoacidemia, notable for elevations of glutamine (normal ammonia), alanine (normal lactate), dibasic amino acids (arginine, lysine and ornithine), threonine and serine. She initially was brought to medical attention by an elevated arginine on newborn screening (NBS) and treated for presumed arginase deficiency with a low protein diet, essential amino acids formula and an ammonia scavenger drug. This treatment normalized plasma amino acids. She had intermittent emesis and anorexia, but was intellectually normal. Arginase enzyme assay and ARG1 sequencing and deletion/duplication analysis were normal. Treatments were stopped, but similar pattern of hyperaminoacidemia recurred. She also had hypercholesterolemia type IIa, with only elevated LDL cholesterol, despite an extremely lean body habitus. Exome sequencing was initially non-diagnostic. Through a literature search, we recognized the pattern of hyperaminoacidemia was strikingly similar to that reported in the Gcgr(-/-) knockout mice. Subsequently the patient was found to have an extremely elevated plasma glucagon and a novel, homozygous c.958_960del (p.Phe320del) variant in GCGR. Functional studies confirmed the pathogenicity of this variant. This case expands the clinical phenotype of GCGR defect in children and emphasizes the clinical utility of plasma amino acids in screening, diagnosis and monitoring glucagon signaling interruption. Early identification of a GCGR defect may provide an opportunity for potential beneficial treatment for an adult onset tumor predisposition disease.
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