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  • br Introduction The glucagon receptor GCGR


    Introduction The glucagon receptor (GCGR) is a G-protein-coupled receptor expressed mainly in the liver and kidney. Upon glucagon binding, it activates the stimulatory G protein (Gs) and increases cAMP level, subsequently transducing glucagon signaling involved in glucose, amino acids and lipid metabolism [1]. Mahvash disease is the only reported human phenotype associated with glucagon receptor defect. It is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome caused by biallelic inactivating mutations in GCGR gene [2]. Since first reported in 2008, 11 cases have been described [3,4]. All are adult patients with variable age at diagnosis (25–74 years old); no pediatric cases have been reported, nor is there much known about the pediatric medical histories of the affected adults. The typical presentation is non-specific abdominal pain and subsequent abdomen imaging study identifies pancreatomegaly with or without clear masses. The pathological findings are characterized by diffuse pancreatic α cell hyperplasia (ACH) with or without PNETs. Although patients have extreme hyperglucagonemia, there is no evidence of glucagonoma syndrome, such as skin rash, stomatitis, hyperglycemia or weight loss, because of the dysfunctional GCGR. In the murine Gcgr−/− model, the complete block in glucagon signaling reduces hepatic uptake and catabolism of amino acids by altering hepatic gene expression of amino Annexin V-Cy3 Apoptosis Kit Plus receptor transporters and catabolic enzymes. As a consequence, circulating plasma amino acids are elevated [5,6]. Hyperaminoacidemia, especial elevated l-glutamine, stimulates mTOR signaling leading to pancreatic ACH and increased glucagon production, thus revealing a hepatic α cell axis as the basis of strong negative feedback mechanism in Gcgr−/− mice [5,6], which is outlined in Fig. 1. Hyperaminoacidemia was also reported in a patient with Mahvash disease [7], however, it is unknown if hyperaminoacidemia is a feature of all cases of GCGR defect, even presymptomatically. Here, we describe the first pediatric case of glucagon receptor defect due to biallelic mutations in the GCGR, uniquely identified by positive newborn screening (NBS) for elevated arginine. Although expanded NBS has allowed the identification of many inborn errors of metabolism, GCGR defect associated with hyperargininemia or hyperaminoacidemia has never been considered or reported though NBS [8]. The similar pattern of plasma amino acids in the Gcgr−/− mouse and our case, previously unrecognized, may represent an early opportunity to detect asymptomatic Mahvash patients.
    Patients and methods
    Discussion All previously reported cases of glucagon receptor defect (Mahvash disease) have been diagnosed in symptomatic adults with the finding of pancreatic ACH with or without PNETs. To our knowledge, this is the first pediatric case of GCGR defect presymptomatically identified by an elevated arginine level on NBS. The similarity of her persistent hyperaminoacidemia to that of the Gcgr−/− mouse model of Mahvash disease lead to the ultimate diagnosis, confirmed by extreme hyperglucagonemia and biallelic inactivating GCGR mutations. Functional studies of the novel homozygous c.958_960del (p.Phe320del) variant in GCGR demonstrated nearly complete inhibition of glucagon signaling. This case adds a pediatric phenotype to the clinical spectrum of human GCGR defect. The hyperaminoacidemia is characterized by elevations of glutamine, alanine, dibasic amino acids (arginine, lysine and ornithine), threonine, and serine after 4–5 h fasting. Essential amino acids, such as phenylalanine and branch-chain amino acids (BCAAs) are usually not elevated unless protein intake is quite high (Table 1). Notably, this pattern can be affected not only by protein intake, but also the timing of specimen collection. Hyperaminoacidemia can be essentially normalized after overnight fasting. Therefore, a normal amino acid profile in the setting of low natural protein intake or prolong fasting does not rule out GCGR defect. Larger et al. reported hyperaminoacidemia, particularly the glucogenic amino acids, in a 54-year old patient with symptomatic GCGR defect. Like our patient, alanine was elevated at 978 μmol/L (normal range, 250–400 μmol/L), but a complete amino acid profile was not provided. Here, we report a detailed characterization of the plasma amino acid pattern from our patient. We propose that this unique amino acid profile can be used to identify other patients with GCGR defect. The characteristic profile will aid biochemical genetics laboratories to consider glucagon signaling abnormalities in the differential diagnosis and ensure appropriate follow-up. Importantly, more patients might be identified by the NBS for elevated arginine level, like our patient, thereby further expanding the spectrum of GCGR defect. Currently, pharmacologic inhibition of the glucagon receptor is a potential treatment of diabetes mellitus. It is unclear if this inhibition could cause a similar hyperaminoacidemia characteristic of GCGR defect. It may be prudent to assess plasma amino acid profiles as part of the clinical trials for these drugs. One long-term consequence could be unintentionally activating the alpha cell axis thereby stimulating ACH and tumor development.