The first pediatric case of glucagon receptor defect due to biallelic mutations in GCGR is identified by newborn screening of elevated arginine

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 α 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. Keywords: Glucagon receptor, Newborn screening, GCGR mutation, Hyperaminoacidemia, Mahvash disease, Pancreatic α cell hyperplasia (ACH), Pancreatic neuroendocrine tumor (PNET

Cell-Free DNA Screening Positive for Monosomy X: Clinical Evaluation and Management of Suspected Maternal or Fetal Turner Syndrome

Initially provided as an alternate to evaluation of serum analytes and nuchal translucency for the evaluation of pregnancies at high-risk of Trisomy 21, cell-free DNA (cfDNA) screening for fetal aneuploidy, also referred to as non-invasive prenatal screening (NIPS), can now also screen for fetal sex chromosome anomalies (SCAs) such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a SCA resulting from the complete or partial absence of the second X chromosome, allows for medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility protection and support as well improved neurocognitive outcomes. However, cfDNA screening for SCAs and monosomy X in particular is associated with high false positive rates and low positive predictive value. A cfDNA result positive for monosomy X may represent fetal TS, maternal TS, or confined placental mosaicism. A positive screen for monosomy X with discordant results of diagnostic fetal karyotype presents unique interpretation and management challenges due to potential implications for previously unrecognized maternal Turner syndrome (TS). . The current international consensus clinical practice guidelines for the care of individuals with TS throughout the lifespan do not specifically address management of individuals with a cfDNA screen positive for monosomy X. The objective of this manuscript is to provide context and expert-driven recommendations for maternal and/or fetal evaluation and management when cfDNA screening is positive for monosomy X. We highlight unique challenges of cfDNA screening that is incidentally positive for monosomy X, present recommendations for determining if the result is a true positive and discuss when diagnosis of TS is applicable to the fetus or the mother. While we defer the subsequent management of confirmed TS to the clinical practice guidelines, we highlight unique considerations for these individuals initially identified through cfDNA screening