ABSTRACT
Cytosolic PEPCK deficiency (PCKDC) is a rare autosomal recessive inborn error of metabolism, which can present with hypoglycemia, lactic acidosis, and liver failure. It is caused by biallelic pathogenic variants in the PCK1 gene. Only four PCK1 variants have been previously reported in seven patients with PCKDC, and their clinical course of this condition has not been well characterized. Here, we report a Hispanic male with novel biallelic PCK1 variants, p.(Gly430Asp) and p.(His496Gln), who had a unique clinical presentation. He presented with a new onset of growth failure, elevated blood lactate, transaminitis, and abnormal urine metabolites profile, but he has not had documented hypoglycemia. Growth restriction happened due to insufficient caloric intake, and it was improved with nutritional intervention. PCKDC is a manageable disorder and therefore appropriate nutritional and clinical suspicion from typical lab abnormalities which lead to molecular confirmation tests are essential to prevent poor clinical outcomes.
Subject(s)
Codon, Nonsense , Energy Intake/genetics , Failure to Thrive/genetics , Growth Disorders/genetics , Intracellular Signaling Peptides and Proteins/genetics , Phosphoenolpyruvate Carboxykinase (GTP)/genetics , Amino Acid Sequence , Birth Weight , Child, Preschool , Citric Acid Cycle , Cytosol/enzymology , Failure to Thrive/blood , Failure to Thrive/urine , Female , Food Preferences , Genotype , Growth Disorders/blood , Growth Disorders/urine , Humans , Infant Food , Intracellular Signaling Peptides and Proteins/deficiency , Male , Microcephaly/genetics , Pedigree , Phosphoenolpyruvate Carboxykinase (GTP)/deficiency , Pregnancy , Pregnancy Complications , Seizures , Sequence Alignment , Sequence Homology, Amino AcidABSTRACT
Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and neurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.
Subject(s)
Bone Resorption/pathology , MAP Kinase Signaling System , Proto-Oncogene Proteins p21(ras)/genetics , Signal Transduction , Absorptiometry, Photon , Adolescent , Adult , Amino Acids/urine , Biomarkers/urine , Bone Density , Bone Resorption/genetics , Bone Resorption/urine , Case-Control Studies , Child , Child, Preschool , Chromatography, High Pressure Liquid , Cohort Studies , Collagen/urine , Costello Syndrome/genetics , Costello Syndrome/pathology , Costello Syndrome/urine , DNA Mutational Analysis , Ectodermal Dysplasia/genetics , Ectodermal Dysplasia/pathology , Ectodermal Dysplasia/urine , Facies , Failure to Thrive/genetics , Failure to Thrive/pathology , Failure to Thrive/urine , Female , Genetic Testing , Heart Defects, Congenital/genetics , Heart Defects, Congenital/pathology , Heart Defects, Congenital/urine , Humans , Hydrolysis , Male , Noonan Syndrome/genetics , Noonan Syndrome/pathology , Noonan Syndrome/urine , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Young AdultABSTRACT
As a simple non-invasive test of possible pancreatic insufficiency 10 healthy infants, 13 infants with cystic fibrosis, and nine infants with unexplained diarrhoea and failure to thrive were given an emulsion containing fluorescein dilaurate and mannitol by mouth. A spot urine specimen was collected and results expressed as urinary fluorescein to mannitol ratios. Sensitivity of the test was 96% and specificity was 95%.
Subject(s)
Exocrine Pancreatic Insufficiency/diagnosis , Fluoresceins , Mannitol , Cystic Fibrosis/urine , Diarrhea/urine , Exocrine Pancreatic Insufficiency/urine , Failure to Thrive/urine , Female , Fluorescein , Fluoresceins/analysis , Humans , Infant , Male , Mannitol/urine , Sensitivity and SpecificityABSTRACT
In 1962 Bartter et al. described a clinical syndrome characterized by growth and mental retardation, hypokalemic alkalosis, increased aldosterone secretion rate and increased plasma angiotensin II concentration in the presence of normal blood pressure. The inheritance pattern has been reported as autosomal recessive or as sporadic. Since that time 37 cases have been reported in pediatric age, describing a wide spectrum of clinical and biochemical features. For the diagnosis the following criteria must be present: hypokalemia, hypochloremia, alkalosis, hyperreninemia in the presence of a normal blood pressure and elevated urinary K and Cl excretion, in the absence of other conditions that might cause similar features. A case of Bartter's disease is herein reported with our experience in the diagnosis, treatment and follow-up.
