Chapter 10 Endocrine Disorders 199 Ketoacidosis ■ Essentials of Diagnosis • Ketonemia defined as blood ketone (β-hydroxy butyrate) >1 mM/L with hyperglycemia • Ketoacidosis defined as venous pH <7.30 with hyperglycemia and ketonemia • Symptoms of ketoacidosis—dehydration, fever, vasodilation, hyperglycemia, Kussmaul respiration, neurologic signs of cere- bral edema (lethargy, headache, dilated pupils), severe abdominal pain (usually a result of hepatic swelling) • Cerebral edema may result from ketoacidosis or may be second- ary to overhydration with hypotonic fluids ■ Differential Diagnosis • Drug-induced hyperglycemia (ketosis rare)—steroids, thiazides, minoxidil, diazoxide, β-blockers • Glucagon-secreting tumors elevate blood sugar (ketosis rare) • Hyperthyroidism, fever, stress elevate blood sugar (ketosis rare) • Patients with type 2 diabetes may be hyperglycemic enough to have hyperosmotic symptoms without ketosis • Alcoholic ketoacidosis occurs with sudden alcohol withdrawal. Rare in children • Extremely high fat diet or starvation causes ketosis with normo- glycemia • The abdominal pain associated with ketoacidosis may suggest a surgical abdomen, especially appendicitis ■ Treatment • Principles of therapy in ketoacidosis—restore fluid volume, inhibit lipolysis, restore normal glucose utilization using insulin, correct total body sodium and potassium depletion, correct acidosis, pre- vent or treat cerebral edema • Ketonemia without acidosis—give 10–20% of total daily insulin dose subcutaneously (H, NL, or regular insulin) every 2–3 hours with oral fluids until ketonuria resolves • Caution must be exercised in treating fluid deficits in diabetic ketoacidosis to avoid hyponatremia and cerebral edema ■ Pearl Hypocalcemia can occur during treatment of diabetic ketoacidosis if all IV potassium is given as potassium phosphate. Hypophosphatemia results if no potassium phosphate is given. Use 50% potassium chloride or acetate and 50% potassium phosphate. 10 This page intentionally left blank 11 11 Inborn Errors of Metabolism Glycogen Storage Diseases 203 Galactosemia 204 Hereditary Fructose Intolerance 205 Disorders of Energy Metabolism 206 Disorders of the Urea Cycle 207 Phenylketonuria (PKU) 208 Hereditary Tyrosinemia 209 Maple Syrup Urine Disease (Branched-Chain Ketoaciduria) (MSUD) 210 Homocystinuria 211 Nonketotic Hyperglycinemia (NKH) 212 Propionic and Methylmalonic Acidemia 213 Isovaleric Acidemia 214 Multiple Carboxylase Deficiency 215 Glutaric Acidemia Type I 216 Long- and Medium-Chain Acyl-CoA Dehydrogenase Deficiency 217 Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency (Lesch-Nyhan Syndrome) 218 Lysosomal Disorders 219 Peroxisomal Disorders 220 Carbohydrate-Deficient Glycoprotein (CDG) Syndromes 221 Smith-Lemli-Opitz (SLO) Syndrome 222 201 Copyright © 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use. This page intentionally left blank Chapter 11 Inborn Errors of Metabolism 203 Glycogen Storage Diseases ■ Essentials of Diagnosis • Caused by enzyme defects in the synthesis and degradation of glycogen • Hepatic forms (I, III, IV, VI, IX) usually produce hepatomegaly, growth failure, fasting hypoglycemia, and acidosis • Myopathic forms produce weakness, rhabdomyolysis • Screening tests—low serum glucose with fasting. Elevated serum lactate, triglycerides, cholesterol, uric acid, and creatine kinase (in myopathic forms). Generally normal transaminases (except in type IV) • Confirmation by specific enzyme assay on leukocytes, liver, or muscle ■ Types of Glycogen Storage Disease • Type Ia (von Gierke disease) glucose-6-phosphatase deficiency produces typical hepatomegaly, hypoglycemia, acidosis • Type Ib glucose-6-phosphatase transporter deficiency also pro- duces neutropenia with recurrent infection • Type II acid maltase deficiency (Pompe disease). Infantile form produces hypertrophic cardiomyopathy and macroglossia • Type III—debrancher enzyme deficiency, less severe symptoms • Type IV—brancher enzyme deficiency causes progressive cirrhosis • Type V and VII—muscle phosphorylase deficiency and phos- phofructokinase deficiency • Type VI—hepatic phosphorylase deficiency—similar to Ia but milder • Type IX—phosphorylase kinase deficiency ■ Treatment • In hepatic forms, prevent fasting hypoglycemia and lactic acido- sis. Frequent meals by day; support blood glucose during sleep with cornstarch feeding or enteral/parenteral carbohydrate admin- istration • In hepatic forms—monitor for late development of hepatic ade- noma, gout, focal segmental glomerulosclerosis • Enzyme replacement therapy may be effective in infantile Pompe disease, but cardiomyopathy usually requires cardiac transplant ■ Pearl Hypoglycemia and massive hepatomegaly with normal spleen and normal serum transaminases should prompt evaluation for glycogen storage disease in infants, especially in the presence of acidosis, “unex- plained” seizures, or failure to thrive. 11 204 Current Essentials: Pediatrics Galactosemia ■ Essentials of Diagnosis • Autosomal recessive defect in galactose-1-phospate uridyltrans- ferase • Galactose-1-phosphate accumulates in liver and renal tubules after lactose ingestion causing liver damage and renal Fanconi syndrome • Milk-fed infants develop emesis, acidosis, direct hyperbiliru- binemia, high transaminases, hepatomegaly, and hepatic dys- function • Cataracts develop secondary to galactitol accumulation in the lens • In severe enzyme deficiency, there is increased risk of language deficit, ovarian failure, mental retardation, tremor, and ataxia even with adequate dietary therapy • Lactosuria, proteinuria, aminoaciduria, and hematuria present. Reducing substances present in urine without glucosuria • Diagnosis by elevated galactose-1-phosphate in red cells or enzyme assay on red blood cells. Newborn screening available ■ Differential Diagnosis • Sepsis of the newborn • Milder variants of galactosemia have better prognosis • Hereditary fructose intolerance, urea cycle abnormalities produce neonatal liver dysfunction and emesis ■ Treatment • Newborn screening allows for early dietary therapy • Lifelong avoidance of lactose with calcium supplementation • Monitor compliance with diet by measuring galactose-1-phosphate concentration in red blood cells ■ Pearl Newborns with Escherichia coli septicemia should be evaluated for galactosemia. 11 Chapter 11 Inborn Errors of Metabolism 205 Hereditary Fructose Intolerance ■ Essentials of Diagnosis • Autosomal recessive deficiency of fructose-1-phosphate aldolase • Hypoglycemia and tissue accumulation of fructose-1-phosphate after ingestion of fructose • Symptoms—failure to thrive, vomiting, direct hyperbilirubine- mia, hepatomegaly, fructosuria, proteinuria, aminoaciduria, and liver failure upon ingestion of fructose or sucrose • Fructose-1-phosphate aldolase is assayed in liver biopsy • IV fructose loading test causes a diagnostic hypoglycemia and hypophosphatemia but is a significant risk to the patient ■ Differential Diagnosis • Galactosemia • Glycogen storage disease (especially type IV) • Neonatal severe bacterial infections • Acute or chronic hepatitis • Neonatal iron storage disease ■ Treatment • Strict dietary avoidance of fructose and sucrose • Vitamin supplementation • Monitor dietary compliance by transferrin glycoform analysis ■ Pearl Sucrose (disaccharide of fructose and glucose) is found in so many foods and medications that diet management of fructose intolerance is difficult. Later, children voluntarily avoid fruits and sweets. They develop dental caries so rarely that a dentist sometimes makes this diagnosis. 11 206 Current Essentials: Pediatrics Disorders of Energy Metabolism ■ Essentials of Diagnosis • Most of the common disorders of mitochondrial metabolism involve pyruvate dehydrogenase (PD) and mitochondrial respira- tory chain complexes • Disorders of gluconeogenesis are less common—pyruvate car- boxylase deficiency, fructose-diphosphatase deficiency, glycogen storage disease type I • Elevated lactate in blood or cerebrospinal fluid (CSF) with normal lactate/pyruvate ratio in PD deficiency and increased ratio in res- piratory chain abnormalities • Symptoms involve many systems—variable dysfunction of brain, muscles, kidney, endocrine, cardiac, gastrointestinal, liver, pan- creas • Inheritance is both autosomal recessive and maternal via the mito- chondrial genome • Ragged red fibers and abnormal mitochondria are found in skele- tal muscle. Enzyme assay in fibroblasts or muscle available in some cases ■ Differential Diagnosis • Secondary lactic acidosis caused by hypoxia, ischemia, or sam- pling error • Multiple carboxylase deficiency • D-Lactic acidosis—bacterial fermentation in the intestine pro- duces D-lactate, which causes encephalopathy when absorbed in large quantities. D-lactic acidosis is often missed because most laboratories measure only L-lactate. • Fatty acid oxidation defects ■ Treatment • Treatments for PD deficiency have variable effectiveness— ketogenic diet, lipoic acid, dichloroacetate, and thiamine • Treat coenzyme Q deficiency with exogenous coenzyme Q • Treatment of respiratory chain defects—coenzyme Q and riboflavin occasionally helpful ■ Pearl Suspect disorders of energy metabolism when infants present with aci- dosis accompanied by chronic dysfunction or deterioration of several organ systems at the same time. 11 Chapter 11 Inborn Errors of Metabolism 207 Disorders of the Urea Cycle ■ Essentials of Diagnosis • Ammonia produced during catabolism of amino acids is excreted as urea through the action of the urea cycle enzymes • Defects in ornithine transcarbamoylase, carbamoyl phosphate synthetase, arginosuccinate synthase, and arginosuccinate lyase present in neonates with hyperpnea, emesis, alkalosis, hyperam- monemia, and fatal encephalopathy • Milder defects in these enzymes have milder encephalopathy and hyperammonemia during intercurrent illness or high protein intake • Arginase deficiency presents with spastic tetraplegia and behav- ioral changes in childhood • Elevated serum ammonia is the key to initial diagnosis • Newborn screening available in many states ■ Differential Diagnosis • Glutaric acidemia type II and other fatty acid oxidation defects • Acute or chronic liver failure causes hyperammonemia • Propionic acidemia and other organic acidopathies • Transient hyperammonemia of the newborn • Mitochondrial ornithine transporter defect produces high serum ammonia, ornithine and homocitrulline (HHH syndrome) ■ Treatment • Hemodialysis required in severely affected neonates • In hyperammonemic crisis, protein intake should be stopped and glucose given • IV arginine increases nitrogen excretion in citrullinemia and arginosuccinic aciduria • Sodium benzoate and sodium phenylacetate increase ammonia excretion in all urea cycle defects • Long-term therapy—low protein diet, supplemental oral arginine, citrulline, sodium benzoate, or sodium phenylacetate • Liver transplantation may be curative but does not reverse brain injury caused by neonatal hyperammonemia ■ Pearl A neonate with tachypnea, alkalosis, and vomiting should be evaluated immediately for a urea cycle defect. Stop oral protein intake and give IV glucose while awaiting initial laboratory evaluation. 11 208 Current Essentials: Pediatrics Phenylketonuria (PKU) ■ Essentials of Diagnosis • Deficiency of phenylalanine hydroxylase occurs in 1:10,000 Caucasian births. Autosomal recessive • Symptoms—mental retardation, hyperactivity, seizures, light com- plexion, eczematoid skin rash • Severe deficiency associated with serum phenylalanine >20 mg/dL on regular diet. Low or normal serum tyrosine and normal pterins • Newborn screening is highly reliable ■ Differential Diagnosis • Normal offspring of mothers with PKU may have transient hyper- phenylalaninemia at birth • Dihydropteridine reductase deficiency produces elevated pterin metabolites, seizures, and psychomotor regression secondary to neuronal serotonin and dopamine deficiency in affected infants • Defects in biopterin synthesis produce low serum pterins and variable phenylalanine. Symptoms include myoclonus, tetraple- gia, dystonia, oculogyric crises • Benign tyrosinemia with moderate hyperphenylalaninemia occurs in premature infants due to transient 4-hydroxyphenylpyruvic acid oxidase deficiency ■ Treatment • Lifelong limitation of dietary phenylalanine to maintain serum level <6 mg/dL • Dietary therapy is most effective when started at birth, but may also improve hyperactivity, irritability, and distractibility if started later in life • Poorly controlled diet during pregnancy causes mental retardation, microcephaly, growth retardation, and congenital heart disease in the fetus ■ Pearl Control of PKU during pregnancy is important as elevated phenylala- nine is teratogenic. Female patients should be encouraged to use con- traceptives to prevent accidental conception and accidental injury to the fetus. 11 [...]... to child abuse unless metabolic screening is performed Chapter 11 Inborn Errors of Metabolism 217 Long- and Medium-Chain Acyl-CoA Dehydrogenase Deficiency ■ Essentials of Diagnosis • • • • • ■ Deficiency of very-long- and medium-chain acyl-CoA dehydrogenase (VLCAD, MCAD, and long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD]) cause episodic hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, and... thromboembolic events, and lens dislocations 212 Current Essentials: Pediatrics Nonketotic Hyperglycinemia (NKH) ■ Essentials of Diagnosis • • • • • 11 ■ Differential Diagnosis • • • • • • ■ Autosomal recessive deficiency of various subunits of the glycine cleavage enzyme system Glycine accumulation in brain disturbs neurotransmission of the glycinergic and N-methyl-D-aspartate receptor In severe disease, newborns... in cerebral development • 30–60% of the genetic material deleted from 5p in most patients • 80% of mutations are sporadic • 10– 15% of cases due to translocation, mosaicism, ring formation • ■ Pearl The 5p deletion is of paternal origin in about 80% of de novo cases 12 234 Current Essentials: Pediatrics Williams Syndrome (7q-) ■ Essentials of Clinical Diagnosis At birth—small for gestational age, elfin... LCHAD may develop HELLP syndrome (hypertension, elevated liver function tests, and low platelets) 218 Current Essentials: Pediatrics Hypoxanthine-Guanine Phosphoribosyl Transferase Deficiency (Lesch-Nyhan Syndrome) ■ Essentials of Diagnosis • • • • • 11 ■ Differential Diagnosis • • • ■ Hypoxanthine-guanine phosphoribosyltransferase (HPRT) converts hypoxanthine and guanine to inosine and guanosine monophosphate... functions in the neonate are affected, especially in association with hepatic functional abnormalities, consider type Ia CDG syndrome 11 222 Current Essentials: Pediatrics Smith-Lemli-Opitz (SLO) Syndrome ■ Essentials of Diagnosis Autosomal recessive deficiency of 7-dehydrocholesterol δ7reductase • Neonatal onset microcephaly, poor growth, mental retardation, dysmorphic facies, 2–3 toe syndactyly, heart... hereditary fructose intolerance, mitochondrial disease Tylenol overdose Many chronic liver diseases have elevated serum amino acids including tyrosine Niemann-Pick type C Neonatal hemochromatosis Treatment 2-( 2-nitro-4-trifluoromethylbenzoyl )-1 ,3-cyclohexanedione (NTBC) decreases production of toxic metabolites and improves liver, renal, and neurologic disease • When started early, NTBC reduces the risk... and Maroteaux-Lamy syndrome This therapy is only effective for non-neurologic symptoms • ■ Pearl Accumulation of abnormal mucopolysaccharides and lipids causes abnormalities of bone, viscera, CNS, and RE system Growth failure, neurodegeneration, organomegaly, and coarse facies are typical findings in many of these conditions 11 220 Current Essentials: Pediatrics Peroxisomal Disorders ■ Essentials of... carcinoma • Liver transplant is curative • ■ Pearl This autosomal recessive condition is especially common in Scandinavia and in the Chicoutimi-Lac St Jean region of Quebec 11 210 Current Essentials: Pediatrics Maple Syrup Urine Disease (Branched-Chain Ketoaciduria) (MSUD) ■ Essentials of Diagnosis • • • • • 11 ■ Autosomal recessive deficiency of enzyme catalyzing oxidative decarboxylation of keto acid forms... Dysmorphology Trisomy 21 (Down Syndrome) 2 25 Trisomy 18 226 Fragile X Syndrome 227 Myotonic Dystrophy (DM1) 228 Friedreich Ataxia 229 Turner Syndrome 230 12 Klinefelter Syndrome (XXY) 231 Wolf-Hirschhorn Syndrome (4p-) 232 Cri Du Chat Syndrome (5p-) 233 Williams Syndrome (7q-) 234 Spectrum of 22q Deletion (DiGeorge Syndrome,... chromosome 4 Deletion of 4p16 (also called 4p-) Pearl The developmental abnormalities of nose, orbits, and forehead are said to resemble the ancient Greek warrior helmet Chapter 12 Genetics and Dysmorphology 233 Cri Du Chat Syndrome (5p-) ■ Epidemiology and Clinical Diagnosis • • • • • • ■ Diagnosis • • • ■ 1:20,000 50 ,000 live births Neonates have high-pitched cat-like cry, which disappears by age 2 years . and Medium-Chain Acyl-CoA Dehydrogenase Deficiency ■ Essentials of Diagnosis • Deficiency of very-long- and medium-chain acyl-CoA dehydro- genase (VLCAD, MCAD, and long-chain 3-hydroxyacyl-CoA dehydrogenase. “unex- plained” seizures, or failure to thrive. 11 204 Current Essentials: Pediatrics Galactosemia ■ Essentials of Diagnosis • Autosomal recessive defect in galactose-1-phospate uridyltrans- ferase •. elevated serum amino acids including tyrosine • Niemann-Pick type C • Neonatal hemochromatosis ■ Treatment • 2-( 2-nitro-4-trifluoromethylbenzoyl )-1 ,3-cyclohexanedione (NTBC) decreases production of