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Eric Niederhoffer SIU-SOM

Year Two Review Part 1. Eric Niederhoffer SIU-SOM. Outline. Newborn screening Glycolytic pathway Pentose phosphate pathway Fructose pathway Pyruvate metabolism and citric acid cycle β-Oxidation Urea cycle Branched-chain amino acids Aromatic amino acids Cholesterol pathway

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Eric Niederhoffer SIU-SOM

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  1. Year Two Review Part 1 Eric Niederhoffer SIU-SOM

  2. Outline • Newborn screening • Glycolytic pathway • Pentose phosphate pathway • Fructose pathway • Pyruvate metabolism and citric acid cycle • β-Oxidation • Urea cycle • Branched-chain amino acids • Aromatic amino acids • Cholesterol pathway • Steroid pathway

  3. Newborn Screening • Amino acid disorders • Arginemia/arginase deficiency • Arginosuccinyl CoA lyase deficiency • Citrullinemia/argininosuccinatesynthetase deficiency • Homocystinemia/cystathionine β-synthase deficiency • Maple syrup urine disease • Phenylketonuria • Tyrosinemia • Fatty acid oxidation disorders • Carnitine transporter deficiency • Carnitine/acylcarnitinetranslocase deficiency • Carnitinepalmitoyltransferase deficiency Type 1 • Carnitinepalmitoyltransferase deficiency Type 2 • Glutaricacidemia Type 2 • Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency • Medium-chain acyl CoA dehydrogenase deficiency • Short-chain acyl CoA dehydrogenase deficiency • Short-chain 3-hydroxyacyl CoA dehydrogenase deficiency • Trifunctional protein deficiency • Very long-chain acyl CoA dehydrogenase deficiency

  4. Newborn Screening • Organic acids disorders • β-Ketothiolase deficiency • Glutaricacidemia Type 1 • Glutaricacidemia Type 2 • Holocarboxylasesynthetase deficiency • 3-Hydroxy-3-methylglutaryl CoA lyase deficiency • Isobutyryl CoA dehydrogenase deficiency • Isovaleicaciduria • Methylmalonicacidemia • Methylmalonicacidemia with homocystinuria • Propionic acidemia • 3-Methylcrotonyl CoA carboxylase deficiency • 2-Methylbutyryl CoA dehdrogenase deficiency • Other disorders • α-Thalassemia • Congenital adrenal hyperplasia • Cystic fibrosis • Critical congenital heart disease • Congenital hypothyroidism • Galactosemia • Sickle cell disease

  5. Glycolytic Pathway glucose Hexokinase (glucokinase) ATP glucose-6-phosphate Glucose phosphate isomerase fructose-6-phosphate Phosphofructokinase-1 ATP fructose-1,6-bisphosphate Aldolase Aldolase Triose phosphate isomerase dihydroxyacetone phosphate glyceraldehyde-3-phosphate NAD+ Glyceraldehyde-3-phosphate dehydrogenase Bisphosphoglyceratemutase 1,3-bisphosphoglycerate NADH 2,3-bisphosphoglycerate ATP 3-Phophoglycerate kinase 3-phosphoglycerate 2,3-Bisphosphoglycerate phosphatase Phosphoglyceratemutase 2-phosphoglycerate Enolase phosphoenolpyruvate ATP Pyruvate kinase Lactate dehydrogenase lactate pyruvate NAD+ NADH

  6. Glycolytic Pathway Disorders • Hexokinase– rare autosomal recessive, nonspherocytic hemolytic anemia. • Phosphoglucoseisomerase– rare autosomal recessive, hemolytic anemia, less common neurological problems. • Phosphofructokinase – (Glycogen storage disease type VII; Tarui disease) rare autosomal recessive, three subtypes (classic, infantile onset, and late onset), myoglobinuria, hyperuricemia, hemolytic anemia when erythrocyte isoform is involved. Avoid high carbohydrate meals. • Adolase – rare autosomal recessive, three genes (ALDOA, mainly muscle; ALDOB, mainly liver, some kidney and intestine; ALDOC, mainly brain), ALDOA has myopathy and hemolytic anemia. ALDOB (hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis, treat by restricting fructose. • Triosephosphateisomerase– rare autosomal recessive, congenital hemolytic anemia, progressive neuromuscular dysfunction, susceptibility to bacterial infection, and cardiomyopathy. • Glyceraldehyde-3-phosphate dehydrogenase– rare autosomal recessive, very little information available.

  7. Glycolytic Pathway Disorders • Bisphosphoglyceratemutase/phosphatase–rare, hemolytic anemia, polycythemia, increased hemoglobin affinity for O2. • Phosphoglycerate kinase– rare X-linked recessive, two forms, chronic hemolytic anemia, myopathic (myoglobinuria) with muscle symptoms especially upon exercise. • Phosphoglyceratemutase– rare autosomal recessive, mainly affects skeletal muscle. • Enolase– rare autosomal recessive, affects muscle, exercise intolerance. • Pyruvate kinase–autosomal recessive, most common inherited cause of nonspherocytic hemolytic anemia (normochromic, normocytic, and reticulocytosis), pallor, jaundice, fatigue, dyspnea, tachycardia and splenomegaly. Treatment is primarily supportive, avoid impact sports with splenomegaly, avoid large doses of salicylates, supplement with folic acid and B vitamins, use blood transfusions with decreased hemoglobin concentrations. • Lactate dehydrogenase– rare autosomal recessive, two forms, LDHA is mainly skeletal muscle, LDHB mainly heart muscle, LDH is tetramer of combination of LDHA and LDHB subunits. LDHA deficiency symptoms include fatigue, muscle pain, exercise intolerance, rhabdomyolysis, and myoglobinuria. LDHB deficiency is asymptomatic.

  8. Pentose Phosphate Pathway Glucose-6-phosphate dehydrogenase Lactonase 6-phosphogluconate glucose-6-phosphate 6-phosphoglucono-δ-lactone NADP+ NADP+ NADPH 6-Phosphogluconate dehydrogenase NADPH ribulose-5-phosphate Transketolase fructose-6-phosphate Ribulose phosphate 3 epimerase Ribose-5-phosphate isomerase xylulose-5-phosphate ribose-5-phosphate glyceraldehyde-3-phosphate Transketolase Transaldolase erythrose-4-phosphate sedoheptulose-7-phosphate fructose-6-phosphate glyceraldehyde-3-phosphate

  9. Pentose Phosphate Pathway Disorders • Glucose-6-phosphate dehydrogenase– X-linked recessive, most common disease-producing enzymopathy, hemolytic anemia most often triggered by bacterial or viral infections, oxidative drugs (sulfonamides and malarials), or eating fava beans (favism). Treatment is supportive, bed rest and oxygen, avoid triggers (drugs, diet, environmental). • Ribose-5-phosphate isomerase– very rare (single report), leukoencephalopathy and peripheral neuropathy. • Transketolase– very rare (single report), liver cirrhosis and hepatosplenomegaly.

  10. Fructose Pathway fructose Fructokinase ATP fructose-1-phosphate Aldolase B Triose phosphate isomerase dihydroxyacetone phosphate glyceraldehyde glyceraldehyde-3-phosphate Triose kinase ATP

  11. Fructose Pathway Disorders • Fructokinase– autosomal recessive, benign. • AldolaseB– autosomal recessive,(hereditary fructose intolerance) vomiting, hypoglycemia, failure to thrive, cachexia, hepatomegaly, jaundice, coagulopathy, coma, renal Fanconi syndrome, severe metabolic acidosis. Treatment by restricting fructose intake.

  12. Pyruvate Metabolism and Citric Acid Cycle Lactate dehydrogenase lactate pyruvate Pyruvate dehydrogenase NAD+ NADH acetyl-CoA Pyruvate carboxylase 2ATP NADH Citrate synthase oxaloacetate citrate Malate dehydrogenase Aconitase NAD+ malate isocitrate NAD+ Fumarase Isocitrate dehydrogenase NADH fumarate α-ketoglutarate NAD+ Succinate dehydrogenase α-Ketoglutarate dehydrogenase succinate succinyl-CoA Succinyl-CoA synthetase FADH2 FAD+ NADH GTP GDP

  13. Pyruvate and Citric Acid Cycle Disorders • Pyruvate dehydrogenase– rare, mostly sporadic, X-linked recessive (E1 α-subunit), autosomal recessive (X protein and E3 subunit), developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, seizures (all dependent on amount of residual enzyme activity, <15% incompatible with life), increased serum and CSF lactate and pyruvate concentrations, increased serum and urine alanine; for E2 enzyme deficiency, hyperammonemia and increased nonspecific serum amino acid concentrations; for E2 enzyme deficiency, increased serum branched-chain amino acids concentrations, increased serum and urine α-ketoglutarateconcentrations, enzyme assays on leukocytes, fibroblasts. Treatment by limiting carbohydrates and increasing fats, supplement with thiamine, carnitine, and lipoic acid. • Pyruvate carboxylase – rare, autosomal recessive, poor feeding, vomiting, and lethargy, Mental, psychomotor, growth retardation, poor or degenerative neurologic development, metabolic acidosis, increased serum lactate and pyruvate concentrations, increased serum lactate to pyruvate concentration ratio, decreased serum glucose during fasting, hyperalaninemia, hypercitrullinemia, hyperlysinemia, and decreased serum aspartic acid concentrations, hyperammonemia, increased CSF lactate, pyruvate, glutamic acid and proline concentrations, decreased CSF glutamine concentrations, enzyme assay of leukocytesor culturedfibroblasts, absence of pyruvate carboxylase mRNA. Treatment with thiamine, lipoicacid, dichloroacetate, citrate, and aspartic acid.

  14. Pyruvate and Citric Acid Cycle Disorders • Lactate dehydrogenase– rare autosomal recessive, two forms, LDHA is mainly skeletal muscle, LDHB mainly heart muscle, LDH is tetramer of combination of LDHA and LDHB subunits. LDHA deficiency symptoms include fatigue, muscle pain, exercise intolerance, rhabdomyolysis, and myoglobinuria. LDHB deficiency is asymptomatic. • α-Ketoglutaratedehydrogenase– autosomal recessive, psychomotor retardation, hypotonia, ataxia and convulsions (symptoms of Leigh syndrome), sudden death, myocardiopathy, hepatic disorders, hyperlactacidemia, increased serum glutamine concentrations, increased urine glutaric acid, enzyme assay of leukocytes, fibroblasts. • Succinate dehydrogenase– autosomal recessive, four subunit genes (SDHA, SDHB, SDHC, SDHD), SDHA leads to encephalomyopathy, other genes associated with tumour formation, enzyme assay of leukocytes, fibroblasts. • Fumarase–very rare, autosomal recessive, microcephaly, severe developmental delay, distinctive facial features, brain malformation, seizures, failure to thrive, hypotonia, increased urine fumarate, succinate, citrate, enzyme assays of cultured fibroblasts, lymphoblasts, or white blood cells, molecular genetic testing. Treatment is supportive.

  15. β-Oxidation Very long chain = C14 to 20 palmitate Long chain = C10 to 14 carnitine shuttle palmitoyl-CoA (C16) FAD Medium chain = C6 to 10 Acyl-CoA dehydrogenase FADH2 trans-𝚫2-enoyl-CoA enoyl-CoA dehydratase acetyl-CoA C4 C6 C8 C10 C12 L-3-hydroxyacyl-CoA NAD+ L-3-Hydroxyacyl-CoA dehydrogenase NADH 3-ketoacyl-CoA CoASH thiolase myristoyl-CoA (C14) acetyl-CoA

  16. β-Oxidation Disorders • Medium-chain acyl CoA dehydrogenase– autosomal recessive, preprandial irritability, lethargy, jitteriness, sweating, seizures, tachypneic, somnolent, mildly enlarged liver, decreased serum bicarbonate concentration, increased serum anion gap, hypoglycemia, hypoketonuria, hyperammonemia, increased urine monocarboxylic fatty acids and dicarboxylic organic acids (adipic, C6; suberic, C8; sebacic, C10; and dodecanedioic,C12), enzyme assay, molecular genetic testing. Treatment with increased calories from carbohydrates and protein, limited fats, avoid periods of fasting. • Very long-chain acyl CoA dehydrogenase – autosomal recessive, cardiomyopathy, hypotonia, hepatomegaly, hypoketotichypoglycemia, increased serum C14:1, C14:2, C14, and C12:1 straight-chain acyl-carnitine esters, 3-hydroxy-acyl carnitine esters, and unsaturated acyl-carnitineesters, enzyme assays, molecular genetics testing. Treatment with increased calories from carbohydrates and protein, medium-chain triglycerides, avoid periods of fasting. • Long-chain 3-hydroxyacyl CoA dehydrogenase – autosomal recessive, cardiomyopathy, hypotonia, hepatomegaly, hypoketotic hypoglycemia, decreased serum carnitine, increased serum 3-hydroxydicarboxylic derivatives of the C16:0, C18:1, and C18:2 species, increased urine 3-hydroxylated dicarboxylicacids, enzyme assay, molecular genetics testing. Treatment with increased calories from carbohydrates and protein, medium-chain triglycerides, avoid periods of fasting.

  17. Urea Cycle aspartate acetyl CoA + glutamate citrulline argininosuccinate Argininosuccinatesynthetase N-Acetylglutamate synthase Ornithine transcarbamoylase CoA HCO3- N-acetylglutamate⊕ Argininosuccinatelyase Carbamoyl phosphate synthetase carbamoyl phosphate arginine H2O Arginase NH4+ ornithine urea

  18. Urea Cycle Disorders • N-Acetylglutamate synthase– very rare autosomal recessive,lethargy, poorly-controlled breathing rate or body temperature, seizures, coma, hyperammonemia, increased serum alanine and glutamine urine orotic acid within reference range. Treatment is low protein intake. • Carbamoylphosphatesynthetase– rare, autosomal recessive, early-onset lethargy, seizures, hyperammonemia, serum ammonia concentrations are usually 10-20 times higher than reference range. Treatment is reduced protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. • Ornithine transcarbamoylase– rare, X-linked recessive, early- or late-onset, lethargy, poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased urine oroticacid, enzyme assays. Treatment is restricted protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate.

  19. Urea Cycle Disorders • Argininosuccinatesynthetase– rare, autosomal recessive, two forms (type I more common than II). Type I lethargy, poor feeding, vomiting, seizures, and loss of consciousness, type II confusion, restlessness, memory loss, abnormal behaviors (such as aggression, seizures, and coma, hyperammonemia, increased serum citrulline, increased urine orotic acid, enzyme assay of cultured fibroblasts. Treatment is restricted protein diet and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. • Argininosuccinatelyase– rare, autosomal recessive, lethargy, poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased serum and urine argininosuccinic acid, increased serum citrulline, glutamine, alanine, and lysine, increased urine orotic acid, enzyme assay of cultured fibroblasts. Treatment is low-protein diet, arginine supplementation and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate. • Arginase– very rare (least common urea cycle defect), autosomal recessive, delayed development, protein intolerance, spasticity, hyperammonemia (sometimes), assay for erythrocyte arginase activity. Treatment is low-protein diet andadministration of oral sodium benzoate or sodium phenylbutyrate to reduce ammonia concentration when appropriate.

  20. Branched-Chain Amino Acids valine isoleucine leucine Aminotransferase Aminotransferase Aminotransferase α-keto-β-methylvalerate α-ketoisovalerate α-ketoisocaproate Branched-chain α-ketoacid dehydrogenase α-methylbutyl CoA isobutyl CoA isovaleryl CoA propionyl CoA 3-hydroxy-3-methylglutaryl CoA Propionyl CoA carboxylase D-methylmalonyl CoA HMG CoA lyase L-methylmalonyl CoA Methylmalonyl CoA mutase succinyl CoA acetoacetate

  21. Branched-Chain Amino Acid Disorders • Branched-chain α-ketoacid dehydrogenase – rare, autosomal recessive, newborn screening, poor feeding, vomiting, lethargy, and developmental delay, sweet odor of affected infants' urine, increased serum leucine and isoleucine concentrations, increased alloisoleucine concentrations by day 6, increased urine alpha-hydroxyisovalerate, lactate, pyruvate, and alpha-ketoglutarate concentrations, enzyme assay of lymphocytes or cultured fibroblasts (not necessary for diagnosis). Treatment is dietary restriction of branched-chain amino acids and supplementation of thiamine as appropriate. MSUD Express for juveniles and adults. • Propionyl CoA carboxylase– autosomal recessive, failure to thrive due to feeding intolerance and vomiting, ketoacidosis, dehydration, shock, increased serum anion gap and ketones, decreased urine pH, increased urine β-hydroxy propionic acid, lactic acid, and methylcitrate concentrations, enzyme assays of leukocytes. Treatment with restriction of branched-chain amino acids.

  22. Branched-Chain Amino Acid Disorders • MethylmalonylCoA mutase– autosomal recessive, seizure, encephalopathy, stroke, hypotonia, lethargy, failure to thrive, hepatosplenomegaly, increased serum ammonia, glycine, propionic acid, and methylmalonicacid concentrations, increased urine methylmalonic acid, methylcitrate, propionic acid, and 3-hydroxypropionate concentrations. Treatment with protein restriction and carnitine supplementation. • 3-Hydroxy-3-methylglutaryl CoA lyase– rare, autosomal recessive, vomiting, diarrhea, dehydration, lethargy, hypotonia, non-ketotic hypoglycemia, metabolic acidosis, increased serum 3-hydroxy isovaleryl-carnitineand 3-methylglutaryl-carnitine concentrations, increased urine 3-hydroxy-isovaleric, 3-methylglutaric, glutaric, 3-methyl-glutaconic, 3-hydroxy-3-methyl-glutaric acids and 3-methyl-crotonyl-glycine concentrations. Treatment with limiting fasting periods, low-leucine diet, and supplementation of carnitine.

  23. Aromatic Amino Acids phenylalanine Phenylalanine hydroxylase dopamine norepinephrine epinephrine Aromatic amino acid decarboxylase tyrosine homogentisate Tyrosinase Homogentisate oxidase 4-maleylacetoacetate DOPA quinone fumarylacetoacetate Fumarylacetoacetase acetoacetate fumarate

  24. Aromatic Amino Acid Disorders • Phenylalanine hydroxylase– autosomal recessive, newborn screening, fair skin and hair, intellectual disability, musty or mousy odor, epilepsy, extrapyramidal manifestations, eye abnormalities, increased serum phenylalanine concentrations. Treatment with phenylalanine restriction. • Aromatic amino acid decarboxylase– very rare, autosomal recessive, severe developmental delay, hypotonia, muscle stiffness, difficulty moving, athetosis, lethargy, feed poorly, startle easily, sleep disturbances, oculogyric crises, increased CSF L-dopa, 5-hydroxytryptophan and 3-orthomethyldopa concentrations, decreased CSF homovanillic acid and 5-hydroxyindoleacetic acid concentrations, enzyme assay. Treatment with vitamin B6, dopamine agonists, and MAO inhibitors. • Tyrosinase– rare, autosomal recessive, oculocutaneousalbinism, hair and skin depigmentation, decreased visual acuity, photophobia, iris transillumination, nystagmus, pigment deficiency in the peripheral retina, enzyme assay of hair bulb, molecular genetic testing. Treatment with nitisinone and address visual problems. • Homogentisate oxidase– rare, autosomal recessive, alkaptonuria, excreted urine becomes black in color, arthritic symptoms confined chiefly to the spine, hips, and knees, increased urine homogentisicacid concentrations, polymerase chain reaction test. Treatment with vitamin C and reduction of dietary phenylalanine and tyrosine. • Fumarylacetoacetase– rare, autosomal recessive, cabbagelike) odor, renal tubular dysfunction, failure to thrive, increased serum tyrosine and methionine concentrations, increased urine succinylacetone concentrations, aminoaciduria. Treatment with nitisinone and low-tyrosine, low-phenylalanine diet.

  25. Cholesterol Pathway Δ7-reductase 3-hydroxy-3-methylglutaryl CoA 7-dehydrocholesterol cholesterol HMG CoA reductase Δ24-reductase Δ24-reductase mevalonate Δ7-reductase Mevalonate kinase 7-dehydrodesmosterol desmosterol Δ5-dehydrogenase phosphomevalonate cholesta-7,24-dien-3β-ol Δ8,Δ7-isomerase isopentenyl pyrophosphate lathosterol zymosterol farnesyl pyrophosphate Squalene synthase lanosterol squalene

  26. Cholesterol Pathway Disorders • Mevalonate kinase – rare, autosomal recessive, less- and more-severe types, less-severe (Hyperimmunoglobulinemia D syndrome) has fever episodes with lymphadenopathy, abdominal pain, joint pain, diarrhea, skin rashes, and headache, more-severe (Mevalonicaciduria) has (fever or no fever) developmental delay, progressive ataxia, progressive problems with vision, and failure to gain weight and grow at the expected rate, unusually small, elongated head, increased serum immunoglobulins A and D concentrations (less-severe type), increased urine excretion of mevalonicacid, enzyme assays. Treatment is supportive. • 7-Dehydrocholesterol reductase (3β-Hydroxysteroid-Δ7-reductase)– autosomal recessive (Smith-Lemli-Opitzsyndrome),dysmorphicfacial features, microcephaly, second-toe and third-toe syndactyly, intrauterine growth retardation, short stature, abnormally low weight for height, hypotonia, distinctive shrill cry, decreased serum cholesterol concentrations, increased serum dehydrocholesterol concentrations. Treatment is supportive. • Δ8,Δ7-isomerase– X-linked dominant (CHILD syndrome), dysmorphic facial features, microcephaly, second-toe and third-toe syndactyly, intrauterine growth retardation, short stature, abnormally low weight for height, hypotonia, distinctive shrill cry, decreased serum cholesterol concentrations, increased serum dehydrocholesterol concentrations. Treatment is supportive

  27. Steroid Pathway cholesterol Desmolase (CYP11A1) 17-Hydroxylase (CYP17A1) 17-Hydroxylase (CYP17A1) pregnenolone 17α-hydroxypregnenolone dehydroepiandrosterone 3β-Hydroxysteroiddehydrogenase 3β-Hydroxysteroiddehydrogenase 3β-Hydroxysteroiddehydrogenase progesterone 17α-hydroxyprogesterone androstenedione 17-Hydroxylase (CYP17A1) 17,20-Lyase (CYP17A1) Aromatase 21-Hydroxylase (CYP21A2) 21-Hydroxylase (CYP21A2) 17-Ketoreductase 11-deoxycorticosterone 11-deoxycortisol testosterone estrone 11-Hydroxylase (CYP11B1) 11-Hydroxylase (CYP11B1) 17-Keto-reductase Aromatase corticosterone estradiol Aldosterone synthase (CYP11B2) 5α-Reductase cortisol dihydroxytestosterone aldosterone

  28. Steroid Pathway Disorders • Desmolase– very rare (lipoid adrenal hyperplasia), autosomal recessive poor weight gain, vomiting, males are undervirilized, dehydration, hyperpigmentation, increased serum ACTH, hyponatremia, hyperkalemia, metabolic acidosis. Treatment with saline and fludrocortisone, female also with estrogen replacement. • 17-Hydroxylase – very rare (congenital adrenal hyperplasia), autosomal recessive, patients with XX or XY karyotypes are phenotypic females or ambiguous genitalia, hypertension, hypokalemia, metabolic alkalosis, increased serum progesterone, corticosterone, and deoxycorticosterone concentrations, decreased 17-hydroxyprogesterone, estrogens, and androgens concentrations. Treatment with glucocorticoid and estrogen replacement, salt restriction, diuretics as appropriate. • 3β-Hydroxysteroiddehydrogenase – very rare (congenital adrenal hyperplasia), autosomal recessive, ambiguous genitalia or female genitalia, hyperpigmentation, increased serum 11-deoxycortisol and deoxycorticosterone, increased ratio of 24-hour urine metabolite of 11-deoxycortisol to metabolite of cortisol. Treatment with glucocorticoid and mineralocorticoid therapy as appropriate.

  29. Steroid Pathway Disorders • 21-Hydroxylase– very rare (most common congenital adrenal hyperplasia), autosomal recessive, males have failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, shock, accelerated growth and skeletal maturation; in addition, females have ambiguous genitalia at birth, later in childhood with precocious pubic hair, clitoromegaly, increased serum 17-hydroxyprogesterone concentrations, increased urine pregnanetriolconcentrations. Treatment with glucocorticoid and mineralocorticoid therapy as appropriate. • 11-Hydroxylase– very rare (congenital adrenal hyperplasia), autosomal recessive, androgen excess, masculinization of female newborns and precocious puberty in male children, hypertension, increased serum 11-deoxycortisol and deoxycorticosterone, urine 17-ketosteroids, dehydroepiandrosterone, dehydroepiandrosteronesulfate, and androstenedione, and testosterone. Treatment with glucocorticoid replacement and antihypertensive therapy. • Aromatase –very rare, autosomal recessive, virilization manifests as pseudohermaphroditism in female infants, affected males do not present with obvious defects at birth, tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity, increased serum testosterone concentrations. Treatment with estrogen replacement.

  30. Steroid Pathway Disorders • Aldosterone synthase – rare, autosomal dominant, autosomal recessive, severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood, increased serum renin activity, decreased serum aldosterone concentrations, increased serum 18-hydroxycorticosterone. Treatment with mineralocorticoid therapy (fludrocortisone) and sodium supplementation. • 5α-Reductase– rare, autosomal recessive, ambiguous genitalia, clitoral-like phallus, markedly bifid scrotum, pseudovaginalperineoscrotal hypospadias, rudimentary prostate, uterus and fallopian tubes are absent, testes are intact and usually found in the inguinal canal or scrotum, amniocentesis or chorionic villus sampling show XY karyotype, fluorescent in situ hybridization results positive for sex-determining region, increased serum testosterone-to-dihydrotestosterone ratio, molecular genetics studies. Treatment considerations of gender assignment. • 17-Ketoreductase – rare, autosomal recessive, characterized by clitoromegaly, posterior labioscrotal fusion and perineal blind vaginal pouch, testes are inguinal or in the labioscrotalfolds,internal urogenital tract (epididymides, vasa deferentia, seminal vesicles, ejaculatory ducts) well developed; prostate and Müllerian structures are absent, baseline and post-human chorionic gonadotropin stimulation hormonal evaluation shows increased androstenedioneand decreased testosterone concentrations, with an increased androstenedione-to-testosterone ratio. Treatment considerations of gender assignment.

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