Year Two Review Part 1 Eric Niederhoffer SIU-SOM

Outline

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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

Newborn Screening

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Amino acid disorders

Arginemia/arginase deficiency Arginosuccinyl CoA lyase deficiency Citrullinemia/argininosuccinate synthetase deficiency Homocystinemia/cystathionine β-synthase deficiency Maple syrup urine disease Phenylketonuria Tyrosinemia

Fatty acid oxidation disorders

Carnitine transporter deficiency Carnitine/acylcarnitine translocase deficiency Carnitine palmitoyl transferase deficiency Type 1 Carnitine palmitoyl transferase deficiency Type 2 Glutaric acidemia 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

Newborn Screening

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Organic acids disorders

β-Ketothiolase deficiency Glutaric acidemia Type 1 Glutaric acidemia Type 2 Holocarboxylase synthetase deficiency 3-Hydroxy-3-methylglutaryl CoA lyase deficiency Isobutyryl CoA dehydrogenase deficiency Isovaleic aciduria Methylmalonic acidemia Methylmalonic acidemia 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

Glycolytic Pathway

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

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Glycolytic Pathway Disorders

Hexokinase

– rare autosomal recessive, nonspherocytic hemolytic anemia.

Phosphoglucose isomerase

common neurological problems.

– rare autosomal recessive, hemolytic anemia, less

Phosphofructokinase

carbohydrate meals.

– (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

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.

Triosephosphate isomerase

– rare autosomal recessive, congenital hemolytic anemia, progressive neuromuscular dysfunction, susceptibility to bacterial infection, and cardiomyopathy.

Glyceraldehyde-3-phosphate dehydrogenase

information available.

– rare autosomal recessive, very little

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Glycolytic Pathway Disorders

Bisphosphoglycerate mutase/phosphatase

increased hemoglobin affinity for O 2 .

– rare, hemolytic anemia, polycythemia,

Phosphoglycerate kinase

– rare X-linked recessive, two forms, chronic hemolytic anemia, myopathic (myoglobinuria) with muscle symptoms especially upon exercise.

Phosphoglycerate mutase

– 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.

Pentose Phosphate Pathway

Glucose-6-phosphate dehydrogenase glucose-6-phosphate Lactonase 6-phosphoglucono δ-lactone 6-phosphogluconate 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 erythrose-4-phosphate Transaldolase sedoheptulose-7-phosphate fructose-6-phosphate glyceraldehyde-3-phosphate

Pentose Phosphate Pathway Disorders

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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

peripheral neuropathy.

– very rare (single report), leukoencephalopathy and

Transketolase

– very rare (single report), liver cirrhosis and hepatosplenomegaly.

Fructose Pathway

fructose Fructokinase ATP fructose-1-phosphate Aldolase B glyceraldehyde Triose phosphate isomerase dihydroxyacetone glyceraldehyde-3-phosphate phosphate Triose kinase ATP

Fructose Pathway Disorders

• •

Fructokinase

– autosomal recessive, benign.

Aldolase B

– 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.

Pyruvate Metabolism and Citric Acid Cycle

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

Pyruvate and Citric Acid Cycle Disorders

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Pyruvate dehydrogenase

serum and urine and lipoic acid.

– 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 α-ketoglutarate concentrations, enzyme assays on leukocytes, fibroblasts. Treatment by limiting carbohydrates and increasing fats, supplement with thiamine, carnitine,

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 leukocytes or culturedfibroblasts, absence of pyruvate carboxylase mRNA. Treatment with thiamine, lipoic acid, dichloroacetate, citrate, and aspartic acid.

Pyruvate and Citric Acid Cycle Disorders

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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-Ketoglutarate dehydrogenase

– 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.

acetyl-CoA

β-Oxidation

Medium chain = C6 to 10 palmitate carnitine shuttle Very long chain = C14 to 20 Long chain = C10 to 14 palmitoyl-CoA (C 16 ) Acyl-CoA dehydrogenase FAD FADH 2 trans-

𝚫

2 -enoyl-CoA enoyl-CoA dehydratase C4 C6 C8 C10 C12 L-3-hydroxyacyl-CoA NAD + L-3-Hydroxyacyl-CoA dehydrogenase NADH 3-ketoacyl-CoA myristoyl-CoA (C 14 ) thiolase CoASH acetyl-CoA

β-Oxidation Disorders

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Medium-chain acyl CoA dehydrogenase

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.

– autosomal recessive, preprandial

Very long-chain acyl CoA dehydrogenase

of fasting.

– autosomal recessive, cardiomyopathy, hypotonia, hepatomegaly, hypoketotic hypoglycemia, increased serum C14:1, C14:2, C14, and C12:1 straight-chain acyl-carnitine esters, 3-hydroxy-acyl carnitine esters, and unsaturated acyl-carnitine esters, enzyme assays, molecular genetics testing. Treatment with increased calories from carbohydrates and protein, medium-chain triglycerides, avoid periods

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 dicarboxylic acids, enzyme assay, molecular genetics testing. Treatment with increased calories from carbohydrates and protein, medium-chain triglycerides, avoid periods of fasting.

Urea Cycle

aspartate acetyl CoA + glutamate N-Acetylglutamate citrulline Argininosuccinate argininosuccinate synthetase synthase Ornithine HCO

3 -

CoA transcarbamoylase

N-acetylglutamate

⊕

Carbamoyl phosphate Argininosuccinate synthetase carbamoyl lyase phosphate arginine NH

4 +

Arginase H

2

O ornithine urea

Urea Cycle Disorders

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N-Acetylglutamate synthase

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.

– very rare autosomal recessive, lethargy, poorly-

Carbamoylphosphate synthetase

– 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

poorly-controlled breathing rate or body temperature, seizures, hyperammonemia, increased urine orotic acid, enzyme assays. Treatment is restricted protein intake, increased carbohydrates and lipids, and glycerol phenylbutyrate to reduce ammonia concentrations when appropriate.

– rare, X-linked recessive, early- or late-onset, lethargy,

Urea Cycle Disorders

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Argininosuccinate synthetase

– 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.

Argininosuccinate lyase

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.

– rare, autosomal recessive, lethargy, poorly-controlled

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 and administration of oral sodium benzoate or sodium phenylbutyrate to reduce ammonia concentration when appropriate.

Branched-Chain Amino Acids

isoleucine Aminotransferase α-keto-β-methylvalerate valine Aminotransferase α-ketoisovalerate leucine Aminotransferase α-ketoisocaproate α-methylbutyl CoA Branched chain α-ketoacid dehydrogenase 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

Branched-Chain Amino Acid Disorders

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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

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.

– autosomal recessive, failure to thrive due to feeding

Branched-Chain Amino Acid Disorders

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Methylmalonyl CoA mutase

– autosomal recessive, seizure, encephalopathy, stroke, hypotonia, lethargy, failure to thrive, hepatosplenomegaly, increased serum ammonia, glycine, propionic acid, and methylmalonic acid 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-carnitine and 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.

Aromatic Amino Acids

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

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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

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.

– very rare, autosomal recessive, severe

Tyrosinase

– rare, autosomal recessive, oculocutaneous albinism, 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 homogentisic acid 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.

3-hydroxy-3-methylglutaryl CoA

Cholesterol Pathway

7-dehydrocholesterol Δ 7 -reductase cholesterol HMG CoA reductase mevalonate Mevalonate kinase Δ 24 -reductase 7-dehydrodesmosterol Δ 24 -reductase Δ 7 -reductase desmosterol phosphomevalonate Δ 5 -dehydrogenase cholesta-7,24-dien 3β-ol Δ 8 ,Δ 7 -isomerase isopentenyl pyrophosphate lathosterol zymosterol farnesyl pyrophosphate Squalene synthase squalene lanosterol

Cholesterol Pathway Disorders

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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 (Mevalonic aciduria) 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 mevalonic acid, enzyme assays. Treatment is supportive.

7-Dehydrocholesterol reductase (3β-Hydroxysteroid-Δ 7 -reductase)

– autosomal recessive ( Smith-Lemli-Opitz 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.

Δ 8 ,Δ 7 -isomerase

supportive – 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

Steroid Pathway

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

Steroid Pathway Disorders

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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-Hydroxysteroid dehydrogenase

mineralocorticoid therapy as appropriate.

– 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

Steroid Pathway Disorders

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21-Hydroxylase

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 pregnanetriol concentrations. Treatment with glucocorticoid and mineralocorticoid therapy as appropriate.

– very rare (most common congenital adrenal hyperplasia), autosomal

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, dehydroepiandrosterone sulfate, 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.

Steroid Pathway Disorders

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Aldosterone synthase

sodium supplementation.

– 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

5α-Reductase

markedly bifid scrotum, pseudovaginal perineoscrotal 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.

– rare, autosomal recessive, ambiguous genitalia, clitoral-like phallus,

17-Ketoreductase

– rare, autosomal recessive, characterized by clitoromegaly, posterior labioscrotal fusion and perineal blind vaginal pouch, testes are inguinal or in the labioscrotal folds, 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 androstenedione and decreased testosterone concentrations, with an increased androstenedione-to testosterone ratio. Treatment considerations of gender assignment.