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)
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
Bisphosphoglycerate mutase
1,3-bisphosphoglycerate
2,3-bisphosphoglycerate
NAD+
Glyceraldehyde-3-phosphate
dehydrogenase
NADH
3-Phophoglycerate kinase
2,3-Bisphosphoglycerate phosphatase
ATP
3-phosphoglycerate
Phosphoglycerate mutase
2-phosphoglycerate
Enolase
phosphoenolpyruvate
Pyruvate kinase
Lactate dehydrogenase
lactate
pyruvate
NAD+
NADH
ATP
Glycolytic Pathway Disorders
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Hexokinase – rare autosomal recessive, nonspherocytic hemolytic anemia.
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Phosphoglucose isomerase – rare autosomal recessive, hemolytic anemia, less
common neurological problems.
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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.
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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.
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Triosephosphate isomerase – rare autosomal recessive, congenital hemolytic
anemia, progressive neuromuscular dysfunction, susceptibility to bacterial
infection, and cardiomyopathy.
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Glyceraldehyde-3-phosphate dehydrogenase – rare autosomal recessive, very little
information available.
Glycolytic Pathway Disorders
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Bisphosphoglycerate mutase/phosphatase – rare, hemolytic anemia, polycythemia,
increased hemoglobin affinity for O2.
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Phosphoglycerate kinase – rare X-linked recessive, two forms, chronic hemolytic
anemia, myopathic (myoglobinuria) with muscle symptoms especially upon exercise.
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Phosphoglycerate mutase – rare autosomal recessive, mainly affects skeletal muscle.
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Enolase – rare autosomal recessive, affects muscle, exercise intolerance.
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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.
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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.
Pentose Phosphate Pathway
Glucose-6-phosphate
dehydrogenase
Lactonase
6-phosphogluconate
glucose-6-phosphate
6-phosphoglucono-δ-lactone
NADP+
NADPH
6-Phosphogluconate
dehydrogenase
NADP+
NADPH
ribulose-5-phosphate
Transketolase
fructose-6-phosphate
Ribulose phosphate
3 epimerase
glyceraldehyde-3-phosphate
Ribose-5-phosphate
isomerase
xylulose-5-phosphate
ribose-5-phosphate
Transketolase
Transaldolase
erythrose-4-phosphate
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 diseaseproducing 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).
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Ribose-5-phosphate isomerase – very rare (single report), leukoencephalopathy and
peripheral neuropathy.
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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
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Fructokinase – autosomal recessive, benign.
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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
Lactate dehydrogenase
NAD+
pyruvate
Pyruvate dehydrogenase
NADH
acetyl-CoA
Pyruvate carboxylase
2ATP
NADH
Citrate synthase
oxaloacetate
citrate
Malate dehydrogenase
Aconitase
NAD+
malate
isocitrate
NAD+
Fumarase
Isocitrate dehydrogenase
NADH
α-ketoglutarate
NAD+
fumarate
α-Ketoglutarate dehydrogenase
Succinate dehydrogenase
succinate
FADH2
succinyl-CoA
Succinyl-CoA synthetase
FAD+
GTP
GDP
NADH
Pyruvate and Citric Acid Cycle Disorders
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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-ketoglutarate concentrations, enzyme assays on leukocytes, fibroblasts.
Treatment by limiting carbohydrates and increasing fats, supplement with thiamine, carnitine,
and lipoic acid.
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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.
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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.
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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.
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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.
β-Oxidation
palmitate
Very long chain = C14 to 20
Long chain = C10 to 14
carnitine shuttle
palmitoyl-CoA (C16)
Medium chain = C6 to 10
FAD
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
myristoyl-CoA (C14)
thiolase
acetyl-CoA
CoASH
β-Oxidation Disorders
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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.
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Very long-chain acyl CoA dehydrogenase – 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
of fasting.
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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
citrulline
argininosuccinate
Argininosuccinate
N-Acetylglutamate
synthetase
synthase
Ornithine
CoA
HCO3
transcarbamoylase
N-acetylglutamate ⊕
Argininosuccinate
Carbamoyl phosphate
lyase
synthetase carbamoyl
phosphate
arginine
H2O
Arginase
+
NH4
ornithine
urea
Urea Cycle Disorders
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N-Acetylglutamate synthase – very rare autosomal recessive, lethargy, poorlycontrolled breathing rate or body temperature, seizures, coma, hyperammonemia, increased
serum alanine and glutamine urine orotic acid within reference range. Treatment is low protein
intake.
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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.
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Ornithine transcarbamoylase – rare, X-linked recessive, early- or late-onset, lethargy,
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.
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.
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Argininosuccinate lyase – 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.
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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
leucine
Aminotransferase
α-ketoisovalerate
Aminotransferase
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
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.
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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.
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.
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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, 3hydroxy-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
tyrosine
Aromatic amino acid decarboxylase
homogentisate
dopamine
norepinephrine
epinephrine
Tyrosinase
Homogentisate oxidase
4-maleylacetoacetate
DOPA quinone
fumarylacetoacetate
Fumarylacetoacetase
acetoacetate
fumarate
Aromatic Amino Acid Disorders
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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.
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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, 5hydroxytryptophan and 3-orthomethyldopa concentrations, decreased CSF homovanillic acid
and 5-hydroxyindoleacetic acid concentrations, enzyme assay. Treatment with vitamin B6,
dopamine agonists, and MAO inhibitors.
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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.
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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.
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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
Δ7-reductase
cholesterol
HMG CoA reductase
Δ24-reductase
Δ24-reductase
mevalonate
Mevalonate kinase
7-dehydrodesmosterol
Δ7-reductase
desmosterol
Δ5-dehydrogenase
phosphomevalonate
cholesta-7,24-dien-3β-ol
Δ8,Δ7-isomerase
isopentenyl pyrophosphate
lathosterol
farnesyl pyrophosphate
Squalene synthase
squalene
lanosterol
zymosterol
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 (lesssevere type), increased urine excretion of mevalonic acid, enzyme assays. Treatment is
supportive.
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7-Dehydrocholesterol reductase (3β-Hydroxysteroid-Δ7-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.
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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
Steroid Pathway
cholesterol
Desmolase (CYP11A1)
17-Hydroxylase (CYP17A1)
17-Hydroxylase (CYP17A1)
pregnenolone
17α-hydroxypregnenolone
dehydroepiandrosterone
3β-Hydroxysteroid
dehydrogenase
3β-Hydroxysteroid
dehydrogenase
3β-Hydroxysteroid
dehydrogenase
progesterone
17α-hydroxyprogesterone
androstenedione
17-Hydroxylase (CYP17A1)
17,20-Lyase (CYP17A1)
Aromatase
21-Hydroxylase
21-Hydroxylase
17-Ketoreductase
(CYP21A2)
(CYP21A2)
11-deoxycorticosterone
11-deoxycortisol
11-Hydroxylase
(CYP11B1)
testosterone
11-Hydroxylase
(CYP11B1)
Aromatase
estrone
17-Ketoreductase
corticosterone
Aldosterone synthase
(CYP11B2)
aldosterone
5α-Reductase
cortisol
dihydroxytestosterone
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.
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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.
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3β-Hydroxysteroid dehydrogenase – 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.
Steroid Pathway Disorders
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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
pregnanetriol concentrations. Treatment with glucocorticoid and mineralocorticoid therapy as
appropriate.
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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 17ketosteroids, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione,
and testosterone. Treatment with glucocorticoid replacement and antihypertensive therapy.
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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 – rare, autosomal dominant, autosomal recessive, severe saltwasting 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.
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5α-Reductase – rare, autosomal recessive, ambiguous genitalia, clitoral-like phallus,
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-todihydrotestosterone ratio, molecular genetics studies. Treatment considerations of gender
assignment.
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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-totestosterone ratio. Treatment considerations of gender assignment.