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Paediatric Biochemistry > Congenital Adrenal Hyperplasia > Flashcards

Congenital Adrenal Hyperplasia Flashcards

1
Q

What are some features of Congenital Adrenal Hyperplasia in clinical practice?

A
  • Typically, an autopsy finding
  • Autosomal Recessive pattern of inheritance
  • Mutation of genes for enzymes involved in steroidogenesis lead to a defect in normal steroidogenesis
  • Leads to deficiency in steroid end products and accumulation of precursors proximal to the block
    • There can also be an excess of other steroid end products
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2
Q

What are some enzyme defects in Congenital Adrenal Hyperplasia?

A
  • 21 hydroxylase deficiency - 1:15,000
  • 11β hydroxylase deficiency - 1:100,000
  • 3β hydroxysteroid deficiency - rare
  • 17α hydroxylase deficiency - 1:1,000,000
  • 5α reductase deficiency
  • Cytochrome P450 oxidoreductase deficiency 1:200,000
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3
Q

What are clinical features of CAH?

A

Due to Increase ACTH secretion

  • Hyperpigmentation

Due to decreased cortisol biosyntheisis

  • Poor Appetite
  • Poor weight gain
  • Fatigue
  • Vomiting
  • Weakness
  • Hypoglycaemia

Due to mineralocorticoid biosynthesis

  • Dehydration
  • Hyponatraemia
  • Hyperkalaemia

Due to Increased adrenal androgen biosynthesis

  • Virilization

Decrease adrenal androgen biosynthesis

  • Undermasculinisation
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4
Q

What is the spectrum of genital development in males with 21 Hydroxylase deficiency?

A

Males have a more generous penis

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5
Q

What is the spectrum of genital development in females with 21 Hydroxylase deficiency?

A

Females have less develop reproductive organ. Features can include:

  • Prominent Clitoris
  • Urethral opening in perineum
  • Labia Roguse and partially fused
  • No palpable gonads
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6
Q

What are biochemical tests for diagnosis of Congenital Adrenal Hyperplasia?

A
  • ACTH
  • 17-hydroxy Progesterone
  • Deoxycortisol
  • Renin
  • Aldosterone
  • Cortisol
  • Synacthen Test
  • DHEAS
  • Androstenedione
  • Testosterone
  • Plasma Electrolytes: K+, Na+, Urea
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7
Q

What are methods for urine steroid profiling for steroid metabolites?

A
  • Thin layer chromatography
  • Gas chromatography
  • Gas chromatography – mass spectrometry (GC/MS)
  • Liquid chromatography tandem mass spectrometry (LC/MS/MS)
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8
Q

What are features of liquid chromatography tandem mass spectrometry for urine steroid proiling for steroid metabolites?

A

Superior to immunoassays. Gives Two types of data

  • Quantitative data for individual metabolites
  • Diagnostic ratios of precursor metabolites to product metabolites
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9
Q

In what conditions can urine steroid profiling for steroid metabolites be used for CAH?

A

Female:

  • 21-hydroxylase deficiency
  • 3β-hydroxysteroid deficiency
  • 11β hydroxylase deficiency

Male:

  • 3β-hydroxysteroid deficiency
  • 17α hydroxylase deficiency
  • 5α reductase efficiency
  • Cytochrome P450 oxidoreductase deficiency
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10
Q

What are some genetic classifications of 21 hydroxylase deficiency?

A
  • Class C – non classical
  • Class B - classical simple virilising
  • Class A – classical simple virilising
  • Null – Classical salt wasting
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11
Q

What are biochemical features of 21 Hydroxylase deficiency?

A
  • Increase Androgen formation in Zona Reticularis (androstenedione and testosterone)
  • High Progesterone and 17-hydroxy progesterone
  • High ACTH
  • Low cortisol and aldosterone
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12
Q

What is the presenation of 21 Hydryoxylase deficiency?

A
  • High potassium
  • Low/normal sodium
  • Not feeding
  • Sleeping
  • Drowsy
  • Hyperpigementation
  • Larger Penis
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13
Q

What is the treatment for 21 Hydroxylase deficiency?

A
  • Hydrocortisone
  • Fludrocortisone
  • Sodium Chloride
  • Monitor 17-OHP, androstadienes, ACTH, Testosterone, Renin and Electrolytes every 3-4 months
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14
Q

What are features of 11β-hydroxylase deficiency CAH?

A
  • 2nd most common cause of CAH (1 in 100,000 to 200,000)
  • CYP11B1 is located on chromosome 8 accounts for 5-8% of cases
  • More common in Israeli population of Moroccan Jewish origin (1 in 5000 to 7000)
  • Characterised by Hypertension
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15
Q

What is the biochemical presentation of 11β-hydroxylase deficiency CAH?

A
  • High Renin
  • High Androgen
  • Low Cortisol
  • High 11-Deoxycorticosterone and 11-deoxycortisol
  • USP: Looks at 11 deoxycortisol metabolites to cortisol metabolites
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16
Q

How is 11β-hydroxylase deficiency CAH managed?

A
  • Explain CAH to Parents
  • Hydrocortisone (no fludrocortisone)
  • Monitor blood ACTH, 11-DOC, and Androgens
17
Q

What are features of 17α-hydroxylase defects?

A
  • Rare, 1:50,000 new-borns. Accounts for about 1% cases worldwide
  • Gene for CYP P450C17 on chr 10q24
  • 17α-hydroxylation & 17,20-lyase involved
18
Q

What is the biochemical presentation of 17α-hydroxylase defects?

A
  • Chronic High ACTH
  • Mild Glucocorticoid deficiency, not life threatening
  • High Deoxycortisol and Corticosterone
  • Low Renin
  • Low Sex steroids (Normal female appearance, no adrenarche and puberty and Undervirilisation in males)
  • Sodium Retention and Hypertension
  • Hypokalaemia
19
Q

What are forms of of 3β-HSD-II deficiency CAH?

A

Classical (severe)

  • Steroid synthesis in both adrenal cortex & gonads (testes, ovary) is affected
  • ∆5 > ∆4 compounds
  • Excess circulating androgen precursor steroids (DHEA) converted to androgens outside the adrenal (eg. liver)
    • 46XX: mild virilisation of females
    • 46XY: undervirilisation of males

Non-classical (mild)

  • Females: Premature adrenarche, hirsutism, virilism, oligomenorrhoea
20
Q

What are types of 3β-HSD-II deficiency CAH?

A
  • Type I: placenta, peripheral tissues
  • Type II: adrenals, gonads
21
Q

Wht are biochemical abnormalities of 3β-HSD-II deficiency CAH?

A
  • High DHEA which gets converted into a small amount of androenstiodine in other tissues
  • High 17-OHP
  • Low sodium, high potassium
22
Q

What is PORD?

A

P450 oxidoreductase (POR) is a mandatory electron donor enzyme to all microsomal cytochrome P450 (CYP) enzymes

23
Q

What are key enzymes affects in PORD?

A

Multiple key enzymes indirectly affected

  • 17α-hydroxylase (CYP17A1)
  • 21-hydroxylase (CYP21A2)
  • P450 aromatase (CYP19A1)
24
Q

What is the effect of PORD?

A

Partial deficiency in steroidogenesis involving

  • Glucocorticoid leads to partial adrenal insufficiency
  • Sex steroid synthesis leads to undervirilisation in 46XY and virilisation of 46XX

Skeletal abnormalities leads to Antley-Bixler syndrome

25
Q

What are biochemical consequences of PORD?

A
  • High level of Progesterone and 17-OHP
  • High levels of Androgens – dihydrotestosterone through backdoor pathway
26
Q

What causes Lipoid CAH?

A
  • StAR gene defect features
  • StAR increases transport of cholesterol into mitochondria promotes steroidogenesis. It is not an enzyme
27
Q

What does abscence of StAR lead to?

A
  • Steroidogenic cells make steroids at about 14% of the StAR-induced level
  • Fetal testes (and fetal zone of adrenal)
    • Very active steroid synthesis
    • Leydig cells destroyed early so no testosterone. Leads to female external genitalia
  • Sertoli cells undamaged so no AMH. There are no mullerian structures
  • In Adrenals, Mineralocorticoid and glucocorticoid deficiency so salt wasting
28
Q

What are some epidemiological feature of Lipoid CAH?

A
  • Japan and Korea 1 in 250,000 – 300,000 newborns affected
  • Palestinian Arabs
29
Q

What are biochemical consequences of Lipoid CAH?

A
  • High levels of Cholesterol
  • ACTH

Paediatric Biochemistry (31 decks)

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