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Paediatric Biochemistry > Steroid Analysis in Paediatrics with DSD > Flashcards

Steroid Analysis in Paediatrics with DSD Flashcards

1
Q

What is early foetal sex determinaton/differentiation?

A

Determination: Y chromosome directs testes formation from indifferent gonad

Differentiation: Default is female unless influenced by hormones of testes (testosterone/AMH)

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2
Q

How is sex differentiaiton hormonally regulated?

A

Testosterone (Leydig cells) – external genitalia

  • Testosterone and dihydrotestosterone are necessary for the formation of male external genitalia and the descending of the testes.

Anti-Mullerian hormone (Sertoli cells) – genital ducts

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3
Q

What are examples of Sex chromosome DSD?

A
  • 45,X: Turner syndrome (& variants)
  • 47,XXY: Klinefelter syndrome (& variants)
  • 45,X/46,XY: Mixed gonadal dysgenesis and ovotesticular DSD
  • 46,XX/46,XY: Chimeric and ovotesticular DSD
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4
Q

What are examples 46,XX DSD?

A
  • Disorders of gonadal development: ovotesticular DSD, testicular DSD and gonadal dysgenesis
  • Disorders of androgen excess: foetal, foeto-placental, maternal
  • Other disorders: anatomical and syndromic
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5
Q

What are examples of 46,XY DSD?

A
  • Disorders of gonadal development: complete/partial gonadal dysgenesis, gonadal regression and ovotesticular DSD
  • Defect of androgen biosynthesis or action: androgen biosynthesis defects, androgen receptor defects, luteinising hormone receptor defects, AMH hormone/receptor defect
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6
Q

What are steroid metabolic pathways?

A
  • Adrenal glands: glucocorticoid and mineralocorticoid synthesis
  • Gonads: sex steroids (minor: adrenals – pathologically only relevant in females)
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7
Q

What is the basic structure of steroid?

A
  • All steroids have the same basic four ring structure, the cyclopentanoperhydrophenanthrene nucleus.
  • This forms a flat plane with functional groups siting above or below the plane of the ring.
  • 100’s of possible structures makes steroid analysis challenging
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8
Q

What are advantages of using immunoassay for steroid measurement?

A
  • Often cheap
  • High throughput
  • No great deal of operator skill required
  • Often sensitive
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9
Q

What are disadvantages of using immunoassay for steroid measurement?

A
  • Interference from closely related steroids: Neonates, Specific steroid disorders
  • Interference of 11-deoxycortisol in the Siemens Centaur cortisol immunoassay in cases of 11β-hydroxylase deficiency CAH.
  • High concentrations of 3β-hydroxy-5-ene steroids* (mostly sulphate conjugated) from foetal zone in first 2-3 months of life can cause interference in immunoassays
  • First 2-3 days of life, foetal cortisol may be of maternal origin (in process of being cleared)
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10
Q

Why is Urine steroid profiling in the first 2-3 months challenging?

A
  • High concentrations of 3β-hydroxyl-5-ene steroids (steroid sulphates) & low concentrations of cortisol/cortisone metabolites possessing multiple extra hydroxylations (e.g. at carbons 1- and 6-)
  • Creates a complex pattern in initial 2-3 months of life
  • Necessitates conjugate separation on sephadex columns prior to normal urine steroid profiling sample prep method
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11
Q

What are features of GC-MS compred to LC-MS/MS?

A
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12
Q

What are 46,XX DSD disorders of androgen excess?

A

Foetal Congenital adrenal hyperplasia (CAH) due to:

  • 21-hydroxylase (CYP21A2) deficiency – 95% CAH cases, incidence 1 in 10,000
  • 11β-hydroxylase (CYP11B1) deficiency (4-5% CAH cases)
  • 3β-hydroxylase (HSD3B2) deficiency (very rare)

Foeto-placental

  • Aromatase (CYP19A1) deficiency (rare)

Maternal

  • Luteoma of pregnancy (very rare)
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13
Q

What is the clinical presentation of a female with ambiguous genitalia at birth?

A
  • Clitoromegaly
  • Fused labia
  • Skin pigmentation?
  • Salt-wasting (5-7 days after birth)
  • Hypoglycaemia?
  • Inguinal hernia (testes in groin)
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14
Q

What are the investigations for a female with Ambiguous Genitalia at Birth?

A

Karyotype: confirm XX

Abdominal ultrasound to confirm presence of uterus (exclude undescended testes)

Maternal history: exclude virilisation

Blood:

  • 17-hydroxyprogesterone (basal / post-synatchen?)
  • Electrolytes
  • Cortisol /ACTH
  • Renin/aldosterone

Urine: Urine steroid profile

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15
Q

What are features of 21-hydroxylase deficiency?

A

Gene: CYP21A2

46,XX Genital Phenotype: Ambiguous Genitalia

46,XY Genital Phenotype: Normal

Specific biochemical tests:

  • 17-OHP (basal or post-synatcten)
  • Urine steroid profile
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16
Q

What are clinical signs of 11β-hydroxylase deficiency?

A

Hypertension (11-deoxycorticosterone)

  • presentation can occur throughout life as per 21-hydroxylase deficiency
17
Q

What are clinical signs of 21-hydroxylase deficiency?

A

Variable degree of adrenal failure dep on severity of defect, therefore presentation can be

Classical:

  • salt-wasting (both sexes)
  • virilisation in females

Non-classical:

  • mineralocorticoid production sufficient so do not salt-waste
  • presentation due to androgen excess (neonates: ambiguous genitalia; childhood: precocious puberty; adulthood: amenorrhoea/fertility issues
18
Q

What are features of 11β-hydroxylase deficiency?

A

Gene: CYP21A2

46,XX Genital Phenotype: Ambiguous Genitalia

46,XY Genital Phenotype: Normal

Specific biochemical tests:

  • 11-deoxycortisol (basal or post-synatcten)
  • Urine steroid profile
19
Q

What are features of 3β-hydroxysteroid deficiency?

A

Gene: HSD3B2

46,XX Genital Phenotype: Clitoromegaly

46,XY Genital Phenotype: Ambiguous

Specific biochemical tests: Urine steroid profile (but only reliable >2-3 months post-term birth)

20
Q

What are signs of 3β-hydroxysteroid deficiency?

A
  • Primary adrenal failure
21
Q

What are feature of P450 Oxido-reductase defects?

A

Gene: POR

46,XX Genital Phenotype: Ambiguous

46,XY Genital Phenotype: Ambiguous

Specific biochemical tests: Urine steroid profile

22
Q

What are signs of P450 Oxido-Reductase deficiency?

A
  • Sometimes associated with Antley- Bixler syndrome
23
Q

What do invesitgations show in 21 Hydroxylase Deficiency?

A

Blood:

  • ↑ 17OHP (& 21-deoxycortisol & androgens, ↓ cortisol)

Urine:

  • ↑17OHP metabs (esp. 17-hydroxypregnanolone, pregnanetriol and 11-oxopregnanetriol & androgen metabs; ↓ cortisol metabs)
24
Q

What is required to test non-classical CAH due to CYP21A2?

A

In non-classical CAH synatchen testing may be required

25
Q

What are the pitfalls in 3β-HSD deficiency measurements?

A
  • Overlap between 3β-HSD and normal in first 2 months of life (high 3β-OH-5-ene steroids, low cortisol/cortisone), especially if birth pre-term
  • Diagnosis made if this pattern continues beyond 3 months
26
Q

What happens if there is aromatase deficiency in CAH?

A
  • In normal pregnancy the foetal adrenals produce large amounts of androgen precursors (DHA & its metabolites); these are normally converted to oestrogens by the placenta
  • In CAH, excess androgens produced by foetus do not virilise mother, because the placenta protects her by conversion to oestrogen.
  • Aromatase deficiency in the foetus affects the placenta as well, so androgens remain at high levels in both maternal and fetal circulations and virilise both.
27
Q

What are the results shown in 11β-Hydroxylase deficiency?

A

Blood:

  • ↑11-deoxycortisol & androgens
  • ↓cortisol

Urine:

  • ↑11-deoxycortisol/11-deoxycorticosterone and androgen metabolites
  • ↓cortisol metabolites
28
Q

What is Micropenis?

A

Micropenis: Penis has a stretched length <50 mm

29
Q

What is Hypospadius?

A

Incomplete tubularisation of the urethral plate

  • relatively common (1 in 300 live births) but many non-steroid causes
30
Q

What is Cryptochidism?

A

Testes not descended into scrotum

  • common – uni- or bilateral - 2-3% at term, 1% at 1 year
31
Q

What are some disorders of androgen deficiency within individuals of 46 X,Y DSD?

A
  • 7-Dehydrocholesterol reductase (DHCR) deficiency – Smith Lemli Opitz syndrome
  • Cholesterol to pregnenolone conversion defects (StAR, CYP11A1 deficiency) – lipoid adrenal hyperplasia
  • CAH due to 3β-hydroxysteroid dehydrogenase (HSD3B2) deficiency
  • CAH due to 17a-hydroxylase (CYP17A1) deficiency
  • Isolated 17,20 lyase (CYP17A1) deficiency – not CAH (since glucocorticoid production intact)
  • Cytochrome b5 (CYPB5A) deficiency – Cyt b5 a facilitator of 17,20 lyase activity
  • Cytochrome P450 oxidoreductase (POR) deficiency
  • 17β-hydroxysteroid dehydrogenase (HSD17B3) deficiency
32
Q

What are investigations undertaken in a poorly masculinised male at birth?

A
  • Karyotype: confirm XY
  • Ultrasound/physical examination to locate testes
  • Blood: Cortisol, Gonadotrophins, Androgens
  • HCG stimulation test: Measure testosterone, SHBG, DHT & androstenedione
  • Urine: Urine steroid profile
33
Q

What are features of 5a-reductase deficiency?

A
  • Micropenis
  • Bifid scrotum
  • Hypospadias
  • Rudimentary prostate

Diagnosis: increased T/DHT ratio?

34
Q

What are features of 17a-Hydroxylase deficiency?

A
  • Most severe: female external genitalia so raised female but present w/ primary amenorrhoea
  • Undescended testes
  • Hypertension (increased 11-deoxycorticosterone with low renin/aldo
35
Q

What are investigations for 17a-Hydroxylase deficiency?

A

Blood:

  • ↑ progesterone
  • ↓cortisol/androgens

Urine:

  • ↑ cortisosterone, 11-deoxycorticosterone & progesterone metabs
  • ↓cortisol & androgen metabs

Paediatric Biochemistry (31 decks)

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