Congenital Adrenal Hyperplasia

Description

• • Group of inherited genetic disorders leading to impaired steroidogenesis
  • Presence of adrenal glands
  • Absence of adequate cortisol synthesis

• adrenal insufficiency by dysfunction of

  • adrenal gland (primary)
  • pituitary gland (secondary)

• 21-hydroxylase deficiency (Classic form)

  • Most common (>90%) [📖]
  • autosomal-recessive disorder
  • chromosome 6p21.3
  • mutation in CYP21A2

Classification

• Classic form
  • severe form: 0-5% enzyme activity
• deficiency of cortisol, aldosterone and adrenaline and overproduction of adrenal androgens [📖]
  • Low intra-adrenal levels of cortisol -> adrenomedullary dysplasia -> deficiency in adrenalin [📖]
  • salt wasters (75%):
    • 0% enzyme activity
    • deficiency in cortisol and aldosterone synthesis [📖]
  • simple virilisers:
    • <5% enzyme activity
    • elevated concentrations of androgens [📖]
    • some ability to produce aldosterone
  • Prevalence
    • 1:15,000-16,000 in Europe and the USA [📖]
    • 1:19,000 in Japan [📖]
    • 1:14,000-18,000 worldwide [📖]
• Non-classic form:
  • 20-50% enzyme activity
  • slightly elevated androgen concentrations
  • Prevalence
    • 1:200 in the USA [📖]
    • 4.0–7.5% Carrier frequency in Europe [📖] [📖] [📖]

Genetic background

Figure from [📖].

Available treatment approaches

• management of CAH should account for biological effects and interrelationship between glucocorticoid, mineralocorticoid and adrenal steroids

Glucocorticoid therapy

• re-set hormonal imbalance by replacing deficient hormones
• fail to replicate the physiological cortisol circadian rhythm
• usually supraphysiological doses to achieve sufficient reduction in androgen biosynthesis
• formulations
  • short-acting: Hydrocortisone
    • 6–8 h
    • preferred in children with CAH: short half-life and the lowest growth suppressing effect [📖] [📖]
  • intermediate-acting: Prednisone, Prednisolone, Methylprednisolone
    • 12–36 h
  • long-acting: Dexamethasone
    • 36–54 h
• 1/3 of adults receive hydrocortisone and 2/3 long-acting glucocorticoids
  • UK cross-sectional CAH adult study (CaHASE) from 17 centres (n = 203) [📖]
  • cross-sectional study from our USA centre (n = 244) [📖]

Mineralocorticoid therapy

• to correct aldosterone deficiency
• small enzyme activity and aldosterone production is not sufficient to maintain normal intravascular volume [📖] [📖]

• therapy received during childhood ~> a taller height outcome compared when not received [📖]

• formulation

  • 9α-fludrocortisone
    • 18–36 h
    • risk factor of hypertension in children aged <8 years [📖] [📖]
    • adolescents have reduced (18.5% -> 4.9%) risk of hypertension
  • All glucocorticoids (except dexamethasone) have mineralocorticoid activity
    • potency of 0.1 mg of fludrocortisone is achieved by ~40 mg of hydrocortisone [📖]
    • potency of 1.0 mg of hydrocortisone is achieved by 0.1 mg of fludrocortisone [📖]

List of works used for litor literature review: - [📖]

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