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Updated: May 23 2021

Congenital Adrenal Hyperplasia (CAH)

  • Snapshot
    • A 27-year-old G1P0 woman present to the labor and delivery floor for labor. She received little prenatal care due to poor insurance. After 2 hours, she successfully delivered vaginally a 7 lbs baby girl. A physical examination of the newborn demonstrates clitoral enlargement and labial fusion. A week later, the infant is brought to the emergency room for inability to feed. She is underweight and dehydrated by appearance with a low blood pressure. (21-hydroxylase deficiency)
  • Introduction
    • Introduction
      • clinical definition
        • refers to several disorders characterized by genetic defects in the proteins and enzymes involved in cortisol biosynthesis
        • includes:
          • 17α-hydroxylase deficiency
          • 21-hydroxylase deficiency
          • 11β-hydroxylase deficiency
      • demographics
        • 21-hydroxylase deficiency is the most common form (over 95% of cases)
      • pathogenesis
        • decreased cortisol production (due to defective proteins/enzymes) releases the feedback inhibition of cortisol on the pituitary and increases the production of corticotropin (ACTH)
        • high levels of ACTH causes adrenal hyperplasia, excessive accumulation of cortisol precursors, and/or overproduction of ACTH-dependent adrenal steroids within other pathways
      • clinical syndromes
      • Overview of Congenital Adrenal Hyperplasia
      • Enzyme Deficiency
      • Presentation
      • Blood Pressure
      • Mineralocorticoids
      • Sex Hormones
      • Cortisol
      • [K+]
      • 17 α-hydroxylase
      • XY: ambiguous genitalia, undescended tests
      •  XX: lacks secondary sexual development
      • 21- hydroxylase
      • XX: virilization
      •  Salt-wasting in infancy
      •  Precocious puberty in children
      • 11 β-hydroxylase
      • XX: virilization
      • ↓ Aldosterone↑
      • 11-deoxycorticosterone (↑ BP)
  • 17α-hydroxylase Deficiency
    • Defect of the CYP17A1 gene, leading to defective CYP17A1 enzyme, which catalyzes both the 17-hydroxylase and the 17,20-lyase reaction
    • Leads to accumulation of cortisol precursor with mineralocorticoid activity
      • demographics
        • prevalence is the highest in Brazil
    • Presentation
      • hypertension
      • hypokalemia
      • primary amenorrhea
      • absence of secondary sexual characteristics
      • ambiguous genitalia during infancy (in 46,XY patients with partial form)
      • diffuse skin pigmentation
    • Studies
      • elevated 17-hydroxyprogesterone/androstenedione ratio
      • elevated corticosterone
      • elevated ACTH
      • low cortisol, androgens, and estrogens
      • genetic testing
    • Treatment
      • spironolactone
        • blocks mineralocorticoid receptor
      • low-dose estrogen for puberty induction
      • genital surgery and testosterone replacement may be indicated for 46,XY patients with disorder of sex development
    • Complications
      • disorder of sex development
      • testicular adrenal rest tumors
  • 21-hydroxylase Deficiency
    • Most common form
    • Defects of the CYP21A2 gene leads to defective 21-hydroxylase enzyme, which is responsible for the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol
    • Large amounts of 17-hydroxyprogesterone is diverted to the synthesis of androgens and its precursors
    • Presentation
      • diffuse skin hyperpigmentation and hypotension
      • classic form (more severe)
        • present during the neonatal/early infancy period
          • adrenal insufficiency with salt wasting
          • genital ambiguity in females
      • simple virilizing (childhood-onset)
        • genital ambiguities during toddler years
        • mineralocorticoid deficiency is less significant
        • no salt-wasting
      • non-classic form (late-onset)
        • present later in life with signs of androgen excess
          • premature pubarche
          • females may present with hirsutism, menstrual irregularity, infertility, and acne
          • no neonatal genital ambiguity
          • some patients may remain asymptomatic
    • Imaging
      • adrenal ultrasound
        • abnormal results (e.g., adrenal limb width > 4mm, lobulated surface, or abnormal echogenicity)
    • Studies
      • high 17OHP levels
        • the USA offers this as a part of neonatal screen
      • cosyntropin (ACTH) stimulation test will demonstrate absent/low response
      • high renin activity
      • genetic testing
    • Treatment
      • emergent management of any salt-wasting crisis
      • glucocorticoid replacement
      • mineralocorticoid replacement
      • consider reconstructive surgery for virilized 46,XX patients
    • Complications
      • salt-wasting crisis
      • disorder of sex development
      • growth abnormalities (due to high estradiol)
      • testicular adrenal rest tumors
  • 11β-hydroxylase Deficiency
    • Defect of CYP11B1 gene leads to defective 11β-hydroxylase activity, which is responsible for the conversion 11-doxycorticosterone (DOC) and 11-deoxycortisol to corticosterone and cortisol respectively
    • Accumulation of 11-dexosyteroid precursors leads to the overproduction of mineralocorticoid DOC and androgen precursor dehydroepiandrosterone sulfate (DHEAS)
      • demographics
        • accounts for up to 5% of adrenal steroidogenic defects
    • Presentation
      • hypertension
      • hypokalemia
      • female newborns have ambiguous genitalia
      • premature adrenarche
      • signs of hyperandrogenism (e.g., hirsutism, menstrual irregularities, and acne)
    • Studies
      • high levels of serum 11-dexoycortisol concentrations
      • cosyntropin (ACTH) stimulation test will demonstrate absent/low response
      • genetic testing
      • low renin activity
    • Treatment
      • glucocorticoid replacement
      • spironolactone
        • eplerenone is used in male patients
      • surgical reconstruction may be inidicated in 46.XX with virilization
    • Complications
      • disorder of sexual development
      • adrenal crisis
      • testicular adrenal rest tumors
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