Updated: 5/23/2021

Congenital Adrenal Hyperplasia (CAH)

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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 Congential Adrenal Hyperplasia 

Enzyme Deficiency

Presentation

Blood Pressure

Mineralcorticoids Sex Hormones Cortisol [K+]

17α-hydroxylase

  • XY: ambiguous genitalia, undescended tests
  • XX: lacks secondary sexual development
21-hydroxylase
  • XX: virilization
  • Salt-wasting in infancy
  • Precocious puberty in children
11β-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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Questions (4)
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(M2.EC.17.4867) A 17-year-old girl presents to her primary care physician for a wellness checkup. The patient is currently doing well in school and plays soccer. She has a past medical history of childhood obesity that was treated with diet and exercise. The patient states that her menses have not changed, and they occur every 1 to 3 months. Her temperature is 99.5°F (37.5°C), blood pressure is 127/70 mmHg, pulse is 90/min, respirations are 13/min, and oxygen saturation is 98% on room air. The patient's BMI at this visit is 22.1 kg/m^2. On physical exam, the patient is in no distress. You note acne present on her face, shoulders, and chest. You also note thick, black hair on her upper lip and chest. The patient's laboratory values are seen as below.

Hemoglobin: 14 g/dL
Hematocrit: 42%
Leukocyte count: 7,500/mm^3 with normal differential
Platelet count: 177,000/mm^3

Serum:
Na+: 137 mEq/L
Cl-: 101 mEq/L
K+: 4.4 mEq/L
HCO3-: 24 mEq/L
BUN: 27 mg/dL
Glucose: 90 mg/dL
Creatinine: 1.0 mg/dL
Ca2+: 10.1 mg/dL
Testosterone: 82 ng/dL
17-hydroxyprogesterone: elevated
AST: 12 U/L
ALT: 10 U/L

Which of the following is associated with this patient's most likely diagnosis?

QID: 109655
1

Deficiency of 11-hydroxylase

12%

(1/8)

2

Deficiency of 17-hydroxylase

0%

(0/8)

3

Deficiency of 21-hydroxylase

38%

(3/8)

4

Insulin resistance

50%

(4/8)

5

Malignancy

0%

(0/8)

M 6 D

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