Overview
Definition:
Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive genetic disorder affecting steroidogenesis
The salt-wasting crisis is the most severe form, characterized by deficient synthesis of cortisol and aldosterone, leading to life-threatening electrolyte and metabolic disturbances in neonates.
Epidemiology:
The incidence of classic CAH is estimated to be 1 in 10,000 to 1 in 20,000 live births
The salt-wasting form accounts for approximately 70-75% of classic CAH cases
Carrier frequency varies among ethnic groups.
Clinical Significance:
Prompt recognition and management of the salt-wasting crisis are critical to prevent mortality
It is a medical emergency requiring immediate stabilization and ongoing treatment
Understanding the pathophysiology is vital for differentiating it from other causes of neonatal shock and electrolyte imbalance.
Clinical Presentation
Symptoms:
Failure to thrive
Poor feeding
Vomiting
Lethargy
Irritability
Dehydration
Signs of shock
Ambiguous genitalia in 46,XX females (virilization).
Signs:
Hypotension
Tachycardia
Poor perfusion
Cold extremities
Hyperpigmentation (ACTH stimulation)
Hyponatremia
Hyperkalemia
Metabolic acidosis
Hypoglycemia
Female virilization (clitoromegaly, labioscrotal fusion)
Male virilization may be subtle.
Diagnostic Criteria:
Diagnosis is suspected based on clinical presentation and confirmed by hormonal assays
Definitive criteria include markedly elevated 17-hydroxyprogesterone (17-OHP) levels, especially after ACTH stimulation, and low cortisol and aldosterone levels.
Diagnostic Approach
History Taking:
Focus on the timeline of symptoms: onset of vomiting, poor feeding, lethargy
Family history of CAH or adrenal insufficiency
Maternal history of virilization during pregnancy
Birth history (e.g., male infant with ambiguous genitalia).
Physical Examination:
Thorough assessment for signs of dehydration and shock (capillary refill, skin turgor, mental status)
Detailed examination of external genitalia in all neonates to assess for virilization
Assess for hypospadias in males and clitoromegaly in females
Palpate for undescended testes in males.
Investigations:
Electrolytes: Hyponatremia (Na < 130 mEq/L), hyperkalemia (K > 5.5 mEq/L), hypochloremia
Glucose: Hypoglycemia (BG < 40 mg/dL)
Renal function tests: Elevated BUN/creatinine
Blood gas analysis: Metabolic acidosis
Hormonal assays: 17-hydroxyprogesterone (17-OHP) is key
levels > 200 ng/dL on day 2-3 of life are highly suggestive, and > 1000 ng/dL confirm diagnosis in symptomatic neonates
ACTH stimulation test is diagnostic if baseline levels are equivocal
Renin activity: Elevated plasma renin activity indicates aldosterone deficiency
Androstenedione and testosterone: Elevated
Cortisol: Low.
Differential Diagnosis:
Other causes of neonatal shock: Sepsis
Hypovolemic shock
Cardiogenic shock
Other endocrine disorders: Hypothyroidism
Panhypopituitarism
Adrenal hemorrhage
Renal salt wasting: Bartter syndrome, renal tubular acidosis
Pseudohypoaldosteronism.
Management
Initial Management:
Immediate resuscitation is critical
Intravenous fluid resuscitation with normal saline to correct dehydration and hypotension
Glucose supplementation (dextrose infusion) to manage hypoglycemia
Correction of electrolyte imbalances: aim for Na 135-145 mEq/L, K < 5.0 mEq/L
Treat acidosis with sodium bicarbonate if severe.
Medical Management:
Hydrocortisone (stress dose) to replace cortisol deficiency
For neonates: 25 mg/m²/day divided into 3 doses, or 10-12.5 mg every 8 hours
Fludrocortisone acetate to replace aldosterone deficiency: 0.1-0.2 mg orally daily, adjusted based on renin activity and electrolytes
Sodium chloride supplementation may be needed orally or in feeds (e.g., 1-2 grams/day) until fludrocortisone is effective or if significant sodium loss persists.
Surgical Management:
No immediate surgical intervention is required for the crisis itself
However, surgical correction of ambiguous genitalia in virilized females is typically delayed until later childhood after diagnosis and hormonal stabilization, allowing for proper sex assignment
Genetic counseling and psychological support are crucial.
Supportive Care:
Continuous monitoring of vital signs, fluid balance, electrolytes, and glucose
Strict intake-output charting
Nutritional support with adequate caloric intake
Close follow-up with pediatric endocrinologists and geneticists
Education of parents on disease, medication administration, and stress management.
Complications
Early Complications:
Adrenal crisis (untreated or undertreated)
Severe hyponatremic or hyperkalemic crisis leading to cardiac arrhythmias or seizures
Dehydration and shock
Hypoglycemic seizures.
Late Complications:
Growth retardation
Steroid-induced side effects (obesity, Cushingoid features, bone demineralization)
Subfertility or infertility
Psychological issues related to gender assignment and chronic illness
Accelerated bone maturation and early puberty if over-replaced with glucocorticoids
Osteoporosis.
Prevention Strategies:
Newborn screening for CAH using 17-OHP levels
Early diagnosis and initiation of treatment in all symptomatic infants
Consistent adherence to medication regimen
Patient and family education on recognizing signs of adrenal insufficiency and implementing stress dosing protocols during illness or injury.
Prognosis
Factors Affecting Prognosis:
Timeliness of diagnosis and treatment
Severity of the salt-wasting presentation
Adherence to lifelong medication
Management of intercurrent illnesses and stress
Genetic factors and completeness of enzyme deficiency.
Outcomes:
With appropriate treatment, the prognosis for survival is excellent
Affected individuals can achieve normal growth and development
Management of sexual development and fertility requires specialized care
Long-term endocrinological monitoring is essential.
Follow Up:
Lifelong follow-up with a pediatric endocrinologist is mandatory
Regular monitoring of growth, bone age, hormonal levels (17-OHP, renin activity), electrolytes, and steroid side effects
Annual review of medication dosages and patient/family education
Genetic counseling and reproductive planning.
Key Points
Exam Focus:
The salt-wasting crisis is a neonatal emergency characterized by hypoglycemia, hyponatremia, and hyperkalemia due to cortisol and aldosterone deficiency in 21-hydroxylase deficiency CAH
Elevated 17-OHP is the hallmark diagnostic test
Treatment involves glucocorticoid, mineralocorticoid replacement, and electrolyte/glucose correction.
Clinical Pearls:
Always consider CAH salt-wasting in any neonate presenting with shock, vomiting, and unexplained electrolyte abnormalities, especially if there is a history suggestive of adrenal insufficiency or ambiguous genitalia
Stress dosing of glucocorticoids is critical during illness
Monitor renin activity to guide fludrocortisone therapy.
Common Mistakes:
Delayed diagnosis due to misinterpretation of ambiguous genitalia or attributing symptoms to common neonatal issues like feed intolerance or sepsis alone
Inadequate fluid resuscitation or glucose supplementation
Incorrect dosing or lack of fludrocortisone in salt-wasting CAH
Failure to recognize the need for stress dosing during intercurrent illnesses.