Congenital Adrenal Hyperplasia (CAH)

1. Clinical Overview

Summary

Congenital Adrenal Hyperplasia (CAH) encompasses a group of autosomal recessive disorders characterized by enzymatic defects blocking cortisol synthesis in the adrenal cortex. The pituitary responds to low cortisol by secreting excess ACTH, which causes adrenal hyperplasia and shunts hormone precursors into the androgen pathway. [1,2]

21-Hydroxylase Deficiency (21-OHD) accounts for > 95% of all CAH cases and is the most common cause of:

• Ambiguous genitalia in genetic females (46,XX)
• Life-threatening salt-wasting crisis in neonates
• Primary adrenal insufficiency in childhood [3,4]

The condition represents one of the most common autosomal recessive disorders affecting humans, with incidence varying by ethnicity and population. Early diagnosis is critical: delayed recognition of salt-wasting CAH carries significant morbidity and mortality risk in the neonatal period. [5,6]

Clinical Pearls

The "Silent" Male Infant: Female infants with CAH are typically identified at birth due to virilized genitalia (clitoromegaly, labial fusion). In contrast, male infants have normal-appearing external genitalia and are often discharged home without diagnosis. These males present at 7-21 days of life in cardiovascular collapse (salt-wasting crisis). Any male infant presenting with "sepsis-like" shock, hyponatraemia, and hyperkalaemia has CAH until proven otherwise. [7,8]

Pyloric Stenosis vs CAH: Both conditions present with a vomiting male infant at 2-3 weeks of age. The critical distinguishing feature:

• Pyloric Stenosis: Hypochloraemic metabolic alkalosis (K ↓, Cl ↓, pH ↑)
• CAH Salt-Wasting: Hyperkalaemic metabolic acidosis (K ↑, Na ↓, pH ↓) Always check U&Es before assuming pyloric stenosis. [9]

Precocious Puberty Paradox: Children with non-classic CAH or poorly controlled classic CAH develop excess androgens, causing rapid skeletal growth (tall child at age 6-8 years) and early pubic hair/genital development. However, advanced bone age leads to premature epiphyseal fusion, resulting in short final adult height - often 1-2 standard deviations below genetic potential. [10,11]

Newborn Screening Limitations: While 17-OHP screening is standard in many countries (USA, Australia, New Zealand), the UK does not perform universal CAH screening. False positives occur in preterm infants and stressed neonates. False negatives can occur in salt-wasting forms due to delayed 17-OHP rise in the first 24-48 hours. [12,13]

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2. Epidemiology

Demographics

Incidence and Prevalence:

• Classic CAH (21-OHD): Approximately 1 in 15,000-18,000 live births globally [14,15]
• Non-classic CAH: 1 in 200-1,000 (higher in certain populations) [16]
• Carrier frequency: 1 in 60 in general population [17]

Ethnic Variation:

• Highest incidence: Yupik Eskimos of Alaska (1 in 280)
• European descent: 1 in 15,000-20,000
• Ashkenazi Jews: Higher non-classic CAH prevalence (1 in 27 carriers) [18]

Phenotype Distribution

The severity of 21-OHD correlates with residual enzyme activity: [19,20]

1. Classic Salt-Wasting (75% of Classic CAH)

   • less than 1% enzyme activity
   • Complete absence of functional cortisol and aldosterone synthesis
   • Presents in neonatal period (Day 7-21) with adrenal crisis
   • Ambiguous genitalia in females
   • Hyperpigmentation in both sexes

2. Classic Simple Virilizing (25% of Classic CAH)

   • 1-2% enzyme activity
   • Sufficient aldosterone to prevent salt crisis
   • Inadequate cortisol; excess androgens
   • Virilization present at birth in females
   • Males may present later with precocious pseudopuberty

3. Non-Classic (Late-Onset) CAH

   • 20-50% enzyme activity
   • Adequate baseline cortisol and aldosterone
   • Mild androgen excess
   • Presentation in late childhood, adolescence, or adulthood
   • Symptoms: Premature pubarche, hirsutism, acne, oligomenorrhoea, infertility [21]

Genetics

Inheritance Pattern:

• Autosomal recessive
• CYP21A2 gene located on chromosome 6p21.3
• Adjacent to CYP21A1P pseudogene (inactive)
• Gene conversion and recombination between gene and pseudogene account for ~75% of mutations [22,23]

Common Mutations:

• Large deletions/conversions: Severe (salt-wasting)
• I172N mutation: Most common in simple virilizing
• V281L mutation: Associated with non-classic CAH
• Genotype-phenotype correlation is strong but not absolute (residual enzyme activity determines phenotype) [24]

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3. Pathophysiology

The Adrenal Steroid Biosynthesis Pathway

The adrenal cortex synthesizes three classes of steroid hormones from cholesterol: [25]

Zona Glomerulosa:

• Produces mineralocorticoids (aldosterone)
• Regulated by renin-angiotensin system and potassium
• Requires 21-hydroxylase enzyme

Zona Fasciculata:

• Produces glucocorticoids (cortisol)
• Regulated by ACTH from pituitary
• Requires 21-hydroxylase enzyme

Zona Reticularis:

• Produces adrenal androgens (DHEA, androstenedione)
• Does NOT require 21-hydroxylase
• Pathway remains open when 21-hydroxylase blocked

The 21-Hydroxylase Block

Enzymatic Defect: 21-Hydroxylase (encoded by CYP21A2) catalyzes two critical reactions:

1. Progesterone → 11-Deoxycorticosterone (DOC) [mineralocorticoid pathway]
2. 17-Hydroxyprogesterone (17-OHP) → 11-Deoxycortisol [glucocorticoid pathway]

Consequences of Block:

1. Cortisol Deficiency:

• Inadequate stress response
• Hypoglycaemia (reduced gluconeogenesis)
• Loss of negative feedback → ↑ ACTH → ↑ MSH → hyperpigmentation
• Inability to mount stress response during illness [26]

2. Aldosterone Deficiency (in salt-wasting forms):

• Renal sodium loss → hyponatraemia → hypovolaemia → shock
• Potassium retention → hyperkalaemia → cardiac arrhythmia risk
• Hydrogen ion retention → metabolic acidosis
• Activation of renin-angiotensin system (plasma renin activity elevated) [27]

3. Androgen Excess:

• Precursors (17-OHP, progesterone) accumulate
• Shunt into intact androgen pathway
• DHEA and androstenedione overproduced
• Peripheral conversion to testosterone and dihydrotestosterone (DHT)
• Effects:
  • In utero virilization of female fetuses (clitoromegaly, labial fusion)
  • "Post-natal virilization: Premature pubarche, advanced bone age, acne"
  • Accelerated skeletal maturation → premature epiphyseal fusion → short stature [28,29]

Molecular Pathophysiology

ACTH Hypersecretion:

• Low cortisol fails to suppress hypothalamic CRH and pituitary ACTH
• Chronic ACTH stimulation causes:
  • Bilateral adrenal hyperplasia (glands may be 4-6 times normal size)
  • Increased melanocyte-stimulating hormone (MSH) - shares precursor peptide (POMC) with ACTH
  • Skin hyperpigmentation (nipples, scrotum, palmar creases, scars) [30]

Fetal Development: In 46,XX fetuses with classic CAH:

• Androgen exposure begins at 7-8 weeks gestation (onset of fetal adrenal steroidogenesis)
• External genitalia virilize (clitoral enlargement, urogenital sinus formation)
• Internal reproductive organs (ovaries, uterus, fallopian tubes) develop normally (Müllerian structures intact; no anti-Müllerian hormone)
• Severity of virilization at birth depends on genotype and residual enzyme activity [31]

In 46,XY fetuses:

• External genitalia appear normal (androgens expected)
• No clinical signs at birth in most cases

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4. Clinical Presentation

Neonatal Female (46,XX)

Ambiguous Genitalia (Present at Birth): The degree of virilization varies (Prader stages I-V): [32]

• Prader I: Clitoromegaly only
• Prader II: Clitoromegaly + posterior labial fusion
• Prader III: Greater clitoral enlargement + near-complete labial fusion with single urogenital opening
• Prader IV: Phallic structure with urogenital sinus opening at base
• Prader V: Complete masculinization with penile urethra (may be assigned male at birth)

Internal Examination:

• Palpation: No testes palpable (critical diagnostic feature)
• Ultrasound: Uterus and ovaries present
• Karyotype: 46,XX

Salt-Wasting Crisis (if not diagnosed): Even virilized females may develop salt-wasting if untreated, typically Day 7-14 of life.

Neonatal Male (46,XY)

At Birth:

• External genitalia appear normal
• May have scrotal hyperpigmentation (subtle clue)
• Penile length may be slightly increased (androgenic effect)
• Often discharged without diagnosis [33]

Salt-Wasting Crisis (Day 7-21): The classic presentation in undiagnosed males: [34,35]

• Feeding difficulties: Poor feeding, vomiting
• Weight loss: "Failure to thrive" (often > 10% birth weight loss)
• Dehydration: Sunken fontanelle, reduced skin turgor
• Shock: Tachycardia, hypotension, poor perfusion, mottled skin
• Lethargy/Seizures: Due to hyponatraemia and hypoglycaemia
• Misdiagnosis risk: Often initially treated as sepsis; CAH must be excluded

Red Flag Signs:

• Shock + hyperkalaemia (very unusual in neonatal sepsis)
• Hyponatraemia + hyperkalaemia (salt-wasting pattern)
• Hyperpigmentation (ACTH excess)
• Glucose instability

Older Child (Non-Classic CAH or Missed Classic CAH)

Females:

• Premature pubarche: Pubic/axillary hair before age 8 years
• Clitoromegaly (if undiagnosed classic CAH)
• Hirsutism: Excess body hair
• Severe acne: Resistant to standard treatment
• Oligomenorrhoea/Amenorrhoea: Irregular or absent menses
• Infertility: Anovulation due to androgen excess [36]

Males:

• Precocious pseudopuberty: Pubic hair, penile enlargement, acne before age 9 years
• Rapid growth velocity: Tall for age initially
• Advanced bone age: > 2 years ahead of chronological age
• Small testes: Bilaterally small (Tanner stage lags behind virilization)
• Short adult height: Premature epiphyseal fusion [37]

Both Sexes:

• Accelerated skeletal maturation
• Muscular build
• Deep voice (androgenic effect)
• Body odour

Adult Presentation (Non-Classic CAH)

May remain undiagnosed until adulthood: [38]

• Women: Hirsutism, oligomenorrhoea, infertility, PCOS-like presentation
• Men: Usually asymptomatic; occasionally reduced fertility
• Incidental finding on biochemical testing

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5. Clinical Examination

Systematic Approach to Suspected CAH

General Inspection:

• Hydration status: Sunken fontanelle, dry mucous membranes, skin turgor
• Growth parameters: Weight, length, head circumference (plot on centile chart)
• Pigmentation: Look for hyperpigmentation at:
  • Nipples
  • Scrotum/labia
  • Palmar creases
  • Recent scars
  • Linea alba (ACTH and MSH elevation causes melanin deposition) [39]

Cardiovascular:

• Heart rate: Tachycardia in crisis
• Blood pressure: Hypotension in salt-wasting crisis (contrast with hypertension in 11β-hydroxylase deficiency)
• Capillary refill time: Prolonged in shock
• Femoral pulses: Weak in dehydration

Genitalia Examination (Critical):

In Female Neonates:

1. Prader Staging: Document degree of virilization (I-V)
2. Palpation: Carefully palpate labioscrotal folds - absence of testes confirms 46,XX (vs. 46,XY with androgen insensitivity or mixed gonadal dysgenesis)
3. Urogenital opening: Identify number and location of openings
4. Avoid gender assignment until karyotype and imaging complete

In Male Neonates: 5. Penile length: Measure (may be mildly increased) 6. Testicular position and size: Palpate both testes in scrotum 7. Scrotal pigmentation: Dark pigmentation suggests ACTH excess 8. Hypospadias: Exclude (not a feature of CAH)

In Older Children:

• Tanner staging: Assess breast development, pubic hair, testicular volume
• Note discordance: Pubic hair advanced but breast/testicular development delayed
• Measure stretched penile length or clitoral size if indicated

Abdominal:

• Palpable kidneys (may suggest polycystic kidneys or other DSD causes)
• Organomegaly (not typical in CAH)

Musculoskeletal:

• Muscle bulk (increased in androgen excess)
• Bone age assessment: Radiograph left wrist and hand [40]

Neurological:

• Tone and reflexes (hypoglycaemia or severe hyponatraemia may cause hypotonia/seizures)
• Developmental assessment

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6. Investigations

Immediate Investigations (Emergency Setting)

In suspected salt-wasting crisis: [41,42]

1. Urea and Electrolytes:

• Sodium: Typically less than 130 mmol/L (may be less than 120 mmol/L in severe crisis)
• Potassium: > 6.0 mmol/L (cardiac monitoring required if > 6.5 mmol/L)
• Chloride: Elevated or normal
• Urea/Creatinine: Elevated (pre-renal AKI from dehydration)

2. Blood Gas:

• Metabolic acidosis: Low pH, low bicarbonate, normal/low CO₂
• Distinguish from pyloric stenosis (metabolic alkalosis)

3. Glucose:

• Hypoglycaemia common: less than 2.6 mmol/L (cortisol deficiency impairs gluconeogenesis)
• May require glucose bolus and infusion

4. 17-Hydroxyprogesterone (17-OHP):

• Diagnostic hallmark of 21-OHD
• Classic CAH: Typically > 300 nmol/L (> 10,000 ng/dL)
• Non-classic CAH: 30-300 nmol/L (basal or post-ACTH stimulation)
• Take sample BEFORE starting hydrocortisone (treatment interferes with assay)
• Timing: Ideally 0800h sample (diurnal variation) [43]

5. Plasma Renin Activity (PRA) or Direct Renin Concentration:

• Markedly elevated in salt-wasting forms (aldosterone deficiency)
• Useful to distinguish salt-wasting from simple virilizing
• Guides fludrocortisone dosing

6. Cortisol (0900h):

• Usually low or inappropriately normal given stress
• Confirm adrenal insufficiency

7. ACTH:

• Elevated (loss of cortisol negative feedback)
• Typically > 100 pg/mL (normal less than 50 pg/mL)

8. Testosterone, Androstenedione, DHEAS:

• Elevated in virilizing forms
• Useful for monitoring treatment adequacy

Confirmatory Investigations

9. Karyotype:

• Mandatory in all ambiguous genitalia
• Confirm 46,XX in virilized female
• Exclude disorders of sex development (45,X/46,XY mosaicism, ovotesticular DSD, etc.)

10. Pelvic Ultrasound:

• Identify uterus and ovaries in 46,XX infant
• Assess urogenital sinus anatomy
• May show bilateral adrenal hyperplasia (enlarged glands)

11. ACTH Stimulation Test (Synacthen Test):

• Not required in classic CAH (diagnosis clear from basal 17-OHP)
• Used in non-classic CAH: Exaggerated 17-OHP response (> 30 nmol/L at 60 minutes)
• Protocol: Measure 17-OHP at baseline, 30, and 60 minutes after 250 mcg ACTH IV [44]

Genetic Testing

12. CYP21A2 Mutation Analysis:

• Confirms diagnosis
• Provides genotype-phenotype correlation
• Useful for family counseling and prenatal diagnosis
• Common mutations: Gene deletions, I2 splice, I172N, V281L [45]

Genotype-Phenotype Correlation:

• Null mutations (deletions, frameshifts): Salt-wasting
• I172N, P30L: Simple virilizing
• V281L, P453S: Non-classic CAH [46]

Monitoring Investigations (Long-Term)

13. Growth Monitoring:

• Height velocity chart
• Bone age radiograph (left hand/wrist): Annually in growing children
• Target height calculation (mid-parental height)

14. Blood Pressure:

• Monitor for over-replacement (hypertension) or under-replacement (hypotension)

15. Hormonal Monitoring:

• 17-OHP: Target 10-30 nmol/L (over-suppression indicates over-treatment)
• Androstenedione: less than 3 nmol/L
• Testosterone: Age- and sex-appropriate ranges
• Plasma Renin Activity: Keep in upper normal range (indicates adequate fludrocortisone)
• ACTH: Not routinely used (pulsatile secretion) [47]

16. Bone Mineral Density:

• DXA scan in adolescence/adulthood (monitor for glucocorticoid-induced osteoporosis)

17. Testicular Ultrasound (Males):

• Screen for testicular adrenal rest tumors (TARTs) from puberty onwards
• Annual or biennial ultrasound [48]

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7. Management

Emergency Management: Salt-Wasting Crisis

Immediate Life-Saving Measures (ABCDE Approach): [49,50]

A. Airway:

• Assess and secure airway if reduced consciousness

B. Breathing:

• High-flow oxygen
• Monitor respiratory rate and oxygen saturations

C. Circulation:

1. IV Access: Two large-bore cannulae
2. Fluid Resuscitation:
   • 0.9% Sodium Chloride 20 mL/kg bolus over 10-20 minutes
   • Repeat bolus if still shocked
   • Avoid dextrose-only fluids initially (need sodium replacement)
3. Cardiac Monitor: ECG monitoring for hyperkalaemia (tall T waves, widened QRS)
4. Blood Pressure: Invasive monitoring if in ICU

D. Disability:

• Glucose Check: Treat hypoglycaemia with:
  • 2 mL/kg 10% dextrose bolus if less than 2.6 mmol/L
  • "Maintenance fluids: 0.9% saline + 5-10% dextrose"
• GCS/AVPU: Document conscious level

E. Exposure:

• Examine genitalia
• Look for hyperpigmentation

Specific Medical Therapy:

1. Hydrocortisone (Stress Dose):

• 100 mg/m² IV bolus (or 25-50 mg for neonate)
• Followed by 100 mg/m²/day as continuous infusion or divided Q6H
• Continue until crisis resolved (48-72 hours), then switch to oral maintenance

2. Hyperkalaemia Management:

• If K > 6.5 mmol/L or ECG changes:
  • Calcium gluconate 10% 0.5 mL/kg IV over 5-10 minutes (cardioprotective)
  • Salbutamol nebulizer (shifts K+ intracellularly)
  • Insulin-dextrose infusion (0.1 unit/kg insulin + 2 mL/kg 10% dextrose)
  • Sodium bicarbonate if severe acidosis
• Avoid potassium-containing fluids
• Recheck K+ every 2-4 hours

3. Metabolic Acidosis:

• Usually corrects with fluid resuscitation
• Sodium bicarbonate 1-2 mmol/kg IV if pH less than 7.1

4. Fludrocortisone:

• Not required in acute phase (stress-dose hydrocortisone has mineralocorticoid activity)
• Start oral fludrocortisone once oral intake established

Investigations (Before Hydrocortisone):

• Blood: 17-OHP, cortisol, ACTH, renin, U&E, glucose, blood gas
• Urine: Steroid profile (specialist test)

ICU Referral:

• Severe shock requiring inotropes
• Severe hyperkalaemia or arrhythmia
• Seizures or reduced GCS

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Long-Term Medical Management

Goals of Treatment: [51,52]

1. Replace deficient cortisol (prevent adrenal crisis)
2. Replace deficient aldosterone (maintain sodium/potassium balance)
3. Suppress ACTH (reduce androgen excess)
4. Optimize growth and development
5. Minimize glucocorticoid side effects

1. Glucocorticoid Replacement:

Hydrocortisone (Drug of Choice in Children):

• Dose: 10-15 mg/m²/day in children (up to 17 mg/m²/day in infants)
• Divided doses: Three times daily to mimic diurnal rhythm
  • "Example: 40% morning, 30% midday, 30% evening"
  • "OR: 50% morning, 25% lunch, 25% evening"
• Why Hydrocortisone?
  • Short-acting (allows nocturnal ACTH rise to suppress androgens)
  • Minimal growth suppression compared to longer-acting steroids
  • Avoids prednisolone or dexamethasone in growing children (cause growth failure) [53]

Monitoring Adequacy:

• Growth velocity: Best clinical marker (normal = adequate replacement)
• Bone age advancement: Target less than 2 years ahead of chronological age
• 17-OHP levels: 10-30 nmol/L (not over-suppressed)
• Androstenedione: less than 3 nmol/L
• Clinical signs: Absence of virilization, normal energy levels

2. Mineralocorticoid Replacement (Salt-Wasting Forms):

Fludrocortisone:

• Dose: 50-200 mcg daily (higher in infants, lower in older children)
• Single morning dose (long half-life ~3.5 hours allows once-daily dosing)
• Monitoring:
  • "Plasma Renin Activity (PRA): Target upper normal range"
  • "Blood pressure: Avoid hypertension (over-treatment)"
  • "Serum sodium/potassium: Keep normal"

Sodium Chloride Supplementation:

• Infants: 1-2 g/day (divide into feeds)
• Usually discontinued after weaning onto solid diet (adequate dietary sodium)
• Continue in hot climates or gastroenteritis risk [54]

3. Sick Day Rules (CRITICAL):

Patients with CAH cannot mount endogenous cortisol response to stress. Failure to increase glucocorticoid dose during illness can cause adrenal crisis and death. [55]

Education for Parents/Patients:

• Always carry emergency hydrocortisone injection kit
• Medical alert bracelet/necklace: "Adrenal Insufficiency - Needs Hydrocortisone"
• Written action plan provided to family and school

Dose Adjustment Protocol:

IM Hydrocortisone Emergency Dose:

• less than 1 year: 25 mg
• 1-5 years: 50 mg
• 6-12 years: 75 mg

• 12 years: 100 mg

Pre-Operative Management:

• Minor procedures (dental): Double oral dose on day of procedure
• Major surgery: IV hydrocortisone 100 mg/m²/day (divided Q6H) + continue until eating/drinking

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Surgical Management

Feminizing Genitoplasty (46,XX with Virilization):

Indications:

• Prader stage II-V virilization
• Performed to allow normal urination and future sexual function [56]

Timing:

• Controversial: Traditionally performed at 6-18 months of age
• Delayed surgery approach increasingly discussed (allow patient to participate in decision-making)

Procedures:

• Clitoral recession/reduction: Preserve neurovascular bundle
• Vaginoplasty: Create vaginal opening if urogenital sinus present
• Labial separation: Separate fused labia

Complications:

• Vaginal stenosis (may require further surgery in adolescence)
• Reduced clitoral sensation
• Psychological impact of early surgery

Testicular Adrenal Rest Tumor (TART) Management:

TARTs are benign ectopic adrenal tissue in testes, occur in 20-40% of males with CAH: [57,58]

• Screening: Annual testicular ultrasound from puberty
• Treatment:
  • Optimize hydrocortisone dose (suppress ACTH → TART regression in ~50%)
  • Surgical excision if tumors large, symptomatic, or do not respond to medical therapy
  • "Risk: Surgery may damage testicular tissue → infertility"

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Multidisciplinary Team Approach

Essential Team Members: [59]

• Paediatric endocrinologist (lead clinician)
• Paediatric urologist/surgeon (genitoplasty)
• Clinical geneticist (genetic counseling)
• Clinical psychologist (gender identity, body image)
• Specialist nurse (education, sick day rules)
• Fertility specialist (transition to adult care)
• Gynaecologist (females - menstrual irregularities)

Transition to Adult Care:

• Planned transition at 16-18 years
• Adult endocrinology takes over
• Address fertility, sexuality, bone health, cardiovascular risk [60]

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8. Complications

Acute Complications

1. Adrenal Crisis:

• Life-threatening emergency
• Causes: Infection, trauma, surgery, non-compliance, inadequate stress dosing
• Mortality: 0.5% annual risk of death from adrenal crisis [61]
• Prevention: Education, emergency injection training, medical alert bracelet

2. Hypoglycaemia:

• Cortisol deficiency impairs gluconeogenesis
• Risk highest in infants and during illness
• Treatment: IV dextrose + hydrocortisone

3. Severe Hyponatraemia:

• Risk of cerebral oedema if corrected too rapidly
• Correct sodium at less than 10-12 mmol/L per 24 hours

4. Cardiac Arrhythmia:

• Hyperkalaemia-induced (peaked T waves, wide QRS, bradycardia)
• Requires urgent calcium gluconate and potassium-lowering measures

Chronic Complications

5. Growth Impairment: Two mechanisms: [62]

• Under-treatment: Androgen excess → advanced bone age → premature fusion → short stature
• Over-treatment: Glucocorticoid excess → Cushingoid features → growth suppression

Optimal management:

• Monitor growth velocity (should track centiles)
• Monitor bone age annually
• Adjust hydrocortisone to minimum effective dose

6. Obesity and Metabolic Syndrome:

• Glucocorticoid therapy increases appetite and central adiposity
• Increased risk of insulin resistance, dyslipidaemia
• Encourage healthy diet and exercise [63]

7. Osteoporosis:

• Glucocorticoid-induced bone loss
• Monitor bone density (DXA) from late adolescence
• Ensure adequate calcium and vitamin D

8. Testicular Adrenal Rest Tumors (TARTs):

• Prevalence: 20-40% of adult males with CAH
• Bilateral in > 80%
• Mechanism: Chronic ACTH stimulation → ectopic adrenal tissue in testes
• Consequence: Infertility (obstructive azoospermia, Leydig cell dysfunction)
• Prevention: Optimal hydrocortisone control to suppress ACTH [64]

9. Reduced Fertility:

Females: [65]

• Anovulation (androgen excess suppresses HPG axis)
• Cervical mucus abnormalities
• PCOS-like features
• Reduced fertility rate (~60% vs. > 85% general population)
• Improve with optimal CAH control

Males:

• TARTs (see above) - main cause
• Reduced sperm count and motility
• Hypogonadotropic hypogonadism (chronic androgen excess)

10. Psychosocial and Gender Identity Issues:

• Higher rates of anxiety and depression [66]
• Gender dysphoria in 5-10% of 46,XX individuals raised female
• Body image concerns (virilization, surgical scars)
• Psychological support essential

11. Cardiovascular Risk:

• Increased blood pressure in adulthood (glucocorticoid and mineralocorticoid effects)
• Metabolic syndrome
• Monitor cardiovascular risk factors [67]

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9. Prognosis and Outcomes

Survival

With Treatment:

• Excellent survival if diagnosed early and compliant with therapy
• Mortality risk: Mainly from adrenal crisis (0.5-1% per decade) [68]

Without Treatment (Salt-Wasting):

• Fatal within 2-4 weeks in neonatal period

Adult Height

Factors Affecting Final Height: [69]

• Age at diagnosis
• Adequacy of hydrocortisone control
• Bone age advancement
• Genetic height potential

Outcomes:

• Classic CAH: Final height typically 1-2 SD below target height
• Non-classic CAH: Often near-normal height if well-controlled
• Females generally achieve better height than males

Fertility Outcomes

Females:

• Pregnancy possible with optimized CAH management [70]
• Higher risk of miscarriage and preterm labor
• Requires careful monitoring and stress-dose steroids during labor

Males:

• Paternity rates lower than general population (TARTs)
• Assisted reproduction may be required

Quality of Life

Long-Term Studies:

• Overall quality of life lower than general population [71]
• Factors: Chronic medication, body image, surgery, fertility concerns
• Importance of psychological support and peer support groups

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10. Evidence and Guidelines

Key Guidelines

Landmark Evidence

1. Newborn Screening:

• Therrell et al., 1998: 17-OHP screening reduces neonatal death from undiagnosed salt-wasting CAH in males [73]
• White & Speiser, 2000: Cost-effectiveness analysis supports universal screening
• Not yet adopted in UK (concerns: false positives, unclear long-term benefit)

2. Genotype-Phenotype Correlation:

• Krone et al., 2000: Demonstrated strong correlation between CYP21A2 mutations and phenotype severity [74]
• Null mutations (deletions) → salt-wasting
• I172N → simple virilizing
• V281L → non-classic

3. Hydrocortisone Dosing:

• Charmandari et al., 2001: Lower hydrocortisone doses (10-15 mg/m²/day) improve growth without compromising control
• Higher doses (> 15 mg/m²/day) suppress growth

4. TARTs and Fertility:

• Claahsen-van der Grinten et al., 2008: TARTs present in 40% of males; intensified glucocorticoid therapy can induce regression [75]

5. Adult Outcomes:

• Finkielstain et al., 2012: Adult height significantly compromised in CAH; average 10 cm below mid-parental height

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11. Patient and Layperson Explanation

What is CAH?

Imagine your child's adrenal glands (two small glands sitting on top of the kidneys) as a factory that makes three important hormones:

1. Cortisol (the "stress hormone") - helps the body cope with illness, injury, or stress
2. Aldosterone (the "salt hormone") - keeps salt and water balanced in the body
3. Androgens (like testosterone - the "male hormone")

In CAH, there is a genetic "factory fault". The machine (enzyme) that makes Cortisol and Aldosterone is missing or broken. This means:

• The factory cannot make enough Cortisol and Aldosterone
• The "raw materials" pile up and spill over into the only production line that still works: making Androgens (male hormones)

What happens because of this?

Lack of Cortisol:

• Your baby cannot fight stress, infections, or low blood sugar properly
• During illness, your baby needs extra cortisol from medication or can become dangerously unwell

Lack of Aldosterone (in severe forms):

• The kidneys lose salt in the urine → low sodium in blood
• The body keeps too much potassium → high potassium in blood
• This causes dehydration, shock, and can be life-threatening in the first few weeks of life

Excess Androgens:

• In girls: The genitals may look partly male at birth (larger clitoris, fused labia)
• In boys: The genitals look normal at birth, but the baby may develop early puberty signs later
• In both: Fast growth when young, but shorter adult height because bones stop growing too early

What is the treatment?

We give back the missing hormones as medications:

1. Hydrocortisone tablets:

• Replaces the missing cortisol
• Taken 2-3 times a day
• Tells the adrenal glands "we have enough cortisol now" → stops them making too much testosterone

2. Fludrocortisone tablets:

• Replaces the missing aldosterone
• Taken once a day
• Keeps salt and potassium levels normal

3. Salt supplements (in babies):

• Extra salt in milk until the baby is eating solid food

What are "Sick Day Rules"? (VERY IMPORTANT)

When your child gets a fever or infection, their body needs more cortisol to fight the illness. Because they have CAH, their adrenal glands cannot make extra cortisol on their own.

You must give extra hydrocortisone:

• Fever or mild illness: DOUBLE the usual dose of tablets
• Vomiting (cannot keep tablets down): Give emergency injection of hydrocortisone immediately and go to the hospital

Failure to do this can cause "adrenal crisis" - a life-threatening emergency.

Your child should:

• Wear a medical alert bracelet ("Adrenal Insufficiency")
• Have an emergency injection kit at home and school
• Have a written "sick day plan" from the doctor

Will my child be okay?

With proper treatment and monitoring:

• Your child can live a normal, healthy life
• They can go to school, play sports, and have a career
• They need to take medication every day for life
• They need to learn to adjust doses during illness (becomes second nature)

Fertility:

• Many people with CAH can have children
• Some may need help from fertility specialists

Height:

• With good control, your child can reach a normal adult height (though may be slightly shorter than their genetic potential)

What support is available?

• Specialist paediatric endocrinology team
• Specialist nurses for education
• Psychologists (to help with body image, surgery decisions)
• Support groups: CAH Support Group UK, CARES Foundation (USA)

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12. Differential Diagnosis

Ambiguous Genitalia (46,XX Infant)

Virilized Female (46,XX DSD):

1. Congenital Adrenal Hyperplasia (most common)
2. Maternal androgen exposure: Maternal virilizing tumor, exogenous androgens
3. Placental aromatase deficiency: Rare

Distinguish: Measure 17-OHP, karyotype, pelvic ultrasound

Ambiguous Genitalia (46,XY Infant)

Under-virilized Male (46,XY DSD):

1. Androgen Insensitivity Syndrome: Testes present, normal testosterone, unresponsive to androgens
2. 5α-Reductase Deficiency: Cannot convert testosterone to DHT
3. Gonadal Dysgenesis: Dysgenetic testes, low testosterone
4. Biosynthesis defects: 17β-HSD deficiency, StAR deficiency

Distinguish: Testosterone and DHT levels, hCG stimulation test, genetic testing

Salt-Wasting Crisis (Neonate)

Differential Diagnosis of Hyponatraemia + Hyperkalaemia:

1. CAH (most common endocrine cause)
2. Pseudohypoaldosteronism: Aldosterone resistance
3. Addison's Disease: Primary adrenal insufficiency (rare in neonates)
4. Aldosterone Synthase Deficiency: Isolated mineralocorticoid deficiency

Distinguish: 17-OHP (high in CAH), aldosterone/renin (high renin, low aldosterone in CAH)

Precocious Puberty

Differential of Early Pubic Hair (Premature Adrenarche):

1. Non-Classic CAH (check 17-OHP)
2. Idiopathic Premature Adrenarche: Benign, normal 17-OHP
3. Cushing's Syndrome: Androgen excess + hypercortisolism
4. Androgen-Secreting Tumor: Very rare, unilateral adrenal mass

Distinguish: 17-OHP, ACTH stimulation test, DHEAS, imaging

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13. Examination Focus

Common Exam Questions (MRCPCH, FRACP)

1. Diagnosis - Classic Vignette:

"A 14-day-old male infant presents with vomiting, poor feeding, and lethargy. On examination, he is dehydrated and hypotensive. Bloods show Na 118 mmol/L, K 7.2 mmol/L. What is the most likely diagnosis?"

Answer: Congenital Adrenal Hyperplasia (salt-wasting crisis)

2. Biochemistry:

"What is the diagnostic biochemical marker for 21-hydroxylase deficiency?"

Answer: Elevated 17-Hydroxyprogesterone (17-OHP) > 300 nmol/L

3. Genetics:

"What is the inheritance pattern of CAH?"

Answer: Autosomal recessive

4. Management:

"A 5-year-old child with CAH develops fever and vomiting. What should the parents do?"

Answer:

• Cannot tolerate oral medication → Give IM hydrocortisone (emergency injection)
• Call ambulance and go to hospital immediately
• This is an adrenal crisis - life-threatening

5. Ambiguous Genitalia:

"How do you distinguish between a virilized female (46,XX with CAH) and undervirilized male (46,XY with partial androgen insensitivity)?"

Answer:

• Palpate for testes: Absent in CAH (46,XX), present in AIS (46,XY)
• Karyotype: 46,XX in CAH
• 17-OHP: Elevated in CAH
• Pelvic ultrasound: Uterus present in CAH

6. Monitoring:

"What is the best clinical marker of adequate hydrocortisone replacement in a growing child with CAH?"

Answer: Normal growth velocity (child growing along centile lines)

Viva Voce Scenarios

Scenario 1: Salt-Wasting Crisis

"You are the paediatric registrar. A 2-week-old male infant has been brought to A&E in shock. Parents report poor feeding and vomiting for 2 days. Initial bloods show Na 120, K 7.5, glucose 2.1. How do you manage this child?"

Model Answer: "This is a medical emergency - likely salt-wasting adrenal crisis from CAH.

Immediate management (ABCDE):

• Airway: Assess, secure if needed
• Breathing: High-flow oxygen
• Circulation:
  • IV access × 2
  • 0.9% saline 20 mL/kg bolus (repeat if shocked)
  • Cardiac monitor (hyperkalaemia risk)
• Disability:
  • "Treat hypoglycaemia: 2 mL/kg 10% dextrose bolus"
  • Assess GCS
• Exposure: Examine genitalia (scrotal pigmentation?)

Specific treatment:

• Hydrocortisone 25-50 mg IV bolus, then 100 mg/m²/day continuous or Q6H
• Hyperkalaemia management:
  • Calcium gluconate 10% 0.5 mL/kg IV (cardioprotective)
  • Salbutamol nebulizer
  • Insulin-dextrose if K persistently > 7 mmol/L

Investigations (before hydrocortisone if possible):

• 17-OHP, cortisol, ACTH, renin
• Blood gas (metabolic acidosis expected)

Escalate to PICU if inotropes or ventilation needed."

Scenario 2: 11β-Hydroxylase Deficiency

"What is the second most common cause of CAH? How does it differ from 21-hydroxylase deficiency?"

Answer: "11β-Hydroxylase Deficiency accounts for 5% of CAH cases.

Similarities:

• Virilization (androgen excess)
• Low cortisol
• Autosomal recessive

Key Difference:

• 11β-OH deficiency causes HYPERTENSION (vs. hypotension/salt-wasting in 21-OH deficiency)
• Mechanism: Deoxycorticosterone (DOC) accumulates; DOC has mineralocorticoid activity → sodium retention → hypertension

Biochemistry:

• Elevated 11-Deoxycortisol and DOC
• Normal or low 17-OHP

Management:

• Glucocorticoid replacement (same as 21-OH deficiency)
• No fludrocortisone needed (excess mineralocorticoid activity already present)
• May need antihypertensives"

Scenario 3: Gender Assignment

"A neonate is born with ambiguous genitalia. How would you approach this with the parents?"

Answer: "This is a sensitive situation requiring multidisciplinary input and excellent communication.

Initial Approach:

• Avoid guessing gender: "Your baby's genitals are not clearly male or female yet. We need tests to understand why."
• Reassure: "This is rare but we have specialist teams to help."
• Do not assign gender until full investigation complete

Investigations:

• Urgent: Karyotype (46,XX vs. 46,XY), 17-OHP, U&Es (exclude CAH crisis)
• Pelvic ultrasound (uterus/ovaries?)
• Endocrinology and urology review

Multidisciplinary Team:

• Paediatric endocrinologist (lead)
• Geneticist
• Urologist/surgeon
• Psychologist
• Specialist DSD nurse

Gender Assignment:

• Based on karyotype, anatomy, future sexual function, fertility potential
• CAH 46,XX infants almost always raised female (have ovaries, uterus, potential fertility)
• Surgical decisions individualized and increasingly delayed to allow child's participation

Support:

• DSD support groups
• Regular follow-up"

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14. Key Take-Home Points

1. CAH (21-OHD) is the most common cause of ambiguous genitalia and life-threatening salt-wasting in neonates.

2. The "silent male" is at highest risk: Normal genitalia at birth → missed diagnosis → adrenal crisis at Day 7-21.

3. Hyponatraemia + Hyperkalaemia + Shock = CAH until proven otherwise. Measure 17-OHP.

4. Sick Day Rules save lives: Double hydrocortisone dose for fever; IM hydrocortisone + hospital for vomiting.

5. Growth velocity is the best monitor of adequate treatment in children.

6. TARTs affect 20-40% of males: Screen with testicular ultrasound from puberty; optimize ACTH suppression.

7. Fertility is reduced but possible with optimal CAH control and reproductive assistance if needed.

8. Multidisciplinary DSD team essential for ambiguous genitalia management and surgical decisions.

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