Pediatrics (System-Integrated)

Congenital adrenal hyperplasia: recognition and management

Clinical Overview and When to Suspect Congenital Adrenal Hyperplasia

— Loss of cortisol → ACTH-driven hyperplasia → accumulation of precursors shunted into androgen pathway

— Aldosterone synthesis is also impaired in classic forms (salt-wasting variant)

— Classic salt-wasting (~75%): present in first 1–4 weeks of life with vomiting, dehydration, hyponatremia, hyperkalemia, shock

— Classic simple-virilizing (~25%): ambiguous genitalia in 46,XX newborns; 46,XY boys appear normal but virilize early in childhood

— Non-classic (late-onset): adolescent/adult premature pubarche, hirsutism, oligomenorrhea, infertility — often mistaken for PCOS

— Newborn with failure to thrive, vomiting, hyperpigmentation (from elevated ACTH/POMC), and Na↓ / K↑ in week 2 of life

— Atypical genitalia in a newborn (clitoromegaly, fused labia, no palpable gonads in apparently male infant — could be virilized 46,XX)

— Positive state newborn screen showing elevated 17-hydroxyprogesterone (17-OHP)

— Young girl with premature adrenarche (pubic hair <8 yr), advanced bone age, accelerated linear growth

— Adolescent female with hirsutism + irregular menses + family history of CAH or consanguinity

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of cortisol biosynthesis; >95% are due to 21-hydroxylase deficiency (CYP21A2)

Three clinical phenotypes:

When to suspect (Step 3 triggers):

Board pearl: Every U.S. state screens newborns for 21-hydroxylase deficiency by measuring 17-OHP on day 1–3. A positive screen mandates urgent confirmatory testing before the typical day 7–14 salt-wasting crisis. Premature infants have physiologically elevated 17-OHP — interpret with gestational-age-adjusted cutoffs to avoid false positives.

Key distinction: CAH is the most common cause of ambiguous genitalia in 46,XX infants and the most common cause of adrenal insufficiency in children.

Presentation Patterns and Key History

— Onset day 7–14 of life (not at birth — maternal cortisol/aldosterone protects initially)

— Poor feeding, vomiting, lethargy, weight loss, dehydration, hypotension/shock

— Labs: hyponatremia, hyperkalemia, hypoglycemia, metabolic acidosis

— 46,XY boys often missed because genitalia look normal → present sicker

— 46,XX: virilized external genitalia at birth (Prader stages 1–5), normal internal Müllerian structures (uterus, ovaries, upper vagina present)

— 46,XY: appears normal at birth → peripheral precocious puberty by age 2–4 (pubic hair, acne, growth spurt, small testes because LH/FSH suppressed)

— Advanced bone age → tall child, short adult height

— Presents in late childhood through adulthood

— Premature pubarche, severe acne, hirsutism, menstrual irregularity, anovulatory infertility

— Often diagnosed during PCOS workup; higher prevalence in Ashkenazi Jewish, Hispanic, Slavic, Italian populations

— Family history: prior unexplained neonatal death, consanguinity, sibling with CAH, known carrier parents

— Prenatal history: maternal virilization during pregnancy (rare); prenatal ultrasound suggestive of genital atypia

— Newborn screen result — always confirm it was performed and reviewed

— Growth velocity, pubertal milestones, bone age if available

— Salt craving, episodes of dehydration with minor illness (suggests undiagnosed salt-wasting)

Neonatal salt-wasting crisis (classic SW-CAH):

Simple virilizing (classic SV-CAH):

Non-classic CAH (NCCAH):

Key history points to elicit:

Step 3 management: A 12-day-old infant brought in for "poor feeding" — your first three orders are fingerstick glucose, basic metabolic panel, and IV access for normal saline bolus. Do not wait for confirmatory hormone results before treating presumed adrenal crisis.

Board pearl: A 46,XY boy with simple-virilizing CAH and bilaterally small, prepubertal-sized testes but advanced pubic hair = peripheral (gonadotropin-independent) precocious puberty — the giveaway that the androgen source is adrenal, not testicular.

Physical Exam Findings and Hemodynamic Assessment

— Vital signs: tachycardia, hypotension, prolonged cap refill, cool extremities, depressed fontanelle

— Lethargy, weak cry, poor tone, hypothermia

— Hyperpigmentation of areolae, scrotum/labia, and gingival/buccal mucosa (excess ACTH/MSH from POMC cleavage)

— Weight loss >10% from birth weight is a red flag

— 46,XX virilization: clitoromegaly, rugated/fused labia majora mimicking scrotum, single urogenital sinus opening, no palpable gonads

— 46,XY: usually normal phallus and descended testes; isolated hyperpigmentation may be only clue

— Always palpate for gonads in any infant with atypical genitalia — a palpable gonad essentially rules out 46,XX CAH (ovaries don't descend)

— Use Prader staging (1–5) to document virilization

— Tall stature for age with advanced bone age (often >2 SD above chronologic age)

— Tanner pubic hair stage advanced relative to genital/breast development

— Acne, hirsutism, deepening voice in girls; prepubertal testicular volume in boys despite virilization

— Testicular adrenal rest tumors (TART): irregular, firm, often bilateral testicular masses in poorly controlled males — fertility-threatening

— Hirsutism (Ferriman-Gallwey scoring), male-pattern alopecia, acne, oligomenorrhea, subfertility

— Treat as distributive + hypovolemic shock overlay

— 20 mL/kg NS bolus, repeat as needed; correct hypoglycemia with D10 2–5 mL/kg

— Do not correct hyponatremia rapidly — risk of central pontine myelinolysis is low in acute setting but avoid hypertonic saline unless seizing

Newborn with suspected salt-wasting crisis:

Genitourinary exam in newborns (critical):

Older children (simple-virilizing or late diagnosis):

Adolescents/adults with NCCAH:

Hemodynamic assessment in adrenal crisis:

CCS pearl: In a crashing newborn with ambiguous genitalia and shock, draw a "critical sample" (17-OHP, cortisol, ACTH, renin, aldosterone, electrolytes, glucose) before giving hydrocortisone — but never delay steroid administration waiting for the lab tube to fill.

Diagnostic Workup — Initial Labs and Imaging

— Serum 17-hydroxyprogesterone (17-OHP) — the cornerstone diagnostic test

— Classic CAH: usually >10,000 ng/dL (often >20,000)

— Non-classic CAH: morning baseline 200–1,500 ng/dL; if equivocal → ACTH stimulation test

— Healthy newborn: <100 ng/dL after 48 h; preterm/stressed infants run higher

— Basic metabolic panel: hyponatremia, hyperkalemia, mild metabolic acidosis, hypoglycemia

— Plasma renin activity (high) and aldosterone (low/inappropriately normal) confirm mineralocorticoid deficiency in salt-wasters

— Cortisol (low) with ACTH (high) — primary adrenal insufficiency pattern

— Androstenedione and testosterone: elevated; useful for monitoring therapy

— All 50 U.S. states screen for 21-OH deficiency using filter-paper 17-OHP on day 1–3

— False positives: prematurity, low birth weight, illness — adjust by gestational age

— False negatives: prenatal maternal dexamethasone, sample drawn <24 h of life

— Positive screen → immediate confirmatory serum 17-OHP, electrolytes, and clinical evaluation; do not wait

— Obtain in any infant with atypical genitalia alongside hormonal workup (rapid FISH for X/Y available)

— Establishes 46,XX vs 46,XY before sex assignment discussions

— Pelvic/abdominal ultrasound in virilized 46,XX infants: confirms uterus and ovaries (Müllerian structures present because no AMH from testes)

— Identifies enlarged adrenal glands with "cerebriform" pattern

— Genitogram or MRI if anatomy of urogenital sinus is unclear (for surgical planning later)

First-line labs in suspected CAH:

Newborn screening:

Karyotype / chromosomal analysis:

Imaging:

Step 3 management: For a positive newborn screen, order confirmatory serum 17-OHP, electrolytes, glucose, cortisol, ACTH, renin, aldosterone, and a karyotype within 24 hours, and arrange same-day pediatric endocrinology consultation. Do not discharge home pending results.

Board pearl: Elevated 17-OHP + elevated androstenedione/testosterone ratio + low cortisol = 21-hydroxylase deficiency until proven otherwise.

Diagnostic Workup — Confirmatory and Advanced Studies

— Measure baseline 17-OHP, then administer 250 mcg cosyntropin IV/IM, recheck at 60 minutes

— Stimulated 17-OHP >1,500 ng/dL confirms 21-hydroxylase deficiency (classic or non-classic)

— Also measures cortisol response (<18 mcg/dL = adrenal insufficiency)

— Particularly useful for non-classic CAH when baseline 17-OHP is borderline (200–1,000 ng/dL)

— Confirms diagnosis, identifies specific mutation, predicts phenotype severity

— Essential for genetic counseling and prenatal diagnosis planning in future pregnancies

— Common severe mutations: deletions, large gene conversions, splice-site (intron 2 g.655A/C>G), I172N (simple-virilizing), V281L (non-classic)

— Genotype-phenotype correlation is strong but not absolute

— 11β-hydroxylase deficiency (CYP11B1): virilization + hypertension and hypokalemia (elevated 11-deoxycorticosterone has mineralocorticoid activity); elevated 11-deoxycortisol

— 17α-hydroxylase deficiency (CYP17A1): hypertension, hypokalemia, lack of puberty, undervirilized 46,XY and amenorrhea in 46,XX

— 3β-HSD deficiency: salt-wasting + mild virilization in girls (from DHEA), undervirilization in boys; elevated 17-pregnenolone and DHEA

— Lipoid CAH (StAR mutation): severe salt-wasting, all steroids low, undervirilized 46,XY

— Document in any child with premature pubarche or virilization

— Advanced bone age supports peripheral precocious puberty from CAH

ACTH (cosyntropin) stimulation test — gold standard for ambiguous cases:

Genetic testing (CYP21A2 sequencing):

Differentiating other CAH variants (rare but testable):

Bone age (left hand X-ray):

Key distinction: Hypertension + virilization → think 11β-hydroxylase deficiency, NOT 21-OH. Hypertension + delayed puberty/sex steroid deficiency → 17α-hydroxylase deficiency.

Board pearl: Mnemonic — "Deoxy matters": 11β-OH deficiency accumulates 11-deoxycortisol and 11-deoxycorticosterone (the latter causes the HTN).

Risk Stratification and Acute Management Logic

— Hemodynamic instability, hyponatremia, hyperkalemia, hypoglycemia → presumed adrenal crisis → ICU-level resuscitation

— Hemodynamically stable infant with positive newborn screen but normal electrolytes → admit for observation + start treatment + endocrinology consult

— Older child/adolescent with non-classic phenotype → outpatient endocrinology workup

— Step 1: Secure airway, large-bore IV access, continuous cardiac monitoring

— Step 2: Draw critical sample (17-OHP, cortisol, ACTH, renin, aldosterone, electrolytes, glucose) — but do not delay treatment

— Step 3: IV normal saline 20 mL/kg bolus; repeat for ongoing shock

— Step 4: D10W 2–5 mL/kg for hypoglycemia

— Step 5: Hydrocortisone IV stress dose:

— Infants: 25 mg IV bolus, then 25–50 mg/day divided q6h

— Children: 50 mg IV bolus, then 50–100 mg/m²/day

— Adolescents/adults: 100 mg IV bolus, then 100–200 mg/day

— Step 6: Treat hyperkalemia if K >6.5 or ECG changes (calcium gluconate, insulin/dextrose, albuterol; avoid Kayexalate in infants)

— Step 7: Once stabilized → transition to maintenance hydrocortisone + fludrocortisone + sodium chloride supplementation

— Hydrocortisone has mineralocorticoid activity at stress doses and shorter half-life

— Dexamethasone has no mineralocorticoid activity and causes excessive growth suppression

— Prednisone/prednisolone reserved for older children and adults where growth is complete

Triage decision tree at presentation:

Acute adrenal crisis — immediate management (CCS sequence):

Why hydrocortisone (not dexamethasone or prednisone) in infants:

CCS pearl: In CCS, the salt-wasting newborn case requires simultaneous orders: NS bolus + dextrose + hydrocortisone + electrolyte panel + admit to PICU + endocrinology consult. Sequential ordering loses points.

Step 3 management: Hyperkalemia in CAH crisis usually corrects with volume resuscitation and hydrocortisone alone — aggressive K-lowering measures are often unnecessary and risk hypokalemia.

Pharmacotherapy — First-Line Maintenance Regimen

— Hydrocortisone is first-line in children

— Dose: 10–15 mg/m²/day PO divided TID (typical infants 8–10 mg/m²/day)

— Mimics circadian cortisol; highest dose in morning

— Avoid long-acting glucocorticoids (dexamethasone, prednisone) in growing children — cause growth suppression and Cushingoid features

— Adults with completed growth: hydrocortisone 15–25 mg/day, or prednisone 5–7.5 mg/day, or dexamethasone 0.25–0.5 mg qHS

— Fludrocortisone 0.05–0.2 mg PO daily (often 0.1 mg)

— Continue lifelong in classic salt-wasting CAH; some simple-virilizing patients also benefit

— Monitor plasma renin activity as marker of adequate mineralocorticoid replacement (goal: upper-normal range)

— Infants <12 months: 1–2 g/day (17–34 mEq) NaCl added to formula/breast milk

— Usually discontinued when solid foods are established (>1 year)

— Triple the maintenance dose for fever >38.5°C, vomiting, surgery, trauma

— IM hydrocortisone (Solu-Cortef) 50–100 mg emergency kit at home and school; teach all caregivers

— For surgery: hydrocortisone 50–100 mg/m² IV at induction, then continuous infusion or q6h

— Growth velocity, weight, BP

— 17-OHP and androstenedione — goal is suppression but NOT normalization (over-suppression → iatrogenic Cushing)

— Bone age annually

— Renin (for mineralocorticoid dosing)

— DHEAS should be suppressed in well-controlled patients

Glucocorticoid replacement (cornerstone):

Mineralocorticoid replacement (for salt-wasters):

Sodium chloride supplementation:

Stress-dose glucocorticoid coverage (lifelong rule):

Monitoring parameters (visits q3–6 mo):

Board pearl: Over-treatment (Cushingoid, growth failure, bone-age delay) is as harmful as undertreatment (advanced bone age, virilization, TART). The goal is the minimum dose that suppresses excess androgens while allowing normal growth.

Step 3 management: Any classic CAH patient calling with vomiting, fever, or unable to keep down PO steroids → administer IM hydrocortisone immediately and go to ED; do not wait to "see how they do."

Surgical, Reproductive, and Adjunctive Management

— Highly controversial and increasingly individualized

— Historic practice: early clitoroplasty + vaginoplasty in infancy

— Current trend: delay non-urgent genitoplasty until the patient can participate in decision-making, given concerns about identity, sexual function, and informed consent

— Urgent surgery only for urogenital sinus anomalies causing UTIs or urinary obstruction

— Decisions made by multidisciplinary DSD team: endocrinology, urology, psychology, ethics, social work, and family

— Standard recommendation: raise as female — preserved Müllerian structures allow fertility potential, and gender identity typically aligns with chromosomal sex

— However, avoid premature assignment; involve psychology and follow gender identity development

— Develop from ACTH-stimulated ectopic adrenal tissue in testes

— Cause infertility via seminiferous tubule compression

— Detected by testicular ultrasound (recommended starting in adolescence)

— Management: optimize glucocorticoid suppression first; surgery rarely needed

— Women: ovulation often impaired by elevated androgens/progesterone — glucocorticoid optimization restores fertility in most

— Men: TART and elevated adrenal androgens suppress HPG axis → may need gonadotropin therapy

— Pregnancy: continue hydrocortisone (does not cross placenta well); avoid dexamethasone unless treating fetus

— Crinecerfont (CRF1 receptor antagonist) — recently FDA-approved (2024) to reduce glucocorticoid dose burden in classic CAH

— Bilateral adrenalectomy: rarely considered for refractory cases

— Aromatase inhibitors + anti-androgens (experimental) to preserve adult height

Genital reconstructive surgery (46,XX with virilization):

Sex assignment in virilized 46,XX infants:

Testicular adrenal rest tumors (TART) in males:

Fertility considerations:

Investigational/adjunctive therapies:

Key distinction: Even classic salt-wasting CAH patients can achieve biological parenthood with optimal hormonal control. Always discuss fertility proactively, especially in adolescence.

Board pearl: Suspect TART in any adolescent or adult male with CAH and infertility, oligospermia, or testicular masses — ultrasound is the test.

Special Populations — Elderly, Renal, and Hepatic Impairment

— Lifelong glucocorticoid exposure → osteoporosis, glucose intolerance, central adiposity, hypertension, dyslipidemia

— Screen DEXA q2 yr after age 40, lipids/HbA1c annually

— Cardiovascular disease is a leading cause of mortality

— Adrenal insufficiency risk persists lifelong — never abruptly discontinue steroids

— Use the lowest effective dose in adulthood to minimize iatrogenic Cushing

— Many adults transition from hydrocortisone (TID dosing, adherence challenge) to prednisone (BID) or dexamethasone (qHS) once growth is complete

— Modified-release hydrocortisone (Plenadren, Chronocort) approximates circadian rhythm; useful for poor control or adherence

— Hydrocortisone and prednisone do not require dose adjustment in CKD

— Monitor potassium more closely; mineralocorticoid needs may decrease in advanced CKD

— Fludrocortisone — usually still required, but adjust based on BP, edema, and electrolytes

— Avoid NSAIDs (compound hyperkalemia and sodium retention issues)

— Prednisone requires hepatic activation to prednisolone — use prednisolone directly if severe liver disease

— Hydrocortisone is largely hepatically metabolized; consider modest dose reduction in cirrhosis

— Monitor for fluid overload with fludrocortisone in hepatic dysfunction

— CYP3A4 inducers (rifampin, phenytoin, phenobarbital, carbamazepine, St. John's wort) → ↑ glucocorticoid clearance → risk of adrenal insufficiency; may need 2-fold dose increase

— CYP3A4 inhibitors (ritonavir, ketoconazole, clarithromycin, grapefruit) → ↑ glucocorticoid levels → Cushingoid features

— Estrogens (OCPs) increase cortisol-binding globulin, lowering free cortisol availability

CAH in older adults (increasingly relevant as survival improves):

Steroid dose adjustments:

Renal impairment:

Hepatic impairment:

Drug interactions to remember:

Step 3 management: A 55-year-old man with classic CAH starting rifampin for TB — proactively increase his hydrocortisone dose by ~50–100% and educate him on stress-dose rules; do not wait for symptoms of insufficiency.

Board pearl: Chronic supraphysiologic glucocorticoid use is the principal driver of long-term morbidity in CAH — every visit should ask, "Can I reduce this dose?"

Special Populations — Pregnancy and Pediatrics

— Both partners should consider CYP21A2 genetic testing if family history or known carrier status

— Discuss autosomal recessive inheritance: 25% affected, 50% carriers, 25% unaffected per pregnancy

— Optimize maternal glucocorticoid control before conception

— Continue hydrocortisone or prednisolone (both are inactivated by placental 11β-HSD2 → minimal fetal exposure)

— Avoid dexamethasone for maternal treatment — crosses placenta and can suppress fetal adrenals

— Increase dose by 20–40% in third trimester due to increased cortisol-binding globulin

— Stress-dose hydrocortisone during labor: 50–100 mg IV q6–8 h, then taper postpartum

— Mode of delivery: vaginal if pelvic anatomy permits; some women with prior genital surgery require C-section

— Dexamethasone 20 mcg/kg/day maternal, started by week 6–7 of gestation, can suppress fetal ACTH and prevent virilization of an affected 46,XX fetus

— Problem: must start before fetal sex/affected status known → 7 of 8 fetuses treated unnecessarily

— Now considered investigational only by Endocrine Society; requires IRB-approved research protocol

— Long-term neurocognitive concerns in exposed children

— Universal newborn screening will detect; confirmatory testing as above

— Counsel parents about salt-wasting timing (day 7–14)

— Final adult height in classic CAH averages ~1 SD below mid-parental height despite optimal care

— Annual bone age, growth velocity, Tanner staging

— Consider GnRH agonist + growth hormone if central puberty supervenes on advanced bone age (specialist decision)

— Psychosocial support — body image, school accommodations for emergency steroid administration

Preconception counseling:

Maternal management during pregnancy:

Prenatal treatment of fetus (controversial):

Newborn of CAH-affected parent:

Pediatric growth optimization:

Key distinction: Hydrocortisone and prednisolone = safe in pregnancy (placentally inactivated). Dexamethasone and betamethasone = cross placenta — used only when fetal effect is intended (e.g., fetal lung maturity, prenatal CAH suppression).

Board pearl: A pregnant woman with classic CAH needs a clearly documented delivery stress-dose plan in her OB chart by third trimester — a Step 3 patient-safety favorite.

Complications and Adverse Outcomes

— Adrenal crisis: leading cause of mortality; precipitated by illness, surgery, trauma, missed doses, gastroenteritis

— Hypoglycemia in young children during illness — counsel on glucose monitoring

— Hyponatremic seizures in undertreated salt-wasters

— Advanced bone age → premature epiphyseal fusion → short adult stature

— Peripheral precocious puberty in boys with simple-virilizing; can trigger secondary central precocious puberty once bone age >11

— Hirsutism, acne, menstrual irregularity, infertility in females

— Testicular adrenal rest tumors (TART) in males → obstructive azoospermia, infertility

— Adrenal myelolipomas — benign but can grow large

— Growth suppression, weight gain, moon facies, striae

— Insulin resistance, type 2 diabetes, dyslipidemia, hypertension

— Osteoporosis and fragility fractures (cumulative steroid burden)

— Avascular necrosis (rare), cataracts, glaucoma

— Immunosuppression

— Higher rates of anxiety, depression, body-image concerns

— Gender dysphoria is uncommon but somewhat elevated in 46,XX classical CAH; long-term follow-up essential

— Sexual function concerns after genital surgery; relationship and intimacy issues

— Adherence challenges in adolescents — life-threatening if missed stress doses

— Increased prevalence of obesity, MetS, HTN, NAFLD

— Cardiovascular disease drives premature mortality in adults

— Women: pregnancy rates lower than population; improved with subspecialty care

— Men: TART and HPG suppression reduce fertility; optimize glucocorticoid control before pursuing ART

Short-term / acute complications:

Complications of undertreatment (excess androgen):

Complications of overtreatment (iatrogenic Cushing):

Psychosocial complications:

Cardiometabolic morbidity:

Fertility outcomes:

Step 3 management: At every visit for a CAH patient, screen for adherence, stress-dose knowledge, depression (PHQ), BMI, BP, and signs of over/undertreatment — this is the longitudinal exam-tested skill set.

Board pearl: The two leading causes of preventable death in CAH are missed stress dosing during illness and delayed recognition of adrenal crisis.

When to Escalate — ICU, Consult, and Inpatient Triage

— Suspected or confirmed adrenal crisis: shock, AMS, hypoglycemia, severe electrolyte derangement

— Vomiting >2 episodes unable to tolerate oral hydrocortisone

— Fever >39°C or signs of serious infection (e.g., meningitis, pyelonephritis)

— Major trauma, surgery, or significant burns

— Hyperkalemia with ECG changes

— Hemodynamic instability requiring vasopressors after fluid resuscitation

— Severe metabolic acidosis (pH <7.20) or persistent hypoglycemia

— Arrhythmia from hyperkalemia

— Need for continuous hydrocortisone infusion or close electrolyte monitoring

— Any neonate with suspected salt-wasting crisis

— Pediatric endocrinology (mandatory — sometimes telemedicine in rural settings)

— Pediatric urology / surgery for atypical genitalia (early consultation, not necessarily early surgery)

— Medical genetics for confirmatory testing and family counseling

— Psychology/social work for family adjustment, gender identity support

— Neonatology / PICU depending on age and severity

— Maternal-fetal medicine if pregnancy involved

— Stable, mild illness, tolerating PO → outpatient stress-dose oral hydrocortisone (triple dose × 2–3 days), close follow-up

— Stable but vomiting → ED for IV hydrocortisone, observation, then discharge once tolerating PO

— Unstable or septic-appearing → admit, IV stress dose, IV fluids, monitor

— Pediatric → adult endocrinology transition (ages 18–21) is a major dropout point with documented increased mortality — arrange warm handoff

— Discharge from neonatal admission → ensure emergency action plan, IM hydrocortisone kit, follow-up scheduled <1 week

Indications for emergency department / inpatient admission:

ICU admission criteria:

Consultations to initiate:

Triage logic for older child / adolescent presenting acutely:

Transition of care moments (high-risk handoffs):

CCS pearl: When an infant with new CAH is being discharged, your CCS order set must include: emergency hydrocortisone IM kit, written stress-dose plan, MedicAlert bracelet, pediatric endocrine follow-up in 1 week, primary care visit in 3 days, and parental teaching documented.

Step 3 management: Never discharge a CAH patient post-crisis without verbalized parental understanding of stress-dosing — failure to do so is a patient-safety event.

Key Differentials — Other Forms of CAH and Adrenal Insufficiency

— 11β-hydroxylase deficiency (CYP11B1, ~5% of CAH):

— Virilization + hypertension + hypokalemia (no salt-wasting)

— ↑ 11-deoxycortisol, ↑ 11-deoxycorticosterone (DOC has mineralocorticoid activity)

— Low renin (suppressed by DOC excess)

— 17α-hydroxylase deficiency (CYP17A1):

— Hypertension + hypokalemia + sexual infantilism

— 46,XY: phenotypically female or undervirilized (no androgens)

— 46,XX: primary amenorrhea, no pubertal development

— ↑ progesterone, ↑ DOC, ↑ corticosterone; low cortisol despite no Addisonian features

— 3β-hydroxysteroid dehydrogenase deficiency:

— Salt-wasting + mild virilization in girls (DHEA→androgens peripherally), undervirilization in boys (no testosterone)

— ↑ 17-pregnenolone, DHEA; ratios of Δ5/Δ4 steroids elevated

— Lipoid CAH (StAR mutation):

— Severe salt-wasting; all steroids low; 46,XY phenotypically female; massively enlarged adrenals

— Autoimmune adrenalitis (Addison disease): most common in older children/adults; anti-21-hydroxylase antibodies; part of APS-1/APS-2

— Adrenoleukodystrophy (X-linked, ABCD1): boys with neurological decline + adrenal insufficiency; VLCFAs elevated

— Adrenal hemorrhage: Waterhouse-Friderichsen (meningococcemia), birth trauma, anticoagulation

— Adrenal hypoplasia congenita (DAX1): X-linked; salt-wasting in newborn boys + later hypogonadotropic hypogonadism

— Tuberculosis, fungal infection of adrenal glands (developing countries)

— ACTH deficiency from pituitary disease or chronic exogenous steroid suppression

— No hyperpigmentation (low ACTH), no salt-wasting (intact aldosterone via RAAS), normal K

— Key labs: low cortisol + low/inappropriately-normal ACTH

Other CAH enzymatic defects (same category — Step 3 favorites):

Primary adrenal insufficiency (non-CAH):

Secondary/tertiary adrenal insufficiency:

Key distinction: Hyperpigmentation + hyperkalemia = primary adrenal insufficiency (including CAH). Pale, normokalemic, low ACTH = secondary/tertiary.

Board pearl: A virilized child with hypertension is never 21-hydroxylase deficiency — think 11β-OH or 17α-OH instead.

Key Differentials — Other Categories

— Pyloric stenosis: 3–6 weeks old, hypochloremic hypokalemic metabolic alkalosis (opposite of CAH), palpable olive, projectile non-bilious vomiting

— Malrotation with midgut volvulus: bilious vomiting, surgical emergency, requires UGI series

— Sepsis (group B Strep, E. coli, Listeria): similar shock picture; CAH may be misdiagnosed as sepsis or co-exist with it

— Inborn errors of metabolism: ammonia, lactate, urine reducing substances — workup in parallel

— Necrotizing enterocolitis: more common in premature infants; abdominal distension, bloody stools

— Congenital heart disease (ductal-dependent): cyanosis or shock when ductus closes (day 3–14) — overlaps timing with CAH crisis; check pre/post-ductal sats and 4-extremity BPs

— 46,XY disorders of sex development: androgen insensitivity syndrome, 5α-reductase deficiency, gonadal dysgenesis

— Mixed gonadal dysgenesis (45,X/46,XY)

— Ovotesticular DSD: both ovarian and testicular tissue

— Cloacal exstrophy, bladder exstrophy: anatomic issue, not endocrine

— Central (gonadotropin-dependent) precocious puberty: idiopathic (most girls), CNS tumors (most boys); responds to GnRH agonist therapy

— Peripheral precocity:

— McCune-Albright syndrome: café-au-lait, polyostotic fibrous dysplasia, GNAS mutation

— Familial male-limited precocious puberty (testotoxicosis): activating LH receptor

— Adrenocortical tumors: virilizing or feminizing

— Exogenous androgen exposure (testosterone gel from parent)

— PCOS — most common; insulin resistance, ↑ LH:FSH, polycystic ovaries

— Androgen-secreting ovarian or adrenal tumor — rapid virilization, very high testosterone or DHEAS

— Cushing syndrome — purple striae, central obesity, hypertension

— Idiopathic hirsutism — normal androgens

Other causes of neonatal vomiting / dehydration / shock:

Other causes of atypical genitalia in newborns:

Other causes of precocious puberty in children:

Other causes of hirsutism / hyperandrogenism in adolescent females:

Key distinction: Adolescent female with hirsutism — 17-OHP >200 ng/dL fasting morning → workup for non-classic CAH before labeling her as PCOS. Up to 5% of "PCOS" is actually NCCAH.

Step 3 management: Always check a basic metabolic panel in any infant with new-onset vomiting in week 2 of life — it's the cheapest, fastest, most diagnostic move.

Secondary Prevention and Long-Term Plan

— Daily glucocorticoid (and mineralocorticoid for salt-wasters) — never stop

— MedicAlert bracelet or necklace identifying "adrenal insufficiency, steroid dependent"

— Emergency action plan carried at all times (laminated card)

— Home injectable hydrocortisone (Solu-Cortef Act-O-Vial 100 mg) — both home and school/work

— Knowledge of sick-day rules verbalized by patient/family at every visit

— Minor illness, fever <38.5°C, no vomiting: 2× usual dose × 2–3 days

— Moderate illness, fever ≥38.5°C, persistent symptoms: 3× usual dose × 2–3 days

— Vomiting, unable to tolerate PO, severe trauma: IM hydrocortisone immediately + ED

— Surgery: stress-dose plan based on magnitude (minor 25–50 mg, major 100–150 mg/day divided)

— Growth/Tanner staging in children every 3–6 months

— Bone age annually until growth complete

— DEXA scan at growth completion, then every 2–5 years

— Cardiovascular risk screening (BP, lipids, HbA1c) starting in adolescence

— Testicular ultrasound q1–2 yr in males starting in adolescence (TART screening)

— Reproductive counseling at puberty, prior to conception

— Bone health: vitamin D, calcium, weight-bearing exercise

— Mental health screening (PHQ-A, GAD-7) annually

— All routine vaccines including annual influenza

— COVID-19 boosters

— Live vaccines (MMR, varicella) safe at physiologic replacement doses

— Increased priority: pneumococcal vaccination in adults if on higher steroid doses

— Begin anticipatory transition planning at age 12–14

— Formal transition to adult endocrinology by age 18–21 with warm handoff

— Document transition readiness checklist: medication knowledge, sick-day rules, emergency contact, insurance literacy

Lifelong essentials for every CAH patient:

Sick-day rules (memorize for exam):

Annual / periodic preventive care:

Vaccinations:

Transition of care:

Board pearl: A patient who has been on glucocorticoid replacement for any duration and is admitted for surgery or critical illness needs stress-dose steroids — this principle alone has saved lives and is a perennial Step 3 question.

Step 3 management: Never discharge a CAH patient without confirming they have filled the injectable hydrocortisone prescription and demonstrated drawing/administering it.

Follow-Up, Monitoring, and Counseling

— Infants (0–12 months): every 1–3 months

— Children (1–5 yr): every 3 months

— Children/adolescents (>5 yr): every 3–4 months

— Stable adults: every 6–12 months

— Acute illness: phone check-in within 24 hours, in-person if not improving

— Morning (pre-dose) 17-OHP and androstenedione — primary control markers

— Goal: 17-OHP modestly elevated (100–1,000 ng/dL); complete suppression suggests overtreatment

— Androstenedione should be age- and sex-appropriate normal range

— Plasma renin activity for mineralocorticoid adequacy (target upper-normal)

— Electrolytes in salt-wasters; glucose in young children

— Testosterone in females; meaningful in males only after puberty

— DHEAS can be useful but is non-specific

— Length/height, weight, BMI every visit; plot on growth curve

— Bone age (left wrist X-ray) annually until growth plates close

— Tanner staging

— BP at every visit (hypertension can indicate overtreatment with fludrocortisone or 11β-OH deficiency misdiagnosis)

— DEXA every 2–5 years

— Lipid panel, fasting glucose / HbA1c annually

— Testicular ultrasound q1–2 yr in males

— Adrenal/abdominal imaging if symptoms of myelolipoma (large, palpable, or pain)

— Quality-of-life and mental health screening

— Why glucocorticoid is for life — no "drug holidays"

— Stress-dose rules in writing and verbal teach-back

— How to give IM injection — practice with empty syringe quarterly

— What an adrenal crisis looks like and when to call 911

— Genetic implications for future pregnancies and family members

— Nutrition: adequate salt, calcium, vitamin D

— Independence with medications

— Substance use risks (alcohol, recreational drugs interacting with steroid metabolism)

— Sexual health, contraception (OCPs may increase CBG → may need dose tweak)

— Gender identity and sexuality — open, non-judgmental discussion

Visit cadence:

Monitoring labs at each visit:

Growth and development monitoring:

Long-term monitoring (adult patients):

Patient/family education topics (recurring):

Counseling for adolescents:

Board pearl: A morning 17-OHP that is undetectable in a patient with classic CAH is a red flag for overtreatment — back off the dose rather than congratulate yourself.

Ethical, Legal, and Patient Safety Considerations

— Historic practice of early infant clitoroplasty/vaginoplasty in virilized 46,XX babies is increasingly criticized as performed without patient assent

— Patient advocacy groups and several international bodies recommend deferring elective genital surgery until the patient can participate in decision-making

— Current US practice: multidisciplinary team + family-centered counseling; document discussion of risks, benefits, alternatives, and option to defer

— Some states (e.g., California, parts of Europe) have legislative momentum to restrict non-emergent infant DSD surgeries

— Avoid premature sex assignment in atypical genitalia

— Karyotype + hormonal evaluation + imaging before discussing sex of rearing

— Acknowledge that gender identity may diverge from sex of rearing; long-term psychological follow-up is mandatory

— Best practice: age-appropriate, ongoing disclosure starting in early childhood — never "save it" for adolescence

— Concealment is associated with worse psychosocial outcomes

— Parents may need psychological support to navigate disclosure

— Cascade testing of siblings and partners offered

— Discussion of reproductive options: PGD, prenatal diagnosis (CVS week 10–12), preconception carrier screening

— Prenatal dexamethasone: should be done only under IRB-approved research protocols given uncertain long-term cognitive effects; current Endocrine Society guidance does NOT support routine use

— Missed stress doses during gastroenteritis is the leading cause of preventable adrenal crisis death — every clinic visit must include teach-back

— Pediatric-to-adult transition has documented increased crisis rates; warm handoff, shared visit, written summary required

— Surgical perioperative stress dosing errors: ensure surgical and anesthesia teams have a documented plan in the chart; medication reconciliation at every admission

— School-based emergency protocols: written Section 504 plan in US schools; staff trained in IM hydrocortisone

— Newborn screening false negatives: a sick newborn with shock should be treated as possible CAH even with a "normal" screen — clinical judgment overrides the lab

Genital surgery and informed consent (the central ethical issue):

Sex assignment ethics:

Disclosure to the child:

Genetic counseling:

Patient safety pearls (Step 3 transition-of-care emphasis):

Step 3 management: Mandatory documentation in every CAH chart: emergency plan reviewed, IM kit verified in date, family verbalizes sick-day rules, and gender-identity check-in as developmentally appropriate.

High-Yield Associations and Rapid-Fire Facts

— Autosomal recessive; gene CYP21A2 on chromosome 6p21.3 (within HLA region — co-inherited with HLA haplotypes)

— Carrier frequency ~1:50; classic CAH incidence ~1:15,000 live births

— Pseudogene CYP21A1P adjacent → high rate of recombination/conversion → many disease alleles

— Non-classic CAH ~1:1,000 overall, much higher in Ashkenazi Jewish (~1:27), Hispanic, Slavic, Italian

— 21-OH converts: 17-OHP → 11-deoxycortisol and progesterone → 11-deoxycorticosterone

— Block → ↑ 17-OHP, ↓ cortisol, ↓ aldosterone, shunted into androgens (DHEA, androstenedione, testosterone)

— 46,XX: ambiguous genitalia at birth, normal Müllerian structures

— 46,XY: normal at birth, virilization in childhood, prepubertal-sized testes

— Salt-wasting: day 7–14 vomiting, Na↓ K↑ glucose↓, shock

— Hyperpigmentation from ACTH/MSH

— 11β-OH: virilization + HTN, ↑ 11-deoxycortisol

— 17α-OH: HTN + sexual infantilism, ↑ DOC, ↓ androgens

— 3β-HSD: ambiguous genitalia in both sexes

— Lipoid CAH: all steroids low, severe SW

— Hydrocortisone = drug of choice in growing children (10–15 mg/m²/day)

— Fludrocortisone = mineralocorticoid (0.05–0.2 mg/day)

— Stress dose = triple maintenance; IM hydrocortisone for vomiting/trauma

— Dexamethasone: avoid in growing children, avoid in maternal treatment during pregnancy (crosses placenta)

— Crinecerfont (2024 FDA approval): novel CRF1 antagonist that reduces glucocorticoid burden

— Newborn screening universal in all US states

— HLA-B47 associated with classic salt-wasting allele

— APS-2 (autoimmune polyglandular syndrome) is a differential, not associated

— TART in males; adrenal myelolipomas with chronic ACTH stimulation

Genetics and inheritance:

Hormonal cascade memorization:

Classic phenotype clues:

Other CAH "must know":

Pharmacology rapid hits:

Associations:

Board pearl: "Ambiguous genitalia + electrolyte crisis at 2 weeks + hyperpigmentation" = 21-hydroxylase deficiency salt-wasting CAH — the highest-yield neonatal endocrine vignette on the exam.

Board Question Stem Patterns

"A 12-day-old infant presents with vomiting and lethargy. BP 60/30, HR 180, lethargic. Na 121, K 6.8, glucose 38. Genital exam shows enlarged clitoris and posterior labial fusion. Next best step?"

— Answer: IV normal saline bolus + IV hydrocortisone (stress dose) + dextrose. Then draw 17-OHP and karyotype.

"A 4-year-old boy has pubic hair, deepening voice, and is in the 95th percentile for height. Testes are prepubertal (2 mL). Bone age is 8 years. Most likely diagnosis?"

— Answer: Simple-virilizing CAH (21-OH deficiency). Confirm with 17-OHP.

"A 14-year-old girl has hirsutism, virilization, and BP 160/100 with K 3.1. Most likely enzyme deficiency?"

— Answer: 11β-hydroxylase deficiency. Elevated 11-deoxycortisol/deoxycorticosterone.

"A 16-year-old phenotypic girl with no breast or pubic hair development, primary amenorrhea, hypertension, hypokalemia. Karyotype 46,XY. Diagnosis?"

— Answer: 17α-hydroxylase deficiency.

"A 22-year-old woman with hirsutism, oligomenorrhea, and infertility. Testosterone mildly elevated. Morning 17-OHP 600 ng/dL. Next step?"

— Answer: ACTH stimulation test; if stimulated 17-OHP >1,500, diagnose non-classic CAH, treat with low-dose glucocorticoid.

"A known CAH patient on hydrocortisone develops gastroenteritis with vomiting. Unable to keep down medication. Best next step?"

— Answer: Administer IM hydrocortisone (Solu-Cortef) and transport to ED.

"A patient with classic CAH is scheduled for elective surgery. Preoperative plan?"

— Answer: Continue maintenance, add IV hydrocortisone 50–100 mg at induction, then q6h, taper over 1–3 days based on stress.

"A 10-day-old presents with shock; sepsis workup negative. Hyponatremia and hyperkalemia. Hyperpigmented scrotum noted. Next?"

— Answer: Treat as adrenal crisis even without confirmatory labs.

"CAH patient started on rifampin for latent TB. Two weeks later, develops fatigue and hypotension. Cause?"

— Answer: Rifampin induces CYP3A4 → ↑ glucocorticoid clearance → relative insufficiency; increase hydrocortisone dose.

Pattern 1 — Classic neonatal salt-wasting:

Pattern 2 — Boy with peripheral precocious puberty:

Pattern 3 — Hypertensive virilized teenager:

Pattern 4 — Sexual infantilism + hypertension:

Pattern 5 — Adult woman with hirsutism:

Pattern 6 — Sick day / stress dose:

Pattern 7 — Perioperative management:

Pattern 8 — Subtle salt-wasting masquerading as sepsis:

Pattern 9 — Drug interaction:

Board pearl: When you see "hyperpigmentation + electrolyte abnormality in a neonate," the answer almost always involves CAH or primary adrenal insufficiency — start hydrocortisone first, ask questions later.

One-Line Recap

Congenital adrenal hyperplasia — most commonly 21-hydroxylase deficiency — is an autosomal recessive cortisol biosynthesis defect that presents with neonatal salt-wasting crisis, ambiguous genitalia in 46,XX infants, or childhood virilization, and is managed with lifelong hydrocortisone (plus fludrocortisone for salt-wasters), aggressive stress-dose glucocorticoid coverage during illness, and meticulous longitudinal endocrine follow-up.

— Elevated 17-OHP is the single best test (>10,000 ng/dL in classic; ACTH-stimulated >1,500 in non-classic)

— Universal newborn screen catches most classic cases — confirm with serum testing + karyotype + electrolytes

— Hyponatremia + hyperkalemia + hypoglycemia + hyperpigmentation = primary adrenal insufficiency

— Distinguish 21-OH (no HTN) from 11β-OH (HTN, ↑11-deoxycortisol) and 17α-OH (HTN, sexual infantilism)

— IV normal saline bolus + IV hydrocortisone stress dose + dextrose for crisis

— Draw critical sample if possible — but never delay treatment for labs

— Treat as primary adrenal insufficiency even before genetic/hormonal confirmation

— Hydrocortisone 10–15 mg/m²/day (children); fludrocortisone for salt-wasters; salt supplementation in infants

— Triple-dose for illness; IM hydrocortisone + ED for vomiting/trauma

— MedicAlert bracelet, emergency kit, school plan, sick-day rules verbalized at every visit

— Monitor 17-OHP, androstenedione, renin, growth, bone age, BP — balance under- vs over-treatment

— Screen for TART in males, cardiometabolic disease, osteoporosis, and mental health

Diagnosis essentials:

Acute management essentials:

Long-term management essentials:

Step 3 board pearl: The exam tests stress dosing, transition of care, and recognition of adrenal crisis more than esoteric biochemistry — master those three and you will get every CAH question right.