A 12-year-old boy is referred to your pediatric clinic for evaluation of recurrent episodes of non-pruritic swelling of his hands and feet and severe abdominal pain with vomiting. The episodes began 2 years ago and occur every 3-6 weeks, lasting 2-4 days. He is completely asymptomatic between episodes. The swelling does NOT itch and is NOT associated with urticaria. The abdominal pain is severe, colicky, accompanied by nausea and vomiting, and has led to two emergency department visits. During one visit, he underwent an abdominal CT scan that showed bowel wall thickening and ascites. He has never had airway compromise. There is no known drug or food trigger. His father has a history of similar episodes (hand swelling and abdominal pain). The mother is very worried and asks: "What is wrong with my son? Could this be hereditary? How can we prevent these attacks?"
Task for the candidate: You are the pediatrician. Discuss your approach to this patient. Identify the most likely diagnosis (hereditary angioedema – HAE). Differentiate from other causes of angioedema (allergic, ACE inhibitor-induced, acquired angioedema). Describe the pathophysiology (C1 inhibitor deficiency → uncontrolled bradykinin production → increased vascular permeability). Discuss diagnostic tests (low C4, low C1-INH protein and/or function). Outline acute management of attacks (C1-INH concentrate, icatibant, ecallantide; avoid epinephrine, antihistamines, steroids – not effective). Discuss long-term prophylaxis (lanadelumab, berotralstat, C1-INH concentrate, androgens). The examiner will observe your response and ask follow-up questions.
💡 Examiner instruction (interactive): This is a case of hereditary angioedema (HAE) – likely type I or II. The candidate must recognize the key features: (1) recurrent, non-pruritic angioedema (no urticaria) of extremities and gastrointestinal tract, (2) autosomal dominant inheritance (father affected), (3) abdominal pain due to bowel wall edema, (4) normal between episodes. The candidate should: (a) suspect HAE, (b) order complement studies (C4, C1-INH protein, C1-INH function), (c) differentiate from allergic angioedema (no urticaria, no response to epinephrine/antihistamines), (d) manage acute attacks with C1-INH concentrate (Berinert) or icatibant (bradykinin B2 receptor antagonist), (e) avoid epinephrine and antihistamines (ineffective), (f) discuss long-term prophylaxis (lanadelumab – anti-kallikrein antibody, berotralstat – oral kallikrein inhibitor), and (g) counsel about laryngeal edema risk (airway emergency).
🔍 Examiner Questions (interactive) – Click to reveal model answers
❓ Q1 (Examiner): “What is the most likely diagnosis in this 12-year-old with recurrent non-pruritic swelling and abdominal pain? Describe the key clinical features of hereditary angioedema (HAE).”
✅ Candidate's answer:
• Diagnosis:Hereditary angioedema (HAE) – most likely type I or type II.
• Key clinical features of HAE:
1️⃣ Recurrent, non-pruritic, non-pitting angioedema of subcutaneous tissues: hands, feet, face, genitals, trunk.
2️⃣ No urticaria (differentiates from allergic angioedema).
3️⃣ Abdominal attacks: Severe, colicky abdominal pain, nausea, vomiting, diarrhea. Caused by bowel wall edema. May mimic acute abdomen (appendicitis, obstruction).
4️⃣ Laryngeal edema: Most serious complication; can cause airway obstruction and death.
5️⃣ Onset in childhood or adolescence (often around puberty).
6️⃣ Autosomal dominant inheritance (family history present in this patient – father affected).
7️⃣ Asymptomatic between attacks.
• This patient has all classic features.
❓ Q2 (Examiner): “Explain the pathophysiology of hereditary angioedema. Why is it NOT responsive to epinephrine or antihistamines?”
✅ Candidate's answer:
• Primary defect: Deficiency (type I) or dysfunction (type II) of C1 inhibitor (C1-INH), a serine protease inhibitor.
• C1-INH normally inhibits: C1r, C1s (complement pathway), plasma kallikrein, and factor XII (contact system).
• Without sufficient C1-INH:
- Uncontrolled activation of the contact system (kallikrein-kinin system).
- Excessive production of bradykinin (a potent vasodilator that increases vascular permeability).
- Bradykinin binds to B2 receptors on endothelial cells → increased capillary leak → edema.
• Why no response to epinephrine/antihistamines?
- The edema is bradykinin-mediated, NOT histamine-mediated.
- Epinephrine, antihistamines (H1/H2 blockers), and corticosteroids are ineffective in HAE.
- First-line treatment targets bradykinin pathway: C1-INH replacement, bradykinin B2 receptor antagonist (icatibant), or kallikrein inhibitor (ecallantide).
❓ Q3 (Examiner): “What are the different types of hereditary angioedema? Describe type I, type II, and HAE with normal C1-INH.”
✅ Candidate's answer:
• Type I HAE (85% of cases):
- Low C1-INH protein level (quantitative deficiency).
- C1-INH function also low.
- Autosomal dominant inheritance (mutations in SERPING1 gene).
• Type II HAE (15% of cases):
- Normal or elevated C1-INH protein level (qualitative dysfunction).
- Low C1-INH function (functional assay is essential).
- Same clinical presentation as type I.
• HAE with normal C1-INH (type III, rare):
- Normal C1-INH protein and function.
- More common in females; often estrogen-sensitive.
- Associated with factor XII mutations (gain-of-function).
- Treatment is similar (bradykinin-targeted therapies).
• This patient likely has type I or II (family history, onset in childhood).
❓ Q4 (Examiner): “What laboratory tests would you order to confirm the diagnosis of HAE? How do you interpret them?”
✅ Candidate's answer:
• First-line screening test:Complement C4 level – low during attacks and often between attacks (chronic consumption).
• Confirmatory tests (send together):
1️⃣ C1 inhibitor (C1-INH) protein level (antigenic): Low in type I; normal/elevated in type II.
2️⃣ C1 inhibitor (C1-INH) function (functional assay): Low in both type I and type II.
3️⃣ Complement C3: Normal in HAE (helps differentiate from acquired angioedema or autoimmune disease).
• Interpretation:
- Low C4 + low C1-INH protein + low C1-INH function = Type I HAE.
- Low C4 + normal/elevated C1-INH protein + low C1-INH function = Type II HAE.
- If C4 is normal but clinical suspicion is high, repeat during an attack (C4 often drops).
- Genetic testing (SERPING1 mutation analysis) can be performed for confirmation and family screening.
• This patient likely has low C4 and low C1-INH.
❓ Q5 (Examiner): “This patient presents with severe abdominal pain due to an acute HAE attack. What is your immediate management? Are epinephrine or antihistamines effective?”
✅ Candidate's answer:
• Acute management (on-demand treatment):
1️⃣ First-line (FDA-approved for HAE attacks):
- Plasma-derived C1-INH concentrate (Berinert, Cinryze) – IV, 20 U/kg. Replaces missing protein. Most effective for all types of attacks (abdominal, peripheral, laryngeal).
- Recombinant C1-INH (Ruconest) – IV, 50 U/kg (for adults, limited pediatric data).
- Icatibant (Firazyr) – bradykinin B2 receptor antagonist. Subcutaneous injection. Effective for abdominal and peripheral attacks.
- Ecallantide (Kalbitor) – plasma kallikrein inhibitor. Subcutaneous injection (risk of anaphylaxis – requires medical supervision).
2️⃣ Supportive care: IV fluids, analgesics (opioids for severe abdominal pain).
• Epinephrine, antihistamines (H1/H2), and corticosteroids are NOT effective – do not use.
• This patient (abdominal attack) should receive IV C1-INH concentrate or icatibant SC as first-line therapy.
❓ Q6 (Examiner): “What is the most serious complication of HAE? How would you manage a child with acute laryngeal edema?”
✅ Candidate's answer:
• Most serious complication:Laryngeal edema – can cause airway obstruction and death.
• Management of suspected laryngeal edema (medical emergency):
1️⃣ Call for emergency help (activate emergency response).
2️⃣ Administer on-demand HAE medication immediately:
- IV C1-INH concentrate (Berinert) 20 U/kg – preferred.
- If not available, icatibant SC or ecallantide SC.
3️⃣ Airway management:
- High-flow oxygen.
- Prepare for intubation or tracheostomy if airway compromise progresses.
4️⃣ Do NOT rely on epinephrine, antihistamines, or steroids – they are ineffective.
5️⃣ Transfer to ICU for monitoring.
• All patients with HAE should have a written emergency action plan and carry on-demand medication at all times.
• This patient has never had laryngeal edema, but he is at risk.
❓ Q7 (Examiner): “Which patients with HAE require long-term prophylaxis? What are the available options for children?”
✅ Candidate's answer:
• Indications for long-term prophylaxis:
- Frequent attacks (≥1 attack per month).
- Severe attacks (laryngeal edema, disabling abdominal pain).
- Poor quality of life due to fear of attacks.
- History of laryngeal edema (absolute indication).
• Options for pediatric patients:
1️⃣ Lanadelumab (Takhzyro): Human monoclonal antibody that inhibits plasma kallikrein. Subcutaneous injection every 2-4 weeks. FDA-approved for children ≥2 years. Highly effective (reduces attacks by 80-90%).
2️⃣ Berotralstat (Orladeyo): Oral plasma kallikrein inhibitor. Once-daily pill. FDA-approved for children ≥12 years (this patient is eligible).
3️⃣ Plasma-derived C1-INH concentrate (Cinryze): IV every 3-4 days (or twice weekly). Approved for children ≥6 years.
4️⃣ Attenuated androgens (danazol, stanozolol): Increase C1-INH levels. Rarely used in children due to side effects (virilization, growth retardation, hepatotoxicity). Avoid in children when possible.
• For this patient (frequent attacks), lanadelumab or berotralstat are excellent options.
❓ Q8 (Examiner): “This patient needs a dental extraction. How would you provide short-term prophylaxis to prevent an HAE attack?”
✅ Candidate's answer:
• Short-term (pre-procedural) prophylaxis is indicated for surgical, dental, or endoscopic procedures, especially those involving the upper airway or oral cavity.
• Options:
1️⃣ IV C1-INH concentrate (Berinert or Cinryze): 20 U/kg given 1-2 hours before the procedure.
2️⃣ If C1-INH is not available: High-dose androgens (danazol 2.5-10 mg/kg/day) for 5 days before and 2 days after the procedure (less desirable in children).
3️⃣ Icatibant or ecallantide – not approved for prophylaxis, only for acute attacks.
• Procedure: Perform in a facility with emergency airway management capability.
• This patient should receive C1-INH concentrate before dental extraction.
❓ Q9 (Examiner): “What is the differential diagnosis for recurrent angioedema without urticaria?”
✅ Candidate's answer:
• Hereditary angioedema (HAE) – most likely in this case.
• Acquired angioedema (AAE):
- Associated with lymphoproliferative disorders (lymphoma) or autoimmune diseases (SLE).
- Low C1-INH, low C1q (distinguishes from HAE – C1q is normal in HAE).
- Later onset (usually adults).
• Angioedema induced by ACE inhibitors (bradykinin-mediated):
- Onset can be years after starting ACE inhibitor.
- No family history, resolves after stopping ACE inhibitor.
• Idiopathic non-histaminergic angioedema:
- Diagnosis of exclusion after ruling out HAE, AAE, and ACE inhibitors.
- May respond to tranexamic acid or icatibant.
• Other causes: Hypothyroidism, hypereosinophilic syndrome, urticarial vasculitis (but these usually have urticaria).
• This patient has a positive family history and onset in childhood – consistent with HAE.
❓ Q10 (Examiner): “A child with known HAE presents with severe abdominal pain. How can you differentiate an HAE attack from acute surgical abdomen (appendicitis)? What imaging findings suggest HAE?”
✅ Candidate's answer:
• Differentiating features:
- HAE abdominal attack: Colicky pain, nausea, vomiting, diarrhea, no fever, normal white blood cell count (may have elevated CRP).
- Appendicitis: Localized right lower quadrant pain, fever, leukocytosis, vomiting (usually precedes pain).
- HAE often has a history of similar episodes that resolved spontaneously or with on-demand treatment.
• Imaging findings in HAE abdominal attack:
- Abdominal CT: Bowel wall thickening (edema), ascites, dilated loops of bowel (transient).
- Ultrasound: Thickened bowel wall, free fluid.
- These findings are reversible after resolution of the attack.
• Management: If uncertain, treat for HAE attack first (C1-INH concentrate). If no improvement in 1-2 hours, reassess for surgical cause.
- Avoid unnecessary appendectomy.
❓ Q11 (Examiner): “The father is also affected. Should other family members be screened for HAE? How?”
✅ Candidate's answer:
• Yes, all first-degree relatives (parents, siblings, children) of an affected individual should be screened.
• Why screen?
- HAE is autosomal dominant with 50% inheritance risk.
- Asymptomatic relatives may still have attacks (especially abdominal or laryngeal) that could be life-threatening.
- Early diagnosis allows for prophylactic treatment and on-demand medication.
• Screening tests:
- C4 level – low levels are suggestive.
- C1-INH protein level and function – confirmatory.
- Genetic testing (SERPING1 mutation analysis) – definitive.
• This patient's siblings and father's siblings should be screened.
❓ Q12 (Examiner): “What should you teach the patient and his family about managing HAE?”
✅ Candidate's answer:
• Education points:
1️⃣ Recognize early signs of an attack: Tingling, tightness, erythema marginatum (prodromal rash).
2️⃣ Treat attacks early – early treatment (within 1 hour) is more effective.
3️⃣ Carry on-demand medication at all times (C1-INH concentrate for home administration if trained, or icatibant autoinjector).
4️⃣ Emergency action plan:
- For peripheral or abdominal attacks: Self-administer on-demand medication, then contact physician.
- For laryngeal edema (voice change, stridor, difficulty swallowing): Use epinephrine autoinjector? (NO – not effective). Instead, administer C1-INH or icatibant immediately and call 911/ambulance.
5️⃣ Wear medical identification jewelry (alerting to HAE diagnosis).
6️⃣ Avoid triggers: Trauma (including dental procedures), stress, infections, estrogen-containing medications, ACE inhibitors.
7️⃣ Inform school, sports coaches, and employers about the condition and emergency plan.
8️⃣ Regular follow-up with an allergist/immunologist.
• This patient and his family need comprehensive education.
❓ Q13 (Examiner): “What is the prognosis for a child with HAE? Can attacks be prevented entirely?”
✅ Candidate's answer:
• Excellent prognosis with modern treatment.
- With regular prophylaxis (lanadelumab, berotralstat, C1-INH), >90% of patients have <1 attack per month, and many have zero attacks.
- On-demand therapy effectively treats breakthrough attacks within 1-4 hours.
- Mortality from laryngeal edema has decreased dramatically with the availability of C1-INH concentrate and bradykinin-targeted drugs.
• Without treatment:
- Recurrent attacks can cause significant morbidity (missed school/work, emergency visits, unnecessary surgeries).
- Laryngeal edema carries a mortality risk of 10-30% without treatment.
• Long-term outlook:
- HAE is a lifelong condition; there is no cure.
- However, with current therapies, patients can lead normal lives, attend school, play sports, and work.
- This patient should be started on prophylaxis to prevent attacks.
❓ Q14 (Examiner): “How will you counsel the mother who is worried that this condition could be life-threatening and that her son will have frequent painful attacks?”
✅ Candidate's structured answer:
• “I understand your worry. Your son has a condition called hereditary angioedema (HAE). It is a genetic condition that causes episodes of swelling in the hands, feet, abdomen, and sometimes the throat.”
• “The good news is that we have excellent treatments available. We can prevent most attacks with a medication called lanadelumab (a shot every 2-4 weeks) or berotralstat (a daily pill). These medications are very effective and safe for children.”
• “For breakthrough attacks, we will give him a medication to take at the first sign of swelling – either an injectable C1 inhibitor or icatibant. These stop the attack quickly.”
• “The most dangerous type of attack is swelling of the throat (laryngeal edema). But with proper prevention and early treatment, the risk is very low. He should always carry his on-demand medication and wear medical identification jewelry.”
• “Your son can live a normal life – go to school, play sports, have friends. He just needs to be prepared.”
• “We will also test his siblings and other family members because this condition runs in families. Early diagnosis can prevent serious attacks.”
• “You are not alone. We will refer you to an allergist/immunologist who specializes in HAE. There are also patient support groups.”
• “With the right treatment, he will be fine.”
🗣️ Examiner's probing / high-yield points (Hereditary Angioedema):
• "What is the most common type of HAE?" → Type I (85%, low C1-INH protein).
• "What is the mediator of swelling in HAE?" → Bradykinin (not histamine).
• "What is the first-line acute treatment?" → C1-INH concentrate (IV) or icatibant (SC).
• "Are epinephrine and antihistamines effective?" → No – bradykinin-mediated edema.
• "What is the most serious complication?" → Laryngeal edema (airway obstruction).
• "What is the first-line long-term prophylaxis for children?" → Lanadelumab (anti-kallikrein antibody) SC every 2-4 weeks.
• "What lab test is elevated during attacks?" → C4 is low (chronic consumption).
• "What imaging finding is seen in abdominal attacks?" → Bowel wall thickening and ascites on CT.
📘 Hereditary Angioedema (HAE) – Core Revision for TOACS
🔍 Definition Autosomal dominant disorder caused by C1 inhibitor deficiency (type I) or dysfunction (type II), leading to uncontrolled bradykinin production → increased vascular permeability → non-pruritic angioedema.
🩺 Clinical Features Recurrent, non-pruritic angioedema (hands, feet, face, genitals, GI tract). Abdominal attacks: severe colicky pain, vomiting, diarrhea (bowel wall edema). Laryngeal edema: airway emergency. No urticaria. Asymptomatic between episodes.
📋 Diagnosis Low C4 (screening). Confirm with low C1-INH protein (type I) or low C1-INH function with normal protein (type II). C3 is normal. Genetic testing for SERPING1 mutations.
💊 Acute Management C1-INH concentrate (Berinert) 20 U/kg IV or icatibant (bradykinin B2 antagonist) SC. Ecallantide (kallikrein inhibitor) SC. Epinephrine/antihistamines/steroids are NOT effective.
📈 Prognosis Excellent with modern therapy. Mortality from laryngeal edema has dramatically decreased. Patients can lead normal lives with prophylaxis and on-demand treatment.
⭐ High-yield pearls for TOACS (Hereditary Angioedema):
• Non-pruritic swelling + no urticaria + abdominal pain + family history = HAE.
• Mediator = bradykinin (NOT histamine) – epinephrine/antihistamines are INEFFECTIVE.
• First-line acute treatment: C1-INH concentrate (IV) or icatibant (SC).
• First-line long-term prophylaxis in children: Lanadelumab (anti-kallikrein).
• Diagnostic labs: low C4, low C1-INH (protein and/or function).
• Laryngeal edema = airway emergency – treat with C1-INH/icatibant immediately.
• Avoid ACE inhibitors, estrogens, and trauma (including dental procedures without prophylaxis).
🗣️ Candidate's role-play & examiner feedback
💬 To the candidate (role‑play): You will be asked the 14 questions from the Examiner Q&A tab. This station tests knowledge of hereditary angioedema – a genetic disorder causing bradykinin-mediated angioedema (non-pruritic, no urticaria). The candidate must recognize the classic presentation (swelling of extremities, abdominal pain, family history), order diagnostic labs (C4, C1-INH protein and function), differentiate from allergic angioedema, and manage acute attacks (C1-INH concentrate or icatibant – epinephrine/antihistamines are ineffective). Discuss long-term prophylaxis (lanadelumab, berotralstat) and the risk of laryngeal edema (airway emergency). Provide empathetic counseling to the mother – reassure her that with modern treatment, her son can live a normal life.
✅ Discusses short-term prophylaxis for dental/surgical procedures (C1-INH concentrate)
✅ Counsels mother empathetically (excellent prognosis with modern treatment, need for emergency action plan)
📚 Key references: Nelson Textbook of Pediatrics 22e (Chapter 189.1 – Hereditary Angioedema), World Allergy Organization guidelines for HAE, US HAEA (Hereditary Angioedema Association) guidelines, CPSP protocols for angioedema.