What is the diagnosis and prevalence of Type 3 Hereditary Angioedema (HAE) among all diagnosed HAE cases?

Diagnosis and Prevalence of Type 3 Hereditary Angioedema

Type 3 HAE (now called HAE with normal C1INH) is diagnosed by exclusion, with no valid diagnostic tests currently available, and represents a rare subset of HAE cases with normal C1INH levels and function.

Diagnostic Criteria for Type 3 HAE

• Type 3 HAE (HAE with normal C1INH) presents with normal C1INH antigenic and functional levels, as well as normal C4 levels, unlike the more common types 1 and 2 HAE 1

• Diagnosis is based on exclusion after confirming:

  • Recurrent angioedema without hives 1
  • Normal C1INH antigen and functional levels 1
  • Normal C4 levels 1
  • Absence of response to antihistamines, corticosteroids, or epinephrine 1

• Clinical presentation typically includes:

  • Recurrent episodes of non-pruritic, non-pitting angioedema 1
  • Attacks often involving face, extremities, abdomen, genitourinary tract, oropharynx, or larynx 1
  • Symptoms frequently exacerbated by estrogen exposure (pregnancy or oral contraceptives) 1, 2

Genetic Basis and Subtypes

• Unlike types 1 and 2 HAE which are caused by SERPING1 gene mutations, type 3 HAE has been associated with various genetic mutations 3:

  • Factor XII (F12) gene mutations 2
  • Plasminogen gene (PLG-HAE) 3
  • Angiopoietin-1 (ANGPT1) 4
  • Kininogen-1 (KNG1) 3
  • Myoferlin gene (MYOF) 3
  • Heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) 3

• Patients without identified mutations are classified as HAE of unknown cause (HAE-UNK) 1

Prevalence of Type 3 HAE

• Type 3 HAE is rare compared to other forms of HAE 5
• Type 1 HAE accounts for approximately 85% of all HAE cases 1, 6
• Type 2 HAE accounts for approximately 15% of all HAE cases 1, 6
• Type 3 HAE (HAE with normal C1INH) represents a very small percentage of cases, with relatively few reported cases worldwide 2, 4

Diagnostic Algorithm

1. Initial screening: Measure C4, C1INH antigen, and C1INH function 6

   • If all are normal during attacks, consider type 3 HAE 1

2. Exclude other causes:

   • Medication-associated angioedema (ACE inhibitors, ARBs) 1
   • Acquired C1INH deficiency (measure C1q, which is normal in HAE) 6
   • Allergic or idiopathic angioedema (typically responsive to antihistamines) 1

3. Supporting evidence:

   • Family history of similar angioedema (though not required for diagnosis) 1
   • Estrogen-dependence or exacerbation in female patients 2
   • Genetic testing for known mutations (F12, PLG, ANGPT1, etc.) 3, 4

Clinical Pitfalls and Caveats

• Diagnosis is challenging due to lack of specific biomarkers or diagnostic tests 1
• Family history may be unreliable due to variable penetrance, de novo mutations, or unknown family connections 1
• Some patients may experience hives as a separate entity, which can complicate diagnosis 1
• Conventional angioedema treatments (antihistamines, corticosteroids, epinephrine) are typically ineffective 6
• Transient, moderately low C1INH functional levels (32-74% of normal) may be found in women during pregnancy or while taking oral contraceptives, which can complicate diagnosis 2
• Imaging during attacks (especially for abdominal symptoms) is crucial to confirm true angioedema versus other conditions 1

Type 3 HAE remains a diagnosis of exclusion with evolving understanding of its genetic basis. The exact prevalence is difficult to determine due to diagnostic challenges, but it represents a small minority of all HAE cases compared to the more common types 1 (85%) and 2 (15%).