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Table 4 Clinical differentiators between HAE-FXII, HAE-PLG, HAE-ANGPT1, and HAE-KNG1

From: Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor: a systematic review of qualitative evidence

  HAE-FXII N = 446 HAE-PLG N = 146 HAE-ANGPT1 N = 4 HAE-KNG1 N = 6
Genetics
 Specific mutations serving for identification of HAE type c.983C > A [7] c.988A > G [10] c.807G > T [9] c. 1136 T > A [11]
c.983C > G [7]
c.971_1018 + 24del72 [14]
c.892_909dup [15]
Gender ratio Clear female predominance    
 Male 39 25 0 1
 Female 404 70 4 5
 Not reported 3 51 0 0
 Ratio (M:F) 1:10 1:3 0:4a 1:5a
Penetrance High penetrance in females (86%), low in males (4%) [13] nr nr nr
Clinical features
 Average age of onset (years) 20 [13] 31 [10] nr 35 [11]
 Location of attacks Small number of tongue swellings Large number of tongue swellings [10] No tongue swellings Small number of tongue swellings
 Hemorrhages (into the skin swellings or bruising preceding abdominal attacks) 17/446 (3.8%) patients; possibly a unique feature; not observed in other genetically defined types 0 0 0
 Clinical course Some patients have symptoms exclusively when exposed to estrogens (OC, HRT, pregnancy) "estrogen-dependent angioedema" Some patients have exclusively tongue swellings [10]; considered to be a unique clinical feature nr nr
 Deaths by asphyxia (asphyxia rate) 2 (1:225) 3 (1:50) 0 0
Estrogen impact
 Clear impact 252 14 0 2
 No impact 25 48 4 3
Pathogenesis
 Protein change Introduction of new cleavage sites for plasmin in FXII [57]; cleavage of mutant FXII by thrombin and FXIIa [58] Change of the kringle 3 domain of PLG [10] Impairment of ANGPT1 [9] Change of bradykinin cleavage from HMWK [11]
  1. ANGPT1 = angiopoietin, FXII = coagulation factor XII, HAE-ANGPT1 = HAE with a specific angiopoietin-1 gene mutation, HAE-FXII = HAE with a specific FXII gene mutation, HAE-KNG1 = HAE with a specific kininogen-1 gene mutation, HAE-PLG = HAE with a plasminogen gene mutation, HMWK = high molecular weight kininogen, M:F = male:female, N = number of patients, nr = not reported, PLG = plasminogen
  2. a1 family only