Hereditary Angioedema

Literature and regulatory information updated: 4 October 2026.

Bradykinin-mediated angioedema due to C1 inhibitor deficiency or dysfunction (SERPING1; types 1 and 2) and hereditary angioedema with normal C1 inhibitor (F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, DAB2IP and unknown cause)

0. Initial Reference Table

1. Introduction

Hereditary angioedema is a group of genetic disorders defined by recurrent episodes of localised, non-pitting, non-pruritic oedema without urticarial wheals, affecting the skin, gastrointestinal mucosa and upper airway and, unlike allergic or histaminergic angioedema, unresponsive to antihistamines, glucocorticoids or adrenaline [1, 7]. Most forms are mediated by bradykinin, a vasoactive nonapeptide generated by the kallikrein–kinin system, making hereditary angioedema the clinical prototype of bradykinin-mediated angioedema [1]. Its practical significance rests on three features: laryngeal oedema can cause death by asphyxiation, particularly in undiagnosed patients; abdominal attacks mimic an acute abdomen and lead to unnecessary surgery; and the broad range of targeted therapies now available for attacks and prevention has transformed prognosis and shifted the treatment goal to complete disease control and a normal life for the patient [7, 13].

The history of hereditary angioedema parallels that of complement immunology and kinin biology. Heinrich Quincke described acute circumscribed skin oedema in 1882, and William Osler documented a family with five affected generations in the American Journal of the Medical Sciences in 1888, recognising inheritance, abdominal involvement and death from laryngeal oedema [1, 14]. In 1963, Virginia Donaldson and Richard Evans identified absence of serum C1 esterase inhibitor as the biochemical abnormality underlying the disease, a foundational article of the modern era of hereditary angioedema [15]. In the 1970s and 1980s, the role of C1-INH as an inhibitor of plasma kallikrein and activated factor XII was established; the gene, subsequently named SERPING1, was characterised in 1986, and in 1987 Stoppa-Lyonnet and colleagues demonstrated structural gene abnormalities in families with type 1, confirming its genetic basis [1, 16]. Bradykinin was proposed as the likely mediator in 1983, and Nussberger and colleagues demonstrated elevated plasma bradykinin during attacks in 1998, with higher concentrations in blood draining oedematous regions [1, 17].

In 2000, a familial form of angioedema with normal C1-INH was described, initially termed “type 3”, almost exclusively affecting women and aggravated by oestrogens. In 2006, Dewald and Bork identified missense variants in F12 exon 9 in this form, and Cichon and colleagues demonstrated that the NM_000505.4:c.983C>A p.(Thr328Lys) variant increases factor XII amidolytic activity, F12 transcription being upregulated by oestrogens [18, 19]. Between 2018 and 2024, exome sequencing enabled addition of PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1 and DAB2IP to the list of genes associated with hereditary angioedema with normal C1-INH, each initially defined in one or a few families [5, 20–25].

Guidelines evolved in parallel. The international World Allergy Organization and European Academy of Allergy and Clinical Immunology (WAO/EAACI) guideline, revised in 2021, included 28 recommendations developed through Delphi consensus and restricted its scope to types 1 and 2 [7]. The 2025 WAO guidelines, published in 2026, were developed by 40 specialists from 22 countries using GRADE methodology adapted to rare diseases; they propose an endotype classification, unify types 1 and 2 under HAE with C1-INH deficiency, simplify the diagnostic algorithm around functional C1-INH testing, and establish universal access to attack treatment for all patients with a confirmed diagnosis, including those who are asymptomatic [1]. The first international guideline devoted to paediatric patients and the international/Canadian update, with recommendations on breastfeeding and shared decision-making, were also published in 2026 [11, 12]. In France, the HAS PNDS (French National Diagnosis and Care Protocol) published in August 2024 (text dated February 2024) was written by the CREAK reference and competence centres, under the aegis of the MaRIH immuno-haematological rare disease network, and updates the previous version on the basis of expert meetings held from 2018 to 2020 and from 2022 to 2023; its scope is exclusively hereditary angioedema, excluding acquired and drug-induced angioedema, and it adds to the international guidelines emergency algorithms, paediatric doses, prophylaxis criteria and national organisational and funding rules [9]. Figure 1 of the 2025 WAO guidelines presents the endotype classification of recurrent angioedema.

2. Molecular Genetics and Pathophysiology

2.1 The kallikrein–kinin system and the role of C1 inhibitor

C1-INH is a glycosylated serpin (serine protease inhibitor), synthesised mainly in hepatocytes, that forms inactive stoichiometric complexes with its target proteases. It regulates the classical complement pathway (C1r and C1s), the contact system (activated factor XII and plasma kallikrein), fibrinolysis and coagulation [1, 2]. In the contact system, activated factor XII converts prekallikrein to plasma kallikrein; the latter cleaves high-molecular-weight kininogen (HK, encoded by KNG1) and releases bradykinin, which acts on endothelial B2 receptors, increases vascular permeability and produces oedema. Bradykinin is degraded by metalloproteases, including angiotensin-converting enzyme (ACE), aminopeptidase P and carboxypeptidase N [1]. ACE accounts for approximately 75% of bradykinin degradation, and dipeptidyl peptidase IV and neprilysin complete its catabolism, which explains the risk associated with drugs that inhibit these enzymes [9]. Plasmin amplifies factor XII activation, the mechanism underlying the use of antifibrinolytics [9]. Figure 4 of the 2025 WAO guidelines illustrates these pathways.

When C1-INH function falls below approximately 50% of normal, contact system activation is no longer restrained, bradykinin generation increases and attacks occur; studies in mice with double knockout of C1-INH and the B2 receptor confirmed bradykinin's central role [1]. Complement consumption is secondary but diagnostically useful: unregulated activation of the classical pathway consumes C4, which is low in most patients, while C3 remains normal [7]. Each current therapeutic class acts at a point in this cascade: C1-INH replacement, plasma kallikrein inhibition (ecallantide, lanadelumab, berotralstat, sebetralstat), reduced prekallikrein synthesis (donidalorsen), activated factor XII inhibition (garadacimab), and B2 receptor blockade (icatibant) [1].

2.2 SERPING1 and hereditary angioedema with C1-INH deficiency

SERPING1 is located at 11q12.1; molecular analysis should cover all seven coding exons because each can harbour causative variants [1]. The 2020 mutation update documented 748 different variants: 729 in the heterozygous state, ten in the homozygous state and nine compound heterozygous combinations; six probands had gonadal mosaicism, and 72 heterozygous probands and one homozygous proband had de novo variants [2]. Fifty-eight variants affect conserved serpin residues involved in the molecular “mousetrap” mechanism of inhibition (reactive centre loop, gate, shutter, breach and hinge regions) [2].

Type 1 (approximately 85% of cases) results from variants that prevent synthesis or secretion from the mutant allele (deletions, insertions, nonsense and splicing variants, and large rearrangements), with antigenic C1-INH concentration and function both below 50% of normal; reduction below the 50% expected with one functional allele reflects increased consumption and, for some variants, a dominant-negative effect on the normal protein [1, 2]. Type 2 is chiefly caused by missense variants within or near the reactive centre (classically at the Arg444 codon, Arg466 in HGVS numbering that includes the signal peptide), producing a circulating protein at a normal or increased concentration but with impaired function [2, 26]. Phenotypic analysis also identified an “intermediate” pattern in 74 probands with low antigen levels and a residual 105 kDa species after incubation with the target protease [2]. The two types are clinically indistinguishable, which is why the 2025 WAO guidelines combine them as a single condition [1]. Differences in the most prevalent variants between countries are consistent with a dominant-negative pathophysiology, and no single founder variant predominates worldwide [1].

Penetrance is high (approximately 95% over a lifetime), transmission risk to each child is 50%, and up to 25% of cases result from de novo variants; absence of a family history therefore does not exclude the diagnosis [1]. Genotype–phenotype correlation is limited: deletions and other null variants are associated with greater disease risk, but severity varies considerably among relatives carrying the same variant [1]. At the SERPING1 locus, OMIM also records “partial C4 deficiency” (OMIM 120790), an allelic biochemical description of C1-INH deficiency rather than a distinct disease [3].

2.3 Hereditary angioedema with normal C1-INH: gene-specific mechanisms

In HAE-FXII, reported variants cluster in F12 exon 9, in the proline-rich region of the heavy chain: NM_000505.4:c.983C>A p.(Thr328Lys) (designated Thr309Lys in the historical numbering of the mature protein; the most frequent), NM_000505.4:c.983C>G p.(Thr328Arg), the 72 bp deletion NM_000505.4:c.971_1018+24del p.? and the 18 bp duplication published as c.892_909dup (published designation; = NM_000505.4:c.894_911dup p.(Gln300_Thr305dup) after 3′ alignment) [18, 27]. These variants confer gain of function, increasing activated factor XII activity and bradykinin generation without altering plasma factor XII concentration; oestrogen regulation of F12 transcription explains female predominance and the influence of oral contraceptives, pregnancy and hormone therapy [4, 19].

In HAE-PLG, the NM_000301.5:c.988A>G p.(Lys330Glu) variant in plasminogen kringle domain 3, described in 2018, segregates in an autosomal dominant pattern; mutant plasminogen generates bradykinin through a pathway bypassing factor XII and plasma kallikrein [20, 28]. In HAE-KNG1, the NM_001102416.3:c.1136T>A p.(Met379Lys) variant alters the N-terminal bradykinin cleavage site in kininogen; it was described in a German family with six affected individuals [22, 27]. In HAE-HS3ST6, the NM_001009606.4:c.430A>T p.(Thr144Ser) variant in heparan sulphate 3-O-sulphotransferase 6 impairs heparan sulphate biosynthesis and cell-surface interactions of contact system components [24]. In recessively inherited HAE-CPN1, biallelic variants reduce carboxypeptidase N activity to 30% to 50% of the median, with accumulation of bradykinin and the anaphylatoxins C3a and C5a, explaining the association of angioedema with urticaria [1, 5].

A second group appears to result from altered VEGF- and angiopoietin-dependent endothelial barrier function rather than excess bradykinin. In HAE-ANGPT1, NM_001146.5:c.355G>T, p.(Ala119Ser), described in the original article as c.807G>T on the previous transcript version (NM_001146.3, historical numbering that should not be used as a current coding coordinate), reduces angiopoietin-1 multimer formation and binding to the TIE2 (TEK) receptor, with reduced stabilisation of endothelial junctions [21, 29]. In ClinVar (VCV001162304), the same variant has two independent classifications: pathogenic for hereditary angioedema type 5 in the submission based on the original family, and uncertain significance in a clinical laboratory submission reassessed in January 2026; this disagreement reflects that the association rests on a single family [29]. In HAE-MYOF, c.651G>T (p.Arg217Ser) in myoferlin, proposed as a gain-of-function variant, would increase membrane expression of VEGF receptor 2 [23, 30]. In HAE-DAB2IP, p.Asp239Asn in the C2 domain of DAB2-interacting protein, identified in an Argentinian family with three affected generations, alters the subcellular localisation of VEGF receptor 2 [25]. The 2025 WAO guidelines group these three forms into a VEGF endotype and emphasise that bradykinin involvement has not been confirmed in all subtypes, with direct therapeutic implications [1].

2.4 Sex distribution and embryonic selection

Analysis of 1494 offspring of carriers of variants associated with hereditary angioedema showed that fewer sons and more daughters inherit the familial variant than expected for autosomal dominant transmission, and that fewer boys than expected are born in HAE-nC1-INH; the authors propose sex- and variant-dependent selection during early embryogenesis, with an estimated loss of 20% to 25% of male carrier embryos [31]. In HAE-FXII, the sex ratio among symptomatic patients was 1:68, and maternal transmission predominated over paternal transmission (35:14) [4].

2.5 Allelic disorders that must be distinguished from angioedema

The same genes cause disorders with the opposite mechanism. Congenital factor XII deficiency is an asymptomatic laboratory abnormality with markedly prolonged activated partial thromboplastin time (aPTT) and no bleeding tendency; angioedema-causing F12 variants do not manifest as factor XII deficiency and are not detected by measurement of its activity [3]. Type 1 plasminogen deficiency (hypoplasminogenaemia, autosomal recessive) causes ligneous conjunctivitis and fibrin-rich pseudomembranes at multiple mucosal sites; for this disease, human plasminogen concentrate was studied intravenously at 6.6 mg/kg every 2 to 4 days, with lesion improvement in all patients with visible lesions [32]. Severe high-molecular-weight kininogen deficiency due to biallelic truncating KNG1 variants also prolongs aPTT without bleeding, with an estimated prevalence of approximately 1 case per 8 million [33].

3. Clinical Spectrum and Manifestations by Organ System

3.1 General characteristics of attacks

Hereditary angioedema attacks consist of non-pitting, non-pruritic, asymmetric and disfiguring subcutaneous or submucosal oedema that worsens over the first 24 hours and resolves spontaneously within 48 to 72 hours, rarely lasting beyond 5 to 7 days [1]. The French PNDS places spontaneous resolution between 2 and 5 days, considers a duration of less than 24 hours atypical of bradykinin-mediated angioedema and describes marked fatigue after many attacks [9]. Attacks are unpredictable and may affect several sites simultaneously, but are not usually systemic [1]. Without preventive treatment, many patients have attacks every 7 to 14 days, some every 3 days, and others rarely or never [1]. Severity and location vary considerably, even among relatives with the same variant [1].

Prodromal symptoms are frequent and include anxiety, nausea, paraesthesia and fatigue; they have been described in 65% to 70% of attacks, with specificity above 95% but sensitivity of 18% to 64% for predicting an attack, depending on its location [1]. Erythema marginatum, a flat, patterned, non-pruritic erythema, occurs as an initial manifestation in approximately one third of patients and in 42% to 58% of children, and is often mistaken for urticaria, delaying diagnosis [1, 7].

3.2 Skin and subcutaneous tissue

Peripheral attacks affect the face, lips, eyelids, extremities, trunk and genitals. These are the most frequent and earliest manifestations, with mean onset of skin attacks at approximately 11 years [1]. Facial oedema is considered a risk factor for laryngeal involvement [1].

3.3 Gastrointestinal tract

Abdominal involvement occurs in 70% to 90% of patients over their lifetime and is associated with high morbidity. Bowel wall oedema causes severe, prolonged colicky pain, nausea, vomiting and sometimes diarrhoea; it may be accompanied by ascites and, very rarely, hypovolaemic shock [1]. The presentation mimics a surgical abdomen and frequently leads to unnecessary appendicectomies, laparotomies and colonoscopies [1]. Mean age at the first abdominal attacks is approximately 16 years [1]. According to the French PNDS, abdominal imaging during an attack is almost always abnormal: ascites is visible on ultrasound or CT in approximately 90% of attacks and bowel loop wall thickening on CT in approximately 50% [9]. The attack is not accompanied by fever or a biological inflammatory syndrome, but haemoconcentration may cause leucocytosis and a raised haematocrit, presyncope due to hypotension may occur, and the end of the attack is often accompanied by profuse diarrhoea [9]. In children, particularly after the age of 3 years, an abdominal attack may be complicated by acute intussusception [9]. Abdominal pain that persists despite specific treatment or follows an unusual course requires C-reactive protein measurement and imaging to exclude appendicitis, diverticulitis, pancreatitis or biliary colic [9]. Some forms involve only the gastrointestinal tract for years, as in the case described in section 10, in which CT showed jejunal wall oedema and ascites and D-dimer elevations mimicked mesenteric ischaemia [34].

3.4 Upper airway and mortality

Laryngeal oedema accounts for less than 1% of all attacks but occurs at least once in approximately half of patients and is the principal cause of death [1]. In a German cohort of 123 patients, 61 (49.6%) experienced 596 episodes of laryngeal oedema; mean age at the first episode was 26.2 years, almost 80% occurred between ages 11 and 45 years, and the mean interval from onset to peak swelling was 8.3 hours [35]. Analysis of 728 patients from 182 families by the same research group identified 214 deaths, including 70 from asphyxiation during a laryngeal attack; 63 occurred in undiagnosed patients, whose mean survival was approximately 31 years shorter than that of undiagnosed patients who died from other causes [13]. Fatal attacks progressed through three phases: before dyspnoea (mean 3.7 hours), dyspnoea (mean 41 minutes, minimum 2 minutes), and loss of consciousness (mean 8.9 minutes) [13]. Without diagnosis, the risk of death associated with laryngeal oedema is estimated at 20% to 25% [1]. A Brazilian study identified 39 deaths from asphyxiation among 170 patients from 46 families; 87.2% had no previous diagnosis, 41% died outside hospital, and in half of cases more than 8 hours had elapsed since attack onset [1]. Warning symptoms include a foreign body sensation, dysphagia, hoarseness, aphonia, tachypnoea, dyspnoea and stridor; obstruction may develop more rapidly in children because of their narrower airway [11].

3.5 Other sites

Headaches and episodes involving the bladder, chest, muscles, joints, kidneys and oesophagus have each been described in less than 1% of attacks [1]. Some ancestry-associated phenotypic differences have been reported, such as a lower frequency of abdominal attacks in patients from China and Taiwan than in those from Western countries [1].

3.6 Age at onset, puberty and triggers

Attacks may begin at any age but most often start in childhood or adolescence, with a mean age of approximately 11 years and the first attack before age 10 years in approximately 50% of patients [1]. In the series underpinning the WAO/EAACI guideline, half of women had their first attack before age 12 years and 90% by age 23; the corresponding ages in men were 13 and 25 years [7]. The paediatric guideline reports onset between ages 4.4 and 18 years, with a mean of 10 years and no sex difference; attacks are rare in newborns, although one in utero attack and another in a 4-week-old infant have been described [1, 7, 11]. Frequency and severity increase at puberty, and early onset predicts a more severe course [1].

Most attacks are spontaneous, but recognised triggers include physical trauma, dental treatment, surgery and upper airway manipulation, endoscopy, emotional stress, infections, exogenous oestrogens and ACE inhibitors [1]. The French PNDS adds thrombolytics and the potentiation of risk when ACE inhibitors are combined with mTOR inhibitors, gliptins, racecadotril or sacubitril-valsartan, includes positive emotions among emotional triggers and points out that minimal procedures, such as scaling of dental calculus, can precipitate an attack [9]. Following invasive procedures, angioedema usually occurs within 48 hours and affects more than one in five patients, with incidence reaching 30% [1]. SARS-CoV-2 infection is a recognised trigger, without increased infection severity or mortality in patients with hereditary angioedema [1].

3.7 Clinical features of HAE with normal C1-INH

HAE-nC1-INH manifestations resemble those of HAE-C1-INH and do not allow the two groups to be distinguished clinically; some subtypes have later onset, and attacks may be accompanied by local bruising [1]. A systematic review of 602 patients from 220 families with a genetic diagnosis summarises gene-specific differences [27], presented in the following table with data from additional cohorts.

Abdominal attacks in HAE-FXII, as in HAE-C1-INH, lead to unnecessary surgery: in a Brazilian series of 52 patients with normal C1-INH, 32 had an F12 variant, 16 were diagnosed with an acute abdomen and 13 of these underwent surgery [40]. In France, the PNDS records more than one hundred families carrying the F12 variant, mostly of North African origin, with a mean age of 21 years at the first attack and rare cases in men and in prepubertal boys [9]. The same text notes that many patients initially classified as HAE-nC1-INH in fact had non-allergic mast cell-mediated angioedema responsive to antihistamines or omalizumab, which is why resistance to antihistamines must be demonstrated before genetic testing [9].

4. Clinical Recognition and Red Flags

Diagnostic delay has decreased from a mean of 21 years in the 1970s to 7 to 10 years currently, but patients older than 50 years with symptoms since childhood continue to be described, and fewer than 40% receive a diagnosis within the first three years after symptom onset [1]. In a real-world study of more than 600 patients, almost half had been misdiagnosed, with an additional median delay of 1.7 years; absence of a family history increased the likelihood of misdiagnosis by almost 60% [1]. Up to 22% of patients had been classified as having drug hypersensitivity, and one in five had been treated for anaphylaxis [1].

The 2025 WAO guidelines list clinical criteria for suspicion: recurrent skin swelling, particularly of the extremities, face or genitals; recurrent gastrointestinal symptoms (severe, prolonged colicky pain, vomiting) with imaging abnormalities (ascites, bowel wall oedema); swelling of the mouth, tongue or larynx; childhood or adolescent onset in HAE-C1-INH; prodromal symptoms; absence of urticaria (except in HAE-CPN1); lack of response to adrenaline, H1 antihistamines or glucocorticoids; lack of response to quadruple-dose antihistamines and an anti-IgE antibody (in HAE-nC1-INH); and a family history compatible with autosomal dominant inheritance [1]. The “HA4E” mnemonic (Hereditary, recurrent Angioedema, Abdominal angioedema/pain, Absence of urticaria, Absence of response to antihistamines, Estrogen association) has been proposed to support recognition in primary care [1]. The French PNDS defines antihistamine resistance as lack of response to continuous treatment for several weeks, at doses up to four times the authorised dose and, where appropriate, with added omalizumab, and points out that the family history is absent in approximately one quarter of patients because of de novo variants [9]. The diagnostic approach figure of the same text uses a cut-off of 30 years: onset before that age, a family context or oestrogen sensitivity point to a hereditary form, with antigenic and functional C1-INH measurement and testing of SERPING1, F12, PLG and KNG1; onset after 30 years without a family history points to an acquired form, with measurement of C1q and anti-C1-INH antibodies; the diagnosis should be confirmed by a physician at a CREAK centre [9].

Warning signs that should prompt investigation are recurrent angioedema without wheals that does not respond to antihistamines or corticosteroids; unexplained recurrent abdominal pain with ascites or oedematous bowel loops on imaging, particularly with low C4; laryngeal or tongue oedema without an allergic cause; worsening or onset with combined oestrogen–progestogen contraception, pregnancy or hormone replacement therapy; onset or worsening with ACE inhibitors; and a relative with recurrent angioedema or death from asphyxiation [1, 7]. An ACE inhibitor may reveal previously silent hereditary angioedema, so C1-INH should be assessed in these patients [1]. Urticaria or an angioedema-inducing medicine does not exclude the diagnosis, particularly with a positive family history (statement 11 of the 2025 WAO guidelines) [1].

Recognition is more difficult in children because abdominal pain is highly prevalent at this age and upper airway oedema is often mistaken for allergic asthma, pharyngitis or epiglottitis [1]. Women with angioedema without urticaria, normal C1-INH and oestrogen-associated worsening should be actively tested for an F12 variant, particularly those of Western European or African origin [36]. Detection of a variant associated with HAE-nC1-INH in an isolated patient can identify asymptomatic at-risk relatives: in a series of 132 sporadic patients with recurrent angioedema without wheals, normal C1-INH and no response to antihistamines, 10 (7.6%) had F12 p.Thr328Lys and 6 (4.5%) had PLG p.Lys330Glu; family testing identified 11 asymptomatic carriers [41].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Principles

Diagnosis rests on three interrelated components: clinical suspicion, targeted biochemical assessment of complement and, in selected situations, genetic testing [1]. Distinguishing hereditary from acquired angioedema and, within hereditary disease, HAE-C1-INH from HAE-nC1-INH is essential because classification determines therapy, genetic counselling and family screening [1].

5.2 Biochemical tests

The 2021 WAO/EAACI guideline recommends (recommendation 1) that all patients with suspected hereditary angioedema undergo simultaneous measurement of C1-INH function, antigenic C1-INH concentration and C4 in serum or plasma, because their combined diagnostic accuracy exceeds that of any individual test; it also recommends (recommendation 2) confirmation of abnormal results by repeat testing, ideally in a certified laboratory [7]. C4 alone is unsuitable for screening or as the sole diagnostic parameter: sampling during an attack increases sensitivity but not specificity [7]. C3 is normal, and its measurement, like that of CH50, adds no information [1, 7].

The 2025 WAO guidelines simplified the algorithm on the basis of studies showing adequate reproducibility, 100% sensitivity and improved standardisation of the functional assay: they recommend initial assessment using only functional C1-INH testing, provided it is performed in a specialist laboratory with a validated method (statement 1, 85% agreement) [1]. C4 is low in 90% to 95% of patients with HAE-C1-INH outside attacks and almost always during attacks; antigen measurement can confirm type 1 but not type 2, in which antigen is normal or elevated; C1-INH function is below 50% of normal in both types [1]. When functional testing is unavailable, antigen measurement is recommended (a normal result does not exclude the diagnosis), or, if this is also unavailable, C4 to strengthen suspicion; in settings with limited access, ordering all three tests simultaneously is acceptable to avoid loss to follow-up (statements 2 to 5) [1]. Results inconsistent with clinical findings should be repeated, ideally 1 to 3 months later; once the diagnosis is established, repetition is unnecessary, and confirmation should never delay treatment [1, 7]. In countries with fewer resources, dried blood spots allow genetic testing and C1-INH measurement by liquid chromatography–tandem mass spectrometry, with advantages for transport and storage [1]. Figure 5 of the 2025 WAO guidelines presents the algorithm.

The 2024 French PNDS follows a different path from WAO 2025. Outside attacks, it considers simultaneous measurement of C1-INH concentration and functional activity and testing for the causal variant to be essential, and places C4 among the tests useful according to context: a low C4 is not specific (systemic lupus erythematosus, cryoglobulinaemia, acquired angioedema, C4 deficiency), but, combined with reduced C1-INH function, it has a specificity of 98% to 100% and a negative predictive value of 96%, and it is normal in approximately 20% of patients with type 1 [9]. The deficiency is considered demonstrated when functional activity is below 50% of the reference value in two measurements at least one month apart, one of them in a reference laboratory; values between 50% and 60% require a second sample and joint interpretation with the laboratory specialist, in the light of the clinical picture and away from pregnancy or oestrogens [9]. A normal concentration does not exclude the diagnosis, and the C1-INH level does not correlate with clinical severity [9]. As for pre-analytical conditions, tests need not be performed during an attack; samples should be taken at least 2 weeks after a C1-INH concentrate and 1 month after stopping danazol, whereas tranexamic acid and icatibant do not interfere; on oestrogens and in pregnancy values may be physiologically low and are repeated more than 3 months later; sampling and transport conditions should be agreed in advance with the laboratory [9]. During an attack no test is essential: ultrasound (preferred in children) or abdominal CT help in case of doubt; nasofibroscopy when an upper airway attack is suspected is dangerous because of the risk of worsening; measurement of C1-INH during the attack and investigation of bradykinin metabolism are not indicated; and C3 and CH50 outside attacks are of no use [9]. In France, antigenic measurement is reimbursed, but the functional assay belongs to the list of innovative procedures outside the national nomenclature and is not reimbursed in outpatient care [9].

Adapted from table 3 of the 2025 WAO guidelines [1].

Mild reductions in C1-INH activity and C4 are observed more frequently in HAE-FXII than in HAE of unknown cause, but do not in themselves change classification [4]. In HAE-CPN1, the specific biochemical test is plasma carboxypeptidase N activity, reduced to 30% to 50% of the median [5].

5.3 Genetic testing

In HAE-C1-INH, diagnosis is usually biochemical and genetic testing is rarely necessary; identification of a pathogenic SERPING1 variant confirms the diagnosis in uncertain cases [1]. The 2025 WAO guidelines list situations in which SERPING1 testing is useful: segregation in asymptomatic relatives; segregation of a variant of uncertain significance in a proband; prenatal and preimplantation diagnosis; neonatal diagnosis; suspected gonadal mosaicism (more than one affected child of unaffected parents); de novo cases with borderline functional results; and genetic epidemiological and pharmacogenetic research [1]. Analysis should include all seven coding exons and testing for large deletions and duplications; sequencing may miss variants creating cryptic splicing sites, so a negative genetic result does not exclude disease when biochemical findings are unequivocal [1, 7]. Variants should be classified using American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria; a hereditary angioedema variant curation expert panel is being established [1]. In the case in section 10, nonsense variant c.990C>A, p.(Tyr330Ter), absent in both parents, was classified as pathogenic using PVS1 and PS2 criteria [34].

The international consensus on genetics in hereditary angioedema and current guidelines define minimum testing and reporting requirements [42]. Regarding coverage, the laboratory should state whether testing includes sequencing of all coding exons and exon–intron junctions, copy-number variation analysis (deletions and duplications of one or more exons, frequent in SERPING1), deep intronic and regulatory regions, and its sensitivity for mosaicism; with a convincing biochemical phenotype, a negative test does not exclude the diagnosis and should prompt review of coverage before the hypothesis is abandoned [42]. The report should contain the gene, versioned reference transcript (for example, NM_000062.3 for SERPING1 or NM_001146.5 for ANGPT1), Human Genome Variation Society (HGVS) nomenclature at coding DNA and protein levels, zygosity, classification according to ACMG/AMP criteria with the criteria applied, and technical limitations [42]. Variants should be normalised using ClinVar and the MANE transcript, without mixing historical numbering (for example, mature protein numbering for F12 and PLG, or the old ANGPT1 numbering) with standardised nomenclature; where the literature uses historical numbering, both should be provided [29, 42]. A variant of uncertain significance does not become pathogenic through treatment response or partial segregation in a family; segregation studies in these situations investigate the variant rather than constitute predictive testing, and a variant of uncertain significance should not form the basis of prenatal or preimplantation diagnosis [42].

In HAE-nC1-INH, genetic testing is essential: the 2025 WAO guidelines recommend it in patients with strong clinical suspicion and normal C1-INH function (statement 6, 100% agreement) [1]. In most laboratories, the initial approach is targeted testing of F12 exon 9 and PLG c.988A>G, expanded to a panel or exome including ANGPT1, KNG1, MYOF, HS3ST6, CPN1 and DAB2IP [1, 41]. A negative result does not exclude HAE-nC1-INH, which remains classified as of unknown cause (HAE-UNK); families with two simultaneous forms, such as variants in SERPING1 and PLG, have also been described [1].

The French PNDS diverges from the 2025 WAO guidelines in recommending testing for the causal variant in each index case of a new family with HAE-C1-INH: sequencing of the eight exons of SERPING1 (NM_000062.3) and, if negative, testing for rearrangements by multiplex ligation-dependent probe amplification (MLPA); no variant is found in 5% to 10% of patients with C1-INH deficiency [9]. In France the test is performed in two laboratories, the centre's reference laboratory at CHU Grenoble Alpes and the immunology laboratory of the Assistance Publique–Hôpitaux de Paris [9]. In HAE-nC1-INH, the PNDS requires prior clinical characterisation of antihistamine-resistant bradykinin-mediated angioedema and defines a sequence: F12 testing in all patients, particularly when there is an oestrogen trigger or Maghrebi origin, the founder variant p.Thr328Lys being by far the most common (carriers in approximately 7% of sporadic antihistamine-resistant cases and in approximately 12% of women with oestrogen-sensitive angioedema); systematic PLG testing if F12 is negative, with the founder variant p.Lys330Glu in approximately 4%, associated with a family history, tongue swelling and triggering by ACE inhibitors; and KNG1 testing only as second line, in informative families with several affected members [9, 41]. The absence of a variant in these three genes does not exclude the diagnosis [9].

5.4 Special interpretation considerations

In newborns, antigenic and functional C1-INH correspond to approximately 60% to 70% of adult values (70% and 62%, respectively, in cord blood), preterm infants have lower values, and adult levels are reached between 6 months and 1 year of age; cord blood may yield falsely low results and C4 is not useful before 12 months [7, 11]. Complement tests performed in the first year should therefore be repeated after age 1 year, and the 2025 WAO guidelines recommend genetic testing in children younger than 1 year when the diagnosis is probable (statement 30) [1, 11]. The paediatric guideline recommends screening newborns with a positive family history using C4, antigenic and functional C1-INH and/or genetic testing when the familial variant is known, repeating complement testing after 1 year (recommendation 8) [11]. The French PNDS states that C1-INH reaches adult values between 6 and 36 months and proposes, for children of affected families, one of two approaches: antigenic and functional measurement from 6 months of age, repeated after the first year even if the first result is normal; or, if the familial variant is known, presymptomatic genetic testing from birth, on blood or a buccal swab, within a genetics clinic; measurement in cord blood is considered uninterpretable [9]. During pregnancy, plasma C1-INH decreases physiologically and normalises after delivery, so results obtained during pregnancy should be interpreted cautiously and repeated postpartum, with genetic testing if suspicion is high [1, 7].

5.5 Family screening

The WAO/EAACI guideline recommends screening grandparents, parents, siblings, children and grandchildren of patients with HAE-C1-INH using all three biochemical tests (recommendation 28), and prescribing attack treatment immediately after diagnosis, even before the first attack [7]. The 2025 WAO guidelines recommend cascade family screening from each index case, using biochemical or genetic testing according to age and disease type (statement 8, 100% agreement) [1]. Given incomplete penetrance in HAE-nC1-INH, an asymptomatic relative may be a carrier, making genetic screening necessary [36, 41].

5.6 Disease assessment instruments

Disease activity, impact and control should be monitored using validated instruments: the Angioedema Activity Score (AAS), Hereditary Angioedema Activity Score (HAE-AS), Angioedema Quality of Life Questionnaire (AE-QoL), Hereditary Angioedema Quality of Life Questionnaire (HAE-QoL), and Angioedema Control Test (AECT) [1, 7]. The AECT has four questions (symptom frequency, quality-of-life impact, unpredictability and control with current therapy), each scored from 0 to 4, with a total from 0 (no control) to 16 (complete control) [7].

6. Differential Diagnosis

Differential diagnosis is organised by bradykinin-mediated or mast cell-mediated angioedema endotypes [1].

Acquired angioedema has a basic biochemical profile indistinguishable from type 1, and C1q should be measured in any patient with angioedema beginning after age 30 years without a family history; C1q may, however, be normal in acquired disease, particularly during androgen treatment [1, 7]. Laboratory factor XII deficiency, high-molecular-weight kininogen deficiency and type 1 plasminogen deficiency are allelic disorders unrelated to angioedema and should not be interpreted as hereditary angioedema [32, 33].

The French PNDS organises the differential diagnosis into three successive questions (is it angioedema? is it bradykinin-mediated? is it hereditary or acquired?) and points out that approximately 95% of angioedemas are spontaneous mast cell-mediated, equivalent to deep urticaria, 4% allergic mast cell-mediated and less than 1% bradykinin-mediated [9]. To be considered angioedema, the swelling must be non-pitting and non-inflammatory, localised and transient, resolve spontaneously within 5 days at most without sequelae and not be accompanied by fever (except with a triggering infection) or a biological inflammatory syndrome; it may be painful, especially in the abdomen; if any of these features is missing, another diagnosis is sought [9]. Mast cell-mediated angioedema lasts from a few hours to 72 hours, is often accompanied by an atopic background, superficial urticaria or dermographism, may be associated with signs of anaphylaxis and responds to antihistamines at optimised doses; bradykinin-mediated angioedema lasts 2 to 5 days, never less than 24 hours, and is the only type that causes severe abdominal pain lasting 48 to 72 hours or a subocclusive picture [9]. Allergic angioedema appears minutes after exposure to an allergen, with other signs of anaphylaxis, and requires allergological investigation; non-allergic mast cell-mediated angioedema is the most frequent cause, in children and adults, and carries no risk to life [9]. ACE inhibitor-induced angioedema appears from the first week, in half of cases within the first 3 months and sometimes years later; the risk increases with gliptins, mTOR inhibitors, racecadotril or thrombolytics; measurement of C1-INH is recommended to exclude HAE or an acquired deficiency unmasked by the drug, and recurrence after withdrawal should point to a mast cell-mediated cause or HAE-nC1-INH [9]. In acquired angioedema due to C1-INH deficiency, the PNDS describes onset after 40 years, C1-INH function always reduced, low C1q in 70% to 90%, anti-C1-INH antibodies in approximately 50% and an association mainly with marginal zone lymphoma or monoclonal gammopathy; the cut-off used in the diagnostic figures of the same text is 30 years [9].

Alternative diagnoses of localised swelling vary with location; the table summarises the non-exhaustive list in annex 4 of the French PNDS [9].

For angioedema of the face or upper airways of undetermined cause, the CREAK helpline algorithm starts with a high-dose antihistamine (levocetirizine, four tablets orally, or dexchlorpheniramine, two ampoules by slow IV injection) and a call to the helpline if there is no improvement; if the patient takes an ACE inhibitor or underwent thrombolysis less than 6 hours earlier, icatibant 30 mg SC or C1-INH concentrate 20 IU/kg IV (off-label use in this situation) is given as early as possible, the ACE inhibitor is stopped and the patient is referred to the centre; in the others, the antihistamine is repeated and, in the presence of signs of severity, adrenaline is given IM at 0.01 mg/kg (maximum 0.5 mg) or by autoinjector (150 µg below 25 kg; 300 to 500 µg above) [9]. Tranexamic acid should not be prescribed in this situation [9].

7. Treatment and Risk Management Strategies

7.1 General principles

Treatment comprises three components with distinct indications: attack treatment, short-term prophylaxis (before a procedure) and long-term prophylaxis [1, 7]. The stated goal is complete disease control and a normal life for the patient, using a “treat-to-target” strategy reassessed at least annually through shared decision-making [1, 7]. Antihistamines, corticosteroids and adrenaline are ineffective in bradykinin-mediated angioedema and should not be used because they delay specific treatment [1]. Follow-up should be provided by physicians experienced in the disease, with support from a reference centre (statement 48) [1].

General preventive measures include preferring progestogen-only contraception to oestrogens; avoiding ACE inhibitors; maintaining good oral hygiene; vaccination against influenza and COVID-19 and usual infection prevention measures; and considering hepatitis A and B vaccination in patients regularly receiving plasma-derived products [1]. Children should receive the full national vaccination schedule [11]. Patients should have a written action plan, an emergency card and enough medication to treat at least two attacks, carried with them at all times [1].

The French PNDS considers all ACE inhibitors and oestrogens contraindicated; it allows angiotensin II receptor antagonists when renin–angiotensin system blockade has an important benefit, after informing the patient, a multiprofessional decision and monitoring for worsening of attacks, given the controversial data [9]. There is no contraindication to live or inactivated vaccines, nor to school or extracurricular sport; scuba diving is contraindicated [9]. The patient should keep at home the equivalent of treatment for two attacks (two doses of icatibant or of C1-INH concentrate) and carry a care and emergency card, and isolated patients living far from hospitals may register in advance with the emergency medical service of their département [9]. As for donation, blood can be donated without risk to donor or recipient; bone marrow collection by apheresis carries no specific risk, but iliac crest puncture or central line placement may require prophylaxis; liver donation for transplantation is contraindicated, because C1-INH is mainly synthesised in the liver and the disease may manifest in the recipient, whereas other organs and tissues follow the usual criteria [9].

7.2 Attack treatment

All attacks should be considered for treatment; treatment is mandatory with upper airway involvement and should be administered as early as possible. Early treatment is associated with faster resolution and shorter attacks (statements 13A to 13C) [1]. Every patient with a confirmed diagnosis, including asymptomatic patients, should have attack treatment available at home [1]. The 2025 WAO guidelines recommend intravenous C1-INH, icatibant or sebetralstat as first line (statement 14A); ecallantide as second line, only under healthcare professional supervision (statement 15); and solvent–detergent-treated plasma or, if unavailable, fresh frozen plasma as third line (statement 16) [1]. Tranexamic acid and attenuated androgens should not be used for attacks [1]. With signs of upper airway involvement, intubation, cricothyrotomy or tracheotomy should be considered at the initial assessment (statement 17) [1].

Sebetralstat doses differ between labels: the FDA recommends 600 mg per dose and the EMA 300 mg per dose; the 2025 WAO guidelines specify two 300 mg tablets [1, 52, 53]. The 2025 WAO guidelines recommend rounding the 20 IU/kg pdC1-INH dose to the nearest 500 IU to reduce wastage [1].

Pivotal trials document the efficacy of each class. With Berinert® at 20 U/kg, median time to onset of relief was 0.5 hours versus 1.5 hours with placebo, and 0.5 versus 13.5 hours in severe attacks [56]. With nanofiltered C1-INH (1000 U, one or two doses), median time to unequivocal relief was 2 hours versus more than 4 hours with placebo [57]. The main conestat alfa trial included 75 patients randomised to 50 U/kg or placebo [47]. For icatibant, FAST-1 and FAST-2 showed median times of 2.5 versus 4.6 hours (placebo; non-significant difference, possibly because of early rescue medication) and 2.0 versus 12.0 hours with tranexamic acid [58]; in FAST-3, median time to 50% symptom reduction was 2.0 hours versus 19.8 hours with placebo, with rescue medication in 7% versus 40% [50]. With ecallantide, the treatment outcome score at 4 hours was 50 versus 0 with placebo [59]. In the three-arm crossover KONFIDENT trial, 110 patients treated 264 attacks; median time to onset of relief was 1.61 hours with 300 mg, 1.79 hours with 600 mg and 6.72 hours with placebo, while complete resolution within 24 hours occurred in 42.5%, 49.5% and 27.4% of attacks, respectively; severe laryngeal attacks were excluded [52, 60].

Direct comparisons are scarce. Icatibant and C1-INH shorten attacks; icatibant allows faster, more convenient self-administration but requires a second dose more frequently [1]. Self-administration reduces and delays emergency department visits and is feasible from age 8 years and in older patients with a trained caregiver [1]. Even after self-administration, upper airway attacks require immediate hospital assessment because oedema may progress or recur [7, 50].

The French PNDS defines a severe attack by life-threatening risk (face, tongue and upper airways) or by major functional disability (abdominal attacks and peripheral attacks with disability, pain or absenteeism) and reserves mandatory specific treatment for it; non-severe attacks may be left untreated but must be monitored, because they may progress to a severe attack [9]. As first-line treatment it recommends icatibant 30 mg SC in adults, with paediatric dosing by weight (12–25 kg 10 mg; 26–40 kg 15 mg; 41–50 kg 20 mg; more than 50 kg 30 mg; no dose defined below 2 years or 12 kg), injected slowly (over at least 5 minutes in the main text and over 2 to 3 minutes in the school protocol) to reduce the burning sensation; the elimination half-life is 1 to 2 hours, and icatibant should be avoided in acute coronary syndrome, in ischaemic stroke and the following weeks, and after thrombolysis, situations in which C1-INH is preferred [9]. In pregnant or breastfeeding women, in children younger than 2 years or if icatibant is unavailable, C1-INH concentrate 20 IU/kg by slow IV injection is used (10 to 15 minutes for the total dose, without pausing between vials), always administering opened vials in full: for a 60 kg patient, the calculated dose of 1200 IU corresponds to three 500 IU vials, i.e. 1500 IU [9]. The PNDS also recommends 20 IU/kg for Cinryze®, by expert consensus, because the 1000 IU dose in the SmPC required a second administration in approximately one third of cases; improvement is expected to begin after approximately 30 minutes with Berinert® (mean half-life 36 hours) and 45 minutes with Cinryze® (mean half-life 56 hours) [9].

Response is assessed within the first hour (halting of oedema progression or pain relief) and, in a laryngeal attack, at 20 to 30 minutes, with second-line treatment started from 30 minutes [9]. In case of failure, the PNDS prefers switching class (C1-INH after icatibant or icatibant after C1-INH) without a minimum interval, and a further dose of C1-INH likewise requires no interval; a second icatibant injection is reserved for recurrence after initial improvement (rebound effect), with an interval of 6 hours, a maximum of 3 injections in 24 hours (90 mg) and of 8 injections per month [9]. The patient should not be left alone until improvement; they should call the French emergency medical number (15, or 114 by text message if unable to speak) when upper airway or tongue swelling with dysphonia, dysphagia or dyspnoea does not improve after the injection, or when they have a severe attack with no medication at home, and go to the emergency department if a severe attack, including an abdominal one, does not respond to treatment [9]. The text recommends observation for at least 24 hours after treatment of a severe attack and, for patients treated in hospital, allows discharge 2 hours after the onset of improvement, provided they take attack treatment with them and are informed of the risk of recurrence or rebound [9].

In upper airway oedema, the PNDS advises against endoscopy and any invasive ENT examination, as well as the fully supine position [9]. With signs of respiratory distress, airway control is the responsibility of a senior physician, ideally an anaesthetist together with a surgeon, with intubation still possible in the early phase and cricothyroidotomy equipment prepared simultaneously; the absence of desaturation may be falsely reassuring [9]. In the phase of loss of consciousness or cardiorespiratory arrest, immediate cricothyroidotomy or tracheotomy is performed by a senior intensive care physician or ENT surgeon, because an attempt at oro- or nasotracheal intubation is futile in the face of major laryngeal oedema [9]. Any urgent intubation of a patient with HAE for another reason should be accompanied by C1-INH concentrate 20 IU/kg IV at anaesthetic induction [9].

Tranexamic acid never treats a severe attack and must not delay icatibant or C1-INH; in non-severe attacks, in patients without a history or risk factors for thrombosis who report previous efficacy, the PNDS accepts it as an alternative to no treatment, without validated efficacy (adults, including pregnant women: 1 to 2 g every 6 hours for 24 to 48 hours; children: 10 mg/kg 4 to 6 times a day), a position that diverges from the 2025 WAO guidelines [1, 9]. Danazol does not treat an attack, because it acts only after 5 to 10 days [9].

7.3 Short-term prophylaxis

Short-term prophylaxis should be considered before planned procedures with trigger potential, such as dental interventions, airway manipulation or surgery with intubation (statement 19, moderate evidence) [1]. First-line treatment is intravenous C1-INH, preferably plasma-derived, administered less than 6 hours before the procedure (statement 20) [1]. The WAO/EAACI guideline states that the dose is not fully established and that most specialists use 1000 U or 20 U/kg of pdC1-INH; the European SmPC for Cinryze® specifies 1000 IU within the 24 hours before the procedure (500 IU between 10 and 25 kg from 2 to 11 years) [7, 45]. There is evidence of benefit of recombinant C1-INH in reducing post-procedural attacks [7]. When C1-INH is unavailable, attenuated androgens or fresh frozen plasma are second line in high-risk patients (statement 21); table 4 of the 2025 WAO guidelines gives danazol 200 mg two to three times a day for 5 days before and 2 days after the procedure, an off-label use [1]. Tranexamic acid is not recommended for this indication [1]. Attack treatment should be available even after prophylaxis, and in patients well controlled on long-term prophylaxis, situational prophylaxis may be considered for high-risk events [1]. The French PNDS recommends short-term prophylaxis before traumatic dental treatment (extraction, root canal treatment), surgery under general anaesthesia with or without intubation, and any endoscopy, with C1-INH concentrate (Berinert® or Cinryze®) 20 IU/kg in the preceding 6 hours, ideally in the preceding hour; it applies the 20 IU/kg also to Cinryze®, whose SmPC specifies 1000 IU [9, 45]. Icatibant is not used for prophylaxis, and attack treatment (icatibant 30 mg or C1-INH 20 IU/kg) should be available in the recovery room, with the anaesthetist informed of the protocol [9]. In patients already on danazol, for minimally traumatic treatments or procedures, the dose may be increased to 2.5 to 10 mg/kg/day (maximum 600 mg/day) for the 5 preceding days and the 2 following days, without dispensing with immediate availability of specific treatment [9]. For non-traumatic dental treatment, such as scaling, prophylaxis is not mandatory if attack treatment is available for the following 24 hours, and the decision is made case by case with the reference physician [9].

7.4 Long-term prophylaxis

All patients should be assessed for long-term prophylaxis at every visit through shared decision-making considering disease activity, quality of life, treatment burden, resource availability, age-specific approvals and patient preferences (statement 24) [1]. Quality of life is reduced even in patients with few attacks, particularly because of fear of unpredictability, and prophylaxis improves quality of life more than attack treatment alone [1]. Nevertheless, only approximately 50% of patients receive prophylaxis even in high-income countries [1]. First-line options are subcutaneous pdC1-INH, lanadelumab, berotralstat, garadacimab and donidalorsen (statement 26) [1]. Attack treatment must remain available during prophylaxis (statement 25) [1].

Pivotal trials support these options. In COMPACT (subcutaneous pdC1-INH, crossover design), the attack rate was 0.52 per month with 60 IU/kg versus 4.03 with placebo, and 90% of patients had a reduction of at least 50% [61, 70]. In the intravenous nanofiltered C1-INH prophylaxis trial, attacks per 12-week period were 6.26 versus 12.73 with placebo, with highly variable individual responses [46, 57]. In HELP (lanadelumab), involving 125 patients aged 12 years and older, the monthly attack rate was 0.26 with 300 mg every 2 weeks versus 1.97 with placebo (87% reduction) [62, 71]; in extensions lasting more than 2.5 years, patients remained attack-free for approximately 98% of the time [1]. In APeX-2 (berotralstat), the rate was 1.31 attacks per month with 150 mg versus 2.35 with placebo (44.2% reduction), with 58% responders (≥50% reduction) versus 25% [63, 72]; in open-label extensions, the reduction reached up to 90.8% at 96 weeks in good responders [1]. In VANGUARD (garadacimab), involving 64 patients, the monthly rate was 0.27 versus 2.01 with placebo (87% reduction), with a median of zero attacks per month and 62% of patients attack-free for 6 months [65, 67]. In OASIS-HAE (donidalorsen), involving 90 patients, the rate was 0.44 per 4 weeks with monthly administration and 1.02 with administration every 8 weeks, versus 2.26 with placebo (81% and 55% reductions; 87% and 60% from week 5) [68, 73].

These trials differ in population, baseline attack frequency, design (parallel or crossover), duration and outcome definitions, precluding drug ranking through indirect comparisons between trials [67, 71, 72]. An individual median is not equivalent to a population mean: in COMPACT, median reduction in attack number with 60 IU/kg was 95%, while the mean difference from placebo was −3.51 attacks per month (95% CI: −4.21 to −2.81) [70]. Relative reductions must be considered alongside residual absolute rates: a 44.2% reduction with berotralstat corresponded to 1.31 attacks per month and an 87% reduction with lanadelumab to 0.26 attacks per month, values obtained in different populations and periods [71, 72]. In attack treatment trials, “onset of relief” is not synonymous with resolution: in KONFIDENT, median onset of relief was less than 2 hours, but complete resolution within 24 hours occurred in fewer than half of treated attacks [60]. Negative trials also form part of the evidence: in CASPIAN, involving 77 patients with non-histaminergic angioedema and normal C1-INH, the attack rate was 1.82 per month with lanadelumab and 1.78 with placebo (rate ratio 1.02; p=0.90), with a favourable, non-significant trend in subgroups with a known variant (n=5) or a family history without an identified variant (n=13) [74].

No direct comparisons between prophylactic medicines have been published; indirect comparisons and a Cochrane analysis favour lanadelumab and C1-INH over berotralstat for short-term efficacy [1]. Switching follows SmPC-defined regimens: for example, when switching from berotralstat or C1-INH to donidalorsen, the previous medicine is continued for 14 days after donidalorsen starts; when switching from lanadelumab, its last dose is administered 14 days beforehand [69].

When first-line options are unavailable, impractical or not tolerated, the 2025 WAO guidelines suggest intravenous C1-INH, attenuated androgens at the lowest effective dose (preferably no more than 200 mg/day danazol), or antifibrinolytics as second line (statement 27) [1]. Required androgen doses range from the equivalent of 100 mg danazol on alternate days to 200 mg three times daily; doses above 200 mg/day for prolonged periods are not recommended, and the dose is adjusted to clinical response rather than C4 or C1-INH values [7]. Androgens are associated with virilisation, dyslipidaemia, hepatotoxicity and hepatic neoplasms, are contraindicated in pregnancy, and should not be used in children and adolescents because they interfere with growth; six-monthly surveillance (complete blood count, biochemistry, lipid profile and urine) and annual liver ultrasound are recommended (statement 28) [1]. Tranexamic acid (30–50 mg/kg/day in 2 to 3 doses, up to 3 g/day in adults, off-label use) has modest efficacy in HAE-C1-INH and greater efficacy in HAE-nC1-INH with F12 or PLG variants, and is associated with gastrointestinal effects, ocular abnormalities and increased thrombotic risk [1].

The French PNDS defines explicit criteria for proposing long-term prophylaxis: at least one attack per month, five severe attacks per year or attacks with a major impact on quality of life; it allows kallikrein inhibitors from the outset in the most severely affected patients and requires assessment of response at 3 and 6 months, because the effect may be delayed [9]. For lanadelumab, the starting dose is 300 mg SC every 2 weeks from 12 years of age or above 40 kg, with possible spacing to every 3 to 4 weeks after 3 to 6 months without attacks; between 2 and 12 years, 150 mg every 4 weeks up to 20 kg (every 3 weeks if efficacy is insufficient) and 150 mg every 2 weeks between 20 and 40 kg, with the same possible spacing; the adverse effects described are headache, injection-site reactions and mild to moderate hypersensitivity, and the text does not recommend it in pregnancy [9]. Berotralstat is given at 150 mg daily, one capsule with or at the end of a meal, from 12 years of age (and above 40 kg in the paediatric table); the PNDS considers it contraindicated in severe renal impairment and in moderate to severe hepatic impairment, and adverse effects are mainly gastrointestinal and transient [9]. IV C1-INH concentrate is used at 20 IU/kg at least twice weekly, adjusted case by case (Cinryze® is indicated from 6 years of age; Berinert® is used off-label, by expert consensus); in France only the intravenous route is available, with the long-term complications of repeated venous access (loss of venous capital, need for an implantable port, thrombosis, infection) [9].

Danazol (Danatrol®) is reserved for men with HAE-C1-INH without cardiovascular or metabolic comorbidity, informed of the available alternatives: it is started at 200 mg/day for 15 days and reduced to the minimum effective dose, ideally 200 mg once or twice weekly or on alternate days, without exceeding 200 mg/day long term and adjusting according to clinical response rather than laboratory tests; tolerance is reassessed annually, and weight gain or metabolic, cardiovascular or hepatic complications require discontinuation [9]. It is contraindicated in pregnancy (it is not a contraceptive and should be stopped as soon as pregnancy is confirmed), with oncological risk (breast, ovary, prostate), with major cardiovascular risk and with previous thrombosis; it interacts with statins, is associated with hepatic adenoma and venous thrombosis, is not advised in children and adolescents and has no indication in HAE-nC1-INH; it may be used for limited periods, such as travel to places with difficult access to attack treatment [9]. Tranexamic acid, off-label, is used at 25 to 75 mg/kg/day in 2 or 3 doses (2 to 3 g/day on average in adults), orally (1 g/10 mL oral ampoules or 500 mg tablets) or IV (0.5 g/5 mL ampoules); it is of little efficacy in HAE-C1-INH and more useful in HAE-nC1-INH with an F12 or PLG variant, and the PNDS allows it in children younger than 12 years without another approved option and in pregnant women with C1-INH deficiency (maximum 3 g/day); it is contraindicated with previous thrombosis, in thrombogenic situations such as the first 6 weeks after delivery and in epilepsy, and requires annual monitoring of liver and renal function and regular ophthalmological examination [9]. High-dose progestogens are no longer proposed as maintenance treatment, because of the risk of meningioma reported by the French medicines agency (ANSM) [9].

The PNDS chooses long-term prophylaxis according to patient profile, as summarised in the table [9].

7.5 Treatment of hereditary angioedema with normal C1-INH

No medicine has been evaluated in a controlled trial specifically devoted to HAE-nC1-INH; evidence is observational and response depends on the gene [1, 37]. The 2025 WAO guidelines report effective treatment with lanadelumab, intravenous C1-INH, garadacimab or berotralstat in some patients, but emphasise that genetic testing is essential for treatment selection and that lanadelumab has shown no significant benefit in patients with negative genetic testing [1]. In CASPIAN, involving 77 adults with non-histaminergic angioedema and normal C1-INH (5 with F12 or PLG variants, 13 with a family history without a variant, and 59 with idiopathic angioedema), lanadelumab had no significant effect in any subgroup [43].

The 2025–2026 European SmPCs for lanadelumab, berotralstat, garadacimab, donidalorsen and sebetralstat include specific warnings: data in HAE-nC1-INH are limited or absent, subtypes with mechanisms outside the kallikrein–kinin system may not respond, genetic testing according to guidelines is recommended, and treatment should be discontinued if there is no response (after 3 months for lanadelumab, berotralstat and garadacimab, and after 4 months for donidalorsen) [43, 53, 64, 66, 69]. In the phase 2 garadacimab trial, two of three patients with HAE-FXII responded (one becoming attack-free) and remained attack-free during extension; a third discontinued because of inefficacy, and only one of three HAE-PLG patients improved [66]. Three HAE-nC1-INH patients without an identified variant had a 76% reduction in attacks with donidalorsen [69]. An observational analysis of 311 adults with HAE-nC1-INH classified without genetic testing suggested similar efficacy for berotralstat [64].

In the French cohort (287 F12 variant carriers, 38 PLG carriers and 1 KNG1 carrier) and the German cohort, icatibant was effective in 100% of treated HAE-PLG patients; in HAE-PLG, mean attack duration with icatibant was 4.3 hours versus 44.7 hours untreated, and with pdC1-INH 31.5 versus 48.2 hours [37, 75]. For prophylaxis, tranexamic acid rendered 66.7% of HAE-PLG and 37.5% of HAE-FXII patients attack-free; all HAE-FXII patients treated with lanadelumab became asymptomatic, compared with 25% of HAE-PLG patients; progestogens alone reduced attacks by 46.3% in HAE-PLG [37, 75]. In HAE-PLG, corticosteroids and antihistamines produced little or no response, and fresh frozen plasma had no effect in two instances of imminent asphyxiation [75]. A US series of 23 patients with normal C1-INH showed improved control with medicines approved for hereditary angioedema [76]. In HAE-FXII, oestrogen avoidance is part of treatment, and low-dose progestogen-only contraceptives are appropriate [1, 37]. In HAE-MYOF, two patients became attack-free with tranexamic acid 1000–1500 mg/day, one after icatibant use [30]. In HAE-CPN1, the four families responded to tranexamic acid 3 g/day, with montelukast 10 mg/day in some patients, and to icatibant or pdC1-INH for severe attacks, without response to quadruple-dose antihistamines [5]. In HAE-HS3ST6 and HAE-MYOF, lanadelumab response was variable [38]. Doses in all these subtypes are extrapolated from HAE-C1-INH because pivotal trials included only types 1 and 2 [62, 65]. Evidence extrapolation must be distinguished from off-label use, which depends on the label wording, age and jurisdiction. When the indication specifies hereditary angioedema without restricting the mechanism, as in US labels for lanadelumab and garadacimab and European SmPCs for lanadelumab, berotralstat, garadacimab, donidalorsen and sebetralstat, HAE-nC1-INH use is within the indication, although efficacy is extrapolated; when the indication is restricted to C1-INH deficiency, as in European SmPCs for icatibant and conestat alfa, HAE-nC1-INH use is off-label [43, 49, 51, 53, 62, 64–66, 69]. The same reasoning applies to children below the approved age in each jurisdiction (for example, icatibant below age 18 years in the United States, but approved from age 2 years in the EU) and to pregnancy, where absence of data in newer medicine labels implies neither contraindication nor authorisation [50–52, 62, 63, 65, 68].

7.6 Children

In children, the strategy is similar to that in adults, with an individualised action plan, trigger avoidance and attention to quality of life; attack treatment must be permanently accessible, including at school and during activities away from home [1]. The 2025 WAO guidelines recommend intravenous pdC1-INH, icatibant or sebetralstat (the latter from 12 years) as first line for attacks; plasma as second line; intravenous pdC1-INH as first line for short-term prophylaxis; and subcutaneous pdC1-INH, lanadelumab, berotralstat, garadacimab or donidalorsen for long-term prophylaxis, according to approved ages, with antifibrinolytics as second line (statements 31 to 36) [1]. The paediatric guideline recommends intravenous pdC1-INH as first line for attacks from birth to 2 years (recommendation 19) and for short-term prophylaxis at all ages (recommendation 31), and early home treatment (recommendations 22 and 23) [11]. The paediatric icatibant dose in table 4 of the 2025 WAO guidelines is 0.4 mg/kg up to 30 mg, consistent with the weight bands of the European SmPC; in the USA icatibant is not approved below 18 years [1, 50, 51]. Physical activity should be encouraged, avoiding unjustified restrictions [11]. The French PNDS insists on coordination with the school: an individualised care plan (projet d'accueil individualisé, PAI) defines the course of action for swelling of the hands or feet (inform the family, no treatment), facial swelling (inform the family and, if they cannot come within one hour, call the emergency medical service; slow SC icatibant as prescribed), moderate abdominal pain (analgesic) or severe pain with vomiting (icatibant), and signs of severity (swelling of the lips or tongue, breathing difficulty, change of voice, drooling), which require immediate icatibant and a call to 15 or 112, without transport delaying the injection [9]. Prevention of recurrent moderate abdominal attacks is considered a priority, because of the risk of recurrent pain with psychological repercussions and school phobia, and therapeutic education and transition programmes should begin at diagnosis, so that the adolescent gains autonomy [9]. In the PNDS paediatric table, Berinert® is used at 20 IU/kg for attacks and before interventions; Cinryze® at 20 IU/kg for attacks and before interventions from 2 years and at 500 IU every 3 to 4 days for prophylaxis from 6 years; icatibant in weight bands from 2 years and 12 kg, with a transfer kit and graduated syringe; lanadelumab between 2 and 12 years by weight and, from 12 years or 40 kg, 300 mg every 2 weeks; and berotralstat at 150 mg daily above 12 years and 40 kg [9].

7.7 Pregnancy, delivery and breastfeeding

Pregnancy may reduce, increase or leave disease activity unchanged, and the pattern in previous pregnancies only partly predicts that in the next [1, 7]. pdC1-INH is the preferred treatment during pregnancy and breastfeeding, both for attacks and prophylaxis [1, 7]. The 2025 WAO guidelines recommend intravenous pdC1-INH as first-line attack treatment (statement 37); icatibant for potentially severe attacks if pdC1-INH is unavailable or fails (statement 38); plasma as third line (statement 39); no short-term prophylaxis for uncomplicated vaginal delivery unless attack frequency is high (statement 40); intravenous pdC1-INH before invasive procedures and caesarean section, preferably with epidural anaesthesia (statement 41); long-term prophylaxis in high-risk pregnant women (statement 42), using subcutaneous or intravenous pdC1-INH as first line, recombinant C1-INH as second line and antifibrinolytics as third line (statements 43 to 45); and hospital delivery with treatment available (statement 46) [1]. Attacks may occur up to 48 hours after delivery, so surveillance for at least 72 hours is recommended [1]. Androgens are formally contraindicated because they cross the placenta [1, 7]. In the Berinert® label, 20 pregnant women received repeated doses up to 3500 IU per attack, without delivery complications or effects on the 34 newborns [44]. Pregnancy data are insufficient for lanadelumab, garadacimab, berotralstat, donidalorsen and sebetralstat; monoclonal antibodies cross the placenta in the third trimester [52, 62, 63, 65, 68]. Breastfeeding is not discouraged; plasma-derived products and tranexamic acid are considered safe, while androgens should be avoided [1]. The first Portuguese cases of subcutaneous pdC1-INH during pregnancy and breastfeeding were described at Hospital de São João (Porto): two 37-year-old women with type 1 HAE, one treated from 21 weeks' gestation with 4000 U (approximately 43.5 U/kg) every 72 hours, subsequently extended to 96 and 120 hours and continued during breastfeeding, and another starting 2000 U (approximately 45 U/kg) twice weekly six months postpartum because of worsening during breastfeeding; both became attack-free without systemic adverse effects [77]. According to the authors, at the time of the report the only pdC1-INH available in Portugal was an intravenous formulation without an approved long-term prophylaxis indication, illustrating that European authorisation does not guarantee availability in each country [77].

The French PNDS recommends joint follow-up with gynaecology and obstetrics throughout life, from puberty, and a preconception consultation and one in early pregnancy with the reference physician and the obstetrician [9]. Because untreated attacks carry a risk of fetal death in utero, the indications for attack treatment and for long-term prophylaxis should be broad; the options in pregnancy are C1-INH concentrate and tranexamic acid, without authorisation for icatibant, lanadelumab or berotralstat [9]. It recommends vaginal delivery with epidural analgesia, without systematic prophylaxis for uncomplicated delivery in an asymptomatic pregnant woman, provided C1-INH concentrate is available in the delivery room; for caesarean section it prefers regional anaesthesia and makes C1-INH prophylaxis systematic; delivery should take place in a maternity unit with an anaesthetist present and concentrate available, with medical monitoring for the first 24 hours [9]. Breastfeeding is not contraindicated, and attacks in breastfeeding women are treated with C1-INH concentrate or with tranexamic acid (the latter only after 6 weeks postpartum) [9]. In medically assisted reproduction, stimulation protocols with the lowest oestradiol concentrations are preferred, combined oestrogen–progestogen preparations are advised against in the cycles preceding stimulation, and C1-INH prophylaxis is extended throughout the process [9].

For contraception, the PNDS indicates progestogen-only pills as first line (desogestrel 75 µg or levonorgestrel 30 µg daily continuously, etonogestrel implant for 3 years), does not use drospirenone alone as first choice because of its more marked antiandrogenic effect, strongly advises against combined oestrogen–progestogen contraceptives and does not contraindicate the copper or levonorgestrel intrauterine device, provided attack treatment is available at insertion [9]. Cyproterone and dienogest, which are antiandrogenic, may aggravate the disease, and high-dose progestogens (chlormadinone, nomegestrol, medrogestone, promegestone) are no longer recommended as HAE treatment, because of the risk of meningioma, which increases with age, cumulative dose and duration of exposure; when prescribed for another indication, they may reduce attacks and require magnetic resonance imaging surveillance according to the recommendations [9]. After menopause, the course of attacks is unpredictable; for climacteric syndrome, progesterone is proposed as first line, and vaginal oestrogens are permitted [9]. In breast cancer, tamoxifen may trigger attacks in a situation of endogenous oestrogen deprivation (postmenopause or on a gonadotrophin-releasing hormone agonist), because it acts as a weak oestrogen agonist, whereas aromatase inhibitors are always possible and mTOR inhibitors are permitted, provided no ACE inhibitor is combined; attenuated androgens and progestogens are advised against in breast and ovarian cancers, and endometrial cancer contraindicates none of them [9].

7.8 Therapies in development

NTLA-2002 (lonvoguran ziclumeran, lonvo-z) is an in vivo CRISPR-Cas9 gene-editing therapy, administered as a single intravenous infusion, that inactivates KLKB1 (the prekallikrein gene) in hepatocytes. In phase 2, involving 27 patients, 25 and 50 mg doses reduced the monthly attack rate by 75% and 77% relative to placebo, and 73% of patients receiving 50 mg were attack-free during weeks 1 to 16; total plasma kallikrein decreased by 86% with 50 mg [78]. In the phase 3 HAELO trial, involving 80 patients aged 16 years and older with HAE-C1-INH, the monthly rate between weeks 5 and 28 was 0.26 with 50 mg versus 2.10 with placebo (87% reduction), without serious or grade 3 or higher adverse events in the treated group [79]. According to the sponsor's announcement of 8 September 2026, 62% of lonvo-z patients versus 11% of placebo patients remained attack-free and without any hereditary angioedema therapy during the six-month assessment period, and all treatment-emergent adverse events were mild or moderate [80]. On the same day, the FDA accepted the Biologics License Application (BLA) for priority review with a target decision date (PDUFA) of 10 March 2027, with no advisory committee meeting planned; in the EU, lonvo-z has PRIME and orphan designation, without an announced authorisation application [80]. Application acceptance is not authorisation: as of October 2026, lonvo-z remains investigational in both jurisdictions, and gene editing neither corrects the SERPING1 variant nor changes transmission risk to offspring [79, 80].

Deucrictibant, an oral B2 receptor antagonist approximately 20 times more potent than icatibant, is being studied in two formulations: an immediate-release capsule for attacks and an extended-release tablet for prophylaxis [1]. In phase 2 RAPIDe-1, 10, 20 and 30 mg doses reduced attack severity at 4 hours relative to placebo; in phase 2 CHAPTER-1, doses of 20 and 40 mg/day reduced attack rates by 79.2% and 84.5% [81, 82]. The sponsor has released topline results for both phase 3 trials, without peer-reviewed publication yet [83]. In RAPIDe-3 (NCT06343779; 134 patients aged 12 years and older, including types 1 and 2 and HAE-nC1-INH, 20 mg immediate-release capsule), median time to onset of relief was 1.28 hours versus more than 12 hours with placebo, time to the end of progression was 17.47 versus 228.67 minutes, and time to complete resolution was 11.95 hours versus more than 24 hours; 83.0% of attacks were treated with a single capsule [84]. Based on this trial, the FDA accepted the New Drug Application (NDA) for the immediate-release formulation for attack treatment in July 2026, with a PDUFA date of 23 April 2027, and the EMA validated the marketing authorisation application in the same month for assessment through the centralised procedure [85]. In CHAPTER-3 (NCT06669754), 85 patients from 21 countries were randomised 2:1 to a 40 mg daily extended-release tablet or placebo for 24 weeks; mean monthly attack rate was 83% lower than placebo (p<0.0001) in the total population, which included HAE-nC1-INH, and 87% lower in the 80 patients with type 1 or 2, without treatment-related serious adverse events; prophylaxis authorisation applications are planned from the first half of 2027 [86]. These are sponsor announcements, distinct from peer-reviewed publication, a Committee for Medicinal Products for Human Use (CHMP) opinion and an authorisation decision; as of October 2026, deucrictibant is not authorised in either jurisdiction [85, 86]. Navenibart, an anti-plasma kallikrein monoclonal antibody with a half-life of approximately 100 days, reduced the monthly attack rate by a mean of 86.3% in phase 1b/2 and is in phase 3 (ALPHA-ORBIT, NCT06842823), with administration every 3 or 6 months [1, 83, 87]. ADX-324, a small interfering RNA with planned six-monthly subcutaneous administration, is in phase 3 (NCT06960213) [1, 83].

7.9 Comparative regulatory status: United States and European Union

In the European Union, the EMA conducts scientific assessment, and a favourable CHMP opinion is usually followed approximately two months later by the European Commission's authorisation decision, the act authorising the medicine; a favourable opinion is not yet authorisation [48]. European or US authorisation also does not guarantee marketing, reimbursement or access in each country: availability in Portugal depends on marketing by the authorisation holder and INFARMED funding assessment, while in Brazil it depends on ANVISA registration and incorporation into the Unified Health System following CONITEC assessment [48, 77]. The table summarises status on 4 October 2026, distinguishing initial authorisation dates from subsequent extensions.

7.10 French protocol (PNDS 2024): divergences and organisation of access

The French PNDS agrees with the other guidelines on principles (early treatment of attacks, two doses at home, self-administration, prophylaxis before procedures, pdC1-INH in pregnancy), but diverges on several specific points of diagnosis, dose and interval.

In France, icatibant and C1-INH concentrates are hospital-prescribed and dispensed by the hospital pharmacy to outpatients under the rétrocession scheme; lanadelumab and berotralstat are hospital-prescribed but dispensed in community pharmacies; tranexamic acid (Exacyl®, Spotof®) and danazol (Danatrol®) belong to List I and are available in community pharmacies [9]. Conestat alfa (Ruconest®) ceased to be marketed in France on 9 May 2022 and the subcutaneous route of C1-INH is not available, further examples that European authorisation does not guarantee national availability [9].

8. Reproductive Options and Family Counselling

HAE-C1-INH is inherited in an autosomal dominant pattern, with a 50% risk for each child of an affected parent, regardless of sex [1]. Because up to 25% of cases are de novo, the risk to siblings of a proband with a de novo variant is low but not zero because of gonadal mosaicism, documented in six probands in the SERPING1 mutation update; more than one affected child of unaffected parents should raise this possibility and warrants genetic testing [1, 2]. High penetrance (approximately 95%) and highly variable expressivity, even within a family, prevent severity prediction from genotype, and this uncertainty should be explained [1].

In HAE-nC1-INH, counselling must incorporate incomplete penetrance and the influence of sex and oestrogens: in HAE-FXII, most male carriers remain asymptomatic, and in a Spanish cohort 72% of male and 29% of female carriers had no symptoms [36]. Transmission data suggest sex-dependent segregation distortion, with fewer male carriers than expected [31]. In recessively inherited HAE-CPN1, recurrence risk for siblings of an affected individual is 25% [5]. For subtypes described in one or a few families (ANGPT1, KNG1, MYOF, HS3ST6, DAB2IP), gene–disease evidence is limited, and family risks should be communicated with this qualification [1, 27]. In France, genetic counselling takes place in a consultation with the reference physician or a clinical geneticist and includes information on autosomal dominant transmission and incomplete penetrance and construction of the pedigree; informing relatives is a legal obligation (decree no. 2013-527), given the potential severity of attacks and the existence of treatments, and patient and physician agree whether the patient or the physician will pass on the information [9]. Molecular screening covers symptomatic and asymptomatic relatives, including minors, and presymptomatic tests in minors are prescribed or results delivered in a clinical genetics clinic [9].

Invasive prenatal diagnosis and preimplantation genetic diagnosis are possible when the familial variant is identified, and the 2025 WAO guidelines recommend SERPING1 testing in families considering these options (statement 7) [1]. Requests are uncommon, and decisions should account for variability in penetrance and expressivity and the efficacy of current and developing therapies [1]. Invasive procedures during pregnancy (chorionic villus sampling, amniocentesis, surgical termination) warrant short-term prophylaxis with pdC1-INH [1, 7]. Neonatal diagnosis can use genetic testing of cord blood, peripheral blood or a buccal swab when the familial variant is known, since complement is unreliable in the first year [11]. The French PNDS considers that there is no indication for prenatal screening in France, a position that differs from the openness of the 2025 WAO guidelines to individual requests for prenatal or preimplantation diagnosis [1, 9].

Cascade screening of first- and second-degree relatives is recommended in all forms and allows attack treatment to be prescribed before the first attack, education about laryngeal warning signs, and avoidance of predictable triggers such as combined oestrogen–progestogen contraception and ACE inhibitors [1, 7]. The paediatric guideline emphasises that family screening programmes with culturally appropriate education increase detection rates [11]. Progestogen-only contraception is recommended in affected women; this is particularly relevant in HAE-FXII, given oestrogen dependence reported in 49% of French patients [1, 37]. Patient organisations, with Hereditary Angioedema International (HAEi) as the umbrella organisation, are integral to family support (statement 47) [1]. In Europe, the European Reference Network for Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) includes hereditary angioedema in its patient journeys and can support referral and follow-up organisation, while care must still be adapted to each country's medicines, services and funding mechanisms [10]. In France, care is organised by the reference centre for kinin-mediated angioedema (CREAK), accredited in 2006 and renewed in 2011, 2016 and 2023, with its coordinating site at CHU Grenoble Alpes, constituent sites in Paris (Hôpital Saint-Antoine) and Lille and 21 competence centres, including Réunion and Martinique, integrated into the MaRIH health network [9]. CREAK maintains a permanent emergency telephone line, reserved for health professionals and for patients followed at one of its centres, and the reference laboratory for immunology and molecular genetics is located at CHU Grenoble Alpes [9]. The disease is covered at 100% as a long-term condition (ALD 7, severe primary immune deficiency), with a model application form annexed to the protocol; the national therapeutic education programme Éducréak, approved by several regional health agencies since 2012 and disseminated since 2021 through a multicentre teaching kit, is also available remotely; and the patient association AMSAO took part in drafting the protocol [9].

9. Special Considerations: Population Diversity and Epidemiology

Global hereditary angioedema prevalence is estimated at 1:50,000 to 1:100,000, with approximately 1:67,000 for HAE-C1-INH, corresponding to more than 100,000 patients worldwide and suggesting substantial underdiagnosis [1]. The systematic review of epidemiological studies found HAE-C1-INH prevalence of 1.1 to 1.6 per 100,000, but only for North America and Europe, and excluded HAE-nC1-INH because defined criteria were lacking [8]. Orphanet places type 1 in the 1 to 9 per 100,000 category in Europe and considers the prevalence of type 2 and forms with normal C1-INH unknown [6]. Differences in C1-INH deficiency incidence between ethnic groups have not been confirmed [1]. The 2025 WAO guidelines present geographical distribution of reported patients as absolute numbers rather than prevalence because of substantial underdiagnosis bias, and list national guidelines from Argentina, Brazil, Canada, France, Japan, Italy, Slovakia, Spain and the United States [1].

Brazil has the most extensive Latin American data. A study of 50 centres characterised 425 patients with hereditary angioedema (125 with C1-INH deficiency, 180 with F12 variants and 120 of unknown cause) and 92 with acquired angioedema; 31 SERPING1 variants, two F12 variants and two ANGPT1 variants of uncertain significance were identified, and molecular diagnosis was decisive in 34 patients without a family history and in 39% of those with inconsistent biochemical results. Median diagnostic delay was 10 years, and only 10% used specific medication for attacks [88]. The Brazilian multicentre registry, involving 820 patients, reported 68.8% women, 72.4% HAE-C1-INH and 19.4% HAE-FXII, symptom onset at 11.2 years in HAE-C1-INH and 19.4 years in HAE-FXII, and mean diagnostic delay of 1.8 years in those younger than 18 years versus 14.5 years in adults; 52.8% received first-line attack treatment, only 4.8% first-line prophylaxis, and 52% used androgens, with adverse effects in 34.8% [89]. The high proportion of HAE-FXII in Brazil contrasts with other regions and reflects genetic testing availability [89]. In a Brazilian series of 42 HAE-FXII families (195 individuals studied, 134 carriers), 16 of 30 male carriers (53.3%) were symptomatic and only 68.6% of women reported oestrogen influence, fewer than in European series; male sex and absence of hormonal worsening should therefore not deter F12 testing [90]. In Argentina, a national registry of 538 patients reported 76% C1-INH deficiency, 7% HAE-FXII and seven patients with DAB2IP p.Asp239Asn, median onset at 12 years, median diagnostic delay of 10 years, attack treatment prescribed in 88% (icatibant in 76.9%) and prophylaxis in 28.3% (lanadelumab in 58.5% of these) [39].

In Europe, Spain is recognised as one of the regions with the greatest concentration of HAE-FXII in Western Europe, and p.Thr328Lys has been described in families from Spain, France, Germany, Turkey, Brazil and Australia [27, 36]. HAE-PLG has chiefly been described in German and French families, and HAE-ANGPT1 and HAE-MYOF in Italian and Russian families [20, 21, 30, 37]. In Asia, lower abdominal attack frequency has been described in patients from China and Taiwan, and Chinese series have expanded the variant spectrum of MYOF, KNG1 and HS3ST6 [1, 38]. In Spain, a national registry of 444 HAE-C1-INH patients estimated a minimum prevalence of 1.09 per 100,000 inhabitants, with 13.7% of carriers always asymptomatic and mean diagnostic delay of 13.1 years; this is a minimum estimate dependent on case identification [91]. In France, the PNDS estimates approximately 1500 patients with HAE-C1-INH, based on an epidemiological study in Paris extrapolated to the national territory, which is an estimate and not a population-based count; type 1 accounts for approximately 90% and type 2 for approximately 10%, approximately 25% of cases are de novo, mean age at first attack lies between 11 and 13 years (from less than 1 year to more than 40), half of patients have their first attack before 10 years of age, and diagnostic delay may reach approximately 10 years [9]. The concentration in France of families with the F12 variant of North African origin is consistent with the founder effect of the p.Thr328Lys variant [9, 37].

In Portugal, the series of 126 patients followed for 24 years in the Immunoallergology Department of Hospital de Santa Maria (Centro Hospitalar Universitário Lisboa Norte) is the largest published: 45.2% had HAE-C1-INH type 2, far above the approximately 15% described in other populations, reflecting the centre's family composition rather than national distribution; 67.4% developed symptoms before adulthood (mean age 12.6 years), diagnostic delay was long, particularly without a family history (mean 20.7 years), and stress was the most frequently reported trigger [92]. During their course, 95.0% had skin symptoms, 80.7% gastrointestinal symptoms and 50.4% respiratory symptoms; 22 patients (17.5%) had undergone abdominal surgery and 8 (6.3%) intubation or tracheotomy for laryngeal oedema; most received long-term prophylaxis, chiefly attenuated androgens (62.7%) [92]. These figures describe a reference centre's experience and cannot be converted into prevalence or population risk [92]. A Madeira family with type 1 HAE and the novel SERPING1 variant NM_000062.3:c.336_337insC p.(Ser113LeufsTer20), identified with support from a variant prioritisation tool, has also been described [93]. The sources consulted identified no population-based prevalence studies for Portugal, Portuguese-speaking African countries or most countries in Africa, the Middle East and Asia, and HAE-nC1-INH frequency is unknown in all regions [6, 8].

Access inequalities are central to the 2025 WAO guidelines: functional C1-INH assays and genetic testing are rare in low- and middle-income countries, newer medicines are expensive, and prophylaxis is not standard care even in high-income countries [1]. Proposed strategies include safe, less effective alternatives (plasma-derived products, tranexamic acid, low-dose androgens), local plasma fractionation, off-patent medicines (such as generic icatibant), international access programmes, national registries and telemedicine [1]. Pivotal trials predominantly included patients of European ancestry (for example, 86% in VANGUARD, 91% in OASIS-HAE and 84% in KONFIDENT), limiting generalisability of efficacy and safety data [52, 65, 68].

10. Illustrative Clinical Case

10.1 De novo type 1 hereditary angioedema with an exclusively gastrointestinal presentation

A 28-year-old woman had experienced recurrent, self-limited abdominal pain for more than 6 years, without current or previous skin or upper airway oedema and without a family history [34]. During a severe attack, abdominal CT angiography showed jejunal wall oedema and ascites, with marked elevations of D-dimer (>20 mg/L FEU) and fibrin degradation products (>120 mg/L), mimicking mesenteric ischaemia [34]. Retrospective record review identified persistent C4 consumption (0.03–0.05 g/L). Functional C1-INH was below 7.0% and antigenic C1-INH 6.81 μg/mL, confirming HAE-C1-INH type 1 [34]. Exome sequencing identified the nonsense SERPING1 variant NM_000062.3:c.990C>A, p.(Tyr330Ter), absent in both biological parents and classified as pathogenic (PVS1, PS2) [34]. An abdominal attack in May 2025 resolved rapidly after icatibant, and lanadelumab prophylaxis was initiated through shared decision-making, without attacks or adverse effects between June 2025 and June 2026 [34].

The case illustrates several points of this article: absence of a family history does not exclude diagnosis (up to 25% of cases are de novo); unexplained recurrent abdominal pain with oedematous bowel loops and ascites on imaging should prompt C4 and C1-INH measurement; persistently low C4, already documented in the record, enabled diagnostic reassessment; and confirmation of de novo status through parental testing has counselling implications (low sibling risk, 50% risk to the patient's offspring) [1, 34].

10.2 Type 2 hereditary angioedema and family screening

A 36-year-old woman had recurrent facial oedema and dysphagia unresponsive to usual treatment. C4 and C1-INH function were reduced, with a normal antigenic concentration, consistent with HAE-C1-INH type 2 [26]. Exome sequencing identified the pathogenic variant NM_000062.3:c.1397G>A p.(Arg466His), in SERPING1, in the protein's reactive centre. Her three daughters carried the same variant, were asymptomatic or mildly affected, and received counselling and emergency medication. The patient received icatibant for attacks and lanadelumab prophylaxis, remaining attack-free during 7 months of follow-up [26]. The case illustrates the value of cascade screening and prescribing attack treatment to asymptomatic carriers, as recommended by guidelines [1, 7].

10.3 Type 1 hereditary angioedema with exclusively abdominal attacks and a novel SERPING1 variant

In 2026, Matsuura and colleagues described a 30-year-old woman with 10 years of recurrent abdominal pain and unexplained vomiting, without skin oedema [94]. Absence of a clear family history initially suggested acquired angioedema, but young onset prompted genetic testing; lower gastrointestinal endoscopy during an attack showed marked terminal ileal oedema, and laboratory tests revealed low C4 and markedly reduced C1-INH activity [94]. The novel heterozygous variant NM_000062.3:c.852dup p.(Thr285TyrfsTer20) (published as c.852dupT), in SERPING1, established the diagnosis of type 1 HAE [94]. Figures in the original article document imaging findings, endoscopic ileal oedema and molecular investigation (published under CC BY-NC 4.0; not reproduced). The authors advocate genetic confirmation in all cases, a position contrary to guidelines, which define HAE-C1-INH diagnosis as biochemical and reserve genetic testing for selected situations; likewise, endoscopy during an attack was useful in this report but is not routine, and non-invasive imaging with complement measurement is usually sufficient [1, 7, 94]. As in case 10.1, the exclusively gastrointestinal presentation and absence of a family history delayed diagnosis by a decade [34, 94].

11. Prognosis and Long-Term Follow-up

Prognosis depends chiefly on diagnosis and treatment access. Deaths from asphyxiation are concentrated in undiagnosed patients: in the German cohort, 63 of 70 asphyxiation deaths occurred before diagnosis, with a mean loss of approximately 31 years of life [13]. Diagnosis, education and available attack treatment substantially reduce death risk, and patients well controlled on prophylaxis may remain symptom-free for years, even for more than a decade [1]. Disease burden includes school and work absence, anxiety and depression, more frequent in patients with frequent attacks, more than four annual emergency visits in many patients, and unnecessary surgery and investigations [1].

Follow-up should be provided at a centre experienced in hereditary angioedema and includes reassessment of the long-term prophylaxis indication at every visit, at least annually, using a “treat-to-target” strategy; recording attacks and treatments (symptom diary, AAS); periodic assessment of control and quality of life with AECT and AE-QoL; ensuring that patients have unexpired medication for at least two attacks and are trained in self-administration; review of the written action plan and emergency card; and planning short-term prophylaxis before procedures [1, 7]. Patients receiving androgens require six-monthly surveillance (complete blood count, biochemistry, lipid profile, urine and blood pressure) and annual liver ultrasound [1]. For patients receiving garadacimab or lanadelumab, the laboratory should be informed that aPTT may be prolonged through assay interference [43, 66]. For berotralstat, dose increases should be avoided because of QTc prolongation risk, and medicine interactions reviewed [63]. For sebetralstat, interactions with CYP3A4 inhibitors and inducers determine the dose [52, 53].

In children, transition to adult care, information for schools and caregivers, and recognition that severity may increase at puberty form part of follow-up [1, 11]. In women, contraception, pregnancy and menopause (with hormone therapy) require planning, particularly in HAE-FXII [1, 37]. Reference centres, national and international registries, telemedicine and patient organisations are associated with earlier treatment, less emergency care use and greater equity [1].

The French PNDS details the psychosocial impact: anxiety associated with the risk of asphyxia is strong, abdominal attacks are experienced as very painful and some patients have developed opioid dependence, peripheral attacks last at least 2 days and may prevent daily or work activities, absenteeism is frequent and signs of depression have been described in 42% of patients, so psychological support is often useful [9]. Therapeutic education begins at the first visit and includes handing over the care and emergency card, recognition of severe attacks and triggers, use of prophylaxis, the rule of never remaining alone after self-administration, family screening and self-administration training with the person who will give the injection (at least 5 sessions for the intravenous route) [9]. The first visit to a reference or competence centre confirms the diagnosis, explains the disease and treatments, starts the family enquiry, hands over the card and the attack diary, deals with the application for long-term condition coverage, addresses contraception and, in children, the school PAI [9]. At subsequent visits the following are recorded: clinical examination, activity (attack diary, AAS-28, number of severe attacks treated or untreated, emergency department visits, hospital and intensive care admissions), quality of life (AE-QoL), control (AECT over the last 4 weeks or the last 3 months), days of absenteeism, psychological impact, adverse effects and laboratory monitoring of maintenance treatments, and it is confirmed that the patient has at least two treatments for severe attacks and that they and those around them know how to administer them [9].

The table brings together the monitoring intervals of the guidelines and labels.

12. Summary and Final Considerations

Hereditary angioedema is a group of genetic disorders characterised by recurrent skin, intestinal and upper airway oedema without wheals, mediated in most forms by bradykinin and, in a subgroup with normal C1-INH, possibly by the VEGF pathway [1]. The most frequent form results from heterozygous SERPING1 variants causing quantitative (type 1) or functional (type 2) C1-INH deficiency, now grouped as HAE-C1-INH; forms with normal C1-INH are associated with F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1 and DAB2IP variants or remain of unidentified cause [1].

The essential points for clinical practice are as follows. Laryngeal oedema remains a cause of death, particularly before diagnosis, and the first laryngeal attack may be fatal [13]. Absence of a family history does not exclude disease given the frequency of de novo cases [1]. HAE-C1-INH diagnosis is biochemical (C1-INH function as the preferred initial test, with antigen and C4 as support), requires repeat confirmation when results are discordant, and has pitfalls in the first year of life and pregnancy; HAE-nC1-INH diagnosis is genetic [1, 7]. C1q and anti-C1-INH antibodies distinguish acquired angioedema [1]. Every diagnosed patient, even if asymptomatic, should have enough attack treatment for at least two attacks and know how to self-administer it; first-line options are intravenous C1-INH, icatibant and oral sebetralstat [1]. Long-term prophylaxis should be discussed at every visit, aiming for complete control; first-line options are subcutaneous pdC1-INH, lanadelumab, berotralstat, garadacimab and donidalorsen, while androgens and tranexamic acid are now second line [1]. Doses differ between regulatory agencies for some medicines (sebetralstat, paediatric icatibant, berotralstat in hepatic impairment) and should follow the local label [50–53, 63, 64]. In HAE-nC1-INH, response depends on the gene, and European SmPCs recommend genetic testing and discontinuation without response [43, 66]. During pregnancy, pdC1-INH is the treatment of choice and androgens are contraindicated [1]. Cascade family screening, genetic counselling and structured education are part of treatment [1]. The 2024 French PNDS converges with the international guidelines on principles, but requires repeated antigenic and functional measurement and SERPING1 testing in each new family, sets thresholds for long-term prophylaxis, accepts tranexamic acid in non-severe attacks and uses 20 IU/kg for all C1-INH concentrates; these divergences should be known when applying the protocol outside France [9].

Single-dose lonvo-z gene editing demonstrated an 87% reduction in attacks in phase 3, with an FDA decision expected in March 2027; oral deucrictibant has positive phase 3 topline results for attack treatment (RAPIDe-3) and prophylaxis (CHAPTER-3), with an FDA decision on the attack formulation expected in April 2027; navenibart and ADX-324 are in phase 3 [79, 80, 83–86]. None is authorised as of October 2026, and sponsor-reported results do not equal peer-reviewed publication or authorisation. Relevant gaps remain in population-based epidemiology outside Europe and North America, including Portugal (with hospital series but no prevalence studies) and Africa; controlled evidence in HAE with normal C1-INH; gene–disease validation of subtypes described in few families; and equitable diagnostic and treatment access in low- and middle-income countries [1, 8].

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