Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of localized edema caused by a deficiency or dysfunction of C1 inhibitor (C1-INH). This case report presents the clinical features, diagnostic evaluation, and management of a 23-year-old man with HAE. We discuss the challenges of diagnosing and treating this condition, emphasizing the importance of early recognition and appropriate therapeutic interventions.

Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.

Hereditary angioedema (HAE) encompasses a group of diseases characterized by recurrent, genetically mediated angioedema associated with increased vascular permeability primarily due to bradykinin. The disease poses diagnostic challenges, leading to underdiagnosis and delayed therapy. Severe manifestations include laryngeal and intestinal angioedema, contributing to significant morbidity and mortality. If left undiagnosed, the estimated mortality rate of the disease ranges from 25% to 40% due to asphyxiation caused by laryngeal angioedema. There is a pressing need to enhance awareness of hereditary angioedema and its warning signs. The acronym \"H4AE\" may facilitate the memorization of these signs. This study comprehensively reviews clinical, laboratory, and physiopathological features of documented HAE subtypes. The study advocates for an improved HAE classification based on endotypes, building on the knowledge of angioedema pathophysiology. The proposed endotype classification of HAE offers a clear and applicable framework, encouraging advancements in disease understanding and classification.

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic disorder caused by pathogenic variants in the SERPING1 gene and characterised by swelling and a highly variable clinical phenotype. We aimed to identify novel modifying genetic factors predisposing to the clinical symptoms. We performed whole exome sequencing (WES) and comprehensive bioinformatic analysis in symptomatic and asymptomatic (three duos) family members with HAE-C1-INH. Selected variants identified using WES (present in all asymptomatic and absent in symptomatic patients) were determined using Sanger sequencing. We included 88 clinically well-characterised HAE-C1-INH patients from south-eastern Europe (nine asymptomatic) from 42 unrelated families. We identified 39 variants in 23 genes (ANKRD36C, ARGFX, CC2D2B, IL5RA, IRF2BP2, LGR6, MRPL45, MUC3A, NPIPA1, NRG1, OR5M1, OR5M3, OR5M10, OR8U3, PLCL1, PRSS3, PSKH2, PTPRA, RTP4, SEZ6, SLC25A5, VWA3A, and ZNF790). We selected variants in CC2D2B and PLCL1, which were analysed using Sanger sequencing in the entire group of HAE-C1-INH. We found significant differences in the frequencies of the CC2D2B c.190A>G (rs17383738) variant between symptomatic and asymptomatic patients, where heterozygotes were more common in asymptomatic HAE-C1-INH patients in comparison to symptomatic patients (55 % vs 23%; P = 0.049, OR = 4.24, 95% CI 1.07-14.69). Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH. We further demonstrated, in a large cohort, the importance of the CC2D2B gene as a disease-modifying factor. Based on linkage disequilibrium analysis, the CCNJ and ZNF518A genes might also be involved in the clinical variability of HAE-C1-INH.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Hereditary angioedema (HAE) is a rare genetic disease. It is characterized by recurrent attacks of angioedema. Evidence to what extent it affects patient functioning is limited in the pediatric population. We aimed to determine the clinical characteristics and management of Polish children with HAE and to measure the health-related quality of life (HRQoL) of these patients. This cross-sectional study was conducted among 21 pediatric patients and their caregivers, as well as 21 respective controls randomly selected from the general population. During routine follow-up visits, standardized pediatric quality of life questionnaires (PedsQLTM 4.0) were administered to all caregivers and adolescents (≥13 years). Caregivers also completed a structured medical interview regarding the clinical characteristics and treatment of children with HAE during the previous six months. During this period, 57% of patients had low (group I), 24% moderate (group II), and 19% high (group III) HAE activity, corresponding to ≥10 attacks per 6 months. None of the patients received long-term prophylaxis. The children in group III had a lower HRQoL than other groups and controls on all dimensions of the PedsQLTM 4.0. The lowest scores in all groups were observed in the emotional functioning domain. Our data demonstrate that the burden of HAE on the quality of life of pediatric patients and their families encompasses a wide range of daily functioning.

Hereditary angioedema (HAE) and idiopathic nonhistaminergic angioedema (INHA) are ultra-rare diseases whose natural histories and comorbidities are incompletely understood.
To develop a national patient-centric registry to address these deficiencies in our knowledge and improve our ability to assess the real-world impact of therapeutic interventions.
Data from members of the US HAE Association were collected into an online registry between 2009 and April 7, 2021. Cohorts were categorized by reported physician diagnosis. Patient reported data were collected using a series of questionnaires. Demographic, natural history, and family history outcomes of the HAE due to C1 inhibitor deficiency (HAE-C1INH) participants were compared with those of the combined HAE with normal C1 inhibitor (HAE-nl-C1INH) plus INHA group. The prevalence of comorbid conditions in the HAE-C1INH group was compared with the general US population.
A total of 485 HAE-C1INH, 26 HAE-nl-C1INH, and 70 INHA participants were included in the analysis. Delay to diagnosis was shorter in HAE-C1INH (5 vs 11 years), but both had decreasing delays over time. Differences in attack frequency and location were found between the groups. Morbidity surrogates including emergency department visits, hospitalizations, unnecessary abdominal surgeries, and intubations were strikingly high as was mortality with 36.9% of HAE-C1INH and 15.4% of HAE-nl-C1INH participants reporting family members who died from a HAE attack. Females with HAE-C1INH had a significant increase in the prevalence of depression, sleep disorders, kidney disease, anemia, and hepatitis. Cardiovascular comorbidities were significantly reduced in the HAE-C1INH group.
The US HAEA Scientific Registry provides a mechanism to enhance our knowledge of HAE and INHA.

Hereditary angioedema (HAE) is a severe and disabling condition characterized by recurrent episodes of subcutaneous or mucosal swelling in the skin and respiratory and gastrointestinal tracts. HAE due to C1-esterase inhibitor deficiency (C1-INH-HAE) is the most prevalent subtype. The present Iberian study compared C1-INH-HAE treatment guidelines published between 2010 and 2022 to identify the main differences in therapeutic approaches for on-demand treatment and short- and long-term prophylaxis (LTP). HAE guidelines evolved with the availability of new treatments and with a change in the management paradigm towards an individualized, patient-centered approach, where quality of life (QOL) is central. A parallel trend was observed towards increasingly frequent home-based treatment, which potentially facilitates timely interventions, provides greater flexibility and convenience, and is associated with increased QOL, enabling patients to lead more normal lives. Most innovations over the years were made for LTP, together with the advent of new therapies and awareness of patients\' needs. Several prophylactic therapies with a high level of evidence became available, although formal head-to-head comparisons are lacking. The treatment goals became more ambitious, ranging from a reduction in the frequency, severity, and duration of attacks to achieving total disease control and normalization of patients\' lives. The document also addresses relevant items such as changes in terminology (eg, the introduction of designations as \"first-line\") and the introduction of patient-reported outcome measures to assess patients\' perceptions of their self-experienced QOL and well-being. Unmet needs in the management of C1-INH-HAE are identified.

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