Hereditary angioedema presenting as refractory urticaria: a case report

Bradykinin and the Pathogenesis of Hereditary Angioedema

Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1-INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert®, CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE.

Management of hereditary angioedema with C1-inhibitor concentrate during two successive pregnancies

Hereditary angioedema: An orphan but an original disease?

Complex analysis of the national Hereditary angioedema cohort in Slovakia – Identification of 12 novel variants in SERPING1 gene

HEREDITARY ANGIOEDEMA C1-INH REPLACEMENT THERAPY AND COEXISTING AUTOIMMUNE DISORDERS: FINDINGS FROM A CLAIMS DATABASE

The molecular genetic basis of C1 inhibitor (C1 INH) deficiency in a patient with type I hereditary angioneurotic edema was studied. This patient was found to have an abnormally short C1 INH mRNA together with a normal message. Restriction fragment length polymorphism of the C1 INH gene was detected by Southern blot analysis of the patient's DNA after digestion with Pst I or Sac I, and hybridization with a full-length C1 INH cDNA. Hybridization of the same blot with three different fragments of the full-length cDNA suggested that exon VII and portions of both flanking introns were deleted in the C1 INH gene. Northern blot analysis of RNA from cultured monocytes, using a probe corresponding to exon VII, also indicated that the abnormal C1 INH mRNA had a deletion of these nucleotides. To confirm the hypothesis that the short C1 INH mRNA contained a deletion, the involved segment of the patient's C1 INH mRNA was amplified using the polymerase chain reaction (PCR). PCR amplification yielded two C1 INH DNA fragments of different lengths (380 and 160 bp). Southern blot and sequence analysis of both DNA fragments clearly revealed that the smaller 160-bp DNA was derived from the abnormal message and had a deletion of nucleotides corresponding to exon VII.

Rationale:Hereditary angioedema (HAE) is a rare genetic disorder caused by C1 esterase inhibitor (C1-INH) deficiency or dysfunction. Presentation with isolated abdominal pain is uncommon, often leading to diagnostic delays and inadequate pain management. Effective pain control is essential to improve patient comfort and prevent complications.Patient concerns:A 21-year-old male with type II HAE presented exclusively with recurrent severe abdominal pain and experienced a transient loss of consciousness attributed to a pain-induced vagal reflex.Diagnoses:Diagnosis of type II HAE was confirmed based on clinical presentation, laboratory findings of C1-INH dysfunction, and exclusion of other causes of abdominal pain.Interventions:The patient received multidisciplinary care including symptom-based nursing, targeted pharmacological therapy with lanadelumab, psychological support, and nutritional management.Outcomes:Following lanadelumab administration, the patient’s abdominal pain improved significantly within 2 hours and completely resolved within 8 hours. Symptom relief was sustained at 3-month follow-up with no recurrence.Lessons:This case underscores the importance of early recognition of HAE presenting solely with abdominal pain and demonstrates that multidisciplinary, targeted pain management can lead to rapid and sustained symptom relief. Awareness of such atypical presentations is critical for optimizing outcomes in HAE patients.

Missense Mutations in the Proline-Rich Region of Coagulation Factor XII in Hereditary and Idiopathic Angioedema.

要旨 症例は51歳の女性。救急搬送前日より口唇や口腔内の腫脹を自覚。当日は朝から顔面・頸部の腫脹が続き，窒息様の仕草の後に倒れたため救急要請となった。救急隊到着時，家族がCPR実施中であり，CPAを確認。波形はPEA，徐脈であった。当院ドクターカー医師が到着し，喉頭展開すると咽喉頭浮腫による気道閉塞を認めた。声帯は可視できなかったが急峻なJ型に挿管チューブを形成し，経口気管挿管を試みた。声門と思われる位置で抵抗を感じたが挿管に成功した。自己心拍再開し当院搬送となった。気管支鏡検査で喉頭蓋・声門周囲の浮腫は著明であったが感染を疑う所見は乏しく，以前から誘因なく顔が腫れることがあったという既往と同様の症状を肉親も有するという家族歴より遺伝性血管性浮腫（HAE）を疑い検査を行ったところ，C4 1.3mg/dL, C1–INH活性 25%以下と共に低値であった。血管浮腫情報センター（CREATE）に遺伝子解析を依頼したところ，遺伝子の変異を認めHAEと診断された。集中治療管理を継続したが残念ながら脳蘇生が得られず死亡退院となった。HAEは未だ一般の認知度が低く迅速診断法がないこと, C1–INH製剤を常備する医療機関が限られていることなど課題も多い。しかし，早期の診断と適切な気道管理がなされれば血縁家族の罹患発見にも繋がり，心停止は回避可能な疾患である。

Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed.

The possibility of simultaneous measurement of the classical pathway (CP), mannan-binding lectin (MBL)--lectin pathway (LP) and alternative pathway (AP) of complement activation by the recently developed Wielisa method allowed us to investigate the in vivo significance of the C1-inhibitor (C1INH) in three complement activation pathways. Functional activity of the CP, LP and AP were measured in the sera of 68 adult patients with hereditary angioedema (HAE) and 64 healthy controls. In addition, the level of C1q, MBL, MBL-associated serine protease-2 (MASP-2), C4-, C3- and C1INH was measured by standard laboratory methods. MBL-2 genotypes were determined by polymerase chain reaction. Besides the complement alterations (low CP and C1INH activity, low C4-, C1INH concentrations), which characterize HAE, the level of MASP-2 was also lower (P = 0.0001) in patients compared with controls. Depressed LP activity was found in patients compared with controls (P = 0.0008) in homozygous carriers of the normal MBL genotype (A/A), but not in carriers of variant genotypes (A/O, O/O). Activity of CP correlated with LP in patients (Spearman's r = 0.64; P < 0.0001), but no significant correlation was found in the control group and no correlation with AP was observed. In contrast, the activity of CP and AP correlated (Spearman's r = 0.47; P < 0.0001) in healthy controls, but there was no significant correlation in the HAE patients. We conclude that the activation of LP might also occur in subjects with C1INH deficiency, which is reflected by the low MASP-2 and C4 levels.

Hereditary Angioedema with Normal C1 Inhibitor: Clinical Symptoms and Course

Angioedema is nonpitting swelling that involves the deeper subcutaneous and submucosal layers of tissue. Angioedema can be classified as histaminergic, bradykinin mediated, or idiopathic in etiology. Bradykinin-mediated angioedema presents without urticaria, whereas histaminergic angioedema is usually associated with urticaria (i.e., chronic spontaneous urticaria and angioedema) but manifests with isolated angioedema in ∼20% of patients and clinically overlaps with idiopathic angioedema. Bradykinin-mediated angioedema most commonly occurs in hereditary angioedema (HAE) with or without C1-esterase inhibitor (C1-INH) (HAE-C1INH) deficiency, acquired C1-INH deficiency, and angiotensin-converting enzyme (ACE) inhibitor angioedema. HAE is a life-threatening genetic autosomal dominant disorder most commonly due to a mutation in the serpin family G member 1 (SERPING1) gene, which leads to a deficiency in C1-INH, although multiple new genetic mutations have also been described in HAE with normal C1-INH (HAE-nl-C1INH) level. Clinically, patients have edema that can lead to life-threatening laryngeal edema and asphyxiation. HAE-nl-C1INH describes patients with similar symptoms to those with HAE-C1INH deficiency but have normal C1-INH function and are distinguished by various genetic mutations and a family history of angioedema. Acquired C1-INH deficiency also mimics HAE with symptoms but is due to circulating anti-idiotypic antibodies, leading to either C1-INH consumption or inactivation. Patients are often diagnosed with underlying malignant, lymphoproliferative, or autoimmune disorders. ACE-inhibitor angioedema classically presents with facial, tongue, and oral cavity swelling not associated with pruritus accompanied by normal laboratory studies. Treatment involves stopping the ACE inhibitor though recurrence can occur for a few weeks to months after discontinuation. Idiopathic angioedema is the largest category and is diagnosed when patients experience angioedema without an identifiable etiology with nl-C1INH function and no family history of angioedema. Idiopathic angioedema is further characterized into histaminergic or nonhistaminergic angioedema, depending on the response to high-dose antihistamines. Given the considerable impact of angioedema, physicians and patients must collaborate to craft personalized management strategies. For those with HAE, short- and long-term prophylaxis and on-demand therapy must be considered.

A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor