Hereditary angioedema with recurrent abdominal pain in a patient with a novel SERPING1 gene mutation: A case report

Abstract

BACKGROUND

Hereditary angioedema (HAE) is a rare, potentially fatal disorder that may present solely with non-specific gastrointestinal symptoms.

CASE SUMMARY

We report a 30-year-old woman with a 10-year history of recurrent, unexplained abdominal pain and vomiting, without any cutaneous edema. The initial presentation suggested acquired angioedema because of the lack of a clear family history. However, the early age of onset prompted genetic testing. Lower endoscopy performed during an acute attack provided crucial evidence, revealing marked edema of the terminal ileum. Laboratory tests demonstrated low complement C4 levels and severely reduced C1 esterase inhibitor activity. Genetic analysis revealed of a novel heterozygous frameshift mutation in SERPING1 (p.Thr285Tyrfs*20, c.852dupT), establishing the diagnosis of HAE type 1.

CONCLUSION

HAE can be fatal from laryngeal edema and intestinal involvement and should be considered in patients with recurrent abdominal pain.

Key Words: C1 inhibitor; Complement C4; SERPING1 gene; Frameshift mutation; Hereditary angioedema; Gastrointestinal edema; Case report

Core Tip: This study highlights that hereditary angioedema should be considered in cases of recurrent abdominal pain, even in the absence of typical edema or family history. Although the initial presentation mimicked acquired angioedema, the early onset prompted SERPING1 gene testing, revealing a novel frameshift mutation. This case emphasizes the importance of genetic confirmation for hereditary angioedema diagnosis in atypical cases, as timely diagnosis is crucial because the condition can be potentially life-threatening.

INTRODUCTION

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent, transient, and localized angioedema of the skin, gastrointestinal (GI) tract, and airway mucosa, where laryngeal involvement carries a fatal risk[1]. This condition results from a quantitative or qualitative deficiency of C1 esterase inhibitor (C1-INH) caused by mutations in the SERPING1 gene, leading to uncontrolled bradykinin production and increased vascular permeability[2]. HAE has an estimated prevalence of 1 in 50000[3].

HAE is classified into type 1 (decreased C1-INH levels) and type 2 (functionally abnormal C1-INH), collectively designated HAE-C1-INH, as well as HAE with normal C1-INH[4]. Differentiating HAE from acquired angioedema (AAE) poses a significant diagnostic challenge, as both conditions share similar clinical presentations, low complement C4 levels, and reduced C1-INH function. Although AAE typically manifests after the age of 40[5] and low C1q levels may be suggestive, these markers are often unreliable[6]. Furthermore, reliance on family history can be misleading, as de novo mutations account for approximately 25% of HAE cases[7,8]. Consequently, SERPING1 gene testing is indispensable for definitive diagnosis.

In the present case, we report a case of HAE with a novel T frameshift mutation involving a thymine in exon 5 (c.852dupT) of SERPING1, confirming HAE-C1-INH.

CASE PRESENTATION

Chief complaints

A 30-year-old woman presented to the emergency department with a 5-day history of abdominal pain and vomiting.

History of present illness

The patient had experienced recurrent abdominal symptoms with a similar presentation once a year over the past 10 years. During this period, no obvious symptoms of cutaneous or laryngeal edema were noted.

History of past illness

She had no past medical history other than recurrent episodes of acute gastroenteritis and no history of surgery. Her only regular medication was rebamipide. Three months prior, she was hospitalized elsewhere for similar symptoms. Although computed tomography revealed ileal edema, upper and lower endoscopy performed after symptom resolution were unremarkable. A capsule endoscopy conducted 2 months before the current visit also yielded no abnormal findings.

Personal and family history

The patient initially denied any family history of edema, though her father had experienced recurrent gastroenteritis-like symptoms.

Physical examination

Upon presentation, the patient exhibited epigastric tenderness but no facial, peripheral, or laryngeal edema. Her respiratory examination was normal.

Laboratory examinations

Blood tests showed a red blood cell count of 5.48 million/μL (reference range: 4.35-5.55 million/μL), white blood cell count of 21500/μL (3300-8600/μL), platelet count of 418000/μL (158000-348000/μL), and glucose level of 149 mg/dL (73-109 mg/dL). Blood urea nitrogen, creatinine, cholesterol, triglycerides, C-reactive protein, and amylase levels were within normal ranges. Complement studies confirmed low C4 levels (3.3 mg/dL) and severely reduced C1-INH function.

Imaging examinations

Ultrasound and computed tomography imaging studies demonstrated marked edema of the pelvic small intestine and ascending colon with moderate ascites (Figure 1). Crucially, lower endoscopy performed during the acute episode revealed pronounced edema of the terminal ileum (Figure 2).

Figure 1 Imaging examinations. A: Abdominal ultrasound showing significant edema of the pelvic small intestine and ascending colon, and a moderate amount of ascites; B: Abdominal computed tomography scan showing significant edema of the pelvic small intestine and ascending colon, and a moderate amount of ascites.

Figure 2 Lower endoscopy showing edema in the terminal ileum.

FINAL DIAGNOSIS

Because the family history was initially unremarkable, HAE and AAE were both considered. However, the patient’s young age and recurrent episodes, combined with the profound C4 and C1-INH activity reduction, strongly suggested HAE. Genetic testing of the SERPING1 gene was performed after obtaining informed consent. Direct sequencing of exon 5 identified a novel heterozygous insertion of T:C.852dupT, resulting in a frameshift mutation (Figure 3). This finding confirmed the diagnosis of HAE type 1. Subsequent testing of her father, whose history of recurrent enteritis was then re-evaluated, identified the same SERPING1 variant, establishing familial inheritance.

Figure 3 Polymerase chain reaction/single-strand conformation polymorphism showing an abnormal band in exon 5 of SERPING1. Direct sequencing of exon 5 revealed a T frameshift mutation between bases 8490 and 8491.

TREATMENT

During hospitalization, the patient received supportive therapy, including intravenous ranitidine hydrochloride (100 mg diluted in 100 mL saline solution, administered twice daily). Following the definitive diagnosis of HAE type 1, an intravenous infusion of human C1-INH concentrate (1000 IU, prepared by reconstituting and diluting two 500-IU vials in 100 mL normal saline) was administered during subsequent acute abdominal attacks.

OUTCOME AND FOLLOW-UP

The patient’s abdominal symptoms resolved rapidly, and she was discharged. For long-term management, she was prescribed subcutaneous icatibant acetate for on-demand use during intermittent abdominal attacks, achieving excellent long-term control under routine outpatient follow-up.

DISCUSSION

HAE must be incorporated into the differential diagnosis of recurrent, unexplained abdominal pain, regardless of concomitant cutaneous findings. This case powerfully illustrates the diagnostic dilemma intrinsic to GI-dominant HAE, given the decade-long delay in diagnosis, in part because multiple evaluations conducted during asymptomatic intervals were unrevealing. This underscores the transient nature of bradykinin-mediated edema and mandates a high index of suspicion among gastroenterologists. Distinguishing HAE from AAE remains difficult based solely on clinical and serological markers; furthermore, dependence on family history is often misleading because of the frequency of de novo mutations. Thus, genetic testing of SERPING1 is indispensable for definitive diagnosis[7]. Crucially, this case substantiates the critical diagnostic value of lower endoscopy performed during the acute attack, which clearly revealed the characteristic mucosal and submucosal edema, a finding rarely documented in the literature. This report provides two key contributions: First, identification of a novel heterozygous frameshift mutation (c.852dupT) in SERPING1, expanding the known genetic spectrum of HAE type 1; and second, validation of the strategy of acute-phase bowel assessment in establishing the diagnosis of GI-predominant HAE. Early diagnosis is essential for timely initiation of appropriate targeted therapy, which is crucial to prevent fatal outcomes associated with laryngeal edema and other life-threatening complications.

CONCLUSION

HAE should be considered in recurrent, unexplained abdominal attacks, even without cutaneous manifestations or a clear family history. Because interval investigations may appear normal, evaluation should be prioritized during an active attack. Definitive diagnosis requires genetic testing, as demonstrated by identification of a novel SERPING1 mutation in this patient.