Case 1: Recurrent abdominal pain in an adolescent girl

A 12-year-old girl presented to the emergency department with a three-day history of worsening, colicky periumbilical and lower abdominal pain. Associated symptoms included anorexia, nausea and nocturnal awakening. This was preceded by two days of upper respiratory tract infection symptoms including malaise, cough and fever.

Vital signs demonstrated fever (38.8°C), tachycardia (heart rate 148 beats/min) and tachypnea (respiratory rate 28 breaths/min), but normal blood pressure and oxygen saturation on room air. Abdominal examination demonstrated tenderness in the mid and left lateral abdomen, with palpable fullness in the left lower quadrant.

Elevated white blood cell count (15.7×10⁹/L), platelet count (426×10⁹/L), C-reactive protein level (17 mg/L [161.9 nmol/L]), erythrocyte sedimentation rate (16 mm/h) and normal serum albumin were noted. Abdominal ultrasound identified marked ascites and isolated bowel wall thickening of the sigmoid colon.

The patient was admitted for observation. Gastroenterology and Pediatric Surgery were consulted regarding the abdominal pain and ultrasound findings. On further history, it was discovered that the patient had a five-year history of stereotypical recurrent abdominal pain. These episodes were much milder than at the time of presentation, and they occurred up to twice per month, resolving spontaneously within two days. Further history suggested the underlying diagnosis.

CASE 1 DIAGNOSIS: HEREDITARY ANGIOEDEMA

Family history was significant for hereditary angioedema (HAE) in the patient’s mother and brother. Both experienced recurrent episodes of swelling of the face and extremities in addition to abdominal pain. HAE was not initially suspected in our patient due to the absence of associated facial or extremity swelling during her pain episodes. Her abdominal pain improved significantly within 24 h and she was discharged. Complement assays revealed normal C3 (1.73 g/L), low normal C4 (0.13 g/L), decreased C1 esterase inhibitor (C1INH) (0.07 g/L) and low C1 esterase inhibitor (C1INH) functional activity (<35%), consistent with a diagnosis of HAE.

HAE is a multisystem disease characterized by episodes of sub-cutaneous or submucosal edema. Prevalence ranges from 1:10,000 to 1:50,000 without race or sex predominance. The two classic forms of HAE are due to autosomal dominant mutations in SERPING1, located on chromosome 11, which encodes for C1INH. Mutations result in reduced C1INH production and/or activity. This leads to abnormal activation of the classical complement pathway and the production of vasoactive substances that increase vascular permeability. Type I HAE (85% of cases) is associated with decreased C1INH levels and low C1INH functional activity. Type II HAE (15% of cases) is defined by normal or elevated levels of C1INH protein but with reduced function. A third form of HAE has been recently described, in which C1INH function is normal.

The majority of patients present during childhood, with nearly one-half exhibiting symptoms before 10 years of age. Symptoms may worsen during puberty. Triggers include infections, stress, minor trauma, elevated estrogen states such as menstruation or pregnancy, and medications including estrogen-containing oral contraceptives and angiotensin-converting enzyme inhibitors. Many episodes occur without an identifiable precipitating factor.

Most patients report prodromal symptoms 12 h to 36 h before the onset of an attack including fatigue, malaise, gastrointestinal complaints and erythema marginatum. Frequently involved sites during an attack are the skin (100%), abdomen (97%) and larynx (54%). Isolated organ involvement has been described. Cutaneous manifestations include nonpitting and nonpruritic extremity or facial swelling. Laryngeal swelling may lead to vocal changes or life-threatening upper airway obstruction. Abdominal angioedema manifests as cramping and can be accompanied by nausea, vomiting or diarrhea. Ultrasonography may reveal bowel wall thickening with ascites.

Symptom intensity increases over 12 h to 24 h after onset, generally subsiding within 48 h to 72 h. In contrast, angioedema from an allergic reaction is characterized by rapid onset, accompanied by wheeze and urticaria. The pattern of HAE attacks range from periodic to clusters with varying intervals of remission in between, with patients averaging up to three attacks per month.

Testing for HAE should be prompted by a compatible history and physical examination. A family history of HAE strongly suggests the diagnosis, although 25% of cases are due to spontaneous mutations. There can also be marked variability in symptoms within affected members of the same family. The recommended initial screen includes measurement of serum C4, C1INH antigenic protein and C1INH functional activity level. False-positive and -negative test results may be observed in patients younger than one year of age; therefore, results should be interpreted cautiously and tests repeated after one year of age.

Management of HAE in children involves treating acute attacks and preventing their recurrence. Plasma-derived C1INH is effective in rapidly improving symptoms in moderate-to-severe attacks. If unavailable, fresh frozen plasma can also be used to inhibit a flare. Other treatment options in adult patients include ecallantide (a kallikrein inhibitor) and icatibant (a bradykinin B2 receptor antagonist); however, there are no published data regarding their use in children. Corticosteroids and antihistamines are not beneficial in HAE attacks. Prevention begins with avoiding known triggers and receiving prophylactic treatment before selected surgical procedures.

CLINICAL PEARLS

• HAE is characterized by recurrent attacks of subcutaneous or submucosal edema, and may present with isolated gastrointestinal involvement. A high index of suspicion is required because misdiagnosis can result in reduced quality of life and unnecessary treatments or surgeries.

• Although a thorough family history is important, 25% of cases are due to spontaneous mutations and presentations may vary among family members. Genetic counselling is an important part of the management of patients with this disorder and may help to avoid unnecessary investigations in other affected family members.

• The management of HAE involves treating severe attacks using plasma-derived C1NH and preventing flares through the avoidance of triggers and prophylaxis before surgical procedures.