Indian Pediatrics 1999;36:187-189 

Hereditary Angioneurotic Edema

Arun K. Baranwal,
Surjit Singh
Lata Kumar
 

From the Allergy - Immunology Unit, Department of Pediatrics; Postgraduate Institute of Medical Education and Research, Chandigarh 1600/2, India.

Reprint requests: Dr. Lata Kumar, Professor and Head Department of Pediatrics, PGIMER, Chandigarh 160 OJ 2, India. .

Manuscript Received: December 30,1997; Initial review completed: March 31, 1998;
Revision Accepted: September 8, 1998.
 

Usually angioedema is allergic in origin, but one distinctive form is inherited and termed as 'Hereditary Angioedema'. Though this condition is very rare, one should be aware of its consequences, as these can be life-threatening. We report 'here two cases which we had the occasion to manage recently. To the best of our knowledge, hereditary angioedema has never been previously reported in Indian literature.

Case Reports

Case 1: A 3-year-old girl presented with recurrent swelling of hands, feet and periorbital area since the age of one and a half years. Each episode used to last 24-28 hours and subside spontaneously. These used to occur every 15-20 days. Swellings were not associated with itching, redness, warmth, rash or change in voice. During such episodes, she also used to have abdominal pain, associated with non-bilious, non-projectile vomiting.


General physical and systemic examination were unremarkable. Her mother had also been having similar complaints with hoarseness of voice and choking noted during some of the episodes.

Investigations revealed normal blood counts (Hb-9.2 g/dl, TLC-9200 I cu . mm, DLC-P63, L33, M2 and E2, absolute eosinophil count-1841 cu mm). and erythrocyte sedimentation rate 13 mm in 1st hour. Serum electrolytes, renal functions and routine urine examination were normal. Anti-nucIear factor was negative.

Child was put on danazol (4 mg/kg/day) given once daily. On follow up she has remained asymptomatic except for one episode of periorbital swelling of left eye without any associated abdominal pain, seven. months after starting treatment. Mother was also put on danazol-100 mg twice daily, which was subsequently increased to 100 mg three times a day. With this the frequency of her episodes has reduced from once every fortnight to once in 2-3 months. Severity of swelling is also less than before.

Case 2: An 8-year-old boy, presented with recurrent swelling of different body parts since the age of one and a half years. Initially he used to have episodes of perineal swelling, involving penis and scrotum, which used to be non-pitting and non-itching, and used to . subside in 2-3 days. Such episodes occurred once every 4-5 months. Later he started developing swelling of hands, forearm, feet, face and neck. The frequency of these episodes gradually increased to once every fortnight. The episodes were not associated with any rash, itching, conjunctival injection, respiratory distress, wheeze or change in voice. No diurnal variation was noted. For last one year he had also been having abdominal pain during such episodes-this was intermittent, colicky and associated with bilious vomiting. The abdominal pain at times used to continue for 6-7 days leading to absenteeism from school.

There was no family history of such episodes. General physical and systemic examination was unremarkable. During hospital stay he developed swelling of left hand which was non-pitting, non-tender, non-itching and was not associated with any local rise of temperature. He also had abdominal pain which was relieved with antispasmodics.

Investigations revealed normal blood counts (Hb-ll.8 g/dl, TLC-5200/ cu mm, DLC-P70 L20 M2 E8 and absolute eosinophil count - 416/ cu mm), serum electrolytes and urine routine examination. Anti-nuclear factor was negative. Serum C4 level was reduced (16.8 mg/dl against normal value of 20-50 mg/dI).

Child was put on danazol (l0 mg/kg once a day). On follow up the dose was gradually reduced to 2.5 mg/kg once a day as the child continued to be asymptomatic.

Discussion

The term "Hereditary Angioneurotic Edema (HAE)," was coined by Osler in 1888(1)and the autosomal dominant pattern of inheritance was pointed out by Crowder and Crowder(2) in 1917. Our first case is having definite family history, but this is lacking in the second case, thereby suggesting a spontaneous mutation. HAE is a disease of classic pathway of complement activation, due to deficiency of a glycoprotein C1 esterase inhibitor (C1EI). This is synthesized in the liver and has a biological half-life of 64 hours(1). C1EI deficiency allows unopposed activation of Cl, thereby leading to production of C2- kinin(3), which results in extravasation of intravascular fluid in various tissue planes leading to angioedema. Histamine and other inflammatory mediators do not seem to have any causative role in this type of angioedema.

Though this is an inherited disorder, for some unknown reason children usually remain asymptomatic during the first few months of life(1). It may be noted that both of our patients developed symptoms after the first year of life. Frequency of episodes varies from one per week to very occasional attacks. The frequency as well as severity of episodes increases towards adolescence and decreases later in life(1).

Unlike allergic angioedema, patients with HAE usually have no itching .associated with the swelling and this is a useful clinical pointer to the diagnosis. Commonest sites of involvement are limbs, face and perineal area. Gastrointestinal involvement is also common as was seen in both of our patients. Laryngeal involvement was seen in the mother of the first case. Laryngeal edema can be life threatening as it may evolve into complete laryngeal obstruction.

The clinical diagnosis of HAE is usually strroghtf6rward. Diagnosis is made by demonstrating low serum C 1EI activity (<5 mg/dl, against normal value of 18±5 mg/dl), persistent low levels of C4 (normal value 20-50 mg/ dl) and low levels of C3 temporarily during acuteepisode(4). Estimation of C4 levels is a useful simple screening test for HAE arid the! diagnosis can be confirmed by assay of serum C1EI activity(1). Facilities for measurement of C1El activity are not easily. available in India. C4 levels were documented to be low in the second patient but this investigation could not be done in the first case.

Management of such cases involves treatment of acute episodes, maintenance therapy and short term prophylactic regime. Acute episodes may require symptomatic management with antispasmodic and prokinetic agents for gastrointestinal symptoms, and airway maintenance for laryngeal involvement. Epinephrine, antihistamines and corticosteroids are usually not effective(1). For life threatening episodes replacement therapy(5) with purified C1EI is recommended. This product is now available in our country. For maintenance therapy impeded androgens (danazol/stanazolol) are the drugs of choice(6,7). They act by increasing synthesis. of ClEI protein by the liver. Both of our patients have .done well on maintenance therapy with danazol.

For short term prophylaxis, as for instance before surgery, a higher dose of danazol (10 mg/kg/day) or stanazolol (0.25 mglkglday) should be used for 5 days prior to the intervention. Infusion of two units of fresh frozen plasma on the eve of surgery and then two units just prior to surgery has also been suggested(8), though the. ideal management involves parenteral administration of purified C1EI.

RAE is a rare but life threatening condition which is potentially treatable. If children are having mild to moderate episodes, they can be left untreated, but should remain under close supervision. Maintenance therapy should be considered. only when child is having laryngeal obstruction (partial or complete), episodes of facial and neck swelling or incapacitating attacks which interfere with normal activities of the child as was the casein both of our patients. Although, stanazolol has lesser androgenic effects as compared to danazol, experience with the former in this condition is rather limited.
 

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