1083 Diagnosis, Clinical Manifestation and Therapy in Childrenwith Hereditary Angiooedema

I. Martinez-Saguer, E. Rusicke, E. Aygoren-Pursun, T. Klingebiel, W.

Kreuz; 1J.-W. Goethe University Hospital Frankfurt, Germany, Frankfurt,

GERMANY.

RATIONALE: The clinical symptoms of the hereditary angioeodema are

recurrent episodes of skin swellings and intestinal and laryngeal edema that

results from the deficiency of C1-inhibitor (C1-INH).

METHODS: A total of 82 pediatric patients with diagnosed HAE are fol-

lowed up for a period up to 15 years. Until August 2006 67 patients from 46

families with HAE were evaluated. We monitored C1-INH activity and

-antigen, C4- and CH50-complement, age at diagnosis and age at first man-

ifestation. Furthermore frequency and localization of attacks, savety and

efficacy of replacement therapy with C1-INH concentrate in acute edema

were observed.

RESULTS: All patients showed low levels of C1-INH-activty at the range

of 1-47%. Decreased levels of C4 were found in 94.1% of patients. The age

of diagnosis was 4.9 years in median. Symptomatic patients (37/67) pre-

sented with subcutaneous edema of extremities (24), face (25), larynx

(10) and gastrointestinal manifestations (30). The initial manifestation of

HAE occurred at the age of 0.4-15.8 years. Acute attacks were treated suc-

cessfully with 10-35 IU/kg bw of C1-INH concentrate. No side effects dur-

ing all infusions of C1-INH concentrate were observed; no seroconversion

for HAV, HBV, HCV, HGV or HIV was detected.

CONCLUSIONS: Manifestation of HAE in children occurs at the age of 5

years in median and is throughout associated with low levels of C1-INH-

activity and C4-complement. 6out of 37 patients had symptoms in the first

year of life. Therefore diagnosis of HAE is necessary as soon as possible. In

case of attacks C1-INH-concentrate was effective, safe and well tolerated.

1084 New Mutations of C1 inhibitor (SERPING1/C1NH) GeneAssociated with Hereditary Angioedema in a EuropeanPopulation

C. Drouet1, M. Cicardi2, E. Pappalardo2, N. Monnier1, O. Roche3, A. Tor-

dai4, I. Wagenaar-Bos5, R. Perricone6, A. Bygum7, K. Bork8, M. Tosi9, M.

Lopez-Trascasa3; 1University Joseph Fourier, Grenoble, FRANCE, 2Uni-

versity of Milan, Milan, ITALY, 3University Hospital La Paz, Madrid,

SPAIN, 4National Medical Center, Budapest, HUNGARY, 5Sanquin Re-

search Center, Amsterdam, THE NETHERLANDS, 6University Tor Ver-

gata, Rome, ITALY, 7University of Odense, Odense, DENMARK,8Johannes Gutenberg University, Mainz, GERMANY, 9University of

Rouen, Rouen, FRANCE.

RATIONALE: Hereditary angioedema (HAE) is caused by mutations in

the SERPING1/C1NH gene with subsequent C1Inh deficiency, either at an-

tigenic level or serpin function, or both. One-hundred and eighty-eight mu-

tations have already been described as established in the HAE database

(http://hae.biomembrane.hu/; Kalmar et al 2005 Hum Mutat 25: 1-5).

METHODS: Genomic DNAwas extracted using conventional procedures

from EDTA blood samples. Mutation analysis was carried out by (i) scan-

ning methods for point mutations or small insertions/deletion (denaturing

HPLC, SSCP), with (ii) subsequent sequencing of exon(s) and (iii) quanti-

tative exon multiplex PCR or southern blot analysis after BclI digestion in

cases of rearrangement(s).

RESULTS: One-hundred and seven new mutations have been identified

(four as de novo mutations), missense/nonsense (59/107; 55.1%), microde-

letions/-insertions (25/107; 23.4%), mutations affecting RNA splicing ac-

tivity as assayed on monocyte transcripts (10/107; 9.3%), gross deletion/

duplication of �1 exon (13/107; 12.1%). Only ten mutations were recur-

rent. One patient was found carrying a double mutation. Eleven missense

mutations associated with HAE type II or intermediate type, and the corre-

sponding positions have been localized in the 3D-model of the serpin do-

main of C1Inh (RCSB PDB id 1M6Q; Bos et al 2002, Immunobiology 205:

518-533). But our methods were unsuccessful for �4% HAE patients

investigated.

CONCLUSIONS: These results emphasize the high susceptibility of this

gene to mutation and raise the difficulties for a phenotype/genotype corre-

lation in HAE disease.

from the PreHAEAT european group, with funding as follows European

Concerted Action PREHAEAT EC Contract QLG1 2002-0135.

Funding: European Communities

1085 Treatment With Pasteurized C1 Inhibitor Concentrate InSkin Swelling Attacks Of Patients With HereditaryAngioedema

P. Staubach, K. Bork; Department of Dermatology, University of Mainz,

Mainz, GERMANY.

RATIONALE: To assess the efficacy and safety of a pasteurized C1 inhib-

itor concentrate (Berinert P, ZLB Behring, Germany) in skin swelling

attacks of patients with hereditary angioedema due to C1 inhibitor

deficiency.

METHODS: Between 1976 and 2005, a total of 1,828 skin swelling

attacks in 43 patients were treated with 500 (1445 attacks) or 1,000 units

(383 attacks) of Berinert P. The time to relief, the duration of the swelling,

and the severity of symptoms were documented during personal interviews

using standardized questionnaires and compared to 6.625 untreated skin

swelling attacks in the same patients.

RESULTS: The 1,828 skin swelling attacks affected face (440 attacks),

hands and arms (721 attacks), feet and legs (516 attacks), genitals (122 at-

tacks), and the trunk (29 attacks). The mean time to relief of symptoms was

1.3 hours (SD 1.4 hours) in all treated attacks versus 60 hours (SD 26.4

hours) in all untreated attacks. The mean duration of the attacks was short-

ened from 88 hours (SD 40.8 hours) (untreated attacks) to 40.8 hours (SD

33.6 hours) (treated attacks). All patients responded to treatment. In 24 at-

tacks of 4 patients the course of the treated attacks was not shortened but

symptoms were milder compared to untreated attacks. C1 inhibitor con-

centrate was more effective when injected early in the attacks compared

to late injections. There were no drug-related side effects.

CONCLUSIONS: The C1 inhibitor concentrate Berinert P is highly ef-

fective and safe in treating skin swellings in patients with hereditary

angioedema.

1086 Icatibant, a Potent and Selective Bradykinin B2 ReceptorAntagonist, is Effective in Treating Patients withHereditary Angioedema (HAE)

R. J. Levy, S. Goodman; Family Allergy and Asthma Center, P.C.,

Atlanta, GA.

RATIONALE: Bradykinin is implicated as the central mediator of symp-

toms in attacks in patients with HAE. We report the effect of Icatibant

administered subcutaneously (SC) in treating HAE attacks in 2 patients

in our clinic.

METHODS: As part of an open-label extension study, patients with HAE

were treated with Icatibant 30 mg SC after symptom onset during abdom-

inal or cutaneous attacks. Efficacy endpoints included the time for the onset

of symptom relief and time to complete resolution of symptoms.

RESULTS: Subject #1, a 34-year-old female with >5 years history of

HAE, had 12 attacks (abdominal n56, cutaneous n56; average duration

3 days) in the previous year. She was treated with Icatibant for 4 separate

attacks (abdominal n53, cutaneous n51) over 4 months. Subject #2, a 23-

year-old male with an 18-year history of HAE, had 14 attacks in the previ-

ous year (abdominal n56, cutaneous n58; average duration 1 day). He was

treated with Icatibant for 2 separate abdominal attacks 1 month apart. The

onset of symptom relief after all doses was rapid (subject #1, range 11-26

min; subject #2, range 14-17 min). Complete resolution of symptoms oc-

curred after treatment as soon as 90 min in subject #1 and 300 min in sub-

ject #2. Injection site reactions (mild irritation, wheal and flare) occurred

after all treatments but were transient and resolved spontaneously. Both

patients stated positive satisfaction following treatment with Icatibant.

CONCLUSIONS: Icatibant provided rapid and complete resolution of

symptoms following HAE attacks in both patients.

Funding: Jerini AG

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 1

Abstracts S277

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