Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema.

Hereditary angioedema (HAE) is an autosomal dominant disease that manifests as intermittent acute swellings of the skin and mucosal surfaces, which, in the gastrointestinal tract and larynx, may even be fatal. HAE results from functional deficiency of the C1 inhibitor (C1INH) protein, which plays a key role in the classical pathway of complement activation. C1INH is the sole inhibitor of the activated proteases C1r and C1s, and is the major regulator of activated coagulation Factor XII and plasma kallikrein, which limits the generation of the vasoactive peptide bradykinin. In this paper, we report on the genetic analysis of 173 families (including 326 members) with a clinical diagnosis of HAE. Direct sequencing, Southern blotting and quantitative PCR by the MLPA method were used to screen for mutations in C1INH (SERPING1). In 142 families (82.1%), a causative C1INH gene mutation could be identified. A total of 80 novel point mutations of C1INH not published previously were detected in 96 pedigrees (including 172 members). Our results corroborate C1INH (SERPING1) deficiency as a disease of extreme allelic heterogeneity with almost each individual family carrying their own mutation. Routine molecular genetic analysis is an effective way of confirming the clinical diagnosis and identifying mutation carriers early on before any clinical manifestation becomes apparent. It is, therefore, a valuable tool in prevention and adequate treatment of acute and life-threatening oedema.

Retrochorionic hematoma in congenital afibrinogenemia: resolution with fibrinogen concentrate infusions.

Without treatment, pregnancies in patients with congenital afibrinogenemia terminate in miscarriage at 5-6 weeks of gestation. Animal model studies have suggested that implantation site bleeding contributes to miscarriage in afibrinogenemia; however, retrochorionic hematoma in human congenital afibrinogenemia has not been previously observed. A patient with congenital afibrinogenemia receiving fibrinogen prophylaxis developed a retrochorionic hematoma in the first trimester. With continuous intensified fibrinogen concentrate replacement the hematoma resolved over 6 weeks, and the patient delivered a healthy infant. Median fibrinogen levels in the first trimester were 48 mg/dL and in second and third trimester 44 mg/dL. Median fibrinogen levels under 60 mg/dL may be adequate to maintain pregnancy in patients with congenital afibrinogenemia, although it is possible that higher levels might reduce the risk of hemorrhagic events.