Hereditary Carboxypeptidase N deficiency, a clinical situation presenting with urticaria and angioedema

Background: Carboxypeptidase N (CPN) plays a major role in anaphylatoxin inactivation and is critical for bradykinin catabolism. CPN deficiency is a rare and underdiagnosed condition. Its pathophysiology has been shown as a function of anaphylatoxin and kinin accumulation, prone to mast cell and endothelium activation and sustaining inflammatory processes. We aimed to study families with homogeneous presentations for clinical and biological observations and genetics. Methods: Four families presenting with a CPN deficiency have been included. The study comprised clinical records of patients, biological parameters of anaphylatoxin/kinin metabolism, analysis of variants by next-generation sequencing and Sanger sequencing. Variants were classified as affecting splicing, benign to deleterious or disease causing according to algorithms (HSF , SIFT , Polyphen-2 , MutationTaster ). Results: Patients had chronic spontaneous urticaria and swellings, mainly on face/lips, but also with abdominal pain or laryngeal symptoms. Plasma samples from affected patient displayed low CPN activity, mostly below 50% of median value. We detected 3 variants in CPN1 gene encoding the catalytic 85-kDa subunit of CPN, c.533G>A, c.582A>G and c.734C>T. The families carried these variants in combination, e.g. [c.533G>A];[c.533G>A] (n=2), [c.533G>A(;)c.582A>G] (n=1) and [c.533G>A(;)c.734C>T] (n=1). Family studies revealed that variant combinations associated with CPN deficiency segregated with both symptoms and CPN activity. Conclusions: CPN deficiency has been found associated with combinations of CPN1 variants, with c.533G>A when present on both alleles or in combination with c.582A>G or c.734C>T. It is associated with a high risk of chronic spontaneous urticaria and/or swellings, consistently with anaphylatoxin and bradykinin accumulation.