Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a potentially life-threatening condition characterized by recurrent episodes of subcutaneous or submucosal swelling. This study investigates the association between HAE-nC1-INH and carboxypeptidase N (CPN) deficiency in four unrelated families. Patients presented with angioedema and urticaria, primarily on the face and lips, along with abdominal pain or laryngeal symptoms. Plasma CPN activity was significantly reduced in affected individuals, ranging from 30% to 50% of the median value. Genetic analysis identified three variants in the CPN1 gene: c.533G>A, c.582A>G, and c.734C>T. These variants were associated with CPN deficiency and HAE-nC1-INH symptoms in affected family members. CPN is a zinc-metallopeptidase that regulates bradykinin and anaphylatoxin metabolism, playing a key role in inflammation and vascular permeability. CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, leading to angioedema and urticarial symptoms. The study found that CPN1 variants, particularly c.533G>A and c.582A>G, were inherited in an autosomal-recessive manner and were associated with the clinical phenotype. These variants affect the catalytic activity of CPN, potentially leading to reduced enzyme function and increased symptom severity. The study highlights the importance of genetic testing in diagnosing HAE-nC1-INH and CPN deficiency. The findings suggest that CPN1 variants may be a significant contributor to the pathogenesis of HAE-nC1-INH. The results also emphasize the need for a comprehensive approach to diagnosis, including clinical, biological, and genetic evaluation, to understand the dysregulation of the kallikrein-kinin pathway in HAE-nC1-INH. The study provides insights into the genetic basis of HAE-nC1-INH and CPN deficiency, which may have implications for the development of targeted therapies.Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a potentially life-threatening condition characterized by recurrent episodes of subcutaneous or submucosal swelling. This study investigates the association between HAE-nC1-INH and carboxypeptidase N (CPN) deficiency in four unrelated families. Patients presented with angioedema and urticaria, primarily on the face and lips, along with abdominal pain or laryngeal symptoms. Plasma CPN activity was significantly reduced in affected individuals, ranging from 30% to 50% of the median value. Genetic analysis identified three variants in the CPN1 gene: c.533G>A, c.582A>G, and c.734C>T. These variants were associated with CPN deficiency and HAE-nC1-INH symptoms in affected family members. CPN is a zinc-metallopeptidase that regulates bradykinin and anaphylatoxin metabolism, playing a key role in inflammation and vascular permeability. CPN deficiency may contribute to bradykinin and anaphylatoxin accumulation, leading to angioedema and urticarial symptoms. The study found that CPN1 variants, particularly c.533G>A and c.582A>G, were inherited in an autosomal-recessive manner and were associated with the clinical phenotype. These variants affect the catalytic activity of CPN, potentially leading to reduced enzyme function and increased symptom severity. The study highlights the importance of genetic testing in diagnosing HAE-nC1-INH and CPN deficiency. The findings suggest that CPN1 variants may be a significant contributor to the pathogenesis of HAE-nC1-INH. The results also emphasize the need for a comprehensive approach to diagnosis, including clinical, biological, and genetic evaluation, to understand the dysregulation of the kallikrein-kinin pathway in HAE-nC1-INH. The study provides insights into the genetic basis of HAE-nC1-INH and CPN deficiency, which may have implications for the development of targeted therapies.