Hereditary angioedema with a mutation in the PLG gene is a novel type of HAE. It is associated with a high risk of tongue swellings.

and Lys380. Met-Lys-bradykinin-Ser-Ser is cleaved from HMWK by the neutrophil proteinase-3 (PR3). The N-terminal cleavage site is between AA p.Leu378 and Met379. It is highly probable that the reported AA change modifies the bradykinin-forming process pointing toward a previously unreported pathomechanism of HAE. We consider that the described KNG1 variant changing the Nterminal cleavage site of bradykinin from HMWK and LMWK could lead to a functionally active but aberrant bradykinin in HAE-KNG1.An aberrant bradykinin could change the process of the inactivation by enzymes such as aminopeptidase 2, angiotensin-converting enzyme, and others, possibly resulting in a prolonged half-life time and thus a higher than normal activity of this mutant bradykinin.Similar to bradykinin, Lys-bradykinin is a high-affinity agonist for the human B2 receptor. It can be cleaved to bradykinin by an arginine aminopeptidase (AAP) in plasma. We cannot rule out that the novel mutation also leads to a modified Lys-bradykinin. Another possibility could be that the mutant HMWK is more easily activated.We are planning to demonstrate the cleaved HMWK products.The results, reported here, strongly support our assumption that the new variant in the KNG1 gene leads to a novel type of HAE, HAE with normal C1-INH and a specific variant in the KNG1 gene or HAE-KNG1.

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Summary Background Hidradenitis suppurativa (HS) is a rare, debilitating neutrophilic dermatosis characterized by chronic inflammation of hair follicles. Many inflammatory conditions may accompany HS. Objectives To investigate the association of variants of the MEFV gene with a complex HS phenotype. Methods Firstly, we identified the clinical characteristics of 119 patients with HS with a complex phenotype (Hurley stage III disease and/or additional inflammatory symptoms). Then, we searched for MEFV variants among these patients. The odds ratios (ORs) for pathogenic MEFV mutations were calculated using data from these patients with HS and 191 healthy controls. Results The male/female ratio was higher, and the mean age of onset was earlier, in our complex HS group compared with patients with HS in general. Five of the patients with HS (4·2%) had a diagnosis of familial Mediterranean fever (FMF) with a standardized morbidity ratio of 45 [95% confidence interval (CI) 16·50–99·84, P < 0·001] when compared with the frequency of FMF in the general Turkish population. Of the patients with complex HS, 38% were positive for pathogenic variants of MEFV. The OR for carrying a pathogenic MEFV allele was 2·80 (95% CI 1·31–5·97, P < 0·001). Conclusions The frequency of MEFV mutations in the group of patients with complex HS was higher than that in healthy controls, suggesting that MEFV mutations may contribute to the pathogenesis of HS. Understanding the role of autoinflammation in HS is of fundamental importance for the development of novel therapies.

Hereditary angioedema (HAE) is a life-threatening disease characterized by recurrent episodes of subcutaneous and mucosal swellings and abdominal cramping. Corticosteroids and antihistamines, which are usually beneficial in histamine-induced acquired angioedema, are not effective in HAE. Therefore, diagnosing HAE correctly is crucial for affected patients. We report a family from Northern Germany with six individuals suffering from recurrent swellings, indicating HAE. Laboratory tests and genetic diagnostics of the genes SERPING1 , encoding C1 esterase inhibitor (C1-INH), and F12, encoding coagulation factor XII, were unremarkable. In three affected and one yet unaffected member of the family, we were then able to identify the c.988A > G (also termed c.1100A > G) mutation in the plasminogen ( PLG) gene, which has recently been described in several families with HAE. This mutation leads to a missense mutation with an amino acid exchange p.Lys330Glu in the kringle 3 domain of plasminogen. There was no direct relationship between the earlier described cases with this mutation and the family we report here. In all affected members of the family, the symptoms manifested in adulthood, with swellings of the face, tongue and larynx, including a fatal case of a 19 year-old female individual. The frequency of the attacks was variable, ranging between once per year to once a month. In one individual, we also found decreased serum levels of plasminogen as well as coagulation factor XII. As previously reported in patients with PLG defects, icatibant proved to be very effective in controlling acute attacks, indicating an involvement of bradykinin in the pathogenesis.