The CC2D2B is a novel genetic modifier of the clinical phenotype in patients with hereditary angioedema due to C1 inhibitor deficiency.

Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic disorder caused by pathogenic variants in the SERPING1 gene and characterised by swelling and a highly variable clinical phenotype. We aimed to identify novel modifying genetic factors predisposing to the clinical symptoms. We performed whole exome sequencing (WES) and comprehensive bioinformatic analysis in symptomatic and asymptomatic (three duos) family members with HAE-C1-INH. Selected variants identified using WES (present in all asymptomatic and absent in symptomatic patients) were determined using Sanger sequencing. We included 88 clinically well-characterised HAE-C1-INH patients from south-eastern Europe (nine asymptomatic) from 42 unrelated families. We identified 39 variants in 23 genes (ANKRD36C, ARGFX, CC2D2B, IL5RA, IRF2BP2, LGR6, MRPL45, MUC3A, NPIPA1, NRG1, OR5M1, OR5M3, OR5M10, OR8U3, PLCL1, PRSS3, PSKH2, PTPRA, RTP4, SEZ6, SLC25A5, VWA3A, and ZNF790). We selected variants in CC2D2B and PLCL1, which were analysed using Sanger sequencing in the entire group of HAE-C1-INH. We found significant differences in the frequencies of the CC2D2B c.190A>G (rs17383738) variant between symptomatic and asymptomatic patients, where heterozygotes were more common in asymptomatic HAE-C1-INH patients in comparison to symptomatic patients (55 % vs 23%; P = 0.049, OR = 4.24, 95% CI 1.07-14.69). Our study identified novel genetic factors that modify the clinical variability of HAE-C1-INH. We further demonstrated, in a large cohort, the importance of the CC2D2B gene as a disease-modifying factor. Based on linkage disequilibrium analysis, the CCNJ and ZNF518A genes might also be involved in the clinical variability of HAE-C1-INH.

Hereditary angioedema due to C1-inhibitor deficiency in Macedonia: clinical characteristics, novel SERPING1 mutations and genetic factors modifying the clinical phenotype.

OBJECTIVE: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disease, characterized by swellings. We aimed to characterize on a clinical and molecular basis C1-INH-HAE patients in the Republic of Macedonia. RESULTS: All 15 patients from six unrelated families were diagnosed with C1-INH-HAE type I, with a mean age of symptom onset of 11 years and an average delay of diagnosis of seven years. Patients reported on average 31 angioedema attacks/year, with a median clinical severity score (CSS) of 7. We identified three known mutations and two new mutations (c.813_818delCAACAA and c.1488T > G) that were reported for the first time. To address the genotype-phenotype association, a pooled analysis including 78 C1-INH-HAE south-eastern European patients was performed, with additional analysis of F12-46C/T and KLKB1-428G/A polymorphisms. We demonstrated that patients with nonsense and frameshift mutations, large deletions/insertions, splicing defects and mutations at Arg444 exhibited an increased CSS compared with missense mutations, excluding mutations at Arg444. In addition, the CC F12-46C/T polymorphism was suggestive of earlier disease onset. DISCUSSION: Genetic analysis helped identify the molecular basis of C1-INH-HAE given that causative mutations in SERPING1 were detected in all patients, including an infant before the appearance of clinical symptoms. We identified two novel mutations and further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and CC F12-46C/T predisposes patients to earlier disease onset. KEY MESSAGES • In the present nationwide study, we aimed to characterize on a clinical and molecular basis patients with hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) in the Republic of Macedonia. • Causative mutations in SERPING1 were detected in all 15 C1-INH-HAE patients from six Macedonian families, including an infant, before the appearance of clinical symptoms. • We identified three known mutations and two novel mutations (c.813_818delCAACAA and c.1488T > G). These findings further corroborated the genotype-phenotype relationship, wherein mutations with a clear effect on C1-INH function predispose patients to a more severe disease phenotype and the CC F12-46C/T polymorphism predisposes patients to earlier disease onset.

Henoch-Schönlein purpura in an adult patient: extragastric, cutaneous manifestation of helicobacter pylori infection.

Today there is evidence that Helicobacter pylori has a critical role in different extragastric diseases. The discovery of a number of other new Helicobacter species has stimulated research into different extragastric diseases, in which an infectious hypothesis is plausible. Enterohepatic Helicobacter species have been hypothesized to play a role in different disorders including the extragastric manifestations of H. pylori infection. The authors present a case of Henoch-Schönlein purpura in an adult patient with Helicobacter pylori infection and disease regression after triple anti-Helicobacter eradication therapy. The patient was monitored, over a follow-up period of almost 9 years after eradication of Helicobacter pylori presence, by clinical examination as well as serological findings. There was no disease reccurence during the follow-up period and no markers of Helicobacter pylori reinfection. Since disease recurrence occurs throughout weeks to months, the authors conclude that Henoch-Schonlein purpura is a possible extragastric, cutaneous manifestation of Helicobacter pylori infection.

Frequency of delayed-type hypersensitivity to contact allergens in palmo-plantar psoriasis.

UNLABELLED: Psoriasis is a common, chronic, genetically determined, T-cell-mediated inflammatory dermatosis. The aim of this study is to determine the frequency of delayed-type hypersensitivity to contact allergens in palmo-plantar psoriasis and their importance in provoking and/or perpetuating the same. MATERIALS AND METHODS: 101 patients with different clinical forms of psoriasis were included in our study. The patients were divided into two groups, on the base of the clinical aspects and localizations of the lesions. The first group consisted of 38 patients with palmo-plantar psoriasis. The second, control, group of patients with psoriasis vulgaris but without lesions on palms and soles included 63 cases. The patch-tests were performed on all 101 patients. RESULTS: In the first group of patients with palmo-plantar psoriasis, the patch-tests were positive in 15 patients (39.5%). Only 8 patients (12.7%) had positive results of patch-testing in the control group (psoriasis without palmoplantar involvement). The study showed a highly statistically significant difference in the frequency of positive patch-tests between the two investigative groups (p < 0.01). In the first group of patients with palmo-plantar psoriasis there was noted a statistically significant greater number of positive patch-tests. CONCLUSION: The results of our study showed a statistically significant bigger number of positive patch-tests in patients with palmo-plantar psoriasis, which confirmed the role of contact allergens in the triggering and/or perpetuating of the lesions. Therefore, it is necessary for patch-testing to be included as a diagnostic procedure in patients with psoriasis unresponsive to conventional topical treatment. It is possible that avoiding selected antigens may alleviate chronic, recalcitrant psoriasis.