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Diagnosis of hereditary angioedema

100%

Kőhalmi K. V., Cervenak L., Farkas H.

Alergia Astma Immunologia - przegląd kliniczny

2018

vol. 23

issue 4

168-174

Hereditary angioedema (HAE) is a rare disorder characterized by acute episodes of edema formation in the subcutis and/or the submucosa. The clinical picture of the disease resembles that of histamine-mediated angioedema, nevertheless bradykinin release is involved in the pathomechanism of HAE. The diagnosis of HAE can be established from the clinical manifestations, the family history, as well as the findings of complement and genetic tests. Currently, the six types of hereditary angioedema are distinguished: types I and II of hereditary angioedema with C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) and the following types of hereditary angioedema with normal C1-INH levels: hereditary angioedema caused by a mutation in the Factor XII gene (FXII-HAE), the angiopoietin-1 gene (ANGPT1-HAE), and the plasminogen gene (PLG-HAE) – and hereditary angioedema of unknown origin (U-HAE). Current options for the laboratory diagnosis of angioedemas include means for identifying C1-INH-HAE, FXII-HAE, ANGPT1-HAE, PLG-HAE and acquired angioedema with C1-INH deficiency (C1-INH-AAE). No laboratory method is available currently for diagnosing the other types of angioedemas such as idiopathic histaminergic acquired angioedema (IH-AAE), idiopathic non-histaminergic acquired angioedema (InH-AAE), acquired angioedema related to angiotensin-converting enzyme inhibitor (ACEI-AAE), and U-HAE. These disease types can be identified only by indirect methods, i.e. by exploring medical and family history, observing the clinical manifestations and the therapeutic response, as well as by excluding the presence of C1-INH deficiency, FXII-HAE, ANGPT1-HAE, and PLG-HAE.

Coexistent systemic mastocytosis and essential thrombocythemia complicated with monoclonal gammopathy and hypocomplementaemia

64%

Varkonyi J., Rausz E., Pánczél P., Sperlagh M., Varga L., Farkas H., Csomor J., Füle T., Karádi I.

Open Medicine

2012

vol. 7

issue 6

742-746

Hematological neoplasms associated with systemic mast cell disease are most frequently of myeloid origin. There are a few reports, however, of systemic mastocytosis (SM) cases associated with lymphoid or plasma cell neoplasms as well. In this report, the authors present a case of SM (with D816V mutation in the c-KIT gene) associated with JAK2 V617F mutation negative essential thrombocythemia. The leading symptom of the 78-year-old female was recurring hydrothorax that responded only to interferon alpha therapy. During the first year of therapy, the patient developed insulin-dependent diabetes and hypothyroidism. The hematological workup also revealed IgG kappa monoclonal gammopathy that was non-progressive in the following next three years. Low levels of complements without known clinical significance accompanied the entire picture.

Aspects of hereditary angioedema genotyping in the era of NGS: The case of F12 gene

52%

Vatsiou S., Zamanakou M., Loules G., González-Quevedo T., Porębski G., Juchacz A., Bova M., Suffritti C., Firinu D., Csuka D., Manousakis E., Valerieva A., Staevska M., Magerl M., Farkas H., Germenis A. E.

Alergia Astma Immunologia - przegląd kliniczny

2018

vol. 23

issue 4

205-210

Objective. To screen a cohort of patients diagnosed with non-FXII angioedema for carriage of variants of F12 gene. Material and methods. DNA samples from 191 patients suffering from primary angioedema with normal C1-INH, 54 samples from non- -affected family members, and 161 samples from C1-INH-HAE (154 type I, 7 type II) patients were included in the study. The F12 gene was genotyped by targeted NGS (100% coverage of translated regions). Sanger sequencing was performed for the verification of all identified variants and family segregation studies. Results. The pathogenic F12 variant c.983C>A was detected in three patients from two unrelated families initially diagnosed as U-HAE. Six additional mutations were identified, four of which were characterized as benign (c.41T>C, c.418C>G, c.1025C>T, c.530C>T) and two of uncertain significance (c.1530G>C, c.1768T>G). Two synonymous variants (c.756C>T and c.711C>T), the common polymorphism c.619G>C, and the functional polymorphism c.-4T>C were detected in allele frequencies similar to those presented in the ExAC database for the European population. One more not yet reported synonymous variant (c. 1599A>G) was also found. Conclusion. Analyzing the entire translated region of F12 gene is important in order to identify new variants that possibly affect HAE expressivity. Interestingly, genetic analysis of F12 supports not only the diagnosis of FXII-HAE but also the correct exclusion diagnosis of U-HAE.

Cel. Przesiewowe badanie kohorty pacjentów z rozpoznanym obrzę- kiem naczynioruchowym innym niż zależny od FXII w kierunku nosicielstwa wariantów genu F12. Materiał i metody. Do badania włączono próbki DNA 191 pacjentów cierpiących na pierwotny obrzęk naczynioruchowy z prawidłowym C1-INH, 54 zdrowych członków rodzin oraz 161 pacjentów z C1-INH-HAE (154 typ I, 7 typ II). Gen F12 był genotypowany metodą NGS (obejmującą cały rejon poddany translacji). Sekwencjonowanie metodą Sangera zostało wykonane celem weryfikacji wszystkich zidentyfikowanych wariantów i badań segregacyjnych rodzin. Wyniki. U trzech pacjentów z dwóch niespokrewnionych rodzin pierwotnie zdiagnozowanych jako U-HAE wykryto patogenny wariant F12: c.983C>A. Zidentyfikowano sześć dodatkowych mutacji, z których cztery zostały określone jako łagodne (c.41T>C, c.418C>G, c.1025C>T, c.530C>T), a dwie jako mutacje o niepewnym znaczeniu (c.1530G>C, c.1768T>G). Stwierdzono dwa warianty synonimiczne (c.756C>T oraz c.711C>T), pospolity polimorfizm (c.619G>C) oraz czynnościowy polimorfizm c.-4T>C z częstością alleliczną podobną do podawanej w bazie ExAC dla populacji europejskiej. Wykryto również jeden nie raportowany dotychczas wariant synonimiczny (c. 1599A>G). Wnioski. Analiza całego rejonu genu F12 poddawanego translacji jest ważna dla identyfikowania nowych wariantów, które mogą oddziaływać na ekspresję HAE. Ponadto, analiza genetyczna F12 pozwala nie tylko na potwierdzenie rozpoznania FXII-HAE, ale również prawidłowe wykluczenie rozpoznania U-HAE.

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2 Alergia Astma Immunologia - przegląd kliniczny

1 Open Medicine

2 2018

1 2012

3 Farkas H.

1 Bova M.

1 Cervenak L.

1 Csomor J.

1 Csuka D.

1 Firinu D.

1 Füle T.

1 Germenis A. E.

1 González-Quevedo T.

1 Juchacz A.

1 Karádi I.

1 Kőhalmi K. V.

1 Loules G.

1 Magerl M.

1 Manousakis E.

1 Porębski G.

1 Pánczél P.

1 Rausz E.

1 Sperlagh M.

1 Staevska M.

1 Suffritti C.

1 Valerieva A.

1 Varga L.

1 Varkonyi J.

1 Vatsiou S.

1 Zamanakou M.

Search results

Diagnosis of hereditary angioedema

Coexistent systemic mastocytosis and essential thrombocythemia complicated with monoclonal gammopathy and hypocomplementaemia

Aspects of hereditary angioedema genotyping in the era of NGS: The case of F12 gene