Genetics and clinical phenotype of Erdheim-Chester disease: A case report of constrictive pericarditis and a systematic review of the literature

Lorenzo Bartoli; Francesco Angeli; Andrea Stefanizzi; Michele Fabrizio; Pasquale Paolisso; Luca Bergamaschi; Alessandro Broccoli; Pier Luigi Zinzani; Nazzareno Galiè; Paola Rucci; Alberto Foà; Carmine Pizzi

doi:10.3389/fcvm.2022.876294

Genetics and clinical phenotype of Erdheim-Chester disease: A case report of constrictive pericarditis and a systematic review of the literature

Front Cardiovasc Med. 2022 Aug 11:9:876294. doi: 10.3389/fcvm.2022.876294. eCollection 2022.

Authors

Lorenzo Bartoli^{1

2}, Francesco Angeli^{1

2}, Andrea Stefanizzi^{1

2}, Michele Fabrizio^{1

2}, Pasquale Paolisso^{3

4}, Luca Bergamaschi^{1

2}, Alessandro Broccoli^{2

5}, Pier Luigi Zinzani^{2

5}, Nazzareno Galiè^{1

2}, Paola Rucci⁶, Alberto Foà^{1

2}, Carmine Pizzi^{1

2}

Affiliations

¹ Institute of Cardiology, Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy.
² Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
³ Cardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium.
⁴ Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
⁵ Institute of Hematology "L. e A. Seràgnoli", Sant'Orsola-Malpighi Hospital, IRCCS, Bologna, Italy.
⁶ Division of Hygiene and Biostatistics, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Abstract

Background: Erdheim-Chester disease (ECD) is a rare form of histiocytosis. An increasing number of genetic mutations have been associated with this syndrome, confirming its possible neoplastic origin. Recently, a connection between the BRAF mutational status and a specific phenotype was described; however, no studies have yet evaluated the correlations between other mutations and the clinical features of the disease.

Objectives: This study aims to clarify the association between the clinical phenotype and genetic mutations identified in the neoplastic cell lines of ECD.

Methods: We describe a case of ECD characterized by pericardial involvement and a KRAS mutation shared with chronic myelomonocytic leukemia. Hence, through a meta-analysis of individual participant data of all genetically and clinically described cases of ECD in the literature, we aimed to elucidate the association between its clinical phenotype and baseline genetic mutations.

Results: Of the 760 studies screened, our review included 133 articles published from 2012 to April 2021. We identified 311 ECD patients whose genotype and phenotype were described. We found five main genes (BRAF, KRAS, NRAS, PIK3CA, and MAP2K1) whose mutation was reported at least three times. Mutation of BRAF led to a neurological disease (183 of 273 patients, 67%; p < 0.001); KRAS- and NRAS-mutated patients mainly showed cutaneous (five of six patients, 83.3%, p < 0.004) and pleural (four of nine patients, 44%, p = 0.002) involvement, respectively; PIK3CA was not associated with specific organ involvement; and MAP2K1 mutations caused the disease to primarily involve the peritoneum and retroperitoneum (4 of 11, 36.4%, p = 0.01).

Conclusion: This work implies a possible influence of baseline mutation over the natural history of ECD, underscoring the importance of a thorough genetic analysis in all cases with the ultimate goal of identifying a possible targeted therapy for each patient.

Keywords: Erdheim-Chester disease; case-report; constrictive pericarditis; genotype; phenotype; precision medicine.

Publication types

Case Reports