Estudio de asociación de genoma completo en la enfermedad de Erdheim-Chester.

Congresos y Conferencias: Comunicación de Congreso - Póster

Genome-wide association study identifies the first germline genetic variant associated with Erdheim Chester disease

[Objective] Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study.[Methods] After quality controls, a cohort of 255 ECD patients and 7,471 healthy donors was included in this study. Afterwards, a logistic regression followed by in silico functional annotation was performed.[Results] A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (p-value=2.75x10-11; OR=2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.[Conclusion] Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.This work was supported by the project “Genome-wide and epigenome-wide association study in patients with Erdheim-Chester Disease”, funded by by Histio UK, and supported in part by the Intramural Research Program of the National Human Genome Research Institute and Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039). M.A.H. is a recipient of a Miguel Servet fellows hip (CP21/00132) from Instituto de Salud Carlos III. L.O.F. was supported by a Juan de la Cierva Incorporación fellowship (IJC2019-040746-I) funded by MCIN/AEI/10.13039/501100011033.Peer reviewe

Erdheim-Chester disease with tendon and muscle involvement: Reports of a rare presentation

Erdheim-Chester disease (ECD) is a rare histiocytic disease that affects multiple systems in the body. While it typically targets long bones, cardiovascular structures, the retroperitoneum, and the central nervous system, reports of tendon and skeletal muscle involvement are scarce. This review presents 2 cases: a case of ECD involving the left Achilles tendon and left abductor hallucis, as well as an unusual manifestation of ECD in the thigh musculature. In Case 1, studies involved a 39-year-old man who initially presented with bone and pituitary involvement. An order for 18F-FDG PET/CT imaging was placed by marked swelling in the patient's left ankle and observed soft tissue fullness on foot radiographs, which revealed a soft tissue mass involving the left Achilles tendon, which arose along the tendon-muscle junction and involved the left abductor hallucis muscle. In Case 2, studies involved a 41-year-old man who initially presented with involvement of the cardiovascular system and retroperitoneum. 18F-FDG PET/CT scan showed an infiltrative right atrial mass and hypermetabolic lesion in the left external obturator muscle, extending to the left pectineus and right quadratus femoris muscle. Involvement of the Achilles tendon and skeletal muscle involvement, including left abductor hallucis muscle and medial thigh muscles, is one of the rare manifestations of ECD. Diagnostic delays were frequent due to the condition's rarity and nonspecific multisystemic symptoms. This should be considered in patients who present with myositis, tendinopathy, and bone pain and have other unexplained multisystemic problems

Clinical and Histopathologic Features of Interstitial Lung Disease in Erdheim–Chester Disease

Limited information is available regarding interstitial lung disease (ILD) in Erdheim–Chester disease (ECD), a rare multisystemic non-Langerhans cell histiocytosis. Sixty-two biopsy-confirmed ECD patients were divided into those with no ILD (19.5%), minimal ILD (32%), mild ILD (29%), and moderate/severe ILD (19.5%), based on computed tomography (CT) findings. Dyspnea affected at least half of the patients with mild or moderate/severe ILD. Diffusion capacity was significantly reduced in ECD patients with minimal ILD. Disease severity was inversely correlated with pulmonary function measurements; no correlation with BRAF V600E mutation status was seen. Reticulations and ground-glass opacities were the predominant findings on CT images. Automated CT scores were significantly higher in patients with moderate/severe ILD, compared to those in other groups. Immunostaining of lung biopsies was consistent with ECD. Histopathology findings included subpleural and septal fibrosis, with areas of interspersed normal lung, diffuse interstitial fibrosis, histiocytes with foamy cytoplasm embedded in fibrosis, lymphoid aggregates, and focal type II alveolar cell hyperplasia. In conclusion, ILD of varying severity may affect a high proportion of ECD patients. Histopathology features of ILD in ECD can mimic interstitial fibrosis patterns observed in idiopathic ILD

Biallelic variants in the RNA exosome gene EXOSC5 are associated with developmental delays, short stature, cerebellar hypoplasia and motor weakness

Abstract The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5–6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAF(V600E) mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAF(V600E)-wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAF(V600E)-wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. SIGNIFICANCE: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders.clos