gdc-0973 and Erdheim-Chester-Disease

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.

Topics: Erdheim-Chester Disease; GTP Phosphohydrolases; Humans; Membrane Proteins; Mutation; Proto-Oncogene Proteins B-raf

Erdheim-Chester Disease (ECD) is a rare form of histiocytosis, characterized by xanthogranulomatous infiltration of multiple organs by lipid-laden histiocytes. It is considered a myeloid inflammatory clonal disorder that mainly affects men with a mean age of 55 years.. We present the case of a 65-year-old man who consulted our Endocrinology Unit because of polyuria and polydipsia of 4 months of evolution, diagnosing central diabetes insipidus associated with pituitary infiltration. Physical examination showed skin lesions he has had for several years, that were papules-nodules in the anterior chest and xantelasma-like in the face and neck, with biopsy compatible with non-Langerhans histiocytosis. The genetic study of the skin biopsy showed the presence of a mutation in MAP2K1, confirming the ECD.. The patient started treatment with interferon alfa, but the response was incomplete and associated with severe intolerance, so given the findings of the genetic study, we decided to indicate treatment with cobimetinib, a potent and selective inhibitor of MEK. After 8 months of treatment, skin lesions have disappeared, as has the pituitary infiltration, with a remarkable improvement in his quality of life.. We present a 65-year-old patient with a rare form of histiocytosis (ECD) who in turn presented an atypical form of ECD and, where the genetic study allowed us to confirm the diagnosis and use targeted therapy with cobimetinib with outstanding results.. La Enfermedad de Erdheim-Chester (ECD) es una rara forma de histiocitosis, caracterizada por la infiltración xantogranulomatosa de múltiples órganos por histiocitos cargados de lípidos. Se la considera un trastorno clonal inflamatorio mieloide que afecta principalmente a hombres con una edad media de 55 años.. Presentamos el caso de un hombre de 65 años que consultó a nuestro Servicio de Endocrinología por poliuria y polidipsia de 4 meses de evolución diagnosticándose diabetes insípida central asociada a infiltración hipofisaria. El paciente presentaba lesiones cutáneas pápulo-nodulares en tórax y xantelasma-símiles en cuello y cara de varios años de evolución, con biopsia compatible con histiocitosis no-Langerhans. El estudio genético de la biopsia cutánea detectó la mutación MAP2K1 confirmando la ECD.. El paciente inició tratamiento con interferón alfa con respuesta incompleta y mala tolerancia por lo que cambiamos el tratamiento a un inhibidor potente y selectivo de MEK, el cobimetinib. Tras 8 meses de tratamiento presenta desaparición de lesiones cutáneas y de la infiltración hipofisaria con notable mejoría de su calidad de vida.. Presentamos el caso de un paciente adulto con una forma rara de histiocitosis (ECD) que a su vez presentó una forma atípica de ECD y, donde el estudio genético nos permitió confirmar el diagnóstico e introducir una terapia dirigida con cobimetinib con excelentes resultados.

Topics: Aged; Azetidines; Biopsy; Erdheim-Chester Disease; Humans; Male; Middle Aged; Mutation; Piperidines; Quality of Life

Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68. We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity.. Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement.

Topics: Aged; Azetidines; Drug Therapy, Combination; Erdheim-Chester Disease; Female; Humans; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Nervous System Diseases; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Rare Diseases; Skin Diseases; Vemurafenib

Topics: Adult; Aged; Azetidines; Erdheim-Chester Disease; Fluorodeoxyglucose F18; Humans; Male; MAP Kinase Signaling System; Middle Aged; Piperidines; Positron-Emission Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Treatment Outcome

Topics: Azetidines; Drug Administration Schedule; Erdheim-Chester Disease; Follow-Up Studies; France; Humans; Imidazoles; Indoles; Molecular Targeted Therapy; Multicenter Studies as Topic; Oximes; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Registries; Retrospective Studies; Sulfonamides; Treatment Outcome; Vemurafenib