Academic Journal
Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome
| العنوان: | Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome |
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| المؤلفون: | Carli, Diana, Cardaropoli, Simona, Tessaris, Daniele, Coppo, Paola, La Selva, Roberta, Cesario, Claudia, Lepri, Francesca Romana, Pullano, Verdiana, Palumbo, Martina, Ramenghi, Ugo, Brusco, Alfredo, Medico, Enzo, De Sanctis, Luisa, Ferrero, Giovanni Battista, Mussa, Alessandro |
| المساهمون: | Carli, Diana, Cardaropoli, Simona, Tessaris, Daniele, Coppo, Paola, La Selva, Roberta, Cesario, Claudia, Lepri, Francesca Romana, Pullano, Verdiana, Palumbo, Martina, Ramenghi, Ugo, Brusco, Alfredo, Medico, Enzo, De Sanctis, Luisa, Ferrero, Giovanni Battista, Mussa, Alessandro |
| سنة النشر: | 2022 |
| المجموعة: | Università degli studi di Torino: AperTo (Archivio Istituzionale ad Accesso Aperto) |
| مصطلحات موضوعية: | MEK inhibitor, RASopathie, Schimmelpenning-Feuerstein-Mims syndrome, cutaneous skeletal hypophosphatemia syndrome, trametinib |
| الوصف: | Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4-year-old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A > G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA-seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch-up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified "core" genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/35999193; info:eu-repo/semantics/altIdentifier/wos/WOS:000855014100001; firstpage:1; lastpage:7; numberofpages:7; journal:GENES, CHROMOSOMES & CANCER; https://hdl.handle.net/2318/1875480; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85138314511 |
| DOI: | 10.1002/gcc.23092 |
| الاتاحة: | https://hdl.handle.net/2318/1875480 https://doi.org/10.1002/gcc.23092 |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.2EDBF009 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/gcc.23092 |
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