Hemifacial myohyperplasia (HFMH) is a rare cause of facial asymmetry exclusively involving facial muscles. The underlying cause and the mechanism of disease progression are unknown. Here, we identified a somatic gain-of-function mutation of PIK3CA in five pediatric patients with HFMH. To understand the physiopathology of muscle hypertrophy in this context, we created a mouse model carrying specifically a PIK3CA mutation in skeletal muscles. PIK3CA gain-of-function mutation led to striated muscle cell hypertrophy, mitochondria dysfunction, and hypoglycemia with low circulating insulin levels. Alpelisib treatment, an approved PIK3CA inhibitor, was able to prevent and reduce muscle hypertrophy in the mouse model with correction of endocrine anomalies. Based on these findings, we treated the five HFMH patients. All patients demonstrated clinical, esthetical, and radiological improvement with proof of target engagement. In conclusion, we show that HFMH is due to somatic alteration of PIK3CA and is accessible to pharmacological intervention.
Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition
Disclosures: B. Periou reported benefitting from fellowship from the Agence Nationale pour la Recherche (RHU CARMMA, ANR-15-RHUS-OOO3). F.-J. Authier reported benefitting from research grants from the Association Française contre les Myopathies via TRANSLAMUSCLE (PROJECT 19507 and 22946) and the Agence Nationale pour la Recherche (RHU CARMMA, ANR-15-RHUS-0003). G. Canaud reported personal fees from Novartis, Vaderis, Ipsen, BridgeBio, and Alkermes outside the submitted work; in addition, G. Canaud had a patent to WO2017140828A1 licensed to Novartis. No other disclosures were reported.
- Award Id(s): 101000948
- Award Id(s): ANR-11-INBS-0006
- Award Id(s): ANR-18-RHUS-005,19-CE14-0030-01
Charles Bayard, Eleonora Segna, Maxime Taverne, Antoine Fraissenon, Quentin Hennocq, Baptiste Periou, Lola Zerbib, Sophia Ladraa, Célia Chapelle, Clément Hoguin, Sophie Kaltenbach, Patrick Villarese, Vahid Asnafi, Christine Broissand, Ivan Nemazanyy, Gwennhael Autret, Nicolas Goudin, Christophe Legendre, François-Jérôme Authier, Thomas Viel, Bertrand Tavitian, Cyril Gitiaux, Sylvie Fraitag, Jean-Paul Duong, Clarisse Delcros, Bernard Sergent, Arnaud Picard, Michael Dussiot, Laurent Guibaud, Roman Khonsari, Guillaume Canaud; Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition. J Exp Med 6 November 2023; 220 (11): e20230926. doi: https://doi.org/10.1084/jem.20230926
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