Hemifacial myohyperplasia is due to somatic muscular PIK3CA gain-of-function mutations and responds to pharmacological inhibition
Charles Bayard, E. Segna, M.A.M. Taverne, Antoine Fraissenon, Quentin Hennocq, Baptiste Periou, Lola Zerbib, Sophia Ladraa, Célia Chapelle, Clément Hoguin, Sophie Kaltenbach, Patrick Villarèse, Vahid Asnafi, Christine Broissand, Ivan Nemazanyy, Gwennhaël Autret, Nicolas Goudin, Christophe Legendre, François‐Jérôme Authier, Thomas Viel, Bertrand Tavitian, Cyril Gitiaux, Sylvie Fraïtag, Jean–Paul Duong Van Huyen, Clarisse Delcros, B. Sergent, Arnaud Picard, Michaël Dussiot, Laurent Guibaud, Roman Hossein Khonsari, Guillaume Canaud
Abstract
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.