First identification of the causes of a rare facial malformation

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Co-markings of skin from mice expressing a PIK3CA gene mutation. Marina Firpion/
Co-markings of skin from mice expressing a PIK3CA gene mutation. Marina Firpion/Guillaume Canaud - Inserm unit 1151

The Translational Medicine and Targeted Therapies research team, headed by Prof. Guillaume Canaud at the Institut Necker-Enfants Malades (Université Paris Cité, AP-HP, Inserm), in collaboration with the maxillofacial surgery team from theHôpital Necker-Enfants Malades AP-HP (Prof. Roman Khonsari and Prof. Arnaud Picard) and the "Shape and Growth of the Skull" laboratory (Prof. Roman Khonsari), studied the PIK3CA pathway in patients suffering from a rare disease affecting facial muscles, hemifacial myohyperplasia. The results of this study were published on September 15, 2023 in the Journal of Experimental Medicine .

Hemifacial myohyperplasia (HFMH) is a rare cause of asymmetry involving exclusively facial muscles1. This disorder is reported in very few patients in the literature2. The genetic causes and mechanisms of progression of HFMH were previously unknown.

Its management has so far been punctuated by misdiagnosis and inadequate strategies, including aggressive attempts at surgical correction3 (muscle remodeling surgeries). The results were always disappointing, with significant sequelae.

The recent discovery of the role played by somatic mutation of genes activating the PIK3CA/AKT/mTOR pathway has opened up new therapeutic prospects for patients.

In particular, gain-of-function mutations4 PIK3CA account for the vast majority of proliferation syndromes.

Canaud and Khonsari and clinicians hypothesized that the PIK3CA/AKT/mTOR pathway was abnormally affected in patients with HFMH.

Five patients with HFMH were included in this study.

A gain-of-function mutation in the PIK3CA gene was found in the facial muscles of these five patients. It resulted in striated muscle cell hypertrophy, mitochondrial dysfunction and hypoglycemia with low circulating insulin levels.

To understand the pathophysiology of muscle hypertrophy, Prof. Canaud’s research team has created a mouse model5 specifically carrying a PIK3CA mutation in skeletal muscle.

Treatment with alpelisib, an approved PIK3CA inhibitor, was able to prevent and reduce muscle hypertrophy in the mouse model with correction of endocrine abnormalities.

Prof. Canaud’s team obtained authorization to treat all five patients with alpelisib, and observed a clear improvement in muscle hypertrophy in all patients, associated with progressive symmetrization of the face. Response to treatment was assessed and confirmed using innovative imaging methods, including 3D photography and artificial intelligence analysis of 2D photographs. These morphological approaches were confirmed by cellular and molecular methods, which demonstrated that alpelisib had a positive and prolonged action on the effects of the PIK3CA gene mutation.

These results finally provide a genetic explanation for patients with hemifacial myohyperplasia, an understanding of the disease mechanisms and a glimpse of a finally effective therapeutic perspective.

[1] Lee et al., 2001

[2] Castillo Taucher et al., 2003; Pereira-Perdomo et al., 2010; Miranda et al., 2010; Siponen et al., 2007; Zissman et al., 2020

[3] Zissman et al., 2020

[4] activating mutation

[5] animal experimentation model on rats or mice