CLINICAL REPORT Masticatory Muscle Defects in Hemifacial Microsomia: A New Embryological Concept  Eglantine Heude, 1 Isabelle Rivals, 2 G erard Couly, 1,3 and Giovanni Levi 1 * 1  Evolution des R egulations Endocriniennes, UMR CNRS 7221, Mus eum National d’Histoire Naturelle, Paris, France 2  Equipe de Statistique Appliqu ee,  Ecole Sup erieure de Physique et de Chimie Industrielles ParisTech, Paris, France 3 Service de Chirurgie Plastique, Maxillofaciale et Stomatologie, H^ opital Necker-Enfants Malades, Paris, France Received 13 December 2010; Accepted 13 April 2011 First arch syndromes correspond to a wide spectrum of human latero-facial congenital anomalies affecting cranial neural crest cells (CNCCs) derivatives of the first pharyngeal arch (PA1). The abnormal traits display variable quantitative expression and are often unilateral. Mandibular skeletal defects are invariably ac- companied by hypoplasia or agenesis of masticatory muscles, but no explanation has been proposed for this association. Indeed, during embryonic development, CNCCs give only rise to skeletal components of the head while muscles derive from cephalic myogenic mesodermal cells (CMMCs). Recent studies on animal models have shown that communication between CNCCs and CMMCs is essential for the development of masticatory muscles: genetic lesions affecting only CNCCs can prevent musculariza- tion of the jaws. To evaluate the involvement of CNCC/CMMC interactions in human craniofacial development, we performed a quantitative analysis of masticatory muscle and mandibular bone volumes on craniofacial CT-scans from 8 children, ages 3 months to 16 years, affected by hemifacial microsomia. We found that: (1) in seven patients the masseter muscle is absent in the affected side; (2) the absence of masseter is correlated neither with the age of the patients nor with the volume and shape of the affected ramus; and (3) in all cases the pterygoid and the temporal muscles are either reduced or absent. Our findings suggest that an early developmental event is the origin of the muscular defects in these patients. We propose that the hypoplasia or agenesis of masticatory muscles derives from a defect in the CNCCs/CMMCs communication during early embryonic development. Ó 2011 Wiley-Liss, Inc. Key words: hemifacial microsomia; CT-Scan; 3D reconstitution; mandible; masticatory muscles; craniofacial development; cranial neural crest cells; cephalic myogenic mesodermal cells INTRODUCTION During jaw development of vertebrate embryos, cranial neural crest cells (CNCCs) from the posterior mesencephalic neural fold and the first rhombomeres migrate to the first pharyngeal arch (PA1) to give rise to the skeletal maxillo-mandibular elements [Couly et al., 2002]. In contrast, masticatory muscles are formed by PA1 cephalic myogenic mesodermal cells (CMMCs) [Couly et al., 1992; Trainor et al., 1994]. Although jaw muscles do not derive directly from CNCCs, these cells are a necessary source of molecular cues for the determination, differentiation, and patterning of CMMCs [Rinon et al., 2007; Grenier et al., 2009; Tokita and Schneider, 2009; Heude et al., 2010]. The CNCCs–CMMCs interaction is necessary to maintain the myogenic program in the CMMCs, leading to masticatory muscle formation. First arch syndromes are human congenital malformations of the face resulting from defects of neural crest skeletal derivatives [Gorlin, 2001]. The specific type of first arch syndrome, hemifacial microsomia, is characterized by asymmetric defects of skeletal proximal PA1 derivatives. The most commonly affected skeletal structures include (1) the ascending ramus of the mandible, which is reduced or absent while distal mandibular components and teeth are not affected; (2) the temporo-mandibular joint; (3) the zygo- matic arch; and (4) most components of the external and middle ear including the incus, the malleus, and the tympanic bone (see, e.g., Additional supporting information may be found in the online version of this article. Grant sponsor: Association Franc ¸aise contre les Myopathies (AFM); Grant sponsor: Agence Nationale pour la Recherche (ANR) project DrOS and project Gendactyl. *Correspondence to: Giovanni Levi, CNRS UMR7221 – MNHN  Evolution des R egulations Endocriniennes, 7, rue Cuvier, 75231 Paris Cedex 05, Paris, France. E-mail: glevi@mnhn.fr Published online 8 July 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ajmg.a.34095 How to Cite this Article: Heude E, Rivals I, Couly G, Levi G. 2011. Masticatory muscle defects in hemifacial microsomia: A new embryological concept. Am J Med Genet Part A 155:1991–1995. Ó 2011 Wiley-Liss, Inc. 1991