Growth charts in <i>FGFR2</i>- and <i>FGFR3</i>-related faciocraniosynostoses.

Abstract

Faciocraniosynostoses (FCS) are malformations affecting the development of the bones of the skull and face, due to the premature closure of one or more craniofacial sutures, mostly secondary to activating <i>Fibroblast Growth Factor Receptor</i> (<i>FGFR</i>) 1-3 mutations. Gain-of-function <i>FGFR3</i> mutations are also responsible for various conditions referred to as osteochondrodysplasia (OCD), characterized by structural and functional abnormalities of growth plate cartilages. We hypothesized that patients with <i>FGFR</i>-related faciocraniosynostoses may present extra-cranial growth anomalies. We retrospectively collected height and weight data from a cohort of 70 patients. Included patients were admitted for <i>FGFR</i>-related FCS between 2000 and 2021 at the Craniofacial Unit of Necker - Enfants Malades University Hospital in Paris, France. We showed that <i>FGFR</i>-related faciocraniosynostoses had significantly reduced heights and weights relative to controls, and that two specific time periods (1-3 years and > 8 years of age) were associated with lower height and weight values. Four patients had received growth hormone treatment but remained below normal values for growth in height and weight. Patients with <i>FGFR</i>-related faciocraniosynostoses have clinically significant extra-cranial anomalies which are not currently investigated and managed in usual protocols; these patients could benefit from a systematic pre-pubertal endocrine assessment. More generally, our results extend the scope of extracranial anomalies in <i>FGFR</i>-related faciocraniosynostoses and support the hypothesis that all conditions with activating <i>FGFR</i> mutations affect both membranous ossification and long bones.