John Pratt-Johnson Lecture
Ocular Aspects of Craniofacial Disorders
Craniofacial disorders may comprise various entities such as clefting anomalies, tumors, e.g., fibrous dysplasia, orbito-facio-cranial trauma, and the craniosynostoses. Each may have significant ocular involvement but the focus of my discussion is the craniosynostoses.
Craniosynostosis is the premature closure of one or more cranial sutures and this may be associated with systemic features or an isolated finding. When a suture closes prematurely growth of the skull continues parallel to the suture but is arrested or retarded perpendicular to it. This results in an irregular shape of the skull. Previously patients with suture synostosis were described as having a particular shaped head such as plagiocephaly, brachycephaly, or scaphocephaly to name a few. These are now better described in terms of the sutures involved, e.g., plagiocephaly is better described as unicoronal synostosis, brachycephaly as bicoronal synostosis, and scaphocephaly as sagittal synostosis.
There are over one hundred syndromic synostoses but the most common craniosynostoses include Pfeiffer, Crouzon, Apert, Saethre-Chotzen, Jackson-Weiss and craniofrontonasal dysplasia. The genetics of the syndromic craniosynostoses have been an area of great interest recently. Mutations in FGFR2 (fibroblast growth factor receptor type 2) have been shown to cause Crouzon, Jackson-Weiss, Apert and Pfeiffer syndromes. Fibroblast growth factor is involved in a variety of activities including mitogenesis, angiogenesis and wound healing. FGFR is a membrane –spanning tyrosine kinase receptor. FGFR2 mutations shown to be responsible for the syndromic craniosynostoses mentioned are thought to cause a gain-of-function effect rather than a loss-of-function effect, which may explain then the increased closure rate of the sutures concerned. Other FGFR types have also been implicated including FGFR1 (Pfeiffer syndrome) and FGFR3 (Crouzon syndrome with acanthosis nigricans, and certain cases of non-syndromic unicoronal synostosis). FGFR3 has also been implicated in some cases of achondroplasia. Crouzon, Apert and Pfeiffer syndromes all share features such as midfacial hypoplasia of varying degrees with shallow orbits, craniosynostoses, but differ from the systemic features involved. Apert patients show marked syndactyly, Pfeiffer patients aberrant thumbs and toes, while Crouzon patients have relatively normal hands. Patients with Saethre-Chotzen syndrome display mild syndactyly with webbing between the fingers and often show ptosis. Some cases of Saethre-Chotzen syndrome have been shown to be due to mutations in the TWIST gene. This is a transcription factor gene, which controls myogenesis. Craniofrontonasal dysplasia is an X-linked dominant condition, in which females only are affected. There is often marked Hypertelorism, craniosynostoses and a very mild cleft of the tip of the nose. Often these patients display longitudinal splits in their nails and this can be a marker for the condition. Jackson-Weiss syndrome is distinguished clinically from Crouzon syndrome on the basis of additional foot anomalies involving enlarged and laterally pointing great toes.