Congenital cranial dysinnervation disorders and more

Abstract

We are syndromologists. We recognize patterns of clinical abnormalities and try to match them to known entities—syndromes. We are excited to diagnose the rare and unusual and are intrigued by the presence of unrecognized clinical findings in patients with previously well-described disorders. Even more challenging are complex clinical syndromes that overlap two or more entities. Are they one, or the other? Or is it a “new syndrome”? The discovery of the genetic basis of syndromes and the availability of clinical molecular testing has allowed the resolution of conflicting opinions about clinical diagnoses. Variable expressivity of genetic diseases had been recognized for decades but has become more appreciated with the availability of molecular proof. Who would have thought that mutations in PAX6 would cause not only aniridia, but also dominant keratitis, Peters anomaly, isolated foveal hypoplasia, or cataracts? Terminology remains problematic in connection with certain conditions that have been named for their describer or for their main signs. Congenital cranial disinnervation disorders (CCDDs) is one group of disorders that has received a lot of attention in recent years because of the discovery of several of the genes that cause individual clinical entities. The CCDDs result from aberrant innervation of the ocular and facial musculature. They generally arise from abnormal development of individual or multiple cranial nerve nuclei or their axonal connections. Although the majority are either proven or suspected to have a genetic etiology, phenocopies occur. While some have only abnormalities of ocular and facial innervation, others have additional consistent systemic malformations that can be attributed to the underlying genetic defect. The CCDDs include Duane syndrome, congenital fibrosis of the extraocular muscles (CFEOM), Mobius’ syndrome, Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS), the Bosley-Salih-Alorainy/Athabaskan Brainstem Dysgenesis Syndromes (BSAS), and an expanding list that may include congenital third and fourth nerve palsies, Marcus Gunn jaw winking ptosis, and others. I have