Recent progress in understanding congenital cranial dysinnervation disorders

Abstract

Background: In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report.

Evidence acquisition: Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders.

Results: At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns.

Conclusions: Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities.

Figure 1

CFEOM1 phenotype. A. Primary position showing marked bilateral ptosis. B. Primary position with lids held showing resting globe position. Both eyes remain infraducted below midline. C. Attempted up gaze showing inability to reach midline with convergence of the visual axis (synergistic convergence).

Figure 2

CFEOM2 phenotype. A. Primary position showing bilateral ptosis and exotropia. B. Primary position with lids held showing resting globe position. C. Patient with right face turn and holding left upper lid to clear pupillary axis. D. Miotic irregular pupil.

Figure 3

CFEOM3B phenotype. All images are in primary position. A. Patient has unilateral ptosis and esotropia. B. Patient has severe bilateral ptosis in primary position despite with marked frontalis effort. C. Same patient as B in primary position with lids held showing resting globe position marked by exotropia and bilateral infraduction.

Figure 4

CFEOM3A phenotype. A. Primary position. B. Right gaze with absent adduction and slight down shoot OS. C. Left gaze with absent adduction, slight down shoot OD, and limited abduction OS. D. Attempted upgaze showing limitation OU with OS unable to reach midline and with development of an esotropia. E. Down gaze fixing OD with slight downward movement OD and only outward movement of non-fixing OS. F. Down gaze fixing OS with slight downward movement OS and only outward movement of non-fixing OD.

Figure 5

HOXA1 Spectrum phenotype. A, B, C. Right gaze, primary gaze, and left gaze of a girl with bilateral Duane retraction syndrome type 3. Note up shoot OS on attempted left gaze. D. Axial CT bone windows of the same patient showing almost no development of the petrous bones except for mastoid air cells. E. MR angiogram of the Circle of Willis in the same patient showing absent left internal carotid artery and relatively large caliber of the basilar and both posterior cerebral arteries.

Figure 6

HGPPS phenotype. A. Primary position. B. Attempted right gaze showing complete gaze palsy. C. Attempted left gaze showing complete gaze palsy. D. Moderately severe scoliosis concave right. E. Hypoplasia of the pons. F. Deep anterior and posterior clefts in the medulla causing the classic “butterfly medulla” appearance.