Congenital cranial dysinnervation disorders (CCDDs) are a group of rare, nonprogressive conditions characterized by abnormal development of the cranial motor nerves and variable ocular motility deficits, ptosis, incomitant strabismus, and facial palsy. Advances in genetics and neuroimaging have revealed that these disorders result from defects in neuronal differentiation or axon guidance of the cranial motor neurons. Duane retraction syndrome, the most common CCDD, results from the absence of the abducens nerve and innervation of the lateral rectus by oculomotor nerve axons; causative genes include CHN1, MAFB, HOXA1, SALL4, and EBF3, although most cases do not have a genetic diagnosis. Congenital fibrosis of the extraocular muscles (CFEOM), results from variants in KIF21A, PHOX2A, TUBB3, or other tubulin genes, and affects the oculomotor and trochlear nerves. Horizontal gaze palsy with progressive scoliosis (HGPPS), caused by ROBO3 loss of function, arises from failure of axonal midline crossing in the brainstem. Moebius syndrome, defined by abducens and facial nerve palsies, has no identified genetic cause and may result from non-Mendelian causes. Additional CCDDs with atypical or syndromic presentations are linked to COL25A1, ECEL1, and ACKR3, although many do not have a genetic explanation. The expanding list of CCDD-associated genes highlights shared developmental pathways, including neuronal differentiation, axon guidance, and microtubule dynamics. Improved genetic diagnosis informs prognosis and multidisciplinary management. This review synthesizes current understanding of CCDDs, emphasizing the shift from phenotypic classification to molecular subtyping, and underscores the importance of ongoing research to resolve genetically unsolved cases and refine diagnostic and therapeutic strategies.
Aufderheide et al. (Mon,) studied this question.