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Congenital Cranial Dysinnervation Disorder
Published in Vivek Lal, A Clinical Approach to Neuro-Ophthalmic Disorders, 2023
Clinical features are usually similar to the classical CFEOM, but the eyes are usually in exotropic position. High-resolution magnetic resonance imaging (MRI) has shown absent cranial nerve III and IV in CFEOM 2 patients. In some patients, the muscles supplied by oculomotor nerve viz. superior rectus, levator palpebrae superioris, inferior rectus, and medial rectus, and that supplied by trochlear nerve viz. superior oblique were found to be small, fibrotic, and thin strand-like (11). Autosomal recessive inheritance with complete penetrance is observed, frequently associated with history of parental consanguinity. The ARIX gene (previously called PHOX2A) encodes a transcription factor that is specifically involved in the determination of the noradrenergic neuronal phenotype. In an animal model, loss of function mutations has resulted in the loss of III and IV cranial nerves (12).
Congenital Central Hypoventilation Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Expressed during neural development in the nuclei of brainstem areas that contain pathways controlling breathing and auditory functions [5], PHOX2B is regulated transcriptionally by itself, as well as E2a and Hand2 at specific sympathetic and enteric nervous system developmental stages. Other proteins that may play a possible role in the regulation of PHOX2B are SOX10, PHOX2A, and HASH1. Further, by forming trimer with Pbx1 and Meis1, Hoxb1 and Hoxb2 also contribute to the regulation of PHOX2B transcription.
Childhood Onset Strabismus: A Neurotrophic Factor Hypothesis
Published in Journal of Binocular Vision and Ocular Motility, 2021
Jolene C. Rudell, Jérome Fleuriet, Michael J. Mustari, Linda K. McLoon
Additional evidence that the main contributor to the development of childhood onset strabismus originates from the central nervous system comes from study of the rarest forms of strabismus, the congenital cranial dysinnervation disorders (CCDDs). The CCDDs are often called “congenital fibrosis of the extraocular muscles” or CFEOM. The majority of these rare genetic CCDDs result in strabismus due to abnormal axon growth in the motor nerves from one or more nuclei of the ocular motor complex.15,16 Mutations in the KIF21A gene causes CFEOM1 and CFEOM3.17KIF21A is a kinesin that is responsible for cargo delivery through retrograde and anterograde axonal transport, and the mutation results in oculomotor nerve loss and muscle atrophy. Similarly, CFEOM2 is caused by mutations in the ARIX/PHOX2A gene, which is critically important for the development and routing of cranial nerves III (oculomotor) and IV (trochlear).18 Interestingly, Ret, a glial cell line-derived neurotrophic factor (GDNF) receptor subunit, also is regulated in part by the PHOX2A gene,19 implicating down-stream neurotrophic factor alterations that could be the sequelae of these motor nerve abnormalities. The absence of the abducens nerve in Duane retraction syndrome can be caused by mutations in SALL4, ROBO3, HOXA1, and the CHN1 gene, which results in mutations in the α2-chimaerin protein which alters normal cytoskeletal dynamics and abducens nerve formation.16,20,21 While rare, these CCDDs demonstrate that some forms of strabismus can result from primary ocular motor nerve maldevelopment.
Advances in the molecular biology and pathogenesis of congenital central hypoventilation syndrome—implications for new therapeutic targets
Published in Expert Opinion on Orphan Drugs, 2018
Simona Di Lascio, Roberta Benfante, Silvia Cardani, Diego Fornasari
PHOX2B is therefore considered a ‘master selector gene’, and its role in lineage commitment has also been clearly demonstrated in vitro by the fact that its forced expression promotes the generation of specific types of neurons (i.e. central noradrenergic and hindbrain visceromotor neurons) from mouse embryonic stem cells [50]. In addition to playing a major role in lineage specification, PHOX2B (together with its paralogue PHOX2A) plays an important role in maintaining neuronal differentiation, at least up to the late embryonic stages [51], thus making it a ‘terminal selector gene’.
Congenital Fibrosis of Extraocular Muscles: A Systematic Review and Meta-Analysis
Published in Journal of Binocular Vision and Ocular Motility, 2023
Joshua M. Van Swol, Walter K. Myers, Shaun A. Nguyen, M. Edward Wilson
Mutations in multiple genes have been identified to cause oculomotor nerve dysinnervation resulting in secondary fibrosis. Inherited mutations in KIF21A (kinesin motor protein) can cause CFEOM1 and less commonly CFEOM3. Inherited PHOX2A (transcription factor necessary for CNIII/IV development) mutations are associated with CFEOM2. Additionally, TUBB3 (microtubule component) inherited mutations are associated with CFEOM3 and less commonly CFEOM1. Sporadic forms of CFEOM may be caused by other gene mutations.4