Congenital Cranial Dysinnervation Disorders

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Congenital Cranial Dysinnervation Disorders (CCDD) is a spectrum of congenital non-progressive disease with a similar underlying etiology. Each has their own pattern of synkinesis resulting in their individual and characteristic clinical features. The more serious causes of ophthalmoplegia, cranial nerve palsy, and congenital ptosis (e.g. neonatal stroke and neoplasm) should be investigated before a further assessment to identify a possibly underlying CCDD is undertaken. The primary management for all CCDD’s is early identification and subsequent correction of any associated clinical feature that may predispose the child to amblyopia.

Disease Entity

Congenital Cranial Dysinnervation Disorders (CCDD) is a spectrum of congenital non-progressive disease with a similar underlying pathophysiology. Early developmental incidents result in strabismus with specific dysinnervation patters for the extraocular muscles (EOMs) and resultant ophthalmoplegia. The CCDD spectrum includes the Marcus Gunn jaw-winking phenomenon, Möbius syndrome, Duane Syndrome, Congenital Fibrosis of the muscles, and other congenital facial palsies.[1]


Heuk first identified a class of congenital mobility eye abnormalities in 1879 that included inferior bulbi that were both convergent and hypertropic, as well as bilaterally weak eyelids. Later, strabismus involving more than two eye muscles, such as congenital fibrosis of extraocular muscles (CFEOM), Duane syndrome, Brown syndrome, and vertical retraction syndrome, came to be known as "global fibrosis syndrome." (Hanisch) In 2002, the European Neuromuscular Centre coined the acronym "CCDD" to describe a collection of congenital neuromuscular disorders.[2][3][4]

Early in development there is dysinnervation of the extraocular muscles, the absence of innervation can lead to weakening or fibrosis of the target muscle and subsequent congenital ophthalmoplegia, ptosis, and aberrant innervation. Many, but not all of the CCDD’s, have an autosomal inheritance pattern while others are sporadic. If a result of a genetic mutation the mutations can be split into two forms of perturbations: gene function critical for correct ocular cranial mortar neuro specification (HOXA1, HOXB1, SALL4, PHOX2A) and those that are necessary for correct axon growth and guidance (TUBB3, TUBB2B, ROBO3, KIF21A, CHN1). However, relatively little is known about the cues that guide the axons to their targets. Mice modified without EOMs still had proper axonal direction and development up to the terminal branches, suggesting that guidance is due to either mesenchymal cues, axon-axon interactions, and/or cell autonomous processes. Muscle-derived cues were however important for terminal branching.[5][6]


Marcus Gunn Jaw winking phenomenon (MGJWS)

Clinical Findings/Physical Exam

MGJWS typically presents with transient upper eyelid retraction or elevation during stimulation of the ipsilateral pterygoid muscle (e.g., smiling, chewing, sucking, jaw protrusion, or even just opening the mouth). This phenomenon is often noticed upon intial feeding. MGJWS can either be unilateral or bilateral and some of the ocular/systemic associations include Duane retraction syndrome, Morning Glory syndrome, and CHARGE syndrome (coloboma, heart defects, choanal atresia, retardation of growth and development, genitourinary abnormalities, and ear abnormalities). [7]


Synkinesis is when there are coordinated movements of the muscles innervated by either the same or a different nerve. In MGJWS there are abnormal connections between the superior branch of the oculomotor nerve (cranial nerve III) and the motor branches of the trigeminal nerve (cranial nerve V) resulting in coordinated synkinetic movement at the terminal muscles. Specifically, the “winking” (levator palpebrae activation) occurs because there is concurrent jaw movement (trigeminal activation). There have been familial cases, but more commonly the phenomenon is idiopathic. It can also be acquired as a result of aberrant nerve regeneration secondary to ocular surgery or trauma. [8]


It is critical to ensure that the resulting congenital ptosis does not cover the visual axis, which could lead to subsequent amblyopia and up to 30-60% of MGJWS have amblyopia that should be treated. To correct any anisometropia, retinoscopy should be performed as soon as possible. If the visual axis is obstructed, surgical correction may be required, however, correcting ptosis in MGJWS is more difficult than in standard idiopathic congenital ptosis. When there is a visual axis obstruction, the ptosis is likely severe, and the best surgical technique may be bilateral frontalis suspension. [9]

Möbius Syndrome

Clinical Findings/Physical Exam

The most commonly affected cranial nerves in Möbius syndrome are the abducens and facial nerves. Thus, patients present most commonly with lateral gaze restriction and facial drooping that does not spare the forehead and brow. Other potentially affected nerves are CN III, IV, V, IX, X, and XII, with possible Poland anomaly (pectoralis minor hypoplasia), dysmorphic facies and extremities, developmental delay, and dysphagia .[10] Early in life, problems with feeding may be the chief complaint, but social problems due to difficulty with facial expression may present as the patient grows. [11]


Most Möbius syndrome cases are sporadic. While loci in chromosome 1 and 13 have been associated with Mobius, including 13q12.2 no single gene has been implicated as the unifying cause. Additionally, a suggested theory that vascular incidents in utero (e.g. from cocaine or misoprostol use during pregnancy) is implicated in the pathogenesis of Möbius syndrome. [10][12]


Physical and speech therapy help patients with Mobius and early rehabilitation has been linked with better functional outcomes. [11]

Duane Retraction Syndrome


Like the other CCDD’s, Duane Retraction Syndrome is a non-progressive ocular motility disorder. It is characterized by absent or dysplastic abducens motor neurons with resulting synkinesis on the lower division of the oculomotor nerve that innervates the medial rectus. Up to 90% of cases are sporadic but the remaining 10% of patients inherit the syndrome in an autosomal dominant fashion - the autosomal dominant type normally presents bilaterally. [13][14]

Clinical Findings/Physical Exam

Because the lateral rectus muscle and the oculomotor nerve are now synkinetic simultaneous contraction of the medial and lateral rectus will produce the globe retraction and narrowing of the palpebral fissure. Ptosis is also a frequent clinical feature in the adducting eye. As strabismus is a very prevalent clinical presentation in children with Duane Retraction syndrome, it is equally crucial to address any amblyopia. [13] The different types of Duane syndrome can occur with abduction, adduction, or a combination of these ocular motor deficits.


Management is similar to the other CCDD’s, it is imperative to identify any factors (associated congenital ptosis and strabismus) that may predispose the child amblyopia early on. [13]

Congenital Fibrosis of the Extraocular Muscles

Clinical Findings/Physical Exam

Congenital fibrosis of the extraocular muscles (CFEOM) is characterized by non-progressive bilateral ophthalmoplegia with or without ptosis involving the oculomotor nerve, or less commonly, the trochlear and abducens nerve. Vertical gaze is more often impaired but variable horizontal gaze impairment can also occur. Patients may have abnormal head positioning such as chin elevation to compensate. Classification of CFEOM is determined by phenotypic manifestations and genetic evaluation. [3][4][15]


CFEOM results from primary dysinnervation of the extraocular muscles innervated by the oculomotor nerve and/or trochlear nerve. Several gene mutations have been identified and vary based on the phenotype of CFEOM. For example, type 1A CFEOM is an autosomal dominant form resulting from heterozygous mutations in the KIF21A gene on chromosome 12 which codes for a kinesin motor protein. Type 1B has the same phenotype but is caused by a mutation in the TUBB3 or TUBB2 gene. CFEOM 2 is a rare form thought to arise from a mutation in the PHOX2A gene while CFEOM 3A is due to TUBB3 gene mutation.[16]


Management of CFEOM is largely focused on treatment of abnormal head posture (AHP) adopted to compensate for the ophthalmoplegia and ptosis which can occur with amblyopia, strabismus, or abnormal binocularity. Several factors contribute to the complexity of surgical management in CFEOM. For example, Strabismus surgery should occur prior to ptosis correction and, due to concerns for exposure keratopathy and absent Bell’s phenomenon, surgical intervention should aim to undercorrect the patient’s ptosis. Additionally, surgical outcomes can be unpredictable due to the restrictive nature of CFEOM. [17]

Differential Diagnosis

●Neonatal stroke

●CHARGE syndrome (Coloboma, Heart defect, Atresia choanae, Renal abnormality, Genital defects, Ear abnormalities)

●Idiopathic congenital ptosis

●Congenital cranial nerve palsies (third, fourth, etc.)

●Neonatal neoplasm (e.g. teratoma, astrocytoma, embryonal tumors)

●Trauma (birth, accidental, and non-accidental)


  1. Assaf AA. Congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorders (CCDDs). Eye (Lond). 2011;25(10):1251-1261. doi:10.1038/eye.2011.38
  2. Hanisch F, Bau V, Zierz S. Congenital fibrosis of extraocular muscles (CFEOM) and other phenotypes of congenital cranial dysinnervation syndromes (CCDD). Nervenarzt. 2005;76(4):395-402. doi:10.1007/s00115-004-1742-3
  3. 3.0 3.1 Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25-27 October, 2002. Neuromuscul Disord. 2003;13(7-8):573-578. doi:10.1016/s0960-8966(03)00043-9
  4. 4.0 4.1 Singh A, Pandey PK, Agrawal A, Mittal SK, Rana KM, Bahuguna C. Congenital cranial dysinnervation disorders. Int Ophthalmol. 2017;37(6):1369-1381. doi:10.1007/s10792-016-0388-z
  5. Whitman MC, Engle EC. Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance. Hum Mol Genet. 2017;26(R1):R37-R44. doi:10.1093/hmg/ddx168
  6. Fels R. Congenital Cranial Dysinnervation Disorders: A Literature Review. Am Orthopt J. 2017;67(1):89-92. doi:10.3368/aoj.67.1.89
  7. Demirci H, Frueh BR, Nelson CC. Marcus Gunn jaw-winking synkinesis: clinical features and management. Ophthalmology. 2010;117(7):1447-1452. doi:10.1016/j.ophtha.2009.11.014
  8. Pratt SG, Beyer CK, Johnson CC. The Marcus Gunn phenomenon. A review of 71 cases. Ophthalmology. 1984 Jan;91(1):27-30.
  9. Morax S, Mimoun G. Traitement chirurgical du syndrome de Marcus-Gunn. Indications et résultats. A propos de 15 cas [Surgical treatment of the Marcus-Gunn syndrome. Indications and results. Apropos of 15 cases]. Ophtalmologie. 1989;3(2):160-163.
  10. 10.0 10.1 Albayrak HM, Tarakçı N, Altunhan H, Örs R, Çaksen H. A congenital cranial dysinnervation disorder: Möbius' syndrome [published correction appears in Turk Pediatri Ars. 2017 Dec 1;52(4):246]. Turk Pediatri Ars. 2017;52(3):165-168. Published 2017 Sep 1. doi:10.5152/TurkPediatriArs.2017.2931
  11. 11.0 11.1 Picciolini O, Porro M, Cattaneo E, et al. Moebius syndrome: clinical features, diagnosis, management and early intervention. Ital J Pediatr. 2016;42(1):56. Published 2016 Jun 3. doi:10.1186/s13052-016-0256-5
  12. Slee JJ, Smart RD, Viljoen DL. Deletion of chromosome 13 in Moebius syndrome. J Med Genet. 1991;28(6):413-414. doi:10.1136/jmg.28.6.413
  13. 13.0 13.1 13.2 Barry BJ, Whitman MC, Hunter DG, Engle EC. Duane Syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; May 25, 2007.
  14. Murillo-Correa CE, Kon-Jara V, Engle EC, Zenteno JC. Clinical features associated with an I126M alpha2-chimaerin mutation in a family with autosomal-dominant Duane retraction syndrome. J AAPOS. 2009;13(3):245-248. doi:10.1016/j.jaapos.2009.03.007
  15. Tawfik HA, Rashad MA. Surgical management of hypotropia in congenital fibrosis of extraocular muscles (CFEOM) presented by pseudoptosis. Clin Ophthalmol. 2013;7:1-6. doi:10.2147/OPTH.S35557
  16. Whitman MC, Jurgens JA, Hunter DG, Engle EC. Congenital Fibrosis of the Extraocular Muscles Overview. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; April 27, 2004.
  17. Whitman MC, Jurgens JA, Hunter DG, Engle EC. Congenital Fibrosis of the Extraocular Muscles Overview. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; April 27, 2004.
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