Congenital Cranial Dysinnervation Disorders

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Article initiated by:

Andrew Go Lee, MD, Evan Wotipka, MD, Melody Ziari, Noor Laylani, M.D., Pamela Davila-Siliezar, MD, Zachary Richards

All contributors:

Andrew Go Lee, MD, Evan Wotipka, MD, Melody Ziari, Pamela Davila-Siliezar, MD, Zachary Richards, Nagham Al-Zubidi, MD, S. Grace Prakalapakorn, MD, MPH, Noor Laylani, M.D., Lan Chang, MD

Assigned editor:

Lan Chang, MD

Review:

Assigned status Up to Date

 by Lan Chang, MD on August 27, 2024.

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Congenital Cranial Dysinnervation Disorders (CCDDs) are a spectrum of congenital non-progressive disease with a similar underlying etiology. Each disorder has its own pattern of synkinesis resulting in 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 CCDDs is early identification and subsequent correction of any associated clinical feature that may predispose the child to amblyopia.

Disease Entity

Congenital Cranial Dysinnervation Disorders (CCDDs) are 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.

History

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.

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 motor neuron 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.

Diseases

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 first noticed upon 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).

Etiology

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.

Management/Treatment

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.

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 . 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.

Etiology

Most Möbius syndrome cases are sporadic. While loci in chromosome 1 and 13 have been associated with Möbius, 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.

Management/Treatment

Physical and speech therapy help patients with Möbius and early rehabilitation has been linked with better functional outcomes.

Duane Retraction Syndrome

Etiology

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.

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. The different types of Duane syndrome can occur with abduction, adduction, or a combination of these ocular motor deficits.

Management/Treatment

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.

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.

Etiology

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.

Management/Treatment

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.

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)