Congenital cranial dysinnervation disorders (CCDDs) are a group of congenital, non-progressive diseases that present with paralytic strabismus due to abnormal innervation (dysinnervation) of the extraocular muscles. In 1879, Heuk first identified a group of congenital ocular motility abnormalities, and in 2002, the European Neuromuscular Centre established the term “CCDD.”
CCDDs are classified based on the affected cranial nerves and occur as isolated ocular motor disorders or as part of syndromes with other neurological and non-neurological features depending on the genetic mutation 1). The main diseases included are as follows.
Each disease has its own pattern of synkinesis and presents with characteristic clinical features.
Marcus Gunn jaw-winking phenomenon, Moebius syndrome, Duane syndrome, and congenital fibrosis of the extraocular muscles (CFEOM) are included. Duane syndrome is the most common, occurring in about 1 in 1,000 people1).
Since CCDDs are congenital, patients rarely notice the abnormality themselves. They are often discovered by family members or healthcare professionals.
Each disease presents a characteristic clinical picture.
MGJWS
Eyelid elevation by trigeminal nerve stimulation: The ipsilateral upper eyelid transiently elevates during actions such as smiling, chewing, sucking, or opening the mouth.
Discovery opportunity: Often first noticed during breastfeeding.
Unilateral or bilateral: Unilateral cases are more common.
Coexisting amblyopia: Amblyopia requiring treatment is present in 30–60% of cases.
Möbius syndrome
Abducens and facial nerve palsy: The abducens nerve (CN VI) and facial nerve (CN VII) are most commonly affected.
Facial drooping: In addition to limited lateral gaze, facial muscle paralysis including the forehead and eyebrows is observed.
Vertical eye movements preserved: Horizontal movement limitation is predominant1).
Associated abnormalities: May include Poland anomaly, limb abnormalities, developmental delay, and dysphagia.
DRS
Abduction limitation and globe retraction: Globe retraction and palpebral fissure narrowing on adduction are common findings.
Type I (most common): Mainly abduction limitation. Type II shows adduction limitation, and Type III shows both adduction and abduction limitation.
Mostly unilateral: Over 80% are unilateral, more common in the left eye.
Compensatory head posture: Often involves head turn 1).
CFEOM
Bilateral ophthalmoplegia: Non-progressive bilateral eye movement disorder with or without ptosis.
Vertical gaze palsy: Vertical impairment is common, and horizontal impairment is also observed to varying degrees.
Compensatory chin elevation: An abnormal head posture is adopted to maintain the visual axis.
MRI findings: Marked hypoplasia of the superior rectus and levator palpebrae superioris muscles, and hypoplasia and abnormal course of the orbital motor nerves1).
In DRS, the inferior branch of the oculomotor nerve aberrantly innervates the lateral rectus, causing simultaneous contraction of the medial and lateral recti, leading to globe retraction. MRI confirms hypoplasia or absence of CN6 and innervation of the lateral rectus by CN31).
The etiology of CCDDs is broadly divided into two major mechanisms in the development of cranial nerves1).
Specific Abnormalities of Neurons
PHOX2A: Homozygous loss-of-function mutation → CFEOM2 (congenital absence of CN3, CN4, and motor nuclei)
HOXA1: Homozygous loss-of-function mutation → bilateral DRS + sensorineural hearing loss + facial nerve palsy + central hypoventilation + vascular malformations + intellectual disability
SALL4: Haploinsufficiency → Duane radial ray syndrome (DRS + upper limb malformations, autosomal dominant)
MAFB: Heterozygous loss-of-function mutation → isolated DRS. Dominant-negative mutation → DRS + hearing impairment
Abnormal Axon Growth and Guidance
KIF21A: heterozygous missense mutation → CFEOM1 (kinesin-4 family motor protein)
TUBB3: missense mutation → CFEOM3 (neuron-specific β-tubulin)
CHN1: heterozygous mutation → DRS (α2-chimaerin). Often bilateral DRS
ROBO3: homozygous mutation → HGPPS (horizontal gaze palsy with progressive scoliosis). Prevents midline crossing of commissural axons
Most cases follow autosomal inheritance, but sporadic cases also occur.
Other associated genes include TUBB2B, ECEL-1, ACKR3, COL25A1, TUBB6, and CDH2 (N-cadherin), which are involved in various CCDD phenotypes1).
Autosomal inheritance is common, but sporadic cases are also frequent. Duane syndrome is sporadic in 90% of cases. In Möbius syndrome, intrauterine vascular disruption has also been suggested as a contributing factor.
First, serious causes such as neonatal stroke or tumor must be ruled out. The diagnosis of CCDDs is based on characteristic clinical findings such as synkinetic patterns, globe retraction, and palpebral fissure narrowing.
Panel testing of causative genes according to the CCDD phenotype is performed.
The main differential diagnoses are shown below.
| Differential diagnosis | Key points for differentiation |
|---|---|
| Neonatal stroke | Acute onset, imaging findings |
| CHARGE syndrome | Multiple congenital anomalies |
| Congenital cranial nerve palsy | Progressive or not |
| Neonatal tumor | Imaging findings, progressive |
The general management principle for all CCDDs is early detection of amblyopia and correction of related clinical symptoms.
The essence of CCDDs is abnormal innervation (dysinnervation) of the extraocular muscles during early development. Identification of causative genes has revealed that inappropriate development of cranial motor neurons and secondary fibrosis of uninnervated muscles are central to the pathology1).
Loss-of-function mutations in transcription factors required for brainstem patterning result in failure to form specific motor neurons1).
Motor neurons are formed, but axons cannot correctly reach the target muscle 1).
The correspondence between causative genes and disease phenotypes is shown below.
| Gene | Phenotype |
|---|---|
| KIF21A | CFEOM1 |
| TUBB3 / TUBB2B | CFEOM3 |
| PHOX2A | CFEOM2 |
| CHN1 | DRS (often bilateral) |
| ROBO3 | HGPPS |
| COL25A1 | Congenital ptosis/DRS |
When one nerve is missing, its normal target muscle attracts other motor neurons. There are also reports of CN6 projecting to the normal target muscle of CN3 when CN3 has a complete aberrant course 1).
In autopsies of CFEOM1 cases with KIF21A mutations, defects in the superior branch of CN3 and motor neurons have been confirmed 1). Additionally, in COL25A1 KO mice, motor axon bundles reach the target muscle but fail to extend into the muscle fascicles 1).
Initially considered a myogenic disease, the identification of causative genes such as KIF21A and TUBB3 revealed it to be a primary neurological disease1). Fibrosis of the extraocular muscles is a secondary change due to lack of innervation.
There are still many unknowns regarding the signals that guide axons to their targets, and the following research is being conducted.
A neurodevelopmental syndrome caused by CDH2 (N-cadherin) mutations has been reported. It presents with a variety of phenotypes including intellectual disability, agenesis/hypoplasia of the corpus callosum, and DRS1).
CXCR4/CXCL12 signaling is involved in the course of CN3, and loss of ACKR3 (CXCR7, a scavenger receptor for CXCR4) has been reported to cause abnormal intraorbital CN3 course1).
There is a rostrocaudal difference in the timing of CN3 axon development. The rostral subpopulation is born earlier and forms the inferior branch, while the caudal subpopulation is born later and forms the superior branch and crosses the midline. The caudal subpopulation has been shown to be more susceptible to CCDD-causing mutations1).
In studies of model mice lacking extraocular muscles, appropriate axon directionality was observed up to the terminal branches. This suggested that guidance is mediated by mesenchymal signals, axon-axon interactions, and cell-autonomous processes, but it also became clear that muscle-derived signals are important for terminal branch formation.
