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Recent Progress in Understanding Congenital Cranial Dysinnervation Disorders

Oystreck, Darren T OC(C), MMedSci; Engle, Elizabeth C MD; Bosley, Thomas M MD

Section Editor(s): Liu, Grant T MD; Kardon, Randy H MD, PhD

Journal of Neuro-Ophthalmology: March 2011 - Volume 31 - Issue 1 - pp 69-77
doi: 10.1097/WNO.0b013e31820d0756
State-of-the-Art Reviews
Japanese Abstract

Background: In 2002, the new term congenital cranial dysinnervation disorder (CCDD) was proposed as a substitute for the traditional concept of congenital fibrosis of the extraocular muscles (CFEOM) based on mounting genetic, neuropathologic, and imaging evidence, suggesting that many, if not all, of these disorders result from a primary neurologic maldevelopment rather than from a muscle abnormality. This report provides an update 8 years after that original report.

Evidence Acquisition: Review of pertinent articles published from January 2003 until June 2010 describing CCDD variants identified under PubMed MeSH terms congenital fibrosis of the extraocular muscles, congenital cranial dysinnervation disorders, individual phenotypes included under the term CCDD, and congenital ocular motility disorders.

Results: At present, a total of 7 disease genes and 10 phenotypes fall under the CCDD umbrella. A number of additional loci and phenotypes still await gene elucidation, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuroimaging, have expanded our understanding of the mechanisms underlying several anomalous eye movement patterns.

Conclusions: Current evidence still supports the concept that the CCDDs are primarily due to neurogenic disturbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cerebrovascular, cardiovascular, and skeletal abnormalities.

Department of Ophthalmology (DTO, TMB), College of Medicine, King Saud University, Riyadh, Saudi Arabia; Division of Neurology (TMB), Cooper University Hospital, Camden, New Jersey; and Departments of Neurology, Ophthalmology, and Medicine (ECE); FM Kirby Neurobiology Center; Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, Massachusetts.

Supported by the National Eye Institute.

E. C. Engle is a Howard Hughes Medical Institute investigator.

Address correspondence to Darren T. Oystreck, OC(C) MMedSci, Department of Ophthalmology, King Abdulaziz University Hospital, Riyadh 11411, Saudi Arabia; E-mail:

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During the last half of the 20th century, pediatric ophthalmologists recognized that certain children were born with congenital ocular motility abnormalities associated with fibrotic extraocular muscles. This observation led to the concept of “congenital fibrosis of the extraocular muscles” (CFEOM) because of the assumption that the primary problem was a congenital abnormality of muscle development (1,2). The most common of these disorders is Duane retraction syndrome (DRS), although a number of other sporadic and familial congenital ocular motility syndromes were also recognized.

As time passed, evidence accumulated that a number of these syndromes had a neurogenic etiology. Therefore, in 2002, an alternative concept of “congenital cranial dysinnervation disorders” (CCDDs) was proposed (3), shifting the focus away from muscle development and toward a likely neurogenic etiology of congenital abnormalities of ocular muscle and facial innervation. Developments in the past 8 years have supported this concept, since all identified genes responsible for CCDDs affect brainstem and/or cranial nerve development. The purpose of this review is to update the original report proposing the CCDD concept (3) because much has happened over the past 8 years. Many of the syndromes described here are uncommon, and a number have autosomal recessive etiologies that make their occurrence more frequent in specific areas of the world. Yet with increased international travel, a patient with any one of these disorders might walk into the office of an ophthalmologist or neurologist anywhere in the world. Therefore, clinicians should be familiar with this heterogeneous group of syndromes. Not included here (or within the CCDD concept) are myopathies, genetic disorders involving the neuromuscular junction, or progressive and/or degenerative ocular motility, and neurologic problems such as chronic progressive external ophthalmoplegia or spinocerebellar atrophy, even if recognized to have a genetic etiology.

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Duane Retraction Syndrome

DRS is the most common CCDD ocular motility disorder and is characterized most commonly by limited abduction (DRS type 1) with variable limitation of adduction together with retraction of the globe and narrowing of the palpebral fissure on attempted adduction. DRS is generally sporadic, typically unilateral, and more common in females. The underlying mechanism is primary absence or hypoplasia of the sixth nerve with dysinnervation of the ipsilateral lateral rectus by a branch of the third nerve (4-6).

Up to 10% of DRS cases may be familial, including autosomal dominant inheritance in several distinct syndromes. The DURS1 locus (MIM %126800; Mendelian Inheritance in Man; was defined after finding overlapping cytogenetic abnormalities on chromosome 8q13 in multiple patients with syndromatic DRS and may reflect a complexity of cytogenetic causes, including disruption of CPAH (7,8). The DURS2 locus was defined by linkage analysis of families segregating dominant DRS (MIM #604356), and affected individuals commonly have bilateral involvement and associated vertical movement anomalies. The responsible gene, CHN1, is involved in ocular motor axon path finding in the development of the sixth nerve and, to a lesser extent, the third nerve (9,10). CHN1 mutations were not found in a cohort of individuals with sporadic DRS (11).

Duane radial ray syndrome (Okihiro syndrome; MIM #607323) is characterized by DRS with hand and, in some cases, upper extremity anomalies and variable expression of cardiac, renal, hearing, and vertebral abnormalities. It is caused by mutations in the SALL4 gene, which is thought to be involved in the patterning of several embryonic structures, such as sixth nerve, limbs, and heart (12,13). DRS may also be associated with other developmental problems, such as the HOXA1 spectrum, while limited abduction and globe retraction can also occur as part of more complicated congenital ocular motility syndromes, such as CFEOM1.

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Congenital Fibrosis of the Extraocular Muscles Type 1 (CFEOM1; MIM #135700)

This is the most common CFEOM phenotype. It is autosomal dominant and has been reported worldwide (14) with primary clinical features including bilateral ptosis and severe restriction of up gaze so that neither eye is able to reach midline (Fig. 1) (15,16). Down gaze and horizontal movements are variably restricted. Misdirected eye movements are common, including bilateral convergence on attempted up gaze (synergistic convergence) and globe retraction with attempted globe movement. Autopsy study and careful orbital imaging show profound atrophy of levator and superior rectus, variable reduction in the size of other extraocular muscles, absence of ocular motor nerves, and optic nerves that are reduced 30% to 40% in cross section (16). CFEOM1 is caused by heterozygous missense mutations in KIF21A, a gene that encodes a kinesin microtubule-associated protein associated with anterograde organelle transport in neuronal cells (15).

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Congenital Fibrosis of the Extraocular Muscles Type 2 (CFEOM2; MIM #602078)

The main clinical features of this autosomal recessive syndrome are bilateral ptosis and absence of adduction, up gaze, and down gaze, creating the appearance of bilateral third nerve palsies (Fig. 2) (17). Abduction is present, although generally limited, and pupils often are variable in size and shape and nonreactive to light even though they do respond to pupillary pharmacologic agents (18). Neuroimaging shows that the third nerves are absent bilaterally (18). The syndrome is caused by homozygous loss-of-function mutations in the PHOX2A gene (17), a homeodomain transcription factor that is prominently expressed in developing third and fourth motor neurons and is essential to their survival. In the mouse, Phox2a also regulates the expression of 2 catecholaminergic biosynthetic enzymes essential for the differentiation and maintenance of the noradrenergic neurotransmitter phenotype (19-21).

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Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3)

This disorder is autosomal dominant, and the ocular motility findings are similar to CFEOM1 except that it is more variable and sometimes associated with the ability to elevate the eyes above the midline (Figs. 3, 4) (22). It is now known to be caused by heterozygous mutations in at least 2 genes, TUBB3 (CFEOM3A; MIM #600638) (23) and rarely KIF21A (CFEOM3B) (24).

TUBB3 is a component of microtubules, and the phenotype of an individual harboring a TUBB3 mutation depends in part on the specific heterozygous missense mutation. Some mutations can be nonpenetrant, while others result in isolated CFEOM3, and in these individuals, the ocular phenotype is quite variable, including individuals with only absent up gaze. Other mutations can cause CFEOM3 in association with facial palsy, peripheral neuropathy, wrist and finger contractures, and intellectual, social, and behavioral impairments. Orbital imaging of individuals with TUBB3 mutations (25) is similar to that found in CFEOM1 resulting from KIF21A mutations (26). With brain MRI, dysgenesis of the corpus callosum and anterior commissure has been reported (23).

Patients have been described with a syndrome that looks similar to CFEOM1, although generally without complete restriction of up gaze, who do not harbor mutations in TUBB3. Several of these individuals do harbor one of the common mutations in KIF21A, and this syndrome is referred to as CFEOM3B. Both TUBB3 and KIF21A have a role in directing growing cranial nerves to a correct termination in extraocular muscles. A CFEOM3C variant (MIM %609384) has been recognized in 3 generations of a single family, where all affected members carry a reciprocal translocation involving chromosomes 2q and 13q (27).

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HOXA1 Spectrum (MIM #601536)

This autosomal recessive syndrome consists most notably of bilateral DRS type 3 (limited adduction and absence of abduction), deafness, and internal carotid and cerebrovascular malformations, and sometimes autism (Fig. 5) (28-30). Some individuals may have associated intellectual disabilities, facial weakness, and/or central hypoventilation (31). Neuroimaging has demonstrated absence of the sixth nerve bilaterally and almost completely absent development of the hearing and vestibular apparatus in the petrous bone (28-30). The syndrome is due to homozygous mutations in HOXA1 that probably cause loss of rhombomere 5 and an early and profound brainstem patterning defect (28). HOXA1 mutations were not found in cohorts of individuals with sporadic DRS (32) or Möbius syndrome (MBS) (33).

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Horizontal Gaze Palsy and Progressive Scoliosis (HGPPS; MIM #607313)

This syndrome is characterized by complete or almost complete bilateral horizontal gaze limitation with full vertical gaze, variable convergence, variable congenital nystagmus, and asynchronous blinking (34). Scoliosis begins in early childhood and is commonly rapidly progressive and severe (Fig. 6) (35). Neuroimaging shows intact sixth nerves bilaterally and deep anterior and posterior clefts in the medulla and lower pons, a large fourth ventricle, and no decussation of the axons within the corticospinal tract, medial lemniscus, or superior cerebellar peduncle (36,37). HGPPS is an autosomal recessive syndrome caused by mutations in ROBO3 (38), a gene that promotes decussation of developing neural tracts in the pons, medulla, and spinal cord (in the mouse model) (39).

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Möbius Syndrome (MBS; MIM %157900)

MBS is the eponym reserved for congenital facial weakness associated with restricted horizontal eye movements. Facial weakness is usually bilateral and asymmetric; limited horizontal eye movements always affect abduction and commonly adduction, while vertical gaze is only rarely affected. Esotropia is common, convergence is variable, Bell's phenomenon is intact, nystagmus is rare, and ptosis is unusual. MBS is frequently accompanied by nonocular and facial features, such as lingual and/or pharyngeal dysfunction, craniofacial dysmorphism, and limb malformations. In most patients, the syndrome is sporadic, although HOXA1 and TUBB3 mutations can result in atypical Möbius phenotypes (23,28). MBS is likely quite heterogeneous in origin and may have more than 1 genetic and/or developmental etiology.

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Hereditary Congenital Facial Palsy

This syndrome causes an autosomal dominant, isolated facial weakness that is often asymmetric and bilateral and is distinct from MBS in that ocular motility is normal. Postmortem pathological studies have shown reduced number of neurons within the facial nerve motor nuclei and poorly developed facial nerve roots. Two genetic loci, termed HCFP1 (MIM %601471) and HCFP2 (MIM %604185), have been defined, but neither gene has been identified yet; there does not appear to be any major phenotypic differences between the loci (40-42).

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Hereditary Congenital Ptosis

Hereditary congenital ptosis is defined as an isolated drooping of the upper eyelid with no accompanying ocular features. Bilateral involvement is common, but unilateral cases have been reported. Severity of ptosis ranges from mild to severe and can be asymmetric in bilateral cases. There are currently 2 loci mapped by linkage analysis: an AD locus on chromosome 1 (43) (PTOS1; MIM %178300) and an X-linked locus (44).

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In 2002, the CCDD concept included 10 syndromes, 2 confirmed genes, and 14 genetic loci. Eight years and more than 80 published articles later, 7 genes are recognized to cause 10 phenotypes (Table 1) and another 6 syndromes are associated with at least 11 genetic loci (Table 2). Every CCDD gene characterized since 2002 has been associated with neuronal development at the nuclear, brainstem, or peripheral nerve level, supporting the hypothesis that CCDDs are neurogenic in origin (3).

With genotypic definitions have come better phenotypic characterizations, including the realization that syndromes caused by different genetic mutations may present confounding clinical similarities. For example, DRS most commonly occurs sporadically but can be caused by heterozygous (10,15) or homozygous (28-30) mutations of several genes. The CFEOM1 (15) and CFEOM3 (23) phenotypes can be quite similar, and severe horizontal gaze restriction is a hallmark of both HGPPS (34) and the HOXA1 spectrum (30).

Some CCDDs include nonocular abnormalities. For example, CFEOM3 due to TUBB3 mutations can be associated with a peripheral neuropathy, joint contractures, and intellectual and behavioral disabilities (23). We now realize that ocular motility and other clinical aspects of these syndromes are variable, and even within families, there is presumably genetic homogeneity. Thus, some patients with HOXA1 mutations may lack ocular motility abnormalities or deafness, 2 of the cardinal clinical features (30). Perhaps, most importantly, certain CCDD diagnoses may call attention to important features of a syndrome such as cerebrovascular maldevelopment and congenital heart disease in the HOXA1 spectrum (28-30).

The North American Neuro-Ophthalmology Society (NANOS) has recently created the NOVEL Rare Disease Registry under which there is now a category for Unusual Congenital Ocular Motility Disorders and Strabismus. The Web site now contains a link ( by which a clinician can contact the stewards, Drs. Thomas M. Bosley and Elizabeth C. Engle, and submit clinical descriptions and genetic material for analysis. We encourage broad participation since such an effort will likely be necessary to clinically and genetically characterize new CCDDs.

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