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Show Recent Progress in Understanding Congenital Cranial Dysinnervation Disorders Darren T. Oystreck, OC(C) MMedSci, Elizabeth C. Engle, MD, Thomas M. Bosley, MD 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 evi-dence, 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 pub-lished 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 elucida-tion, with the anticipation that more syndromes and genes will be identified in the future. Identification of genes and their function, along with advances in neuro-imaging, have expanded our understanding of the mech-anisms underlying several anomalous eye movement patterns. Conclusions: Current evidence still supports the concept that the CCDDs are primarily due to neurogenic dis-turbances of brainstem or cranial nerve development. Several CCDDs are now known to have nonophthalmologic associations involving neurologic, neuroanatomic, cere-brovascular, cardiovascular, and skeletal abnormalities. Journal of Neuro-Ophthalmology 2011;31:69-77 doi: 10.1097/WNO.0b013e31820d0756 2011 by North American Neuro-Ophthalmology Society CONGENITAL FIBROSIS OF THE EXTRAOCULAR MUSCLES TO CONGENITAL CRANIAL DYSINNERVATION DISORDERS 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 observa-tion led to the concept of ‘‘congenital fibrosis of the ex-traocular 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 dysin-nervation 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 hetero-geneous group of syndromes. Not included here (or within Section Editors: Grant T. Liu, MD Randy H. Kardon, MD, PhD 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: darrenoystreck@ymail.com Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 69 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. the CCDD concept) are myopathies, genetic disorders in-volving the neuromuscular junction, or progressive and/or degenerative ocular motility, and neurologic problems such as chronic progressive external ophthalmoplegia or spino-cerebellar atrophy, even if recognized to have a genetic etiology. DISORDERS AFFECTING PREDOMINANTLY OCULAR MOTILITY 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 un-derlying 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 syn-dromes. The DURS1 locus (MIM %126800; Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/omim) was defined after finding overlapping cytogenetic abnor-malities on chromosome 8q13 in multiple patients with syndromatic DRS and may reflect a complexity of cyto-genetic 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 as-sociated 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 re-traction can also occur as part of more complicated congenital ocular motility syndromes, such as CFEOM1. Congenital Fibrosis of the Extraocular Muscles Type 1 (CFEOM1; MIM #135700) This is the most common CFEOM phenotype. It is au-tosomal 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 move-ments are common, including bilateral convergence on attempted up gaze (synergistic convergence) and globe re-traction with attempted globe movement. Autopsy study and careful orbital imaging show profound atrophy of le-vator 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 mi-crotubule- associated protein associated with anterograde organelle transport in neuronal cells (15). Congenital Fibrosis of the Extraocular Muscles Type 2 (CFEOM2; MIM #602078) The main clinical features of this autosomal recessive syn-drome 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, al-though 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). Neuro-imaging 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 homeo-domain 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). Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3) This disorder is autosomal dominant, and the ocular mo-tility 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 phe-notype 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 neu-ropathy, wrist and finger contractures, and intellectual, social, and behavioral impairments. Orbital imaging of 70 Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 re-ferred to as CFEOM3B. Both TUBB3 and KIF21A have a role in directing growing cranial nerves to a correct ter-mination 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). 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 cerebrovas-cular 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 Mo¨bius syndrome (MBS) (33). FIG. 1. CFEOM1 phenotype. A. Primary position showing marked bilateral ptosis. B. Primary position with lids held showing resting globe position. Both eyes remain infraducted below midline. C. Attempted up gaze showing inability to reach midline with convergence of the visual axis (synergistic convergence). FIG. 2. CFEOM2 phenotype. A. Primary position showing bilateral ptosis and exotropia. B. Primary position with lids held showing resting globe position. C. Patient with right face turn and holding left upper lid to clear pupillary axis. D. Miotic irregular pupil. Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 71 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Horizontal Gaze Palsy and Progressive Scoliosis (HGPPS; MIM #607313) This syndrome is characterized by complete or almost com-plete bilateral horizontal gaze limitation with full vertical gaze, variable convergence, variable congenital nystagmus, and asynchronous blinking (34). Scoliosis begins in early child-hood 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). Mo¨bius 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 com-monly adduction, while vertical gaze is only rarely affected. Esotropia is common, convergence is variable, Bell's phe-nomenon 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, cra-niofacial dysmorphism, and limb malformations. In most patients, the syndrome is sporadic, although HOXA1 and TUBB3 mutations can result in atypical Mo¨bius phenotypes (23,28). MBS is likely quite heterogeneous in origin and may have more than 1 genetic and/or developmental etiology. DISORDERS WITH NORMAL OCULAR MOTILITY 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 FIG. 3. CFEOM3A phenotype. A. Primary position. B. Right gaze with absence of adduction and slight down shoot of the left eye. C. Left gaze with absence of adduction, slight down shoot of the right eye, and limited abduction on the left. D. Attempted up gaze is limited bilaterally with the left eye unable to reach midline and becoming esotropic. E. Down gaze fixating with the right eye shows slight downward movement of the right eye and only outward movement of the nonfixating left eye. F. Similarly, down gaze fixating with the left eye shows slight downward movement of the left eye and only outward movement of the nonfixating right eye. FIG. 4. CFEOM3B phenotype. All images are in primary position. A. Patient has unilateral ptosis and esotropia. B. Patient has severe bilateral ptosis in primary position despite marked frontalis effort. C. Same patient as B in primary position with lids held showing resting globe position with exotropia and bilateral infraduction. 72 Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. FIG. 5. HOXA1 spectrum phenotype. A-C. Right gaze, primary gaze, and left gaze of a girl with bilateral Duane retraction syndrome type 3. Note up shoot of the left eye on attempted left gaze. D. Axial CT scan of the same patient shows almost no development of the petrous bones except for mastoid air cells. E. MRA demonstrates absence of the left internal carotid artery, relatively large caliber of the basilar and both posterior cerebral arteries, and asymmetric filling of the transverse sinuses. FIG. 6. Horizontal gaze palsy and progressive scoliosis phenotype. A. Primary position. B. Attempted right gaze showing complete gaze palsy. C. Attempted left gaze showing complete gaze palsy. D. Moderately severe scoliosis concave right. E. Hypoplasia of the pons. F. Deep anterior and posterior clefts in the medulla causing the classic ‘‘butterfly medulla'' appearance (arrows). Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 73 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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). 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 TABLE 1. Genes associated with congenital cranial dysinnervation disorders (CCDDs) Genes Phenotype Main Neuro-ophthalmologic Features Other Features CHN1 DURS2 DRS, often bilateral and associated with vertical motility abnormalities - SALL4 DRRS DRS Variable hand and upper extremity anomalies; variable cardiac, renal, auditory, and vertebral abnormalities KIF21A CFEOM1 Bilateral ptosis; bilateral severe limitation of up gaze in both eyes with less severe limitations in other directions - CFEOM3B As above but up gaze limitation typically not as severe - TUBB3 CFEOM3A Variable unilateral or bilateral ptosis and limitation of up gaze that may not be as severe as CFEOM1; bilateral, asymmetric restrictions in other directions in both the eyes - CFEOM3A plus Similar to or more severe than CFEOM3A, when more severe the findings are bilateral and eyes are exotropic Peripheral neuropathy; facial palsy; wrist and finger contractures; and/or intellectual, social, and behavioral impairments PHOX2A CFEOM2 Bilateral severe ptosis and bilateral palsies of adduction, elevation, and depression with significant exotropia, occurs rarely without exotropia - HOXA1 BSAS Bilateral DRS type 3 or horizontal gaze palsy Bilateral deafness; variable cerebrovascular and cardiovascular anomalies ABDS As above Often more severe phenotype, including facial weakness and central hypoventilation ROBO3 HGPPS Complete or almost complete horizontal gaze palsy Scoliosis, usually severe 74 Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. currently 2 loci mapped by linkage analysis: an AD locus on chromosome 1 (43) (PTOS1; MIM %178300) and an X-linked locus (44). DISCUSSION 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 mutationsmay 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 as-sociated 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 at-tention to important features of a syndrome such as cere-brovascular 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 (http://library.med.utah.edu/ NOVEL/diseases/rare-registry/view/Unusual_Congenital_ Ocular_Motility_Disorders) 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 TABLE 2. Loci associated with congenital cranial dysinnervation disorders (CCDDs) Genetic Loci Phenotype Main Neuro-ophthalmologic Feature Other Features 13q12.1 (cytogenetic; 1 family) CFEOM3C Bilateral ptosis and bilateral limitation of up gaze typically not as severe as CFEOM1; bilateral, asymmetric restrictions in other directions in both the eyes; bilateral excyclotorsion Facial dysmorphism; mental retardation 22pter (cytogenetic in 3 patients) DRS Duane retraction syndrome - DURS1 (cytogenetic) DRS Duane retraction syndrome Contiguous gene deletion syndrome, usually with additional findings 1p22 (cytogenetic in 2 patients) MBS Lower motor neuron facial weakness, often bilateral and asymmetrical; variable restriction of horizontal eye movements Presumed contiguous gene deletion syndrome with variable ptosis, dysmorphism, developmental delay, Poland syndrome, etc 13q12.2-q13 (cytogenetic in 1 family) As above Variable flexion finger contractures 3q21-q22 HCFP1 None Isolated dysfunction of the facial nerve 10q HCFP2 None Isolated dysfunction of the facial nerve 1p34.1-p32 PTOS1 Isolated unilateral or bilateral ptosis - Xq24-q27.1 PTOS2 Isolated unilateral or bilateral ptosis - Oystreck et al: J Neuro-Ophthalmol 2011; 31: 69-77 75 State-of-the-Art Review Copyright © North American Neuro-Ophthalmology Society. 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