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ADC Online First, published on January 29, 2015 as 10.1136/archdischild-2014-307035 Review

The congenital cranial dysinnervation disorders N J Gutowski,1,2 J K Chilton2 1

Department of Neurology, Royal Devon and Exeter Foundation Hospital, Exeter, UK 2 University of Exeter Medical School, Exeter, UK Correspondence to N J Gutowski, Department of Neurology, Royal Devon and Exeter Hospital, Barrack Road, Exeter EX2 5DW, UK; [email protected] Received 14 December 2014 Accepted 7 January 2015

ABSTRACT Congenital cranial dysinnervation disorders (CCDD) encompass a number of related conditions and includes Duane syndrome, congenital fibrosis of the external ocular muscles, Möbius syndrome, congenital ptosis and hereditary congenital facial paresis. These are congenital disorders where the primary findings are non-progressive and are caused by developmental abnormalities of cranial nerves/nuclei with primary or secondary dysinnervation. Several CCDD genes have been found, which enhance our understanding of the mechanisms involved in brain stem development and axonal guidance.

EVOLVING CONCEPT FROM PRIMARY MUSCLE FIBROSIS TO DYSINNERVATION

To cite: Gutowski NJ, Chilton JK. Arch Dis Child Published Online First: [please include Day Month Year] doi:10.1136/ archdischild-2014-307035

Isolated strabismus (squint) is relatively common affecting 1%–5% of the population. It contains a subset of sporadic or familial congenital, nonprogressive ophthalmoplegia with restriction of globe movement, which was originally referred to as ‘congenital fibrosis syndromes’ because the pathological process was thought to be primarily in eye muscles. Accumulating information has challenged this view suggesting a primary neuropathic and a secondary myopathic process. At least five autopsy reports of Duane syndrome (DS), the most common of these disorders, documented anatomical absence of the abducens nerve. Additionally, electromyography revealed paradoxical innervation of lateral rectus by the oculomotor nerve, probably occurring in the absence of normal abducens nerve innervation. DS was also associated with conditions due to anomalous axonal guidance.1 2 In the rarer congenital fibrosis of the external ocular muscles (CFEOM), neuropathological and genetic studies also supported a neurogenic cause. An autopsy study of one affected member of a large CFEOM type 1 family showed absence of the superior division of the oculomotor nerves bilaterally.3 Subsequently, CFEOM type 2 was shown to result from mutations in the PHOX2A gene,4 absence of which, in mouse and zebrafish, resulted in loss of oculomotor and trochlear nuclei and nerves and other changes. A rare autosomal recessive condition associated with these syndromes, familial horizontal gaze palsy with progressive scoliosis (HGPPS), was shown to be due to ROBO3 mutations. This gene encodes a transmembrane receptor required for midline crossing of commissural axons. HGPPS cases have interneuron medial longitudinal fasciculus dysinnervation and also uncrossed corticospinal and dorsal column tracts caused by disruption of axonal hindbrain pathways.5

THE CONGENITAL CRANIAL DYSINNERVATION DISORDERS The concept of the congenital cranial dysinnervation disorders (CCDD) evolved from these findings and was coined in 2002 for a group of congenital, non-progressive, sporadic or familial neuromuscular disorders characterised by abnormal eye, eyelid or facial movement (box 1).2 The CCDDs include DS, CFEOM, Möbius syndrome (MS), congenital ptosis and hereditary congenital facial paresis (HCFP) although this is not an exhaustive list. Although several CCDD genes are known, the list of clinical phenotypes, genetic loci and mutations remains incomplete (table 1). CCDDs can be divided into those which give rise to predominately vertical ocular motility defects resulting from abnormalities in development of oculomotor and trochlear nerves and/or nuclei (CFEOMs and congenital ptosis); those which predominately give horizontal ocular motility defects result from abnormalities in development of the abducens nerve and/or nucleus (DS and Duane radial ray syndrome (DRRS)); those with predominately facial weakness resulting from abnormal development of facial nerve and/or nucleus (HCFP; and with limited ocular abduction— MS). Other congenital dysinnervation disorders, for instance, Marcus Gunn jaw winking (ptosis accompanied by elevation of the ptotic eyelid on lower jaw movement, due to aberrant trigeminal nerve innervation of levator palpebrae superioris (LPS)), which can occur independently or with CFEOM, and crocodile tears (food provoking excessive tearing, due to aberrant facial salivary fibres innervating the lacrimal gland), which can occur with DS, plus other afferent pathway disorders, warrant inclusion as CCDDs. Over the last decade, our knowledge of the range of phenotypes has expanded due to MRI of endophenotypes and increasingly detailed genetic and molecular analysis of the genes involved. A summary of the main findings is provided here along with an indication of the extensive further work still to be undertaken.

DUANE SYNDROME DS is the most common CCDD (prevalence 1:10 000); about 10% are familial, usually autosomal dominant without associated abnormalities. DS is characterised by congenital limitation of horizontal globe movement and some globe retraction on attempted adduction, leading to palpebral fissure narrowing. The balance between the amount of aberrant innervation from the inferior division of the oculomotor nerve to lateral rectus and the reduction/ absence of abducens motor neuron function dictates the type of limitation of horizontal globe

Gutowski NJ, et al. Arch Dis Child 2015;0:1–4. doi:10.1136/archdischild-2014-307035

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Review Box 1 The main features of the congenital cranial dysinnervation disorders (CCDDs). ▸ ▸ ▸ ▸

Congenital Non-progressive Sporadic or familial Developmental abnormalities of one or more cranial nerves/ nuclei ▸ Primary dysinnervation – absence of normal innervation – neurons do not develop or are misguided ▸ Secondary dysinnervation – aberrant developmental innervation by branches of another nerve ▸ Dysinnervation can cause secondary changes in muscle, orbital and bony structures

movement1 2 and is supported by MRI findings.6 Most commonly (∼80%), abduction is affected with normal or minimally defective adduction. This is type 1 DS, and MRI shows absence of the abducens nerve on the affected side.7 In type 3 DS, both abduction and adduction are limited, and in type 2, adduction is limited. Types 1 and 3 DS can occur together in families and, when in the same individual, type 3 is usually in the left eye. From case series, females and the left eye (2:1) in unilateral cases (80%–90%) are more frequently affected although the reasons are unknown.1 2 DS is usually isolated but may be associated with other findings and several cytogenetic loci have been reported.1 8 Two genes have been identified as causes of DS. The DURS2 chromosome locus phenotype consists of isolated autosomal dominant DS which is mainly bilateral (all types 1 or 3 DS or a combination), amblyopia is common and there are a variety of vertical deviations. Mutations in CHN1 account for DURS29; the abducens nerve could not be visualised on MRI in most cases, there were structurally abnormal lateral rectus

Table 1 Summary of the main features of the major CCDDs and their associated genes CCDD

Gene

Main features

Duane syndrome Type 1

CHN1

Restricted horizontal globe movement. Globe retraction on attempted adduction. Limited abduction Globe retraction on attempted adduction. Limited adduction Globe retraction on attempted adduction. Limited abduction and adduction Duane syndrome plus radial dysplasia

Type 2 Type 3

CHN1

Duane radial Ray SALL4 syndrome Congenital fibrosis of the extraocular muscles Type 1 KIF21A Bilateral ptosis, primary position infraduction, limited supraduction, restricted horizontal gaze. Type 2 PHOX2A Bilateral ptosis, large-angle exotropia (divergent squint), limited horizontal and vertical eye movements, poorly reactive pupils Type 3 TUBB3 Asymmetric ptosis, exotropia, variable vertical and horizontal eye movements Möbius syndrome Facial weakness, limited ocular abduction, lingual and/or pharyngeal dysfunction CCDDs, congenital cranial dysinnervation disorders.

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muscles; in addition, the oculomotor and optic nerves were also small indicating a diffuse endophenotype.10 All mutations in CHN1 alter amino acids in the α2 isoform of chimaerin, a GTPase-activating protein, which inactivates the small GTPase Rac, a regulator of downstream intracellular signalling cascades including cytoskeletal dynamics and neurite formation. CHN1 mutations are believed to be gain-of-function and hyperactivate α2-chimaerin resulting in stalling and aberrant branching of the oculomotor nerve.9 Within the oculomotor system, α2-chimaerin acts downstream of the Semaphorin-PlexinA signalling axis which is an important determinant of axon guidance and topographic mapping of neuronal projections.11 DRRS (or Okihiro syndrome) consists of unilateral or bilateral DS (types 1 and/or 3) and unilateral or bilateral radial dysplasia ranging from most commonly thumb hypoplasia to most severely a phocomelic limb (similar to that seen in thalidomide). Other features can include deafness, renal and ocular manifestations. Inheritance is autosomal dominant and it stems from truncating mutations and deletions in the SALL4 gene. Pathogenesis is due to haploinsufficiency of the protein, a putative zinc finger transcription factor.12–14 The MRI endophenotype is more limited in DRRS than DURS2 with hypoplasia of the abducens and probable coinnervation of lateral rectus by the oculomotor nerve.15

PROGRESS IN CFEOM CHARACTERISATION CFEOM is rare ( prevalence ∼1:230 000). Type 1 is the most common CFEOM phenotype. There are symmetrical findings of bilateral ptosis, primary position infraducted globes, limited supraduction, a chin-up head posture to maintain vision and variably restricted horizontal gaze. Inheritance is autosomal dominant. It is most commonly caused by mutations in the KIF21A gene which encodes a kinesin motor protein.16 This is a member of a protein superfamily of microtubule-dependent molecular motors that transport intracellular cargos, such as mRNA, proteins, vesicles and organelles. A hot spot for mutations is in the third coiled-coil stalk region where most movement within the protein occurs (about 70% of mutations cause the amino acid substitution R954W).16 17 Mutation of KIF21A causes axonal stalling and aberrant innervation.18 MRI studies have shown atrophy of LPS and superior rectus muscles and severe oculomotor nerve hypoplasia consistent with the primary clinical findings. The abducens nerve is also affected with lateral rectus dysinnervation, and there is subclinical optic nerve hypoplasia with a 30%–40% reduction in cross-sectional area, broadening the endophenotype.19 The CFEOM type 3 phenotype is variable (table 1). At least one affected family member does not meet CFEOM type 1 criteria. Inheritance is autosomal dominant. Rarely, such cases are due to KIF21A mutations as in CFEOM type 1, but most cases of CFEOM type 3 are due to TUBB3 mutations.20 TUBB3 is β-III-tubulin a neuron-specific isotype of the microtubule protein, one of at least 6 β-tubulins found in mammals and is required for axonal guidance and maintenance. TUBB3 mutations result in a spectrum of nervous system disorders with genotype–phenotype correlations termed the TUBB3 syndromes (table 2).20 21 CFEOM type 3 with facial weakness is outside the classically accepted Möbius phenotype where vertical eye movements are full and eye abduction is reduced. Additionally, although the eye findings seem to be non-progressive, as might be expected in congenital conditions where axonal development is affected, there can be progressive changes (ie, neuropathy) consistent with impaired intra-axonal transport. Gutowski NJ, et al. Arch Dis Child 2015;0:1–4. doi:10.1136/archdischild-2014-307035

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Review Table 2 TUBB3 phenotype–genotype correlations (showing TUBB3 amino acid substitutions) TUBB3

Phenotype

R62Q R262C A302T R262H D417H R380C

Isolated CFEOM type 3 (CFEOM3).

E410K

D417N

CFEOM3 + facial weakness, finger contractures, early onset polyneuropathy, basal ganglia dysmorphisms. CFEOM3 + developmental delay, corpus callosum hypoplasia, basal ganglia dysmorphisms. CFEOM3 + facial weakness, mid-face hypoplasia, developmental delay, corpus callosum hypoplasia, late onset progressive polyneuropathy, Kallmann syndrome (hypogonadotrophic hypogonadism and anosmia). CFEOM3 + axonal polyneuropathy in teens and 20 s, posterior corpus callosum hypoplasia.

CFEOM, congenital fibrosis of the external ocular muscles.

Brain MRI shows abnormalities varying with specific mutations, including dysgenesis of the corpus callosum, anterior commissure, corticospinal tracts and basal ganglia.20 High-resolution orbital MRI shows variable and asymmetric atrophy of LPS and superior rectus, with involvement of other extraocular muscles but sparing superior oblique. Ophthalmoplegia occurs when the oculomotor nerve is

The congenital cranial dysinnervation disorders.

Congenital cranial dysinnervation disorders (CCDD) encompass a number of related conditions and includes Duane syndrome, congenital fibrosis of the ex...
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