Congenital Fibrosis Of The Extraocular Muscles

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2021-01-18

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TUBB3, KIF21A, TUBB2B, PHOX2A, KIF16B, MAP1B, MYF5, PAX6, RYR1, ECEL1, KANK1, SEMA6A, FRMD7

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Summary

Clinical characteristics.

Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least eight genetically defined strabismus syndromes (CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria) characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). In general, affected individuals have severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions at rest and by moving their heads rather than their eyes to track objects. Individuals with CFEOM3A may also have intellectual disability, social disability, Kallmann syndrome, facial weakness, and vocal cord paralysis; and/or may develop a progressive sensorimotor axonal polyneuropathy. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands. Those with CFEOM3 with polymicrogyria also have microcephaly and intellectual disability.

Diagnosis/testing.

The diagnosis of CFEOM is based on ophthalmologic findings, and the subtypes depend on the identification of specific eye findings and associated findings. KIF21A pathogenic variants are associated with CFEOM1A and CFEOM3B. PHOX2A pathogenic variants are associated with CFEOM2. TUBB3 pathogenic variants are associated with CFEOM3A and CFEOM1B. TUBB2B pathogenic variants are associated with CFEOM3A and CFEOM3 with polymicrogyria.

Management.

Treatment of manifestations: Refractive errors may be managed with glasses or contact lenses. Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Corneal lubrication may be helpful. Corrective eye muscle and/or ptosis surgery may be required.

Prevention of secondary complications: Amblyopia therapy to prevent vision loss in the less-preferred eye.

Surveillance: To prevent and treat amblyopia and to address complications of corneal exposure: routine ophthalmologic care with visits every three to four months during the first years of life, and annual or biannual examinations in older affected individuals not at risk for amblyopia. In individuals with specific TUBB3 variants, surveillance for endocrine abnormalities, facial or vocal cord weakness, and interventions for developmental delays are indicated.

Evaluation of relatives at risk: Early clinical diagnosis can lead to early treatment and prevention of secondary complications.

Genetic counseling.

CFEOM is inherited in either an autosomal dominant (CFEOM1, CFEOM3, and CFEOM3 with polymicrogyria) or autosomal recessive (CFEOM2 and Tukel syndrome) manner.

CFEOM1, CFEOM3, and CFEOM3 with polymicrogyria. An affected individual may have inherited a pathogenic variant from an affected parent or have the disorder as the result of a de novo pathogenic variant. Each child of an individual with autosomal dominant CFEOM has a 50% chance of inheriting the pathogenic variant.
CFEOM2 and Tukel syndrome. The parents of a child with autosomal recessive CFEOM are obligate heterozygotes (i.e., carriers of one pathogenic variant). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member.

Diagnosis

The term congenital fibrosis of the extraocular muscles (CFEOM) refers to several syndromes: CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria [Doherty et al 1999, Nakano et al 2001, Yamada et al 2003, Aubourg et al 2005, Tukel et al 2005, Karadeniz et al 2009, Khan et al 2010, Tischfield et al 2010, Cederquist et al 2012].

Suggestive Findings

Congenital fibrosis of the extraocular muscles (CFEOM) should be suspected in individuals with the following clinical features:

Congenital non-progressive ophthalmoplegia (inability to move the eyes) typically with severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze
Ptosis (droopy eyelids) that may range from mild to profound, and can be unilateral

The condition affects part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique).

Typically binocular vision is absent. Refractive errors are common.

Note: For complete description of the eye findings to aid in establishing the diagnosis of a specific form of CFEOM, see Table 1.

Table 1.

Comparison of Types of CFEOM

	CFEOM1	CFEOM2	CFEOM3	Tukel Syndrome	CFEOM3 w/Polymicrogyria
External ophthalmo- plegia	Congenital, non-progressive. bilateral, profound, w/limited upgaze	Congenital, non-progressive, bilateral, profound, w/eyes in exotropic (outward deviating) position	Congenital, non-progressive, bilateral OR unilateral; primarily affecting muscles in the oculomotor distribution ¹	Congenital, non-progressive, bilateral OR unilateral; primarily affecting muscles in the oculomotor distribution ¹	Congenital, non-progressive, bilateral; limited upgaze
Lid position	Congenital non-progressive bilateral ptosis	Congenital non-progressive bilateral ptosis	Normal OR congenital non-progressive bilateral or unilateral ptosis	Normal OR congenital non-progressive bilateral or unilateral ptosis	Congenital non-progressive bilateral ptosis
Primary vertical position of each eye	Infraducted (downward)	Normal or positioned slightly above or below midline	Infraducted or normal (primary position)	Infraducted or normal (primary position)	Infraducted
Vertical eye movements	Inability to elevate eyes above horizontal midline	Severely restricted	Variable restriction w/ or w/out upgaze above midline	Variable restriction w/ or w/out upgaze above midline	Severely limited
Primary horizontal position of each eye	Orthotropic (normal), esotropic (inward), or exotropic (outward)	Typically exotropic; rarely, orthotropic	Orthotropic or exotropic more frequent than esotropic	Orthotropic or exotropic may be more frequent than esotropic	Orthotropic or exotropic
Horizontal eye movements	Normal to severely restricted	Severely restricted; only abduction preserved	Normal to severely restricted	Normal to severely restricted	Variably restricted
Aberrant eye movements	Frequent, especially both eyes turning inward on attempted upgaze	Small amplitude, if present	Sometimes present	Sometimes present	Convergent nystagmus w/attempted upgaze
Forced duction test	Positive for restriction	Positive for restriction	Positive for restriction at least in attempted upgaze	Positive for restriction at least in attempted upgaze	Positive for restriction
Binocular vision	Usually absent	Absent	Rarely present	Rarely present	Usually absent
Refractive errors	Frequently high astigmatism	Frequent	Common	Common	Frequent, high astigmatism
Amblyopia	Frequent; may be strabismic or refractive in nature	Frequent	Frequent	Frequent	Frequent
Pupils	Normal	Often small & sluggishly reactive to light	Typically normal, occasionally small & sluggish	Normal	Normal
Family history	Consistent w/AD inheritance; simplex cases ² observed; parental germline mosaicism can mimic AR inheritance	Consistent w/AR inheritance	Consistent w/AD inheritance; simplex cases ² observed; parental germline mosaicism can mimic AR inheritance	Consistent w/AR inheritance	Consistent w/AD inheritance
Genetics	CFEOM1A: associated w/pathogenic variants in KIF21A CFEOM1B: associated w/path variants in TUBB3	Associated w/path variants in PHOX2A	CFEOM3A: associated w/path variants in TUBB3 or TUBB2B CFEOM3B: associated w/path variants in KIF21A CFEOM3C: refers to cosegregation of CFEOM3 w/a translocation (in 1 family)		Associated w/path variants in TUBB2B
Additional findings	None	Retinal dysfunction	Variably present in CFEOM3A: intellectual & social disability, facial weakness, vocal cord paralysis, Kallmann syndrome, cyclic vomiting, spasticity, progressive sensorimotor axonal polyneuropathy On brain MRI: malformations of cortical development; dysgenesis of: corpus callosum, anterior commissure, corticospinal tracts, & basal ganglia On MRI of cranial nerves & orbits: hypoplasia of the oculomotor nerve & levator/superior rectus muscles	Postaxial oligodactyly or oligosyndactyly of the hands; In one affected person w/an unbalanced translocation: facial dysmorphisms, kyphosis, pectus excavatum, developmental delay, & motor regression	Intellectual disability, polymicrogyria, microcephaly

: AD = autosomal dominant; AR = autosomal recessive
1.: In individuals not meeting CFEOM1 criteria
2.: A single occurrence in a family

Establishing the Diagnosis

The diagnosis of CFEOM is established in a proband with identification of a specific CFEOM phenotype and/or of a heterozygous pathogenic variant in KIF21A, TUBB3, or TUBB2B or biallelic pathogenic variants in PHOX2A by molecular genetic testing (see Table 2).

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered if (1) a pathogenic variant in a particular gene accounts for a large proportion of the disease OR (2) additional factors (e.g., clinical findings, laboratory findings, and ancestry) indicate that a pathogenic variant in a particular gene is most likely. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

For patients with a CFEOM1 phenotype, sequence analysis of KIF21A, followed by sequence analysis of TUBB3 should be performed. All disease-associated alleles reported in KIF21A and TUBB3 have been missense variants; thus, gene-targeted deletion/duplication analysis is not recommended.
For patients with the CFEOM2 phenotype, sequence analysis of PHOX2A should be performed, followed by gene-targeted deletion analysis if no pathogenic variant is found.
For patients with a CFEOM3 phenotype, sequence analysis of TUBB3 should be performed first, followed by sequence analysis of KIF21A. All disease-associated alleles reported in KIF21A and TUBB3 have been missense variants; thus, gene-targeted deletion/duplication analysis is not recommended.

A multigene panel that includes KIF21A, TUBB3, TUBB2B, PHOX2A, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes KIF21A, TUBB3, TUBB2B, and PHOX2A) fails to confirm a diagnosis in an individual with features of CFEOM. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in CFEOM

Gene ¹	Proportion of CFEOM Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ² Detected by Test Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
KIF21A	~55%	81/94 in CFEOM1 ⁵ 5/20 in CFEOM3 ⁶	Unknown ⁷
TUBB3	~35%	15/15 in isolated CFEOM3 ⁸ 27/27 in CFEOM3 with additional neurologic findings ⁹	Unknown ⁷
PHOX2A	~10%	15/15 in CFEOM2 ¹⁰	Unknown ⁷
TUBB2B	<1%	3/3 in CFEOM3 with polymicrogyria ¹¹	Unknown ⁷
Unknown ¹²	NA	NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Yamada et al [2003], Ali et al [2004], Tiab et al [2004], Traboulsi & Engle [2004], Lin et al [2005], Shimizu et al [2005], Yamada et al [2005], Chan et al [2007], Karadeniz et al [2009], Rudolph et al [2009], Yang et al [2010], Khan et al [2011], Wang et al [2011], Luk et al [2013], Ying et al [2013], Ali et al [2014], Kaçar Bayram et al [2015]
6.: Yamada et al [2004], Lin et al [2005], Lu et al [2008], Yang et al [2010]
7.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
8.: Individuals who have the eye phenotype only, with no additional medical conditions. TUBB3 pathogenic variants are associated with familial and simplex occurrences of CFEOM3 [Tischfield et al 2010]; this is referred to as CFEOM3A. TUBB3 pathogenic variants are also a rare cause of CFEOM1; this is referred to as CFEOM1B.
9.: Tischfield et al [2010], Chew et al [2013], MacKinnon et al [2014], Balasubramanian et al [2015], Whitman et al [2016]
10.: Nakano et al [2001], Yazdani et al [2003]. PHOX2A is the only gene in which pathogenic variants are known to cause the CFEOM2 phenotype [Nakano et al 2001, Bosley et al 2006].
11.: Cederquist et al [2012]
12.: A three-generation family that cosegregated CFEOM3 and a balanced/unbalanced reciprocal translocation t(2;13) (q37.3;q12.11) permitted assignment of CFEOM3C, (OMIM 609384) to 13q27.3 [Aubourg et al 2005]. A genome-wide linkage screen of a large consanguineous family whose affected members have a CFEOM3 phenotype and postaxial oligodactyly/oligosyndactyly of the hands, referred to as Tukel syndrome (OMIM 609428), mapped the locus to a 1.5-Mb region on chromosome 21qter [Tukel et al 2005]. See also Shinwari et al [2015].

Clinical Characteristics

Clinical Description

Congenital fibrosis of the extraocular muscles (CFEOM) refers to complex strabismus (eye misalignment) syndromes characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). Magnetic resonance imaging (MRI) suggests that the abducens and optic nerves can also be hypoplastic [Demer et al 2005, Wu et al 2009, Demer et al 2010].

Strabismus is the deviation of the position of one eye relative to the other, resulting in misalignment of the line of site of the two eyes. Individuals with CFEOM typically have incomitant strabismus, in which their misalignment varies with gaze direction. Incomitant strabismus often results from mechanical dysfunction in the orbit or neuromuscular dysfunction at the level of the brain stem, nerve, or muscle. The resting eye position of an individual with CFEOM is often abnormal. In general, hypotropic (downward) and exotropic (outward) positions are more common than hypertropic (upward) and esotropic (inward) positions. Strabismus in individuals with CFEOM can vary within a single family, and this can be particularly remarkable among affected members of families with CFEOM3. Among families with CFEOM1, the vertical strabismus is quite uniform, but the horizontal strabismus can vary.

Congenital non-progressive external ophthalmoplegia. Individuals with CFEOM are born with a severe form of incomitant strabismus referred to as ophthalmoplegia (inability to move the eyes) caused by dysfunction of specific ocular muscles innervated by the oculomotor and trochlear nerves. In general, affected individuals have severe limitation of vertical gaze and variable limitation of horizontal gaze. Individuals with CFEOM compensate for the ophthalmoplegia by maintaining an abnormal head position at rest and by moving their heads rather than their eyes to track objects.

Ptosis is the drooping of the upper eyelid as a result of dysfunction of the levator palpabrae superioris. Individuals with CFEOM often have a compensatory chin-up head posture to both better position their infraducted eyes and to "see under" their droopy lids.

Refractive errors are common but not characteristic.

Amblyopia. Strabismus (with suppression of one eye), refractive error, and ptosis may cause amblyopia, which can lead to permanent loss of vision when untreated.

CNS malformations. Some individuals with CFEOM have been reported to have central nervous system malformations, including agenesis or hypoplasia of the corpus callosum, brain stem hypoplasia, cerebellar hemisphere hypoplasia, absence of the cerebral peduncle in the midbrain, colpocephaly, hypoplasia of the cerebellar vermis, expansion of the ventricular system, pachygyria, polymicrogyria, encephalocele, and/or hydrancephaly [Flaherty et al 2001, Pieh et al 2003, Harissi-Dagher et al 2004]. The CFEOM phenotype in most of these individuals is atypical and meets the criteria of CFEOM3. Other CNS findings include hypoplastic oculomotor nerves, dysmorphic basal ganglia with or without internal capsule hypoplasia, and agenesis or hypoplasia of the anterior commissure [Demer et al 2010, Tischfield et al 2010, Cederquist et al 2012, Chew et al 2013, Balasubramanian et al 2015, Whitman et al 2016].

Non-ocular findings in a subset of individuals with CFEOM3 include facial paralysis, spasticity, cognitive and behavioral impairments, and a later-onset progressive peripheral sensorimotor axonal polyneuropathy, joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), and cyclic vomiting [Tischfield et al 2010, Chew et al 2013].

Marcus Gunn phenomenon and other evidence of misinnervation have been reported in individuals with CFEOM [Pieh et al 2003, Yamada et al 2005, Kaçar Bayram et al 2015]. The Marcus Gunn jaw winking phenomenon manifests as the momentary elevation of a ptotic upper eyelid with specific movements of the jaw. Often first noted in young infants when they are feeding, the phenomenon results from aberrant innervation of the levator palpebrae superioris muscle by axons intended to run in the motor branch of the trigeminal nerve and to innervate the pterygoid muscle. The association of this finding with CFEOM provides additional evidence that these syndromes are primarily neurogenic in cause [Brodsky 1998, Pieh et al 2003].

Tukel syndrome. Affected members of the family with CFEOM3 that maps to the Tukel syndrome locus also manifest bilateral postaxial oligodactyly/oligosyndactyly of the hands, more severe on the right.

Genotype-Phenotype Correlations

Each form of CFEOM has a defined phenotype.

KIF21A pathogenic variants are associated with CFEOM1 and rare cases of CFEOM3. Clinical examinations and high-resolution orbital MRI of individuals with CFEOM1 resulting from several different specific KIF21A pathogenic variants did not reveal a correlation between any specific pathogenic variant and clinical phenotype [Yamada et al 2003, Demer et al 2005].

PHOX2A pathogenic variants are associated with CFEOM2. No correlation between specific PHOX2A pathogenic variants and specific aspects of the CFEOM2 phenotype has been found.

TUBB3 pathogenic variants are associated with CFEOM1B or CFEOM3. Correlations have been found between specific TUBB3A pathogenic variants and the clinical phenotype [Tischfield et al 2010, Chew et al 2013, Whitman et al 2016]:

c.185G>A (p.Arg62Gln): moderate CFEOM3. Brain MRI: normal. No developmental delays or intellectual disability.
c.784C>T (p.Arg262Cys): mild to severe CFEOM3 or CFEOM1B. Brain MRI: anterior commissure hypoplasia, mild corpus callosum hypoplasia, mild basal ganglia dysgenesis. No developmental delays or intellectual disability.
c.785G>A (p.Arg262His): severe CFEOM3, developmental delay, facial weakness, progressive axonal sensorimotor polyneuropathy, congenital joint contractures. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis.
c.904G>A (p.Ala302Thr): variable CFEOM3, developmental delay. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia.
c.1138C>T (p.Arg380Cys): moderate CFEOM3, developmental delay. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis
c.1249G>A (p.Asp417Asn): mild to severe CFEOM3 or CFEOM1B, weakness, progressive axonal sensorimotor polyneuropathy. Brain MRI: anterior commissure hypoplasia, mild corpus callosum hypoplasia, mild basal ganglia dysgenesis.
c.1249G>C (p.Asp417His): severe CFEOM3, developmental delay, facial weakness, progressive axonal sensorimotor polyneuropathy, congenital joint contractures. Brain MRI: anterior commissure hypoplasia.
c.1228G>A (p.Glu410Lys): severe CFEOM3, developmental delay, facial weakness, midface hypoplasia, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), progressive sensorimotor polyneuropathy, vocal cord paralysis, and cyclic vomiting. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis, hypoplastic to absent olfactory bulbs, olfactory sulci, and oculomotor and facial nerves.
c.211G>A (p.Gly71Arg): moderate CFEOM3, developmental delay, hypotonia, thinning or agenesis of corpus callosum, increased and abnormal cortical gyration, basal ganglia and thalamus dysgenesis, brain stem hypoplasia, incomplete rotation of hippocampus, hypoplasia of optic and oculomotor nerves
c.292G>A (p.Gly98Ser): moderate CFEOM3, developmental delay, hypotonia, thinning of corpus callosum, increased and abnormal cortical gyration, basal ganglia and thalamus dysgenesis, brain stem hypoplasia, incomplete rotation of hippocampus, cerebellar vermis hypoplasia with dysmorphic folia, hypoplasia of optic and oculmotor nerves

Many persons with CFEOM3 who have a TUBB3 pathogenic variant also have aberrant eye movements and several have ptotic eyelid elevation associated with synkinetic jaw movements (Marcus Gunn phenomenon). However, the Marcus Gunn phenomenon has also been reported in association with a KIF21A -related CFEOM.

TUBB2B. Only one pathogenic variant (c.1261G>A, p.Glu421Lys) has been associated with both CFEOM and polymicrogyria. Seven other pathogenic variants are associated with polymicrogyria without CFEOM.

Penetrance

Penetrance in CFEOM1A, CFEOM1B, CFEOM2, CFEOM3B, CFEOM3C, and Tukel syndrome is complete.

Penetrance in CFEOM3A can be incomplete and is estimated to be 90% in families harboring the c.784C>T (p.Arg262Cys) substitution [Doherty et al 1999].

Nomenclature

Although long felt to result from primary fibrosis of the extraocular muscles, neuroanatomic [Engle et al 1997, Tischfield et al 2010], genetic [Nakano et al 2001, Yamada et al 2003, Tischfield et al 2010], and neuroimaging [Demer et al 2005, Kim & Hwang 2005, Bosley et al 2006, Lim et al 2007, Wu et al 2009, Demer et al 2010] findings suggest that the various forms of CFEOM result from abnormal development of ocular motor neurons and their processes.

Prevalence

A minimum prevalence of CFEOM is 1:230,000 [Reck et al 1998].

CFEOM1 and CFEOM3 familial and simplex cases have been identified worldwide.

The few individuals reported with CFEOM2 have been offspring of consanguineous unions within Saudi, Turkish, and Iranian families [Traboulsi & Engle 2004].

Differential Diagnosis

The term "congenital cranial dysinnervation disorders (CCDDs)" was coined to refer to disorders of innervation of cranial musculature [Gutowski et al 2003]. The various forms of CFEOM are included in the CCDDs. Other CCDDs include Duane syndrome, Moebius syndrome, and congenital facial palsy.

The following conditions can be confused with CFEOM:

Brown syndrome ("superior oblique tendon sheath syndrome") is characterized by the inability to elevate the adducted eye actively or passively. Most congenital Brown syndrome is simplex (i.e., a single occurrence in a family) and believed to result from anomalies of the tendon or the trochlear apparatus. Rare familial cases have been reported [Iannaccone et al 2002].

Duane syndrome is characterized by horizontal eye movement limitation, narrowing of the palpebral fissure on attempted side gaze (usually adduction), and retraction of the globe on attempted adduction. It is believed to result from abnormal development of the abducens nucleus and nerve (cranial nerve VI).

Although the majority of cases of Duane syndrome are simplex and isolated (i.e., not associated with other malformations), rare families with autosomal dominant or autosomal recessive inheritance of Duane syndrome with or without accompanying anomalies have been reported:

An autosomal dominant locus for Duane syndrome was mapped by linkage analysis to 2q31 (DURS2, OMIM 604356). All affected individuals had bilateral Duane syndrome type 1 or type 3; the prevalence of manifest strabismus and amblyopia was high. Heterozygous missense changes in CHN1 that cosegregated with the affected haplotypes were identified [Miyake et al 2008]. All were predicted to alter amino acids that were conserved in eight different species. CHN1 was subsequently found not to be a common cause of sporadic Duane syndrome [Miyake et al 2010].
A contiguous gene deletion syndrome with Duane syndrome is located on 8q13 (DURS1, OMIM 126800).
SALL4-related disorders. The SALL4-related syndromes include Okihiro syndrome, Duane-radial ray syndrome, acro-renal-ocular syndrome, and IVIC syndrome. These overlapping syndromes are characterized by unilateral or bilateral Duane syndrome and radial ray malformations that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly). Deafness, renal anomalies, and imperforate anus can be coinherited. Inheritance is autosomal dominant.
Heterozygous SALL4 pathogenic variants are associated with most familial cases of these syndromes [Al-Baradie et al 2002, Kohlhase et al 2002]. Individuals who represent simplex cases of isolated Duane syndrome have not been found to harbor pathogenic variants in SALL4 [Wabbels et al 2004]. However, some members of families segregating a SALL4-related disorder have been found to harbor a SALL4 pathogenic variant and to manifest isolated Duane syndrome (without hand or other anomalies) [Al-Baradie et al 2002].
Athabaskan brain stem dysgenesis syndrome (ABDS) [Holve et al 2003] and Bosley-Salih-Alorainy syndrome (BSAS) [Tischfield et al 2005] (OMIM 601536