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  • Neuro-Ophthalmology

    Establishing the diagnosis

    Case Description

    A 17-month-old boy presented to the pediatric ophthalmology clinic for management of ptosis.  He was recently adopted from South Korea, and his adoptive parents were told the ptosis was present from early infancy. No family history or additional past medical history was available.  He was otherwise healthy.

    On examination, severe bilateral ptosis was noted, with an MRD1 of 0 mm bilaterally.  He had a 20 degree chin-up position. Ductions and versions were notable for -5 limitation of elevation bilaterally, convergence on attempted upgaze, -1 limitation of depression, and -2 limitation of abduction bilaterally. Visual acuity was symmetric and normal for his age. Anterior and posterior segment examinations were within normal limits.

    Based on his clinical presentation, he was diagnosed with congenital fibrosis of the extraocular muscles (CFEOM), type 1, which was later confirmed with genetic testing. He subsequently underwent multiple strabismus surgeries, including bilateral disinsertion of the inferior rectus with suturing to the orbital rim, bilateral superior oblique tenotomies, and left lateral rectus recession of 10 mm, as well as bilateral frontalis sling procedures to improve his ptosis, with good results.

    Pertinent clinical features

    CFEOM is a severe form of strabismus with deficits in ocular motility. Patients with this congenital, nonprogressive disorder have restrictive ophthalmoplegia and eye misalignment, with severe congenital ptosis and a resulting prominent chin-up head position. Deficits of vertical eye movements, especially upgaze, are a hallmark of the condition, and patients’ eyes are often stuck in infraduction. The horizontal eye movement deficits are more variable, ranging from full horizontal motility to nearly complete ophthalmoplegia. Eye alignment in primary position can be exotropic, esotropic, or straight.1, 2

    Three forms of CFEOM have been defined – CFEOM1, CFEOM2, and CFEOM3. These CFEOM subtypes were initially grouped by phenotype; however, the phenotypes can overlap, and now that the genetic etiologies have been elucidated, genetic classification can be more informative. 

    CFEOM1 is an autosomal dominant disorder that presents with prominent congenital bilateral ptosis, inability to elevate both eyes above the midline (the eyes are usually 20-30 degrees infraducted), and often restricted horizontal movements. As a result, patients develop a compensatory chin-up head position. It is usually symmetric and not associated with any additional neurologic abnormalities.  CFEOM1 is the “classic” CFEOM phenotype.1, 3

    CFEOM2 is autosomal recessive and characterized by congenital, non-progressive, bilateral ophthalmoplegia and ptosis. The eyes are primarily exotropic and vertically midline, with restriction of both horizontal and vertical eye movements.4

    CFEOM3 is autosomal dominant and presents with a more variable clinical phenotype. Phenotypic expression of CFEOM3 ranges from relatively mild to quite severe, and can range even within the same family.  Patients can have unilateral or asymmetric involvement, ptosis may or may not be present, and patients may retain some ability to elevate their eyes above midline.  Deficits of horizontal motility are also quite variable.  As detailed below, CFEOM3 can also be associated with a variety of other neurological abnormalities.2, 5 As with all types of CFEOM, the eye movement deficits are congenital and non-progressive.

    Risk factors

    Genetics

    Mutations in four genes have been identified to cause CFEOM and all result in deficits in oculomotor nerve innervation of the extraocular muscles.

    CFEOM1 is transmitted in an autosomal dominant fashion, has no ethnic predilection, and is caused by heterozygous missense mutations in KIF21A. KIF21A is a kinesin motor protein that interacts directly with microtubules and moves cargos in an anterograde direction from the cell body to the developing growth cone. It is expressed widely in the cell bodies, axons, and dendrites of multiple neuronal populations from early development through maturity, as well as in extraocular and other skeletal muscles.6-8 In vitro, KIF21A acts as an inhibitor of microtubule dynamics.9 In vivo, CFEOM-causing mutations in KIF21A disrupt normal auto-inhibition of the protein, leading to a constitutively active molecule and increased microtubule association and oculomotor axon stalling.10 Very rarely, KIF21A mutations can also cause the isolated CFEOM3 phenotype (CFEOM3B).11 There are also a few reported families with clinical CFEOM1 who lack KIF21A mutations; for these patients, the underlying genetic mutations have yet to be identified.12

    CFEOM2 is transmitted in an autosomal recessive fashion, and to date has only been identified in consanguineous families from the Middle East. It is caused by loss of function mutations in the gene encoding the transcription factor PHOX2A.13 PHOX2A is a homeodomain transcription factor protein necessary for proper differentiation of the neurons in the oculomotor and trochlear nuclei in the brainstem. Causative mutations result in absence of PHOX2A protein, and result in errors of early motor neuron identity and subsequent failure of the oculomotor and trochlear nerves to develop.4, 13

    CFEOM3 is inherited in an autosomal dominant, or often de novo, manner. It occurs in all ethnic groups, and is caused by heterozygous missense mutations in TUBB3. Eight distinct heterozygous TUBB3 missense mutations have been reported to cause CFEOM3, and most of these have been identified in multiple unrelated individuals with predictable genotype-phenotype correlations.5 TUBB3 encodes a class III beta tubulin isotype component of microtubules, which are dynamic cytoskeletal polymers that provide structure to axons and act as the highways for motor protein transport. Both microtubule dynamics and motor protein transport are critical for proper axon growth and guidance.14 TUBB3 is expressed in all postmitotic neurons in the developing and mature brain.15 CFEOM-causing missense mutations are often but not exclusively in the C-terminal domain of the protein, altering sites of binding of motor and microtubule associated proteins, and have been associated with increased microtubule stability.5, 16 Rarely, TUBB3 mutations cause the classic CFEOM1 phenotype (CFEOM1B).5

    Two additional dominant genetic forms of CFEOM have been reported in single families: CFEOM and polymicrogyria in a family with a TUBB2B mutation,17 and CFEOM associated with a balanced translocation in a second family (CFEOM3C).18  TUBB2B is another beta tubulin isotype. Finally, one additional recessive syndrome, Tukel syndrome, involves CFEOM and postaxial oligodactyly or oligosyndactyly of the hands. The genetic cause of Tukel syndrome has not yet been identified.18

    Differential Diagnosis 

    CFEOM is a clinical diagnosis and can be confused with several other eye movement disorders, especially if the congenital, nonprogressive nature of the condition is not recognized. Eye movements, particularly vertical movements, can be difficult to assess in very young infants. For this reason, we sometimes see that eye movements are noted as full on initial exam, and then later, when the child is more able to participate in the exam, the eye movements are determined to be restricted. This can give the false impression that the condition is progressive, resulting in a misdiagnosis.

    Disorders that should be distinguished from CFEOM include isolated third nerve palsy, chronic progressive external ophthalmoplegia, isolated congenital ptosis, and congenital myasthenic syndrome. Isolated third nerve palsy, either bilateral or unilateral, can be easily confused with CFEOM1 or CFEOM3. They can be distinguished by the more profound restriction of upgaze in CFEOM. Chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disorder, has a later onset and is progressive, but adults with the two conditions can appear similar. Isolated congenital ptosis can be distinguished from CFEOM by the presence of normal eye movements. Congenital myasthenic syndrome can present similarly to CFEOM, but the ptosis is fatigable, and the muscle weakness is of multiple muscle groups, not limited to the extraocular muscles.

    The differential diagnosis also includes other congenital cranial dysinnervation disorders, such as Duane syndrome or horizontal gaze palsy. Some CFEOM3 patients with associated facial palsy or weakness are initially misdiagnosed with Moebius syndrome.19, 20 Revised diagnostic criteria for Moebius syndrome,20 however, require full vertical eye movements, distinguishing these patients from CFEOM patients who have profound deficits of vertical motility. Moreover, unlike patients with classic Moebius syndrome and esotropia, CFEOM3 patients typically have exotropia. Finally, extremely rarely, a slow-growing cavernous sinus lesion such as a sclerosing cavernous hemangioma can initially present as CFEOM3.21

    Associated syndromes 

    CFEOM1 is an isolated eye movement disorder, with no other associated neurological abnormalities.

    CFEOM2 patients have small, sluggish pupils, in addition to eye movement deficits and ptosis.  They can also have subnormal visual acuity consistent with retinal dysfunction22 but do not present with additional neurological abnormalities.

    CFEOM3 occurs in two forms, isolated and syndromic. Like CFEOM1, isolated CFEOM3 is limited to the oculomotor system. In general, these patients have a milder form of CFEOM3 than syndromic patients. It is associated with the mutations resulting in amino acid substitutions R262C, A302T, and R62Q. Syndromic CFEOM3, on the other hand, is associated with mutation-specific combinations of cranial and spinal peripheral neuropathies, developmental delay, intellectual and social disability, and brain malformations.5, 16, 19 D417N mutations, which are often inherited, cause CFEOM3, followed by the development of a progressive axonal sensorimotor polyneuropathy during adult life.5 The remaining syndromic TUBB3 mutations often arise de novo, and result in amino acid substitutions R262H, E410K, D417H, and R380C.  

    While R380C results in a moderate form of CFEOM, patients with E410K, R262H, and D417H substitutions have severe bilateral ocular phenotypes, including exotropia, infraduction, and profound limitation of eye movements. E410K and R262H patients also have facial weakness and vocal cord paralysis. Patients harboring the E410K substitution have facial dysmorphisms, Kallmann syndrome (anosmia with hypogonadal hypogonadism), and can develop an axonal peripheral neuropathy and cyclic vomiting.19 The cyclic vomiting may be responsive to valproic acid. Patients with R262H and D417H substitutions may have congenital joint contractures in addition to onset of a peripheral neuropathy in the first decade of life.

    Most CFEOM3 patients harboring the E410K, R262H, or D417H substitutions have intellectual and social disabilities, and some meet diagnostic criteria for autism spectrum disorder. There are mutation-specific correlations with specific brain malformations including thin-to-absent anterior commissure and corpus callosum, dysmorphic basal ganglia, brainstem hypoplasia, and hypoplastic or absent olfactory sulci, olfactory bulbs, and facial nerves.5, 19 

    Pathophysiology

    As the name, “congenital fibrosis of the extraocular muscles,” suggests, it was originally believed that the disorder resulted from an intrinsic defect of the extraocular muscles, characterized by fibrosis of the muscles and fibrotic adhesions between muscles and Tenon’s capsule.23-25 It is now understood, however, that CFEOM is primarily a disorder of embryonic development and targeting of the oculomotor nerve.26 The hypoplasia of the extraocular muscles is a secondary effect, resulting from decreased innervation. Human autopsy of a CFEOM1 patient showed absence of the superior division of the oculomotor nerve and corresponding motor neurons in the oculomotor nucleus, as well as severe abnormalities of the levator palpebrae and superior rectus muscles.3 MRI data from affected individuals show small or absent orbital motor nerves, with atrophy of the extraocular muscles. This supports the hypothesis that the primary deficit in CFEOM1 is hypoplasia of the oculomotor nerve, most notably of the superior division, with a secondary muscular atrophy.27

    Knock-in mice with disease-causing human mutations in TUBB3 and KIF21A have been generated in the Engle lab and manifest CFEOM phenotypes. Examination of these mice shows errors of growth and guidance of the oculomotor axons, providing additional evidence that the primary pathology in CFEOM is neuronal, not muscular. KIF21A mutant mice exhibit hypoplasia of the superior division of the oculomotor nerve and aberrant branching of the inferior division.10 In TUBB3 mutant mice, the developing oculomotor nerve makes an erroneous turn along its path from the brainstem to the orbit and reaches the wrong position in the orbit. The trochlear and trigeminal nerves also show growth and branching deficits.5

    Patient management: treatment and follow-up

    There are currently no treatments that can restore full functionality and range of motion to the extraocular muscles. Treatment goals must be individualized for each patient based on the patient’s specific pattern of deficits, and usually include management of ptosis and head position, good ocular alignment in primary position, and maximizing visual outcome by prevention or treatment of amblyopia.1

    Treatment of ptosis generally requires frontalis sling due to poor levator function. Care must be taken not to raise the lids too high, as these patients are at an increased risk for subsequent exposure keratopathy, due to their infraduction and poor-to-absent Bell reflex. Generally, a postoperative MRD1 of 1-2mm is suggested as a goal. CFEOM patients who also have facial palsy are at even greater risk of exposure keratopathy due to a poor blink, and ptosis repair must be very conservative and accompanied by aggressive lubrication. If the ptosis is not causing deprivation amblyopia, waiting until after strabismus surgery is preferred, as the lid position may change as a result of strabismus surgery. For patients who develop ocular surface disease, a scleral contact lens can provide substantial relief.

    Strabismus surgery focuses on improving head position and alignment in primary position, while promoting the greatest range of extraocular motion possible. CFEOM1 patients require large bilateral inferior rectus recessions, which can be enhanced with bilateral superior oblique tenotomies, to allow the eyes to come to the vertical midline. Recessions and transpositions are most frequently used, and resections are avoided, because the result of resecting a poorly functioning muscle is unpredictable and often minimal, but surgical plans must be individualized to each patient’s particular pattern of restriction. In some cases, a more profound weakening procedure is needed, such as muscle disinsertion from the eye and subsequent attachment to the orbital rim. Patients often need multiple strabismus surgeries.

    CFEOM patients are at high risk for both deprivation and strabismic amblyopia, and must be monitored and treated appropriately. Ptosis causing deprivation amblyopia must be treated promptly. Amblyopia is treated with patching or atropine therapy in these patients, as it is in other children. Appropriate refractive management also maximizes visual outcomes.

    Children with syndromic CFEOM3 require a team able to address their many developmental needs, including ENT, neurology, developmental pediatrics, endocrinology and orthopedics.  Patients with facial weakness and vocal cord paralysis often need a tracheotomy early in life, but most are successfully decannulated later in childhood.19

    Disease-related complications

    CFEOM can lead to several potential complications. Strabismus is associated with decreased social and occupational opportunities.29 CFEOM patients can also have decreased binocular vision, lack of stereopsis, and amblyopia. As noted above, they are at risk for corneal exposure, particularly after ptosis surgery. CFEOM is associated with an abnormal head position, which can cause both orthopedic and psychosocial problems. Patients with syndromic CFEOM have multiple other complications, based on their mutation-specific combination of associated findings. These include endocrinologic perturbations (such as hypogonadotropic hypogonadism), joint contractures, facial palsy, developmental delay, and intellectual and social disabilities. A genetic diagnosis can help these patients anticipate potential future problems and manage them pre-emptively.

    References

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