A rare association of congenital fibrosis of extraocular muscles with keratoconus and bilateral sensorineural hearing loss: A co-incidence or some syndrome?

Anupam Singh; Shrinkhal; Kavya Subramanian; Aarzoo Juneja; Aditi Saini; Barun Kumar

doi:10.4103/pajo.pajo_100_21

CASE REPORT

Year : 2021 | Volume : 3 | Issue : 1 | Page : 27

A rare association of congenital fibrosis of extraocular muscles with keratoconus and bilateral sensorineural hearing loss: A co-incidence or some syndrome?

Anupam Singh¹, Shrinkhal¹, Kavya Subramanian¹, Aarzoo Juneja¹, Aditi Saini², Barun Kumar³
¹ Department of Ophthalmology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
² Department of Radiodiagnosis, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
³ Department of Cardiology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission	23-Jun-2021
Date of Acceptance	02-Jul-2021
Date of Web Publication	24-Aug-2021

Correspondence Address:
Dr. Anupam Singh
Department of Ophthalmology, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_100_21

Abstract

Congenital fibrosis of extraocular muscles (CFEOM) is an inherited restrictive ocular motility disorder characterized by unilateral or bilateral horizontal and/or vertical gaze impairment with ptosis. Keratoconus is a bilateral asymmetrical corneal ecstatic disease with multifactorial etiology, including complex interaction of both genetic and environmental factors. We report a case of a 29-year-old female who presented with chief complaints of bilateral diminution of vision and drooping of eyelids since early childhood with a history of seizures for 1 year. Visual acuity at presentation was hand movement close to face with accurate projection of rays in both the eyes. Contrast-enhanced magnetic resonance imaging of the brain and orbit revealed partially empty sella, neurocysticercosis, and bilateral atrophy of extraocular muscles. On detailed examination, she was found to have CFEOM type 1A (CFEOM1A, autosomal dominant inheritance) with bilateral advanced keratoconus, bilateral sensorineural hearing loss, bilateral presenile cataract, and neurocysticercosis. The association of CFEOM1A, keratoconus, and sensorineural hearing loss is not reported in the literature to date. Whether this association is co-incidental or part of some new syndrome needs to be evaluated further.

Keywords: Congenital fibrosis of extraocular muscles, keratoconus, ptosis, sensorineural hearing loss

How to cite this article:
Singh A, Shrinkhal, Subramanian K, Juneja A, Saini A, Kumar B. A rare association of congenital fibrosis of extraocular muscles with keratoconus and bilateral sensorineural hearing loss: A co-incidence or some syndrome?. Pan Am J Ophthalmol 2021;3:27

How to cite this URL:
Singh A, Shrinkhal, Subramanian K, Juneja A, Saini A, Kumar B. A rare association of congenital fibrosis of extraocular muscles with keratoconus and bilateral sensorineural hearing loss: A co-incidence or some syndrome?. Pan Am J Ophthalmol [serial online] 2021 [cited 2023 Mar 28];3:27. Available from: https://www.thepajo.org/text.asp?2021/3/1/27/324520

Introduction

Congenital fibrosis of extraocular muscles (CFEOM) is a restrictive ocular motility disorder characterized by unilateral or bilateral horizontal and/or vertical gaze impairment with ptosis. CFEOM is included under congenital cranial dysinnervation disorders, in which dysinnervation of the extraocular muscles is the primary pathology leading to abnormal muscle substructure and ocular motility restrictions.^[1] CFEOM type 1A (CFEOM1A) is the most common among all phenotypes. Inheritance is autosomal dominant with full penetrance. There is a primary defect of the superior division of the oculomotor nerve. It is characterized by congenital bilateral ptosis and bilateral ocular motility disorder, including hypotropia in primary position, upgaze restriction, and variable restriction of horizontal gaze.^[1]

Keratoconus is a bilateral asymmetrical corneal ecstatic disease characterized by corneal distortion and irregular astigmatism, leading to visual impairment. Its etiology is multifactorial including complex interaction of both genetic and environmental factors.^[2] Keratoconus has been associated with numerous ocular and systemic disorders, including Leber congenital amaurosis, brittle cornea syndrome, corneal dystrophies, Down syndrome, and Turner's syndrome.^[2]

We hereby report a case with rare association of keratoconus with CFEOM1A, sensorineural hearing loss, partially empty sella, and presenile cataract. Neurocysticercosis was an incidental finding.

Case Report

A 29-year-old female presented to the ophthalmic outpatient department with chief complaints of bilateral drooping of upper lids and inability to move eyes freely since birth along with gradual, painless progressive diminution of vision in both eyes for the last 7 months. There was a history of recurrent generalized tonic–clonic seizure attacks for the last 1 year, for which she was receiving antiepileptic drugs. She also had a history of redness, pain, and watering in the left eye 4 months back, for which she received treatment from outside, but records were not available. The family history revealed similar lid and ocular movement disorder in her mother, son, and back in the family tree as well [Figure 1]a, [Figure 1]b, [Figure 1]c. There was no history of consanguinity, diplopia, eye rubbing, contact lens wear, muscle weakness, or any other chronic illness.

Figure 1: (a) The pedigree chart of the proband, revealing similar lid and ocular movement findings in her mother, brother, son, and back in the family tree. (b) Clinical photographs of the patient showing bilateral severe congenital ptosis with bilateral brow elevation demonstrating frontalis muscle overaction. (c) Clinical photographs of the son showing bilateral severe congenital ptosis with bilateral brow elevation demonstrating frontalis muscle overaction. (d) Nine-gaze photograph of the patient showing left exotropia in primary position, bilateral hypotropia with restricted extraocular movements in all the gazes

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On examination, she had chin up head posture with visual acuity of hand movement close to face, accurate projection of rays in all four quadrants in both eyes. The intraocular pressure was 10 mmHg and 8 mmHg in the right and left eyes, respectively, by Goldmann applanation tonometry. Further, she had bilateral severe congenital ptosis, poor levator palpebrae superioris action with bilateral brow elevation demonstrating frontalis muscle overaction [Figure 1]b, blue arrow]. Bell's phenomenon was poor in both eyes, and there was no evidence of jaw-winking phenomenon, globe retraction, and lid aperture changes. On Hirschberg's test, she had 7° of left exotropia in primary position, bilateral hypotropia with restricted extraocular movements in all the gazes [Figure 1]d. Pupil was normal in size and reaction (both direct and consensual) in both eyes. On slit-lamp examination, there was bilateral conical protrusion of both the eyes [left more than right, [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d associated with corneal scarring in the left eye in the paracentral inferotemporal quadrant [Figure 2]b, yellow arrow]. Lens was cataractous with nuclear sclerosis grade 1 with dense posterior subcapsular cataract in both eyes [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. Retinoscopy and detailed posterior-segment examination were not possible due to dense posterior subcapsular cataract; however, disc appeared to be normal. Ultrasonography B-scan for posterior segment revealed no abnormality in both the eyes. Forced duction test was positive for inferior recti of both eyes.

Figure 2: (a-d) Slit-lamp photographs of the right eye and left eye under diffuse illumination and slit beam showing bilateral cataractous lens (a-d), conical protrusion of both the eyes (c and d, blue arrow), associated with corneal scarring in the left eye in paracentral inferotemporal quadrant (b, yellow arrow). (e) Anterior-segment optical coherence tomography revealing thinning of both the corneas with 450 μ and 351 μ central corneal thickness in right and left eyes, respectively

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Keratometry showed 46.5 D (K1) and 56.0 D (K2) in the right eye and 40.3 D (K1) and 66.50 D (K2) in the left eye, depicting gross astigmatism in both eyes (left > right). Axial length was 26.4 mm and 27.8 mm in the right and left eyes, respectively. Anterior-segment optical coherence tomography revealed thinning of both the corneas with central corneal thickness of 450 μand 351 μ in the right and left eyes, respectively [Figure 2]e, and scaring of the inferotemporal quadrant in the left eye [Figure 2]e.

Detailed evaluation by multidisciplinary team revealed bilateral sensorineural hearing deficit. There was no abnormality on cardiac evaluation. Repeated nerve conduction study was negative, which excluded myasthenia gravis. There was no other associated body dysmorphism.

Routine blood investigations, liver and kidney function tests, thyroid profile, serum lactate, LDH levels, and CPK-NAC levels were within normal limits. Contrast-enhanced magnetic resonance imaging (CEMRI) of the brain and orbit was suggestive of neurocysticercosis [Figure 3]a, green arrow], partially empty sella [Figure 3]b, blue arrow], and mild-to-moderate atrophy of all the recti [Figure 3]c, MR: Yellow arrow; LR: Red arrow; [Figure 3]d, SR and IR: Orange arrow]. She was advised muscle biopsy and genetic analysis but was refused due to financial constraints.

Figure 3: (a) Axial section of contrast-enhanced magnetic resonance imaging of brain revealing a small T1/T2/FLAIR hypointense lesion with hyperintense rim involving cortex of right frontal (green arrow). (b) Sagittal section on T2 image showing partially empty sella (blue arrow). (c and d) Orbital sections were suggestive of mild-to-moderate atrophy of all the recti; medial recti: Yellow arrow, lateral recti: Red arrow, superior and inferior recti: Orange arrows

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Similar lid and ocular motility presentation was seen in her 3-year-old son [Figure 1]c, for whom cycloplegic refraction under eye ointment atropine revealed +1.5 DS/−3.25 DC × 90° and +1.25 DS/−3.00 DC × 90° in the right and left eye, respectively. Keratometry confirmed the presence of corneal astigmatism, but corneal was grossly normal on slit-lamp examination. The rest of the other ophthalmic findings were insignificant.

Based on all the findings and family history, clinical diagnosis of CFEOM1A with bilateral advanced keratoconus (L > R), bilateral sensorineural hearing loss (L > R), and bilateral presenile cataract with neurocysticercosis was made for the female.

The patient was planned for multidisciplinary approach of management. Ophthalmic plan of management included sequential cataract extraction with bilateral penetrating keratoplasty under guarded visual prognosis. Considering her advanced keratoconus, she was prescribed tear supplement eye drops and advised to strictly avoid eye rubbing. She was referred to the neurology team for the management of neurocysticercosis and to oto-rhino-laryngology team for hearing loss. Considering the autosomal dominant pattern of the disease, she was given proper genetic counseling for further planning of pregnancy. Glasses were prescribed for the boy and he was advised for regular follow-up at every 3 months.

Discussion

CFEOM is a rare ocular motility disorder with an estimated prevalence of 1 in 230,000.^[3] The condition affects part or all of the oculomotor nucleus, oculomotor nerve, trochlear nerve, and muscles innervated by these two nerves.^[4] CFEOM can be associated with various central nervous system malformations, such as agenesis or hypoplasia of the corpus callosum, brain stem, cerebellar hemisphere, cerebellar vermis, absence of the cerebral peduncle in the midbrain, and expansion of the ventricular system.^[4]

Depending upon the gene mutation, CFEOM can be of the following types – CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, and CFEOM-U (Tukel syndrome).

CFEOM1A is the most common phenotype resulting from heterozygous mutations in the KIF21A gene encoding a kinesin motor protein.^[1] It has been mapped to the centromeric region of chromosome 12 (12q12 locus).^[1],[4],[5] It is characterized by bilateral congenital ptosis and bilateral ocular motility disorder, leading to hypotropia in primary position, upgaze restriction, and variable restriction of horizontal gaze.^[1]

Complete bilateral non-progressive external ophthalmoplegia since birth and positive family history in our case without diplopia and body dysmorphism; gave the impression of CFEOM type 1A. CEMRI of brain and orbit revealed bilateral atrophy of extraocular muscles, partially empty sella, and multiple neurocysticercosis lesions in the brain. These findings were consistent with the provisional diagnosis of CFEOM1A, and neurocysticercosis lesions explained the seizures.

Absence of proptosis and diplopia excluded thyroid ophthalmopathy as diagnosis. However, absence of diplopia is also a feature of an entity, chronic progressive external ophthalmoplegia (CPEO), but total ophthalmoplegia since birth in our patient excluded CPEO. Involvement of all the four recti excluded progressive supranuclear palsy, as it typically affects vertical gaze and spares horizontal gaze. Myotonic dystrophy was also considered as one differential which is characterized by both ocular and systemic findings. Ocular symptoms include CPEO, lid lag, and cataract. Distal muscle weakness is common, with activities requiring fine motor control of hands. Our patient did not demonstrate any such muscle weakness, so it was excluded.

The patient also demonstrated presence of advanced keratoconus in both eyes (L > R). Presence of scar in the left eye signified a history of hydrops leading to scarring (possibly correlating with her history of redness and watering in the left eye).

Keratoconus is a multifactorial corneal ectatic disorder with prevalence rates varying from 20 in 100,000 to 1 in 500,000.^[6] Most of the keratoconus cases are sporadic; however, autosomal dominant with reduced penetrance and autosomal recessive mode of inheritance have also been documented.^[2] There is high degree of genetic heterogeneity in this disease as about 17 distinct genomic loci have been mapped for keratoconus.^[2] Li et al. reported several regions of linkage on chromosomes 4, 5, 9, 12, and 14 in keratoconus sib-pair families of White and Hispanic origin.^[7]

Keratoconus is known to be associated with numerous ocular and systemic genetic disorders, including Leber congenital amaurosis, Williams-Beuren syndrome, brittle cornea syndrome, Costello syndrome, corneal dystrophies, Down syndrome, Turner syndrome, Marfan syndrome, Ehlers-Danlos syndrome, and mitral valve prolapse.^[2] This wide spectrum of associations suggests that these disorders share a common underlying genetic mechanism or they may provide environmental triggers for manifestation of keratoconus. However, the exact etiology of increased risk of keratoconus associated with these genetic disorders is still not known.^[2]

KIF21A gene mutation is responsible for CFEOM1A. It has been mapped to the centromeric region of chromosome 12 (12q12 locus).^[1],[4],[5] Several regions of linkage on chromosome 12 have also been reported to be responsible for keratoconus by Li et al.^[7] Miyake et al. reported association of sensorineural hearing loss with deletion of COL2A1 gene due to 12q proximal deletion.^[8] This could be possible underlying etiology for the rare presentation in your patient, that is CFEOM1A with bilateral keratoconus and bilateral sensorineural hearing loss. Presenile cataract and neurocysticercosis can be incidental finding.

CFEOM is a rare disease, however when it is associated with other disorders, need expert multidisciplinary approach for proper management and so as the case of keratoconus. Early clinical diagnosis is important, as it leads to early treatment and prevention of secondary complications. Proper genetic counseling and teaching lifestyle modifications are mandatory for these patients.

To the best of our knowledge, this is a case of rare association between CFEOM1A with keratoconus and sensorineural hearing loss. It is presently unclear that this association is part of a syndrome or just a coincidental finding and therefore needs further evaluation.

Informed consent

The patient gave her informed written consent to publish the case, the images.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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