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Congenital Restrictive External Ophthalmoplegia and Gustatory Epiphora Associated With Fetal Isotretinoin Toxicity
Arch Ophthalmol. 2002;120:1094-1095.
Isotretinoin or Accutane (Hoffman–La Roche Inc, Nutley, NJ; 13-cis-retinoic acid) is a vitamin A analogue that was first
licensed in the United States in 1982 for the treatment of cystic acne. Use
of isotretinoin during pregnancy is teratogenic and is associated with a constellation
of fetal malformations collectively termed retinoic acid embryopathy.1
Retinoic acid embryopathy is characterized by craniofacial abnormalities
in the form of hydrocephalus, microcephaly, a narrow, sloping forehead, hypertelorism,
ear deformities, cleft palate, and micrognathia.1
Systemic anomalies include congenital heart defects and thymic malformation.
Reported ophthalmic findings are microphthalmos, optic nerve hypoplasia, and
cortical blindness.2 We describe a child
exposed to isotretinoin during gestation who sought treatment for congenital
restrictive ophthalmoplegia and gustatory epiphora (crocodile tears syndrome).
Report of a Case
An 11-week-old boy with numerous malformations came to our unit with
a history of poor visual tracking from birth. The child's mother had used
isotretinoin (mean daily oral dosage, 53.3 mg) for acne during the first 9
weeks of her pregnancy. There was no family history of parental consanguinity
or hereditary ocular or systemic disease. The infant was born at term weighing
2.9 kg and was found to have external and middle ear malformations, patent
ductus arteriosus, patent foramen ovale, and gastroesophageal reflux. At age
1 month, he had a seizure. Electroencephalography results were unremarkable,
and magnetic resonance imaging of the orbits and brain revealed no malformations
of the brainstem or cerebral structures; extraocular muscles appeared normal
in size and configuration. Karyotype and fluorescence in situ hybridization
analysis for chromosome 22 deletion demonstrated no abnormalities.
The infant was hypotonic. Craniofacial abnormalities included a prominent
calvaria, a tall forehead, an oblique facial plane, micrognathia, anotia,
and preauricular skin tags (Figure 1).
He had mild bilateral blepharoptosis. Ocular motor examination revealed a
striking limitation in the amplitude and velocity of saccadic, pursuit, and
vestibulo-ocular reflex eye movements in both the horizontal and vertical
planes. Large-angle (30 prism diopters) alternating exotropia was noted with
deficient convergence. Pupillary responses were normal. Cycloplegic retinoscopy
revealed significant hyperopia (+5.00 diopters OU). No funduscopic abnormalities
were noted. Flash visually evoked potential and photopic and scotopic electroretinography
responses were normal for the patient's age. Spectacles were prescribed to
correct the hyperopia.
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Photographs of our patient at age 6 years. Craniofacial abnormalities
characteristic of isotretinoin embryopathy are apparent, including a prominent
calvaria, a tall forehead, an oblique facial plane, micrognathia (A), anotia,
and preauricular skin tags (B and C).
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By 10 months of age, the patient was noted to have epiphora when feeding
(crocodile tear syndrome) and a lack of tear production when crying (emotional
alacrima). At 11 months of age, bilateral lateral-rectus recessions were performed
to correct the exotropia. Forced duction testing during surgery revealed marked
restriction to passive rotation in both horizontal and vertical directions
in each eye, consistent with restrictive myopathy. At age 6 years, he had
a best-corrected visual acuity of 20/30 OU and an intermittent esotropia of
10 prism diopters. The mild bilateral blepharoptosis and the limitation of
versional and vergence eye movements were unchanged.
Comment
Our patient exhibits 2 previously unreported ocular manifestations of
fetal isotretinoin exposure: congenital restrictive external ophthalmoplegia
and gustatory epiphora. The cause of the ophthalmoplegia is not known, but
it may represent a sporadic form of congenital ocular fibrosis syndrome. Congenital
ocular fibrosis syndrome is a collection of nonprogressive, inherited motility
disturbances characterized by "stiff" fibrotic extraocular muscles.3 It is unclear whether congenital ocular fibrosis
syndrome represents a primary congenital myopathy or neuropathy. Recent evidence
suggests that congenital ocular fibrosis syndrome may arise from a loss of
neurons within brainstem ocular motor nuclei during embryologic development.3 The neuronal loss secondarily disrupts myogenesis,
resulting in anomalous muscle development. The presence of congenital gustatory
epiphora in our patient, caused by maldevelopment of the salivary and lacrimal
nuclei within the pons and medulla, suggests a primary brainstem neuropathy
as the cause of the ophthalmoplegia.4
Concomitant gustatory epiphora and ocular motility disturbances have
been reported with fetal thalidomide exposure.5
The thalidomide abnormalities have been ascribed to a toxic insult to the
ocular motor and facial brainstem nuclei before the fifth week of gestation.
The findings in our patient suggest that exposure to isotretinoin during the
early stages of fetal development can produce similar ocular motor abnormalities.
AUTHOR INFORMATION
Medhat F. Guirgis, MD;
Agnes M. F. Wong, MD, PhD;
Lawrence Tychsen, MD
St Louis, Mo
Corresponding author and reprints: Lawrence Tychsen, MD, Room 2S-89,
St Louis Children's Hospital, One Children's Place, St Louis, MO 63110 (e-mail: tychsen{at}vision.wustl.edu).
REFERENCES
1. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313:837-841.
ABSTRACT
2. Fraunfelder FT, LaBraico JM, Meyer SM. Adverse ocular reactions possibly associated with isotretinoin. Am J Ophthalmol. 1985;100:534-537.
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3. Engle EC, Goumnerov BC, McKeown CA, et al. Oculomotor nerve and muscle abnormalities in congenital fibrosis of
the extraocular muscles. Ann Neurol. 1997;41:314-325.
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4. Ramsay J, Taylor T. Congenital crocodile tears: a key to the aetiology of Duane's syndrome. Br J Ophthalmol. 1980;64:518-522.
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5. Miller MT, Strömland K. Ocular motility in thalidomide embryopathy. J Pediatr Ophthalmol Strabismus. 1991;28:47-54.
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SECTION EDITOR: W. RICHARD GREEN, MD
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