Congenital Restrictive External Ophthalmoplegia and Gustatory Epiphora Associated With Fetal// Isotretinoin Toxicity

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).

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.

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.

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.

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@vision.wustl.edu).