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The Case of the Inscrutable Infant
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Sarah Wilson’s* arrival into this world was received with cautious celebration, as it marked the beginning of what would undoubtedly be a long and difficult journey for her and her parents. Mrs. Wilson was able to carry Sarah to term, and when the much-anticipated day finally arrived, Sarah was born via an induced vaginal delivery with no complications and weighing in at 3,910 g.
Sarah was the second of two children in the Wilson family; her older sibling was in excellent health. But before Sarah was born, her parents received disturbing news: The baby had multiple congenital abnormalities that fit the VACTERL sequence (possible vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb defects). Moreover, the prenatal screening detected Dandy-Walker malformation, thoracic hemivertebrae, agenesis of the corpus callosum, ventriculoseptal defect, and polyhydramnios.
Shortly after delivery, Sarah’s oxygen saturations dropped into the 40s and 50s, and her eyes would deviate to the right during these events. She was subsequently intubated and transferred to the neonatal intensive care unit. A neurology consultation was requested out of concern for possible seizure activity. In addition, an EEG was performed, which confirmed the presence of multifocal partial epilepsy.
Sarah subsequently was started on antiepileptics and scheduled to undergo an MRI of her brain when she became clinically stable.
Because of Sarah’s multiple anomalies, a genetics specialist was brought in. Karyotyping was ordered, along with a chromosome microarray to detect any smaller deletions or duplications. Although an extensive search of the London Dysmorphology Database was performed, no single disorder or diagnosis fit the clinical picture.
When the MRI was performed, it confirmed the prenatal findings of hypoplastic vermis (Dandy-Walker variant) and callosal agenesis. The radiologist also noted multiple noncommunicating cysts, a microphthalmic right globe with an irregularly shaped lens, and a hypoplastic optic nerve suggestive of a coloboma (Fig. 1). At this point, we were called in.
We Get a Look
When we first saw Sarah, it was clear that she had asymmetric globe size, with microphthalmic appearance on the right (Fig. 2). She demonstrated aversion to light in both eyes, but it was difficult to evaluate her for afferent pupillary defect. Her IOP, as measured by TonoPen, was 25 mmHg in her right eye and 15 mmHg in her left. Examination of the right anterior segment with a penlight revealed microcornea measuring 6 mm in horizontal diameter, although the medium was clear. The left anterior segment was normal.
The dilated fundus exam of her right eye revealed a prominent hyaloid vessel emanating from the optic disc into the vitreous body, with possible adherence to the posterior lens capsule. In addition, the optic nerve was hypoplastic and poorly demarcated. In the posterior segment, there were multiple large, punched-out, hypopigmented chorioretinal lacunae surrounding the optic disc and concentrated in the macula.
The dilated fundus exam of her left eye revealed similar optic nerve and retinal findings (Fig. 3).
In order to narrow the list of differential diagnoses, we pondered the various causes that might link agenesis of the corpus callosum with ophthalmic findings. These disorders include de Morsier syndrome (septo-optic dysplasia), Joubert syndrome, Aicardi syndrome, Apert syndrome, and Rubinstein-Taybi syndrome.
Based on the clinical triad of the presence of multiple chorioretinal lacunae, a history of infantile seizures, and radiographic findings of callosal agenesis, we proposed the diagnosis of Aicardi syndrome to the primary team.
However, the additional findings of persistent fetal vasculature (PFV) and microphthalmos were complicating factors in the differential diagnosis. We were aware of chorioretinal lacunae being almost pathognomonic for Aicardi syndrome but were less certain of an association of PFV in one or both eyes. This led us to perform an extensive literature search.
Aicardi syndrome is a presumably X-linked dominant disorder classically characterized by partial or complete callosal agenesis, infantile spasms, and pathognomonic chorioretinal lacunae.1 However, it is now well recognized that other findings—including cysts around third cerebral ventricle and/or choroid plexus, cerebral malformations such as polymicrogyria, gross cerebral hemispheric abnormalities, vertebral and rib abnormalities, and vascular malformations and malignancy—are also common.2
Ocular signs. The only consistently present feature of the disease seems to be the chorioretinal lacunae, although other ophthalmic findings have been reported, including optic nerve colobomas and microphthalmos. In addition, less-common ophthalmic findings reported in the literature include PFV, morning glory disc anomaly, optic nerve hypoplasia, iris synechiae, cataract, retinal detachment, scleral ectasia, and retrobulbar cysts.3-5
The lacunae themselves represent areas of absent retinal pigment epithelium with associated thinning of the choroid and sclera. Ocular coherence tomography imaging of lacunae has demonstrated disruption and attenuation of the inner segment/outer segment junction of the retinal photoreceptor cells.6 These retinal findings, combined with the frequent association of optic nerve and intracranial abnormalities, make the visual prognosis grim.
Gender and genetics. The condition is seen almost exclusively in girls, but there have been a handful of case reports of males with the 47,XXY karyotype who had the classic triad of findings and were subsequently diagnosed with Aicardi syndrome. To date, there is no definitive diagnostic test for the syndrome, as the genetic locus has yet to be discovered.
Clinical course. Girls typically present with seizures during the first three months of life. Infantile spasms are most common early on; after that, patients tend to experience ongoing medically refractory epilepsy with a variety of seizure types.2
Neurologic deficits and mental retardation can be profound. Nearly all patients function at a level less than 24 months old, with the majority functioning at less than 6 months old. Most children are unable to walk, form words, or feed themselves; and they often have intractable seizures. Survival is estimated to be 76 percent at 6 years and 40 percent at 14 years.1
Treatment. Treatment, which is provided under the guidance of a neurologist, is generally aimed at controlling seizure activity. In addition, a team approach is usually employed, consisting of physical, occupational, and speech therapy; genetic counseling; orthopedic monitoring for the treatment and prevention of scoliosis-related complications; and routine
We have had no ophthalmic follow-up with Sarah, but her pediatrician reports that she has had only one breakthrough seizure. At present, she requires a high-calorie formula because of her slow growth and development. She also has anemia.
Sarah’s case serves as a reminder of the ophthalmologist’s role in the diagnosis of this very rare and serious disease. In recent years, the diagnosis of Aicardi syndrome has become increasingly complicated, as more cases have been documented in which all three components of the classic triad do not always occur. However, as previously mentioned, it appears that the chorioretinal lacunae are the only uniformly present feature of this disease. Thus, involvement of the ophthalmologist in the evaluation and management of patients with Aicardi syndrome is paramount.
* Patient’s name is fictitious.
1 Aicardi J. Brain Dev. 2005;27(3):164-171.
2 Sutton VR, Van den Veyver IB. Aicardi syndrome. GeneReviews. www.ncbi.nlm.nih.gov/books/NBK1381/. Published June 30, 2006. Last updated April 27, 2010. Accessed July 10, 2012.
3 Hoyt CS et al. Arch Ophthalmol. 1978;96(2):291-295.
4 Corney SH et al. Surv Ophthalmol. 1993;37(6):419-424.
5 Ganesh A et al. Br J Ophthalmol. 2000;84(2):227-228.
6 Martel JN et al. J AAPOS. 2011;15(3):308-310.
Dr. Straka is a resident in ophthalmology at Vanderbilt Eye Institute; Dr. Chang is assistant professor of ophthalmology at Bascom Palmer Eye Institute; and Dr. Donahue is professor of ophthalmology at Vanderbilt. The authors report no related financial interests.