Anterior Chamber Pathology in Alagille Syndrome

Abstract

Background: Alagille syndrome is an autosomal dominant disorder characterized by neonatal cholestasis, characteristic facies, and cardiac abnormalities. Ocular abnormalities include posterior embryotoxon, mosaic pattern of iris stromal hypoplasia, microcornea, optic disc drusen, and pigmentary retinopathy. We present the second report of ocular pathology in two cases of Alagille syndrome. Methods: Gross and histologic preparations of four eyes of two patients. Results: Posterior embryotoxon is seen in both cases, with iris processes extending to the embryotoxon in case 1. Case 1 exhibited distinctly abnormal iris stroma with a prominent cleft separating the anterior and posterior stroma. Lacy vacuolization of the iris pigment epithelium was seen in case 2. Conclusions: Alagille syndrome is primarily a hepatic disorder but presents with several distinct ocular pathologic features, most specifically posterior embryotoxon. This and the unusual iris stroma may be caused by improper migration of neural crest cells due to mutation in the Jagged 1 gene that causes Alagille syndrome. Patients with Alagille syndrome rarely present to ocular autopsy. Pathology findings may help us better understand the pathophysiology of the ocular abnormalities in this disorder.

Characterization of the Spectrum of Ophthalmic Changes in Patients With Alagille Syndrome

“…On the other hand, an autopsy of a 7-month-old boy with ALGS due to JAG1 mutation found thin, atrophic, and hypopigmented RPE with speckled hyperpigmentation scattered throughout the retina, especially in the periphery. 5 Additionally, an autopsy of a 6-year-old boy found extensive retinal pigmentary changes, with a demarcation line 4 mm posterior to the equator sparing the central retina. 11 Another reason that we likely found more peripheral changes is that wide-field cameras are now available to more easily inspect the far periphery.…”

“… 2 The ocular features of ALGS were discovered later 4 and form part of the criteria for diagnosing this disorder. 5 , 6 The classic criteria to diagnose ALGS were established in 1987 and required a paucity of the interlobular bile ducts and at least three of five major features, which included chronic cholestasis, cardiac disease, anomalies of the vertebrae, characteristic facial phenotype, and ocular abnormalities. 7 – 9 Posterior embryotoxon, characterized by a prominent and anterior Schwalbe's line at the junction of the corneal endothelium and the uveal trabecular meshwork, 9 is a major criterion and has been reported as the most frequent ocular finding.…”

“… 9 , 26 The protein encoded by JAG1 is a Delta ligand for the Notch receptor(s). 5 , 10 , 27 , 28 The protein encoded by NOTCH2 is a receptor that mediates molecular signaling between cells. 29 Mutations in these genes contribute to various systemic issues possibly due to a loss of cellular interactions.…”

Multidisciplinary Management of Alagille Syndrome

“…Posterior embryotoxon, Axenfeld anomaly and microcornea are the predominant anomalies of anterior chamber, whereas pigmentary retinopathy, optic nerve head anomalies and abnormal vessels are the typical findings in the posterior segment of the eye. 63 Ophthalmological manifestations are important for diagnosis of ALGS and are included among the major criteria. 64 A majority of the anterior segmental anomalies do not impair the functional status of the patient.…”

Mittendorf’s dot and posterior embryotoxon — incidental findings in a patient with a potentially occludable anterior chamber angle

“…It is visible during slit-lamp examination as a concentric line anterior to the limbus of the cornea. It can be associated with Axenfeld-Rieger syndrome [4] or Alagille syndrome [5]. It may also be an isolated finding in normal patients.…”