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

Abstract

Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome.

Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings.

Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel.

Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.

Figure 1.

Anterior and posterior chamber findings of Alagille syndrome in two siblings. Patient 7 (A–C) with scleral icterus, iris stromal hypoplasia A, and posterior embryotoxon (red arrows) B. Fundus photograph showing a well-demarcated wave border between normal and abnormal retina in the periphery C. Patient 11 (D–F) with an elevated optic disc (black arrows) in the fundus photograph at age 7 D, ultrasonography showing the elevation in optic nerve head (white arrow) E, and autofluorescence 8 years later showing no hyperautofluorescence (i.e. no signal of optic disc drusen) F.

Figure 2.

Multimodal imaging in the left eye of patients with Alagille syndrome. Patient 3 (A–C) at 9-years-old presenting with tortuosity of the retinal vessels and hypopigmented changes in the retinal periphery on fundus photography A. Autofluorescence (FAF) showing a wave border in the periphery separating peripheral hyperautofluorescence from posterior normal autofluorescence B. Optical coherence tomography (OCT) revealed a normal retina structure at the fovea C. Patient 10 (D–F) at 14-years-old presented with attenuated retinal vessels and pigmentary changes with bone spicules on fundus photography D. FAF demonstrated circumferential hyperautofluorescence in the mid-periphery and periphery E. OCT identified ellipsoid zone (EZ) granularity temporal to the fovea and loss of EZ nasal to the fovea F. Patient 11 (G–I) at 15-years-old presented with chorioretinal atrophy in the periphery with few pigmentary changes G. FAF showed circumferential autofluorescence loss H. OCT demonstrated normal retinal structure (I). Patient 13 (J–L) at 19-years-old presented with attenuated retinal vessels nasally, circumferential chorioretinal atrophy in the periphery, and atrophy from inferior nasal to optic disc on fundus photography J. FAF demonstrated autofluorescence loss circumferentially and nasal to the optic disc K. OCT showed mild EZ abnormality near the optic disc L. Patient 16 (M–O) at 22-years-old presented with peripheral retinal changes, mainly nasally on fundus photographs M. FAF demonstrated a wave border between normal and abnormal retina N. OCT showed normal retina structure O. Patient 18 (P–R) at 34-years-old presented with attenuated vessels and diffuse atrophic appearance of the retina with bone spicules P. FAF showed the most severe loss of autofluorescence Q. OCT was characterized by loss of foveal contour and outer retinal atrophy surrounding the fovea R. Patient 21 (S–U) at 41-years-old presented with well-demarcated peripheral chorioretinal changes with bone spicules in the periphery on fundus photography S. FAF demonstrated well-demarcated hypoautofluorescence in the periphery T. OCT showed normal retina structure U.

Figure 3.

The visual field responses correlated with intact areas of autofluorescence in Alagille syndrome. Patient 6 (A, B). Autofluorescence (FAF) in the right eye (OD) showing hypoautofluorescent spots in the periphery and around the vessels, and macular involvement with a hypoautofluorescent ring surrounding the fovea A. The kinetic visual field (KVF) in the right eye showed a central scotoma that corresponds to the macular involvement B. Patient 11 (C, D). FAF OD demonstrated circumferential peripheral hypoautofluorescence C. KVF OD showed mildly constricted isopters to all targets that correspond to peripheral dysfunction D. Patient 13 (E, F). FAF OD showed circumferential peripheral hypoautofluorescence and loss of autofluorescence nasal to the optic disc E. KVF OD showed moderately constricted isopters to all targets, mainly temporal, corresponding to nasal chorioretinal changes F. Patient 16 (G, H). FAF OD showed inferior nasal hypoautofluorescence G. KVF OD demonstrated superior temporal constricted isopter to I4e that probably corresponds to the loss of autofluorescence in the inferior nasal area H. Patient 21 (I, J). FAF OD showed circumferential peripheral hypoautofluorescence and loss of autofluorescence nasal to the optic disc I. KVF shows constriction to all targets, mostly superior temporal, in a pattern corresponding to the autofluorescence loss.