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.

Atypical Focal Choroidal Excavation with Macular Hole in a Patient with Alagille Syndrome

“…The most common ocular abnormalities in AGS were posterior embryotoxon (95%), iris abnormalities (45%), diffuse fundus hypopigmentation (57%), speckling of the retinal pigment epithelium (33%), and optic disc anomalies (76%). Recently, da Palma et al [ 2 ] examined 46 eyes in 23 AGS patients, identifying anterior-segment findings were present in 74% (17/23) of them. Posterior embryotoxon was the most common anterior chamber abnormality, identified in 70% (16/23) of patients.…”

“…Alagille syndrome (AGS) is clinically characterized by neonatal cholestatic jaundice with intrahepatic bile duct hypoplasia [ 1 ]. AGS is an autosomal dominant multiorgan disorder caused by aberrations in the Notch signaling pathway [ 2 , 3 ], with an estimated prevalence of 1 in 30,000 to 70,000 live births [ 2 , 3 ]. The majority (greater than 97%) of cases result from pathogenic variants in the Jagged canonical Notch ligand 1 ( JAG1 ) gene on chromosome 20p12.18 with <1% of cases resulting from mutations in the NOTCH2 gene (1p13) [ 2 , 3 ].…”

“…AGS is an autosomal dominant multiorgan disorder caused by aberrations in the Notch signaling pathway [2,3], with an estimated prevalence of 1 in 30,000 to 70,000 live births [2,3]. The majority (greater than 97%) of cases result from pathogenic variants in the Jagged canonical Notch ligand 1 (JAG1) gene on chromosome 20p12.18 with <1% of cases resulting from mutations in the NOTCH2 gene (1p13) [2,3]. Ocular findings include posterior embryotoxon, iris abnormalities, optic disc anomalies, and fundus changes [1][2][3].…”

“…The majority (greater than 97%) of cases result from pathogenic variants in the Jagged canonical Notch ligand 1 (JAG1) gene on chromosome 20p12.18 with <1% of cases resulting from mutations in the NOTCH2 gene (1p13) [2,3]. Ocular findings include posterior embryotoxon, iris abnormalities, optic disc anomalies, and fundus changes [1][2][3].…”

Alagille syndrome due to a de novo NOTCH2 mutation presenting as prenatal oligohydramnios and congenital bilateral renal hypodysplasia: A case report

“…At present, the diagnosis of ALGS mainly includes liver histology showing bile duct deficiency and three out of five main clinical manifestations, including cholestasis, skeletal abnormalities, congenital cardiac defects, ophthalmological abnormalities, and characteristic facial features. If the first-degree relatives of the patient had been diagnosed with ALGS, then this is considered sufficient for the patient to be diagnosed with ALGS as long as the patient met the two classic criteria ( 8 , 9 ). NOTCH 2 gene mutation was identified as a pathogenic gene in the JAG1/NOTCH2 double heterozygous mouse model in 2002 ( 10 ).…”