THREE-YEAR FOLLOW-UP OF PROGRESSIVE CHORIORETINAL ATROPHY IN ATYPICAL ALAGILLE SYNDROME: A CASE REPORT

We present an adult case of atypical Alagille syndrome with progressive chorioretinal atrophy. During 3-year follow-up, fundus hypoautofluorescence because of chorioretinal atrophy newly developed in the macula region and peripapillary atrophy was enlarged in both eyes. Best-corrected visual acuity worsened and concentric visual field contraction progressed.

Abstract

Purpose:

To report a case of atypical Alagille syndrome with progressive chorioretinal atrophy.

Methods:

Case Report

Results:

A 42-year-old Japanese man presented with atypical Alagille syndrome. At the first visit, funduscopy revealed anterior circumferential chorioretinal atrophy in the peripheral retina and peripapillary region with posterior pole sparing in both eyes. Fundus autofluorescence showed hypoautofluorescence in the peripheral and peripapillary regions, but normal findings in the macular region. After follow-up for 3 years, hypopigmented area with well visualized large choroidal vessels extended to mid-peripheral region. On Fundus autofluorescence images, hypoautofluorescence newly appeared in macular region in both eyes. Perivascular hypoautofluorescence and granular hyperautofluorescence scattering within the posterior pole were also observed. BCVA deteriorated and concentric visual field contraction worsened progressively.

Conclusion:

Alagille syndrome is known to have many ophthalmic manifestations, most of which are stable with minimal threat to vision. In the present case, chorioretinal atrophy progressed during 3-year follow-up, suggesting that progression of chorioretinal atrophy with vision loss may occur over time in Alagille syndrome.

Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with a wide variety of clinical manifestations. Clinically, ALGS is characterized by cholestasis because of bile duct paucity, congenital heart disease, characteristic facial features, and skeletal and ophthalmologic abnormalities.^1,2 Diverse ophthalmic manifestations have been reported, including posterior embryotoxon, optic disc drusen, iris stromal hypoplasia, corectopia, microcornea, strabismus, high myopia, pigmentary retinopathy, and geographic chorioretinopathy.^3,4 Although pigmentary retinopathy may be vision-threatening, especially when the macula is involved, few articles have reported clinical course of chorioretinal atrophy in ALGS.^5,6

We herein report a patient with atypical ALGS manifesting chorioretinal atrophy that progressed during 3-year follow-up.

Case Report

A 42-year-old Japanese man was referred to our department with nyctalopia in both eyes, which started 3 months before visit. His medical history included surgical treatment for atrial septal defect and ventricular septal defect at 2 years old. He also exhibited pulmonary artery stenosis. From age 37 years, he has been on peritoneal dialysis for renal failure.

Ocular examination revealed best-corrected visual acuity (BCVA) of 20/20 in both eyes, with refractive errors of +1.25 diopter (spherical equivalent) in the right eye and +1.0 diopter in the left eye. The intraocular pressure was 17 mmHg in both eyes. Slit-lamp examination revealed bilateral posterior embryotoxon. Funduscopy depicted chorioretinal atrophy in the peripheral retina and also peripapillary region (Figure 1). Fundus autofluorescence (FAF) showed peripheral hypoautofluorescent areas with well-circumscribed borders symmetrically in left and right eyes, and also hypoautofluorescence in peripapillary areas in both eyes. No abnormal FAF findings were observed in the macular region (Figure 2). Optical coherence tomography images of the macular area demonstrated disrupted and discontinuous photoreceptor layers in both eyes (Figure 3). Electroretinogram was not recordable in both eyes, and Goldman perimetry showed concentric visual field contraction in both eyes.

Fig. 1.

Color fundus photographs at the first visit and three years later. At the first visit, images of the right eye (A) and the left eye (B) show well-demarcated anterior circumferential chorioretinal atrophy with pigmentation in both eyes. Three years after the first visit, images of the right eye (C) and the left eye (D) show diffuse choroidal hypopigmentation with increased visibility of the choroidal vessels in mid-periphery in both eyes.

Fig. 2.

Fundus autofluorescence images at the first visit and 3 years later. At the first visit, images of the right eye (A) and the left eye (B) show peripheral hypoautofluorescence corresponding to chorioretinal atrophy in both eyes. Three years after the first visit, image of the right eye (C) shows newly developed hypoautofluorescence in the macular region and extension of the hypoautofluorescence in the peripapillary region along the superotemporal arcade. Image of the left eye (D) shows newly formed hypoautofluorescence in the macular region. Granular hyperautofluorescence scatters diffusely around the macular region in both eyes.

Fig. 3.

Optical coherence tomographic images of the macular area at the first visit and three years later. At the first visit, images of the right eye (A) and the left eye (B) show disrupted and discontinuous photoreceptor layers in both eyes. Three years after the first visit, images of the right eye (C) and the left eye (D) show attenuation of the retinal pigment epithelium and disruption of the outer segment in both eyes.

The patient had distinctive facial features characterized by a triangular face with broad overhanging forehead, deep-set hyperteloric eyes, and a small pointed chin. In addition, MRI showed a butterfly-shaped vertebra. Although molecular genetic testing was performed, gene mutations including JAG1 and NOTCH2 mutations were not detected. The clinical diagnostic criteria for ALGS comprise liver histology showing bile duct paucity together with three of the following five clinical manifestations: cholestasis, ophthalmologic abnormalities, characteristic facial features, cardiac defect, and skeletal abnormalities.² Although our case did not meet all the diagnostic criteria, it met four of the five major clinical features (except cholestasis). The diagnosis of this case was atypical ALGS.

One year after the first visit, he developed cataract in both eyes and underwent operation. Three years after the first visit, BCVA declined to 20/63 in the right eye and 20/32 in the left eye. Visual fields examined by Goldman perimetry were more constricted compared with the first visit. Funduscopy showed diffuse choroidal hypopigmentation with increased visibility of the choroidal vessels in mid-peripheral retina in both eyes (Figure 1). On FAF images, newly developed hypoautofluorescence was found in the macular region, and the hypoautofluorescence in the peripapillary region had extended along the superotemporal arcade in the right eye. Hypoautofluorescence also newly appeared in the macular region in the left eye. Granular hyperautofluorescence scattered diffusely within the posterior pole in both eyes (Figure 2). Optical coherence tomography images at the macular area demonstrated attenuation of the retinal pigment epithelium and disruption of the outer segment in both eyes (Figure 3).

Discussion

Although ALGS has many ophthalmic manifestations, most of them are benign with minimal threat to vision.^3–5 Among them, chorioretinal atrophy has the possibility to deteriorate visual acuity. To date, there are few reports on the clinical course of chorioretinal atrophy in ALGS. Cheema et al⁵ reported an adult with ALGS having retinal atrophy followed over a 10-year period. Although there was progressive retinal electrophysiologic dysfunction, retinal atrophy was stable. However, Bidaguren et al⁶ reported a case of progressive geographic chorioretinal atrophy associated with ALGS. In this report, we present the changes during 3-year follow-up of a 42-year-old male with ALGS manifesting progressive chorioretinal atrophy. Although FAF showed normal findings in the macular region at the first visit, hyperautofluorescence and hypoautofluorescence newly developed in the macular region during 3 years after the first visit. In addition, peripapillary hypoautofluorescence was enlarged radially. Makino et al⁷ reported extensive geographic atrophy of the macula with decreased FAF in a “sleep mask” pattern involving the macula and peripapillary regions. Esmaili⁸ also reported decreased FAF in the macula extending to the peripapillary region. Da Palma et al⁴ suspected that the atrophy progressed in a centripetal direction. In progressive chorioretinal atrophy, progression of chorioretinal atrophy in the macula and peripapillary areas may be connected. As a result of macular involvement, visual function deteriorates. From the above reports of progressive chorioretinal atrophy in ALGS cases, long-term follow-up is necessary.

In this case, the diagnosis of the ALGS was difficult because the patient had no family history, no gene mutation, and no history of neonatal cholestasis or hepatic complications, which are common findings in typical ALGS. Recently, a wide variety of clinical features and manifestations of ALGS are recognized. Gilbert et al⁹ reported that 13 of 401 cases (3.2%) of ALGS were mutation negative. Besides, cases of ALGS with no manifestation of liver disease have been reported.¹⁰ A higher index of clinical suspicion for ALGS is important to avoid missing the diagnosis, and longer follow-up is needed.