Intraretinal hemorrhages and detailed retinal phenotype of three patients with Alagille syndrome

ABSTRACT

Purpose

To explore patterns of disease expression in Alagille syndrome (ALGS).

Methods

Patients underwent ophthalmic examination, optical coherence tomography (OCT) imaging, fundus intravenous fluorescein angiography (IVFA), perimetry and full-field electroretinograms (ffERGs). An adult ALGS patient had multimodal imaging and specialized perimetry.

Results

The proband (P1) had a heterozygous pathogenic variant in JAG1; (p.Gln410Ter) and was incidentally diagnosed at age 7 with a superficial retinal hemorrhage, vascular tortuosity, and midperipheral pigmentary changes. The hemorrhage recurred 15 months later. Her monozygotic twin sister (P2) had a retinal hemorrhage at the same location at age 11. Visual acuities for both patients were 20/30 in each eye. IVFA was normal. OCT showed thinning of the outer nuclear in the peripapillary retina. A ffERG showed normal cone-mediated responses in P1 (rod-mediated ERGs not documented), normal ffERGs in P2. Coagulation and liver function were normal. An unrelated 42-year-old woman with a de-novo pathogenic variant (p. Gly386Arg) in JAG1 showed a similar pigmentary retinopathy and hepatic vascular anomalies; rod and cone function was normal across large expanses of structurally normal retina that sharply transitioned to a blind atrophic peripheral retina.

Conclusion

Nearly identical recurrent intraretinal hemorrhages in monozygotic twins with ALGS suggest a shared subclinical microvascular abnormality. We hypothesize that the presence of large areas of functionally and structurally intact retina surrounded by severe chorioretinal degeneration, is against a predominant involvement of JAG1 in the function of the neurosensory retina, and that instead, primary abnormalities of chorioretinal vascular development and/or homeostasis may drive the peculiar phenotypes.

KEYWORDS:

• Alagille syndrome
• concentric
• JAG1
• retinal hemorrhage
• chorioretinal atrophy
• retinal degeneration

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authorship

All authors attest that they meet the current ICMJE criteria for authorship. Patients were seen as part of their standard of care; images have been de-identified in compliance of HIPPA regulations.

Additional information

Funding

The study was funded through the unrestricted institutional support from Research to Prevent Blindness (New York, NY) and the Paul and Evanina Mackall Foundation Trust (Chicago, IL) granted to the Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania.