Phenotypic and Genotypic Features of a Chinese Cohort with Retinal Hemangioblastoma

Abstract

Purpose: To delineate the genotype and phenotype of RH in a Chinese cohort. Methods: A group of 51 Chinese probands with RH across 76 eyes was assembled and underwent complete retinal imaging examinations. Sanger sequencing and universal primer quantitative fluorescent multiplex-polymerase chain reaction (UPQFM-PCR) were employed for mutation detection in the coding region of the Von Hippel-Lindal (VHL) gene. For frequency calculation, our series was combined with three large cohorts of East Asian descent through a literature review. Results: The Von Hippel-Lindal (VHL) syndrome was excluded in fifteen patients (median age: 32.00 years) with unilateral solitary RH. Thirty-six patients of younger ages (median: 22.00 years, p = 0.008, Mann-Whitney test) conformed to the diagnostic criteria of the VHL syndrome, and thirty-four patients were genetically confirmed. There were four novel variants identified in the VHL gene. Codons 167, 161 and 86 exhibited a mutation occurrence of more than 5% after pooling with literature data, and the large genomic deletion demonstrated a frequency of 17.65%. The RHs were classified as "extrapapillary", "juxtapapillary" and "mixed" types in 53, 7 and 5 eyes, respectively. Almost all extrapapillary RH lesions were found in the peripheral retina. Hemangioblastomas in the central nervous system (CNS) were observed in 25 out of 31 kindreds (80.65%) with full systemic evaluation data. Conclusions: VHL-associated RH might exhibit earlier onset than non-VHL RH. Large genomic deletions were observed at a notably high frequency in the Chinese series with VHL-associated RH, which might be associated with East Asian ethnicity background. RH could potentially serve as an early indicator of CNS hemangioblastoma.

Keywords: Von Hippel–Lindau gene (VHL); genotype; large genomic deletion; phenotype; retinal hemangioblastoma.

Figure 1

The corresponding position of the missense mutants in the current study. The VHL gene comprises three exons and encodes a 213-amino-acid protein. The VHL gene has two domains: the β domain and the α domain. The β domain is roughly 100 residues long and is rich in the β sheet. The α domain is smaller and α-helical. The two domains are held together by two linkers and a polar interface.

Figure 2

Protein sequence alignment of human VHL protein with VHL homologs from other species. The mutated residues are highly conserved during evolution.

Figure 3

Structure of the VHL protein. A. An overview of the VHL protein structure showing the GXEEX repeats in pink, the beta domain in blue and the alpha domain in red, as well as the locations of the p.Tyr112Ser mutation in the beta domain and the p.176delArg mutation in the alpha domain. B. An enlarged view of the p.Tyr112Ser mutation with the wild type shown in red, with the tyrosine shown in ball and stick format, and the ser112 mutant protein shown in red, with the serine in ball and stick format. Little or no change is seen in the backbone protein fold. C. An enlarged view of the p.176delArg mutation with the wild-type protein shown in green and the p.176delArg mutant shown in red. The protein backbone fold is conserved, and changes in the positions of the adjacent tyr175 and arg177 residues are minimal.

Figure 4

Color fundus photography (CFP) of the left eye of case P28. Typical multiple extrapapillary RH in the peripheral retina outside the vascular arcade.

Figure 5

Color fundus photography (CFP) of the left eye of case P49 illustrates both the therapeutic efficacy of laser ablation for retinal hemangioblastomas (RHs) and the progression of retinopathy over a 7-year period without ocular examination or treatment. (A,B): Multiple typical extrapapillary RHs in the peripheral retina outside the vascular arcade, highlighted in (B). (C): Shrinkage of the RHs one year after laser ablation treatment (arrowheads). (D): The patient did not return for ocular examination until 7 years later, presenting with extensive exudative retinal detachment in the temporal region (arrow).

Figure 6

Color fundus photography (CFP) of the right eye of case P32 illustrates the therapeutic efficacy of RH laser ablation. Shrinkage of the RHs (arrows) is evident, along with resolution of exudates in the macula following RH ablation. (A), The patient’s initial visit in our institution showed RH near the vascular arcade surrounded by laser spots. (B,C), After multiple laser treatments, the RH appeared in smaller size and less exudates in the macula. (D), The exudates in macula almost resolved.