TWO CASES OF CRB1-RELATED RETINAL DYSTROPHY ASSOCIATED WITH RETINAL MASSES.

BACKGROUND/PURPOSE: Mutations in CRB1 are associated with variable severity in expression leading to apparent phenotypic diversity. We present two retinal findings. METHODS: We present two unrelated children with CRB1-related retinal dystrophy with a solitary mass visualized on fundoscopy. Both underwent a complete ophthalmologic examination including visual acuity assessment, optical coherence tomography, intravenous fluorescein angiography, and fundus autofluorescence. RESULTS: In one child, a gliotic mass was observed on the superior temporal vessel away from disk. On optical coherence tomography, the mass appeared to be located in the superficial retina and contained discrete internal moth-eaten optically empty spaces as previously reported in the astrocytic hamartomas of tuberous sclerosis. Fundus autofluorescence showed speckled hyperautofluorescence of the lesion. In the other child, there was a calcified mass within the nerve fiber layer just temporal to the optic nerve. On optical coherence tomography, this mass appeared irregular in shape, encapsulated, and had a heterogeneous disorganized interior with hyperreflective areas. CONCLUSION: In this report, we detail two presentations of CRB1-related retinal dystrophy: retinal astrocytic hamartoma and another form of superficial retinal hamartoma. We believe this may represent a manifestation of CRB1 mutations. Recognition of this finding may prevent unnecessary evaluation for tumor cause in patients with CRB1-related retinal dystrophy.

Identification and Management of a Novel PRDM5 Gene Pathologic Variant in a Family With Brittle Cornea Syndrome.

PURPOSE: The aim of this study was to report a novel PRDM5 pathologic variant and ophthalmic findings in a family with 3 children diagnosed with brittle cornea syndrome (BCS). Histopathologic findings and surgical outcome of a child with BCS who underwent full-thickness corneal transplant are described. METHODS: This is an observational case report of a nonconsanguineous Laotian family with 3 siblings diagnosed with BCS. Data collected included visual acuity, cycloplegic refraction, slit-lamp biomicroscopy, dilated fundus examination, corneal pachymetry, corneal topography, and general medical findings. Targeted testing through PRDM5 gene sequencing with copy number variation detection was conducted. RESULTS: The 3 siblings included a 12-year-old boy and 8- and 6-year-old sisters, all of whom presented with myopia, blue-tinted sclerae, thin corneas, and variable corneal scarring. All 3 affected children were found to be homozygous for the PRDM5 gene variant c.1117_1123delinsTTTAATGCTTACAAATGTTTG p.Asp373Phefs*57. Coding sequences of PRDM5 and ZNF469 genes were sequenced in their entirety, and this was the only pathologic variant present in this family. The youngest affected sister developed persistent hydrops with severely decreased vision and underwent penetrating keratoplasty. Histopathology revealed severe corneal thinning, diffuse absence of Bowman layer, and ruptured Descemet membrane scrolls. CONCLUSIONS: Three siblings with clinical signs of BCS, including corneal thinning, myopia, and blue sclerae, were found to have a novel PRDM5 gene pathologic variant. This pathologic variant has not been previously reported, although 1 downstream nonsense pathologic variant has been reported as pathogenic. The similar phenotypes in all affected patients support the pathogenicity of this variant. Surgical management of BCS presents unique challenges due to severe tissue fragility.

Novel CRB1 pathogenic variant in Chuuk families with Leber congenital amaurosis.

The purpose of this article is to determine the cause of Leber congenital amaurosis (LCA) in Chuuk state, Federated States of Micronesia (FSM). In this prospective observational case series, five patients with early-onset vision loss were examined in Chuuk state, FSM, during an ocular genetics visit to study the elevated incidence of microphthalmia. Because of their low vision these patients were incorrectly assumed to have microphthalmia. A complete ophthalmological exam established a clinical diagnosis of LCA. Candidate gene exons were sequenced with a targeted retinal dystrophy panel. Five subjects in three related families were diagnosed with LCA. All five were from Tonoas Island, within the Chuuk Lagoon, with ages ranging from 6 months to 16 years. DNA sequencing of affected individuals revealed a homozygous CRB1 NM_201253.3:c.3134del pathogenic variant, which was heterozygous in their parents. CRB1 genotypes were confirmed by a PCR restriction assay. We report identification of a founder pathogenic variant in CRB1 responsible for autosomal recessive LCA in this isolated community. This discovery will lead to appropriate recurrence risk counseling.

Association of HLA polymorphisms and acetaminophen-related Steven-Johnson syndrome with severe ocular complications in Thai population.

BACKGROUND/AIMS: To investigate the association of genetic polymorphisms of human leucocyte antigens (HLA) class I and II genes with acetaminophen-related Steven-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) who developed severe ocular complications (SOC) in the Thai population. METHODS: A prospective case-control study including 20 unrelated Thai acetaminophen-related SJS/TEN patients with SOC and 60 Thai healthy volunteers, recruited at three university hospitals in Bangkok, Thailand, from September 2014 to August 2019. HLA genes were analysed using PCR amplification followed by hybridisation with sequence-specific oligonucleotide (SSO) probes with bead-based typing kits. The carrier and gene frequencies of individual HLA alleles in patients were compared with those in control volunteers based on dominant assumption using Fisher's exact test. RESULTS: Among HLA class I polymorphisms, HLA-A*33:03, HLA-B*44:03 and HLA-C*07:01 were significantly associated with acetaminophen-related SJS/TEN and SOC with high ORs (95% CI, corrected p value; Pc) in carrier frequency of 5.4 (1.8 to 16.3, Pc=0.0274), 9.0 (95% CI 2.7 to 30.4, Pc=0.0034), and 9.3 (2.8 to 30.2, Pc=0.0022), respectively. There were no significant HLA class II associations with the disease after corrected for a total number of alleles tested. CONCLUSION: HLA-B*44:03 was strongly associated with acetaminophen-related SJS/TEN patients who developed SOC in Thai population. In addition, we also found moderate to strong associations with HLA-A*33:03 and HLA-C*07:01 suggesting their potential roles in the pathogenesis of SOC in acetaminophen-related SJS/TEN.

Association of IKZF1 SNPs in cold medicine-related Stevens-Johnson syndrome in Thailand.

PURPOSE: Our meta-analysis of several ethnic groups (Japanese, Korean, Indian, Brazilian) revealed a significant genome-wide association between cold medicine-related SJS/TEN (CM-SJS/TEN) with severe ocular complications (SOC) and IKZF1 SNPs, suggesting that IKZF1 might be a potential marker for susceptibility to CM-SJS/TEN with SOC. In this study, we examined the association between CM-SJS/TEN with SOC and the IKZF1 SNPs in the Thai population. METHODS: 57 CM-SJS/TEN with SOC and 171 control samples were collected at Chulalongkorn University and Mahidol University. Genomic DNA samples were genotyped for the IKZF1 SNPs at Kyoto Prefectural University of Medicine in Japan using the TaqMan SNP genotyping assay. RESULTS: The four SNPs previously reported to be associated with CM-SJS/TEN with SOC in the Japanese were examined in the Thai samples. Although the number of Thai cases (n = 57) was small, a significant association between CM-SJS/TEN with SOC and IKZF1 SNPs which included rs4917014 (T vs G, OR = 2.9, p = 0.0012, Pc = 0.0049), rs4917129 (T vs C, OR = 2.8, p = 0.0026, Pc = 0.010) and rs10276619 (G vs A, OR = 1.8, p = 0.012, Pc = 0.048) was identified. CONCLUSION: In addition to the Japanese, Korean and Indian populations, Thai cases with CM-SJS/TEN and SOC were significantly associated with IKZF1 SNPs. With our previous report of the critical role of IKZF1 in mucocutaneous inflammation, these results suggest that IKZF1 is important in the pathogenesis of CM-SJS/TEN with SOC.

Effectiveness of voriconazole and corneal cross-linking on Phialophora verrucosa keratitis: a case report.

BACKGROUND: We report a rare case of Phialophora verrucosa fungal keratitis, which required various types of treatment according to the intractable natural history of the disease. CASE PRESENTATION: A 51-year-old Thai man with poorly controlled diabetes received a bamboo branch injury and developed a perforated corneal lesion on his left eye. A pathological study from therapeutic penetrating keratoplasty showed fungal hyphae. This was later identified as Phialophora verrucosa by polymerase chain reaction. This organism was aggressive and recalcitrant because it relapsed with two corneal grafts and was resistant to amphotericin B, natamycin, and itraconazole. However, we found that the efficacy of voriconazole was promising for treating Phialophora verrucosa. We also used corneal cross-linking to establish corneal integrity after the infection was under control. CONCLUSIONS: Because of the chronic nature of Phialophora verrucosa, a patient's first visit may occur many years after trauma, and sometimes clinical presentation might not appear to indicate fungal infection. Therefore, a high index of suspicion is needed in this situation. Voriconazole showed good results in our case. Instead of using a more invasive keratoplasty, we used corneal cross-linking to strengthen the corneal biomechanics. To the best of our knowledge, this is the first case showing the benefit of corneal cross-linking to improve corneal biomechanics in resolved Phialophora verrucosa keratitis.

Association between HLA-B*44:03-HLA-C*07:01 haplotype and cold medicine-related Stevens-Johnson syndrome with severe ocular complications in Thailand.

BACKGROUND: Polymorphisms in human leucocyte antigen (HLA) class I genes have been found to be associated with cold medicine (CM)-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). Because ethnic differences in genetic predisposition to SJS/TEN among different populations have been proposed, we focused on Thai patients and investigated the association between HLA class I genotypes and CM-SJS/TEN with SOC. METHODS: This multicentre case-control study was conducted between September 2014 and August 2017. Seventy-one Thai patients with SJS/TEN with SOC and 159 healthy Thai controls were enrolled. HLA typing was performed. Genetic relationships were analysed using Fisher's exact test. RESULTS: Of 71 patients with SJS/TEN with SOC (28 male, 43 female), 49 (69%) had a history of taking cold medications prior to SJS/TEN onset. The mean age of onset was 26.7±17.1 years (range, 2-77 years). HLA-B*44:03 (OR, 7.2, p=5.5×10-6, pc=1.1×10-4) and HLA-C*07:01 (OR, 6.1, p=7.1×10-6, pc=1.1×10-4) showed significant positive associations with Thai patients with CM-SJS/TEN with SOC. Additionally, 17 of 49 patients with CM-SJS/TEN with SOC (34.7%) significantly harboured the HLA-B*44:03 and HLA-C*07:01 haplotype compared with only 11 of 159 healthy controls (6.9%) (OR=7.1, p=5.5×10-6). CONCLUSIONS: HLA-B*44:03-HLA-C*07:01 haplotype is a potential risk factor for CM-SJS/TEN with SOC in the Thai population. This study supports that HLA-B*44:03 might be a common marker for CM-SJS/TEN with SOC in Eurasia populations, including European, Indian, Japanese and Thai.