Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

[Clinical practice guidelines for albinism].

Albinism is an autosomal or X-linked recessive Mendelian trait in man, which mainly manifests as hypopigmentation and related lesions of eye, skin and hair. At least 18 genes have so far been identified as causative genes for albinism. The mutational spectrum is population-specific. Molecular genotyping of albinism is important for genetic and prenatal diagnosis, and is a prerequisite for the practice of precision medicine. Based on long-term study of albinism in Chinese population, a guideline for the clinical management of albinism is provided.

[Efficacy of surgery on congenital nystagmus with convergence damping].

OBJECTIVE: To evaluate the efficacy of surgery in the treatment of congenital nystagmus with convergence damping. METHODS: Retrospective and comparative case series. Eight patients diagnosed as congenital nystagmus with convergence damping at Beijing Children's Hospital between September 2010 and September 2012 were enrolled in this study. The ages were 9.5 (12, 6) years old, and follow-up was 9 (24, 6) months. All patients received prism induced convergence and the same surgery of bimedial rectus recession and bilateral rectus tenotomy. The best corrected visual acuity, the range of fusion and the nystagmus waveforms were analyzed before and after surgery. RESULTS: The range of fusion was -3.75±1.83° to +19.38±3.16° before surgery and -3.88±1.55° to +19.00±3.02° after surgery; there was no significant difference (t=0.24, P=0.82). The binocular visual acuity increased from 0.21±0.15 without convergence to 0.28±0.18 using convergence; there was significant difference (t=-4.43, P=0.00). The visual acuity was 0.32±0.20 after surgery, significantly different from that before surgery without convergence (t=-5.29, P=0.00), but not significantly different from that before surgery using convergence (t=-2.12, P=0.07). Patients had significant improvements in the frequency (t=3.28, 3.02, P<0.05) and intensity of the nystagmus waveforms when using convergence and postoperatively (t=3.27, 3.48; P<0.05), but there was no significant improvement in the amplitude of the waveforms (t=1.31, 1.57, 0.31, P>0.05). CONCLUSIONS: Surgery for congenital nystagmus with convergence damping can provide expectations for ocular motor and visual results. The range of fusion should be wide enough, and the effect of convergence on the frequency is greater than that on the amplitude.

A gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation.

Albinism is a group of inherited disorders mainly affecting skin, hair and eyes. Here we identify a de novo point mutation, p.R210C, in the TPCN2 gene which encodes Two Pore Channel 2 (TPC2) from a patient with albinism. TPC2 is an endolysosome and melanosome localized non-selective cation channel involved in regulating pigment production. Through inside-out recording of plasma membrane targeted TPC2 and direct recording of enlarged endolysosomal vacuoles, we reveal that the R210C mutant displays constitutive channel activation and markedly increased affinity to PI(3,5)P2. Mice harboring the homologous mutation, R194C, also exhibit hypopigmentation in the fur and skin, as well as less pigment and melanosomes in the retina in a dominant inheritance manner. Moreover, mouse embryonic fibroblasts carrying the R194C mutation show enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification. Our data suggest that R210C is a pathogenic gain-of-function TPC2 variant that underlies an unusual dominant type of albinism.

The first Hermansky-Pudlak syndrome type 9 patient with two novel variants in Chinese population.

Hermansky-Pudlak syndrome 9 (HPS-9) is a recessive disorder caused by BLOC1S6 gene. There are only four variants identified from four HPS-9 patients so far. Here, we reported the first HPS-9 patient in a Chinese population. He had brownish-yellow hair, white skin, brown irises with visual acuity, photophobia and nystagmus. Two novel variants, c.148G>T (p.Glu50*) and c.351dupT (p.Ile118Tyrfs*10) in BLOC1S6 gene were identified by whole-exome sequencing (WES). Absence of platelet dense granules was found by whole-mount platelet electron microscopy and Western blotting assays showed the destabilized BLOC-1 subunits. He had recurrent bruising and was found to have abnormal brain waves by electroencephalogram, but did not develop thrombopenia, immunodeficiency or other symptoms reported in other HPS-9 patients. This is the first case report of BLOC-1 mutation in a Chinese population and our findings expand the mutational spectrum of HPS genes.

Genetic variants and mutational spectrum of Chinese Hermansky-Pudlak syndrome patients.

Hermansky-Pudlak syndrome (HPS) is a rare recessive disorder characterized by oculocutaneous albinism or ocular albinism, bleeding diathesis, and other symptoms such as colitis and pulmonary fibrosis. Eleven causative genes have been identified for HPS-1-HPS-11 subtypes in humans. We have identified 16 newly reported patients including the first HPS-2 case in the Chinese population. In a total of 40 HPS patients, hypopigmentation was milder in HPS-3, HPS-5, and HPS-6 patients than in HPS-1 and HPS-4 patients. HPS-1 accounted for 47.5% (19 of 40) of HPS cases which is the most common subtype. Exons 11 and 19 were the hotspots of the HPS1 gene mutations. In total, 55 allelic variants were identified in HPS1-HPS6 gene, of which 17 variants were previously unreported. These results will be useful for the evaluation of the relationship between HPS genotypes and phenotypes, and for the precise intervention of HPS patients in the Chinese population.

Identification of two Chinese oculocutaneous albinism type 6 patients and mutation updates of the SLC24A5 gene.

Oculocutaneous albinism (OCA) is a rare and heterogeneous disorder characterized by hypopigmentation of the skin, hair and eyes. Thirty OCA type 6 (OCA6) patients with 24 mutations in SLC24A5 have been reported across various populations; however, only one patient has been identified in a Chinese population. This study identifies two novel SLC24A5 frame-shift variants in two unrelated Chinese patients and both are predicted to be pathogenic by American College of Medical Genetics guidelines. The genotypes and phenotypes of all three Chinese OCA6 patients are unique compared with those identified in other populations. All of the mutations identified to date in Chinese OCA6 patients are predicted to be non-functional, a finding that is useful in guiding genetic diagnosis and counseling for OCA6 in China.

Instability of BLOC-2 and BLOC-3 in Chinese patients with Hermansky-Pudlak syndrome.

Hermansky-Pudlak syndrome (HPS) is a rare recessive disorder characterized by oculocutaneous albinism (OCA) or ocular albinism (OA), bleeding tendency, and other symptoms due to multiple defects in tissue-specific lysosome-related organelles. Ten HPS subtypes have been characterized with mutations in HPS1 to HPS10, which encode the subunits of BLOC-1, -2, -3, and AP-3. Using next-generation sequencing (NGS), we have screened 100 hypopigmentation genes in OCA or OA patients and identified four HPS-1, one HPS-3, one HPS-4, one HPS-5, and three HPS-6. The HPS-4 case is the first report in the Chinese population. Among these 20 mutational alleles, 16 were previously unreported alleles (6 in HPS1, 1 in HPS3, 2 in HPS4, 2 in HPS5, and 5 in HPS6). BLOC-2 and BLOC-3 were destabilized due to the mutation of these HPS genes which are so far the only reported causative genes in Chinese HPS patients, in which HPS-1 and HPS-6 are the most common subtypes. The mutational spectrum of Chinese HPS is population specific.

[Lacrimal intubation with the Ritleng system in congenital nasolacrimal duct obstruction in children].

OBJECTIVE: To evaluate the efficacy and complication of the Ritleng lacrimal intubation system in the treatment of congenital nasolacrimal duct obstruction. METHODS: In this retrospective cases series, 148 patients (187 eyes) with congenital nasolacrimal duct obstruction between 2006 and 2007 from Beijing Children's Hospital, whose age ranged from 5 to 40 months (average 13 months), underwent silicone intubation with the Ritleng lacrimal intubation system, who received unsuccessful probing procedure previously. The therapeutic effect including dacryorrhea disappearance and lacrimal passages excretory function regaining was observed and the complications such as epistaxis, lacrimal duct edema or silicone tube prolapse were recorded. The follow-up period was from 4 to 17 months (average 11 months). RESULTS: Dacryorrhea disappeared in 157 eyes (84.0%) within 1 - 3 days after the surgery. The tubes were left in the place for 3 or 6 months. All the 187 eyes were successfully taken out of tubes. As follow-up, the overall successful rate was 95.2% (178/187). Seven eyes (3.7%) relief from symptoms and two eyes (1.1%) were ineffective. 46 cases (52 eyes), whose ages were about 5 months, regained normal lacrimal passages excretory function within 1 month after surgery. Complication included epistaxis (9 eyes) and lacrimal duct edema (9 eyes). The silicone tube prolapsed in eight eyes (4.3%). CONCLUSIONS: The Ritleng lacrimal intubation system is an easy, effective and nontraumatizing procedure for the treatment of congenital nasolacrimal duct obstruction. The lacrimal intubation procedure offers an early and active treatment for congenital nasolacrimal duct obstruct patients.

Analysis of genotypes and phenotypes in Chinese children with tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with serious clinical presentations, an autosomal dominant genetic disorder involving multiple organs and systems. We retrospectively investigated the clinical manifestations and genotypes of 20 Chinese children with TSC to enable informed diagnostic and surveillance recommendations in China. A retrospective analysis of clinical manifestations in 20 children (7.00±5.30 years old) with TSC was conducted. A genetic testing of the genes TSC1 and TSC2 was performed in 14 children.The earliest manifestations of TSC were skin lesions (80% of patients) and seizures (75%). Fourteen of the children presented with retinal hamartomas, and 2 of these underwent eye enucleation at other hospitals through misdiagnosis. On magnetic resonance imaging, 18 children exhibited subependymal nodules, and 16 ones showed cortical nodules. 5 cases of non-renal hamartomas, 5 cases of multiple renal cysts, and 5 cases of cardiac rhabdomyomas were observed. The genotyping of TSC1 and TSC2 in 14 children revealed 11 with mutations in TSC2, 2 with mutations in TSC1, and no mutations of either gene in one patient. Eight of these observed mutations are reported here in for the first time. The illness presentations of the TSC2-mutated patients were more severe than that of patients carrying TSC1 mutations.There were differences in the mutations of TSC genes in Chinese children from those reported in other countries. The described clinical characteristics and genotyping will help pediatric neurologists to understand, diagnosis, and treat TSC.

Clinical feature and waveform in infantile nystagmus syndrome in children with FRMD7 gene mutations.

Infant nystagmus sydrome presents as involuntary eye movement disorder and can affect seriously ocular function. We performed a retrospective study of clinical data and FRMD7 genetic test results in 12 cases of infantile nystagmus syndrome to correlate waveform, stereopsis, and visual acuity. The patients (age 6.40±2.67 years) had FRMD7 mutations as follows: missense in eight cases, shear in two cases, frameshift in one case, and non-frameshift in one case. Horizontal jerk waveform was observed in six cases, versus horizontal pendulum in five cases and dual jerk in one case. The uncorrected visual acuity (24 eyes) was 0.21±0.12, compared with a corrected visual acuity (24 eyes) of 0.32±0.14. All patients had simultaneous perception, versus fusion function in 10 cases (83.33%) and stereoscopic vision in seven cases (58.33%) using the synoptophore. Eleven cases (91.67%) detected the stereo fly, compared with five cases (41.67%) for stereoscopic circles and seven cases (58.33%) for stereoscopic animals by Titmus test. Stereoscopic vision using the synoptophore did not correlate with the frequency, amplitude, or intensity of nystagmus or with corrected binocular visual acuity. The infantile nystagmus syndrome with FRMD7 mutations in our cases was caused primarily de novo and missense mutations. Visual acuity and binocular visual function were significant impaired, and the waveform was generally horizontal jerk. Also, an infrared videonystagmogram can record the frequency, amplitude, and intensity of nystagmus accurately.

Comparison of Color Fundus Photography, Infrared Fundus Photography, and Optical Coherence Tomography in Detecting Retinal Hamartoma in Patients with Tuberous Sclerosis Complex.

BACKGROUND: A sensitive method is required to detect retinal hamartomas in patients with tuberous sclerosis complex (TSC). The aim of the present study was to compare the color fundus photography, infrared imaging (IFG), and optical coherence tomography (OCT) in the detection rate of retinal hamartoma in patients with TSC. METHODS: This study included 11 patients (22 eyes) with TSC, who underwent color fundus photography, IFG, and spectral-domain OCT to detect retinal hamartomas. TSC1 and TSC2RESULTS: The mean age of the 11 patients was 8.0 ± 2.1 years. The mean spherical equivalent was -0.55 ± 1.42 D by autorefraction with cycloplegia. In 11 patients (22 eyes), OCT, infrared fundus photography, and color fundus photography revealed 26, 18, and 9 hamartomas, respectively. The predominant hamartoma was type I (55.6%). All the hamartomas that detected by color fundus photography or IFG can be detected by OCT. CONCLUSION: Among the methods of color fundus photography, IFG, and OCT, the OCT has higher detection rate for retinal hamartoma in TSC patients; therefore, OCT might be promising for the clinical diagnosis of TSC.

Recombinant chicken interferon-alpha inhibits the replication of exogenous avian leukosis virus (ALV) in DF-1 cells.

Chickeninterferon alpha (ChIFNα) belongs to type I IFNs that are important antiviral cytokines. We investigated whether ChIFNα plays a role in avian leukosis virus (ALV) infections of chickens. Firstly, we explored the immune response to ALV in vivo by measuring cytokine expression profiles in the spleens and bursas of chickens during the late stages of ALV-J infection. The results indicated that ALV-J infection could induce a mixed Th1/Th2 cytokine response by elevating levels of both interleukin-2 (IL-2) and IL-10. In contrast, tumor necrosis factor alpha (TNF-α) levels decreased in the spleen while interferon beta (IFNß) and Toll-like receptor 7 (TLR7) expression levels in the bursa increased significantly. This indicated that ALV-J stimulates a Type I IFN response. Next, we found that different ALV subgroups or strains up-regulated chicken IFN regulatory factor 3 (ChIRF-3) promoter activity, suggesting that ALV infection could trigger Type I IFNs pathway in vitro. Accordingly, we further investigated ChIFNα antiviral effects on ALV replication in DF-1 cells by successfully expressing recombinant ChIFNα in Escherichia coli (E. coli) strain BL21. The specific activity of the purified rChIFNα protein was determined to be 4×10(7)U/mL. When added at 4000U/mL, the recombinant protein restrained ALV replication as measured by decreases in viral protein p27 levels and mRNA expression. This new reagent may be useful for prophylactic and therapeutic drug design.

NGS-based 100-gene panel of hypopigmentation identifies mutations in Chinese Hermansky-Pudlak syndrome patients.

Hermansky-Pudlak syndrome (HPS) is a rare recessive disorder characterized by hypopigmentation, bleeding diathesis, and other symptoms due to multiple defects in lysosome-related organelles. Ten HPS subtypes have been identified with mutations in HPS1 to HPS10. Only four patients with HPS-1 have been reported in Chinese population. Using next-generation sequencing (NGS), we have screened 100 hypopigmentation genes and identified four HPS-1, two HPS-3, one HPS-5, and three HPS-6 in Chinese HPS patients with typical ocular or oculocutaneous albinism and the absence of platelet dense granules together with other variable phenotypes. All these patients except one homozygote were compound heterozygotes. Among these mutations, 14 were previously unreported alleles (four in HPS1, three in HPS3, two in HPS5, five in HPS6). Our results demonstrate the feasibility and utility of NGS-based panel diagnostics for HPS. Genotyping of HPS subtypes is a prerequisite for intervention of subtype-specific symptoms.