Continuous oxygen saturation and risk of retinopathy of prematurity in a Japanese cohort.

BACKGROUND/AIMS: We assessed the associations between retinopathy of prematurity (ROP) and continuous measurements of oxygen saturation (SpO2), and developed a risk prediction model for severe ROP using birth data and SpO2 data. METHODS: This retrospective study included infants who were born before 30 weeks of gestation between August 2009 and January 2019 and who were screened for ROP at a single hospital in Japan. We extracted data on birth weight (BW), birth length, gestational age (GA) and minute-by-minute SpO2 during the first 20 days from the medical records. We defined four SpO2 variables using sequential measurements. Multivariate logistic regression was used to develop a model that combined birth data and SpO2 data to predict treatment-requiring ROP (TR-ROP). The model's performance was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Among 350 infants, 83 (23.7%) required ROP treatment. The SpO2 variables in infants with TR-ROP differed significantly from those with non-TR-ROP. The average SpO2 and high SpO2 showed strong associations with GA (r=0.73 and r=0.70, respectively). The model incorporating birth data and the four SpO2 variables demonstrated good discriminative ability (AUC=0.83), but it did not outperform the model incorporating BW and GA (AUC=0.82). CONCLUSION: Data obtained by continuous SpO2 monitoring demonstrated valuable associations with severe ROP, as well as with GA. Differences in the distribution of average SpO2 and high SpO2 between infants with TR-ROP and non-TR-ROP could be used to establish efficient cut-off values for risk determination.

Clinical course of a Japanese girl with Leber congenital amaurosis associated with a novel nonsense pathogenic variant in NMNAT1: a case report and mini review.

Leber congenital amaurosis (LCA), although rare, is one of the most severe forms of early-onset inherited retinal dystrophy (IRD). Here, we review the molecular genetics and phenotypic characteristics of patients with NMNAT1-associated IRD. The longitudinal clinical and molecular findings of a Japanese girl diagnosed with LCA associated with pathogenic variants in NMNAT1 c.648delG, (p.Trp216Ter*) and c.709C>T (p.Arg237Cys) have been described to highlight the salient clinical features of NMNAT1-associated IRD.

Characterization of the Progression Pattern in Retinopathy of Prematurity Subtypes.

PURPOSE: To evaluate differences in the progression pattern among subtypes of retinopathy of prematurity (ROP). DESIGN: Retrospective cohort study. PARTICIPANTS: Premature infants screened for ROP. METHODS: Medical records of 578 premature infants who were screened at the neonatal intensive care unit from September 2009 through March 2016 were reviewed. We matched for the number of patients, gestational age at birth, and postmenstrual age at the first examination between infants with spontaneously regressed ROP and those with treated ROP. A total of 133 premature infants who were born before 27 weeks' gestation were included. MAIN OUTCOME MEASURES: The mean age at onset of any ROP and the duration from the initial examination to onset were compared between infants with regressed ROP and those with treated ROP. The mean age at treatment and the duration from onset to treatment were compared between infants with type 1 ROP and those with aggressive posterior ROP (AP-ROP). Data were analyzed for 1 randomly selected eye for each infant. RESULTS: Of 133 premature infants with any ROP, 67 regressed spontaneously, 43 demonstrated type 1 ROP, and 23 demonstrated AP-ROP. Individual trajectories of ROP progression over time showed that AP-ROP progressed through the stages in a steep linear manner in most cases. In contrast, the type 1 ROP and regressed ROP developed in a slower, stepwise manner. CONCLUSIONS: In infants with ROP, the disease trajectories across ROP stages are different based on the ROP subtype, despite postmenstrual age at onset being comparable across subtypes. Our findings could be useful for managing follow-up screening.

Effect of fluctuation of oxygenation on the development of severe retinopathy of prematurity in extremely preterm infants.

OBJECTIVE: To investigate factors associated with development of severe retinopathy of prematurity (ROP) in extremely preterm (EP) infants. STUDY DESIGN: This retrospective cohort study included 213 EP infants (22 + 0 to 27 + 6 weeks gestation) who were admitted to the neonatal intensive care unit of Osaka Women's and Children's Hospital between 2009 and 2017. Multivariable logistic regression analysis was used to identify neonatal factors associated with severe ROP requiring treatment. RESULT: After adjustments for gestational age (GA), birth weight, sex, red blood cell transfusion, average SpO2, and fluctuations of SpO2 from birth to 32 weeks postmenstrual age, fluctuations of SpO2 (odds ratio [OR]: 2.10, 95% confidence interval [CI]: 1.03-4.27), and low GA (OR: 0.95, 95% CI: 0.91-0.98) were significantly associated with severe ROP. CONCLUSIONS: Fluctuations of SpO2 from birth to 32 weeks postmenstrual age and low GA were significantly associated with development of severe ROP requiring treatment in EP infants.

Retrospective Validation of the Postnatal Growth and Retinopathy of Prematurity (G-ROP) Criteria in a Japanese Cohort.

PURPOSE: We aimed to externally validate the performance of new screening criteria for retinopathy of prematurity (ROP) developed in the Postnatal Growth and Retinopathy of Prematurity (G-ROP) study among a Japanese cohort. DESIGN: Validation of screening criteria. METHODS: We reviewed premature infants screened for ROP between September 2009 and May 2017 at a single institution. The G-ROP criteria, except hydrocephalus, were applied as a prediction model for infants with both a known outcome of ROP and serial measurements of weight gain. We assessed sensitivity and specificity for treatment-requiring ROP, and reduction in the number of infants who receive ROP screening and in the number of retinal examinations. RESULTS: Of 692 premature infants screened for ROP, 537 had information of ROP outcome and weight gain. In this cohort, 81 infants required treatment for ROP; in 218 infants, ROP regressed spontaneously; and 238 infants did not develop any ROP. The G-ROP model reached a sensitivity of 100% (95% confidence interval [CI], 95.4%-100%) and specificity of 28.9% (95% CI, 24.9%-33.2%). No infants required any treatment for ROP before the date of risk determination. The number of infants requiring screening and the number of examinations would have been reduced by 24.5% and 12.9%, respectively. CONCLUSIONS: This is the first validation study of the G-ROP criteria in a developed country other than North America. The criteria demonstrated high sensitivity in this Japanese cohort, even though the criterion of hydrocephalus was excluded.

Favorable outcomes of adequate laser photocoagulation and salvage bevacizumab treatment for aggressive posterior retinopathy of prematurity.

PURPOSE: To evaluate the effect of salvage therapy with bevacizumab after laser photocoagulation for infants with recurrence of zone I aggressive-posterior retinopathy of prematurity (AP-ROP). METHODS: This was a retrospective case series documenting the 2-year outcomes of 8 patients diagnosed with zone I AP-ROP and treated with bevacizumab for recurrence after laser photocoagulation. Prior to intravitreal bevacizumab, additional laser treatment was performed when any skip areas on the avascular retina remained. Anatomical and functional outcomes were evaluated. RESULTS: The median gestational age at birth was 23.7 weeks and the median birth weight was 541.5 g. The median time of initial laser treatment and intravitreal bevacizumab treatment were 32.1 weeks and 36.7 weeks' postmenstrual age, respectively. All 14 eyes developed a normal macular appearance and all 8 patients had visual responses. Visual acuity was measurable in 13 eyes (92%) between the chronological ages of 12-24 months. CONCLUSIONS: and Importance: Adequate laser treatment and salvage intravitreal bevacizumab achieved favorable anatomical and functional outcomes in AP-ROP patients with recurrence.

Siblings with optic neuropathy and RTN4IP1 mutation.

Inherited optic neuropathies (IONs) are neurodegenerative disorders affecting the optic nerve and the nervous system. Dominant and recessive IONs are known. Many of the dominant IONs are caused by mutations of OPA1. Autosomal-recessive IONs are rare. OPA10 is an autosomal-recessive ION due to mutations in RTN4IP1. Patients with RTN4IP1 mutations show extraocular manifestations. We report brothers with optic neuropathy who had novel mutations in the RTN4IP1 gene. This is the first report of Japanese patients with OPA10. They showed extraocular manifestations resembling mitochondrial encephalopathy.

Endocrine status of patients with septo-optic dysplasia: fourteen Japanese cases.

A clinical diagnosis of septo-optic dysplasia (SOD) is made when two or more of the classical triad of optic nerve hypoplasia, pituitary hormone abnormalities or midline brain defects. To date, a clinical study of SOD, regarding its endocrinological features in particular, has not been undertaken in Japan. We retrospectively evaluated 14 SOD patients at our institution. Hormonal dysfunction was present in 78% of cases: ten cases presented combined hypopituitarism and one case presented precocious puberty. GHD and hypothyroidism were the most common endocrinopathies. A thin pituitary stalk and a gradual decrease in hormone secretion were the main characteristics. SOD patients usually visited ophthalmologists during early infancy because of eye problems; however, the medical examination did not always lead to endocrine assessments being made. Consequently, children who have eye problems with optic nerve hypoplasia should undergo head MRI imaging. If diagnosed with SOD, it is very important to evaluate pituitary functions. Their endocrinological status should be followed for a long time, even if they do not exhibit any endocrinological problems at evaluation.

Acute Bilateral Photoreceptor Degeneration in an Infant After Vaccination Against Measles and Rubella.

Importance: Ocular inflammation is occasionally observed after vaccinations, and most of them resolve without permanent visual disturbances. However, there are some rare cases of severe ocular complications following vaccinations. Objective: To report the findings in an infant boy who developed an acute loss of vision bilaterally after Haemophilus influenzae type b, Pneumococcal conjugate vaccination, and measles and rubella vaccination. His vision did not recover. Design, Setting, and Participant: A retrospective review of the medical records of a 13-month-old Japanese boy. Main Outcomes and Measures: Fundus and fluorescein angiographic findings, ultrasonographic and optical coherence tomographic images, and electroretinographic findings. Results: A healthy 13-month-old boy had an acute loss of vision in both eyes 31 days after Haemophilus influenzae type b and Pneumococcal conjugate vaccinations and 24 days after a measles and rubella vaccination. He also developed a common cold 10 days before the vision loss. Ultrasonography showed an exudative retinal detachment 1 day after the onset of the visual reduction; however, his fundi appeared normal 4 days later. His eyes did not pursue objects, and pupillary light reflexes were not present. No signs of anterior uveitis were noted. He was treated with corticosteroids, but his vision did not improve. The retinal vessels gradually attenuated, and diffuse small white punctate lesions appeared in the deep retina. Optical coherence tomography showed a thinner outer nuclear layer and an absent ellipsoid zone. The electroretinograms were nonrecordable. These findings suggested a severe impairment of the photoreceptors, especially their outer segments. Western blot analysis of the patient's sera detected an antibody against recoverin, a calcium-binding protein of photoreceptors. Conclusions and Relevance: We hypothesize that an infection induced severe chorioretinitis with an exudative retinal detachment, which then produced an autoantibody against recoverin. The autoantibody then altered the function of the photoreceptors very rapidly. The initial infection may have been caused by the measles and rubella vaccination. However, because to our knowledge this has not been reported previously, the visual loss after the vaccinations may have been an extremely rare event that was coincidental or may have been related to the vaccination.

Congenital optic tract hypoplasia.

We report a case of isolated unilateral optic tract hypoplasia, described only twice previously. Bilateral optic disk hypoplasia was seen ophthalmoscopically and visual field studies showed an incongruous right homonymous hemianopia. Magnetic resonance imaging showed bilateral hypoplasia of both optic nerves and the left optic tract. Spectral domain optical coherence tomography mapping correlated well with the visual field studies.

Deep intronic GPR143 mutation in a Japanese family with ocular albinism.

Deep intronic mutations are often ignored as possible causes of human disease. Using whole-exome sequencing, we analysed genomic DNAs of a Japanese family with two male siblings affected by ocular albinism and congenital nystagmus. Although mutations or copy number alterations of coding regions were not identified in candidate genes, the novel intronic mutation c.659-131 T > G within GPR143 intron 5 was identified as hemizygous in affected siblings and as heterozygous in the unaffected mother. This mutation was predicted to create a cryptic splice donor site within intron 5 and activate a cryptic acceptor site at 41nt upstream, causing the insertion into the coding sequence of an out-of-frame 41-bp pseudoexon with a premature stop codon in the aberrant transcript, which was confirmed by minigene experiments. This result expands the mutational spectrum of GPR143 and suggests the utility of next-generation sequencing integrated with in silico and experimental analyses for improving the molecular diagnosis of this disease.

Changes in angle of optic nerve and angle of ocular orbit with increasing age in Japanese children.

PURPOSE: To study changes in the opening angle of the optic nerve and the angle of the ocular orbit with increasing age in normal Japanese children. METHODS: We studied 147 normal children (aged 6 months to 18 years) who had undergone CT as a diagnostic procedure. Measurements were performed on axial CT images that included the entire optic nerve of both eyes. The opening angle of the optic nerve was defined as the angle formed by the intersection of a line running through the left optic nerve and a vertical line passing through the centre of the nose. The opening angle of the orbit was defined as the angle formed by the intersection of a line running tangentially along the deep lateral wall of the left orbit and a vertical line passing through the centre of the nose. The relationship between age and these opening angles was analysed by regression analysis. RESULTS: The correlation between age and opening angle of the optic nerve was not significant. In contrast, the opening angle of the orbit decreased relatively rapidly until about 2-3 years of age, and then it stabilised. The decrease in the opening angle of the orbit with increasing age was significant (p<0.001). The relationship between these two parameters was best fitted by a logarithmic regression curve. CONCLUSIONS: Because the opening angle of the orbit decreased significantly with increasing age, this factor must be considered when diagnosing and treating strabismus in children.

Novel nonsense and splice site mutations in CRB1 gene in two Japanese patients with early-onset retinal dystrophy.

PURPOSE: To report novel mutations in the CRB1 gene in two patients with early-onset retinal dystrophy (EORD) and the longitudinal clinical course of EORD. PATIENTS AND METHODS: The patients were two unrelated Japanese children. Standard ophthalmic examinations including perimetry, electroretinography, and optical coherence tomography were performed on both patients. Whole exomes of the patients and their nonsymptomatic parents were analyzed using a next-generation sequence (NGS) technique. RESULTS: Patient 1 was noted to have esotropia and hyperopia at age 3. His decimal best-corrected visual acuity (BCVA) was 0.6 OD and 0.3 OS at age 6 with de-pigmentation of the retinal pigment epithelium (RPE). At age 19, his central vision was still preserved; however, numerous pigment granules were present in the retina. NGS analysis revealed a p.R632X nonsense and c.652 + 1_652 + 4delGTAA splice site mutations in the CRB1 gene. Patient 2 was noted to have hyperopia at age 3. His decimal BCVA at age 6 was 0.3 OD and 0.4 OS with de-pigmented RPE. The degree of retinal pigmentation was increased but his BCVA was good until the age of 14 years. NGS analysis revealed c.652 + 1_652 + 4delGTAA and c.652 + 1_652 + 2insT splice site mutations in the CRB1 gene. CONCLUSIONS: The phenotypes of these novel mutations for EORD are typical of CRB1-associated EORD (LCA8). They were slowly progressive until the second decade of life.

Ophthalmic features of CHARGE syndrome with CHD7 mutations.

Coloboma and various ocular abnormalities have been described in CHARGE syndrome, although the severity of visual impairment varies from case to case. We conducted a multicenter study to clarify the ophthalmic features of patients with molecularly confirmed CHARGE syndrome. Thirty-eight eyes in 19 patients with CHARGE syndrome and confirmed CHD7 mutations treated at four centers were retrospectively studied. Colobomata affected the posterior segment of 35 eyes in 18 patients. Both retinochoroidal and optic disk colobomata were bilaterally observed in 15 patients and unilaterally observed in 3 patients. The coloboma involved the macula totally or partially in 21 eyes of 13 patients. We confirmed that bilateral large retinochoroidal colobomata represents a typical ophthalmic feature of CHARGE syndrome in patients with confirmed CHD7 mutations; however, even eyes with large colobomata can form maculas. The anatomical severity of the eye defect was graded according to the presence of colobomata, macula defect, and microphthalmos. A comparison of the severity in one eye with that in the other eye revealed a low-to-moderate degree of agreement between the two eyes, reflecting the general facial asymmetry of patients with CHARGE syndrome. The location of protein truncation and the anatomical severity of the eyes were significantly correlated. We suggested that the early diagnosis of retinal morphology and function may be beneficial to patients, since such attention may determine whether treatment for amblyopia, such as optical correction and patching, will be effective in facilitating the visual potential or whether care for poor vision will be needed.

[Surgical results of unilateral recession-resection for intermittent exotropia in children: multicenter study in Japan].

PURPOSE: To survey the surgical results of unilateral recession-resection surgery for intermittent exotropia of children through a multicenter study in Japan. SUBJECTS AND METHODS: A retrospective study was performed at 6 Japanese hospitals. A total of 377 patients who underwent the first surgery of unilateral recession-resection, at the ages of 4 to 12 years with a follow-up of more than 3 years were included. Those who had amblyopia or vertical deviation were excluded. Ocular deviations before and after surgery, type of exotropia, the age at surgery and the size of the surgical operations were studied. The change in deviation by surgery (surgical effect; PD/mm) and final deviation between 15PD exodeviation and 10 PD esodeviation was categorized as a cure. Factors affecting to the cure were statistically evaluated. RESULTS: The average age at surgery was 6.7 years, the average of preoperative deviation was 31.6 PD and the average size of surgery (recession + resection) was 11.1 mm. The surgical effect and the preoperative deviation were positively related. Two hundred and sixty cases among the 377 cases (69.0%) were determined as being cured. Preoperative deviation of less than 30 PD (p = 0.02) and one-week postoperative esodeviation (p < 0.001) were significantly related to the cure. CONCLUSIONS: The distribution of surgical age and preoperative deviation of intermittent extropia of children were elucidated. Preoperative deviation under 30PD and esodeviation (overcorrection) at one-week postoperative time were significantly related to the cure.

Submicroscopic deletion in 7q31 encompassing CADPS2 and TSPAN12 in a child with autism spectrum disorder and PHPV.

We performed array comparative genomic hybridization utilizing a whole genome oligonucleotide microarray in a patient with the autism spectrum disorders (ASDs) and persistent hyperplastic primary vitreous (PHPV). Submicroscopic deletions in 7q31 encompassing CADPS2 (Ca(2+) -dependent activator protein for secretion 2) and TSPAN12 (one of the members of the tetraspanin superfamily) were confirmed. The CADPS2 plays important roles in the release of neurotrophin-3 and brain-derived neurotrophic factor. Mutations in TSPAN12 are a relatively frequent cause of familial exudative vitreoretinopathy. We speculate that haploinsufficiency of CADPS2 and TSPAN12 contributes to ASDs and PHPV, respectively.

A case of intraocular yolk sac tumor in a child and its pathogenesis.

While yolk sac tumor is one of the most common malignant germ cell tumors occurring in young children, it is rarely found in extragonadal sites. We report a case of intraocular yolk sac tumor in a 4-year-old boy. The diagnosis was confirmed by histologic examination and by the rapid normalization of serum alpha-fetoprotein level following enucleation. We propose that yolk sac cells can potentially migrate into the eye at 22 days of embryonic life during neural tube formation, when the head and tail of the neuropore open contemporaneously and communicate with the amniotic cavity.

BCOR analysis in patients with OFCD and Lenz microphthalmia syndromes, mental retardation with ocular anomalies, and cardiac laterality defects.

Oculofaciocardiodental (OFCD) and Lenz microphthalmia syndromes form part of a spectrum of X-linked microphthalmia disorders characterized by ocular, dental, cardiac and skeletal anomalies and mental retardation. The two syndromes are allelic, caused by mutations in the BCL-6 corepressor gene (BCOR). To extend the series of phenotypes associated with pathogenic mutations in BCOR, we sequenced the BCOR gene in patients with (1) OFCD syndrome, (2) putative X-linked ('Lenz') microphthalmia syndrome, (3) isolated ocular defects and (4) laterality phenotypes. We present a new cohort of females with OFCD syndrome and null mutations in BCOR, supporting the hypothesis that BCOR is the sole molecular cause of this syndrome. We identify for the first time mosaic BCOR mutations in two females with OFCD syndrome and one apparently asymptomatic female. We present a female diagnosed with isolated ocular defects and identify minor features of OFCD syndrome, suggesting that OFCD syndrome may be mild and underdiagnosed. We have sequenced a cohort of males diagnosed with putative X-linked microphthalmia and found a mutation, p.P85L, in a single case, suggesting that BCOR mutations are not a major cause of X-linked microphthalmia in males. The absence of BCOR mutations in a panel of patients with non-specific laterality defects suggests that mutations in BCOR are not a major cause of isolated heart and laterality defects. Phenotypic analysis of OFCD and Lenz microphthalmia syndromes shows that in addition to the standard diagnostic criteria of congenital cataract, microphthalmia and radiculomegaly, patients should be examined for skeletal defects, particularly radioulnar synostosis, and cardiac/laterality defects.

Progression and timing of treatment of zone I retinopathy of prematurity.

PURPOSE: To clarify the progression of zone I retinopathy of prematurity (ROP) and elucidate the most suitable time and method of treatment. DESIGN: Interventional case series. METHODS: Forty-six eyes of 23 zone I ROP infants were studied at a single institution. Birth weight ranged from 448 to 954 g, and gestational age ranged from 22 to 26 weeks. Fundus examination was started at 29 or 30 weeks postmenstrual age and was performed once or more per week. The first treatment was performed using laser photocoagulation or cryotherapy when zone I ROP progressed to the following criteria. Treatment criteria A included 35 eyes of 18 cases of zone I any stage ROP with plus disease (Early Treatment for Retinopathy of Prematurity [ETROP] type 1), criteria B included five eyes of three cases of zone I stage 3 ROP with or without plus disease (ETROP type 1), criteria C included six eyes of four cases of stage 1 or stage 2 ROP without plus disease; the demarcation lines belonged, in large part, within the zone I area. RESULTS: Hazy media such as corneal opacity, miotic pupil, tunica vasculosa lentis, and hazy vitreous persisted until approximately 32 weeks postmenstrual age. The mean period between stage 1 and stage 3 mild was one week, that between stage 1 and stage 3 moderate was 1.7 weeks, and that between stage 1 and stage 3 severe was 1.3 weeks. The period between stage 1 and the first treatment was zero to 20 days, and 60.9% of all the cases were treated within 10 days after stage 1. Six of 46 eyes had unfavorable outcomes. Surgical results of our treatment were comparable or better than those of other reports. CONCLUSIONS: Immediate treatment was required when zone I ROP was diagnosed behind persistent hazy media.