High Incidence of CPLANE1-Related Joubert Syndrome in the Products of Conceptions from Early Pregnancy Losses

Background: The fetal monogenic causes of early pregnancy losses (EPLs) are mainly unknown, with only a few articles on the subject published. In our previous study of EPLs using whole-exome sequencing analysis, we confirmed a genetic diagnosis of CPLANE1-related Joubert syndrome (JS) in three EPLs from two couples and identified a relatively common CPLANE1 allele among our population (NM_001384732.1:c.1819delT;c.7817T>A, further after referred as "complex allele"). Pathogenic variants in the CPLANE1 (C5orf42) gene are reported to cause JS type 17, a primary ciliopathy with various system defects. Aims: To examine the hypothesis that the CPLANE1 "complex allele," whether homozygous or compound heterozygous, is a common cause of EPLs in our population. Study Design: Cohort study/case-control study.ontrol study. Methods: In this study, we used polymerase chain reaction-based methods to screen for CPLANE1 "complex allele" presence among 246 euploid EPLs (< 12 gestational weeks) from families in North Macedonia. We also investigated the impact of this allele in 650 women with EPLs versus 646 women with no history of pregnancy loss and at least one livebirth, matched by ethnic origin. Results: We found a high incidence of JS in the total study group of EPLs (2.03%), with a considerably higher incidence among Albanian families (6.25%). Although not statistically significant, women with EPLs had a higher allele frequency of the CPLANE1 "complex allele" (AF = 1.38%) than the controls (AF = 0.85%; p = 0.2). Albanian women had significantly higher frequency of the "complex allele" than the Macedonians (AF = 1.65% and 0.39%, respectively; p = 0.003). Conclusion: To the best of our knowledge, this is the highest reported incidence of fetal monogenic disease that might cause EPLs. Targeted screening for the CPLANE1 "complex allele" would be warranted in Albanian ethnic couples because it would detect one JS in every 16 euploid EPLs. Our findings have a larger impact on the pathogenesis of pregnancy loss and contribute to a better understanding of the pathogenicity of the variants in the CPLANE1 gene.

Operative Surveillance of Airway Hemangiomas in PHACE Syndrome.

OBJECTIVE: PHACE is a rare syndrome that can present with airway hemangiomas. Management for these patients is variable and the utilization of operative endoscopic airway evaluation has not been described. The objectives of this study were to identify the incidence of airway symptoms in patients being evaluated for PHACE syndrome and determine the utility of operative endoscopy. METHODS: An IRB-approved retrospective cohort study was conducted on consecutive pediatric patients with head and neck infantile hemangioma (IH) evaluated in a multi-disciplinary vascular anomalies center between 2013 and 2019. Patients were included if they were being worked up for PHACE syndrome and had an otolaryngology evaluation. Demographics, clinical, and surgical variables were collected. RESULTS: There were 317 patients with head and neck IH. Thirty-six patients met inclusion criteria. The majority of patients were female (31/36; 86.1%) and less than half of the patients (15/36; 41.7%) were eventually diagnosed with PHACE syndrome. Median age at presentation was 2 months (range 0-82 months). A total of 28/36 (77.8%) of patients were managed with propranolol. The majority of the patients presented without aerodigestive symptoms; however, 16/36 (44.4%) of patients presented with symptoms such as stridor, hoarseness, and dysphagia. A total of 20/36 (55.6%) of patients underwent operative endoscopy. A total of 8/20 (40.0%) of patients who underwent operative endoscopy had operative intervention. Of the entire cohort, only 2/15 (13.3%) patients diagnosed with PHACE were found to have a subglottic hemangioma. Both patients presented with stridor. CONCLUSION: Operative endoscopy remains useful in the workup of PHACE syndrome to identify subglottic hemangiomas, however there may be relatively low yield in asymptomatic patients. In office flexible laryngoscopy may be a less invasive means to examine the subglottic region. A multi-center prospective study would be necessary to evaluate incidence of subglottic hemangiomas in asymptomatic patients evaluated for PHACE.

Demographics and histopathological characteristics of enucleated microphthalmic globes.

Microphthalmia is a rare ocular anomaly with a poorly understood etiology that is most likely related to heritable and/or environmental factors. Many papers have been published pertaining to the clinical manifestations and management of this condition; however, few reports have reported detailed histopathological findings, which are the focus of this study, in addition to highlighting the basic demographics in these cases. This was a retrospective, observational study of all consecutive enucleated microphthalmic globes (with or without cysts) at 2 tertiary eye hospitals in Riyadh, Saudi Arabia. Globes were classified into 2 groups: severe microphthalmos (axial length or mean diameter less than 10 mm in infancy or 12 mm after age 1 year) and mild microphthalmos based on larger measurements. Clinical and demographic data collected included sex, age at enucleation, eye involvement, nationality/region, consanguinity, family history of eye anomaly, pregnancy, systemic disease, or syndromes. For histopathological data, a descriptive analysis was mostly performed. For correlations of some of our qualitative data, Fisher's exact test was used. Eleven cases (6 mild and 5 severe microphthalmos) were initially identified with a female to male ratio of 4:7. Ten patients were Saudis, 7 of whom were from the central region. Consanguinity was found in 36% (4/11), and 3 of them had other ocular or systemic abnormalities (duodenal atresia, microcephaly, kidney agenesis, cryptophthalmos, and dysmorphic facial features). Histopathological data were available for 10 cases, half of which showed a coloboma and/or anterior segment anomaly. There was no significant correlation among gender, severity of microphthalmos or the presence of coloboma, although severe microphthalmic globes had a higher median of abnormal intraocular structures (9-interquartile range = 2 compared to 6-interquartile range = 1 in the mild group). Aphakia was found in half of the globes with associated anterior segment dysgenesis. We have concluded that microphthalmos is a visually disabling congenital anomaly that can be isolated or associated with other periocular or systemic anomalies, possibly in relation to consanguinity in our cases. Congenital aphakia was found in half of these cases and was mostly associated with absent Descemet's membrane and agenesis of anterior chamber angle structures, supporting previously suggested embryological concepts. These findings necessitate further wider genetic testing and proper premarital counseling in Saudi Arabia.

Prevalência de alterações oculares em lactentes no primeiro ano de vida / Prevalence of ocular alterations in infants in the first year of life

Objetivo: Analisar a prevalência de anormalidades oculares em um grupo de lactentes e descrever quais delas não seriam detectadas pelo teste do reflexo vermelho (TRV); analisar os aspectos críticos para o cuidado das anormalidades oculares encontradas. Introdução: Dados globais em relação à prevalência e causas de alterações oculares são escassos, em função da dificuldade de realizar trabalhos de base populacionais. Estima-se que atualmente existam cerca de 1.4 milhões de crianças com deficiência visual em todo o mundo e que metade dos casos sejam atribuídos à causas que têm prevenção ou tratamento. A deficiência visual na infância tem impacto direto sobre todos os aspectos do desenvolvimento infantil. O TRV é um método de rastreio de alterações na transparência dos meios oculares implementado no estado do Rio de Janeiro desde 2002. Ele tem auxiliado na prevenção da deficiência visual na infância, através da detecção precoce de alterações na transparência dos meios oculares. Métodos: Foi realizado um estudo transversal, dentro de um estudo de coorte prospectivo que avaliou mulheres gestantes e seus recém-nascidos (ZIP Study International Cohort Study of Children Born to Women Infected with Zika Virus During Pregnancy). As gestantes do estudo original foram recrutadas em 8 clínicas da família do município do Rio de Janeiro e seus recém-nascidos foram submetidos a um exame oftalmológico no primeiro ano de vida. Foi realizado o exame externo para avaliação das pálpebras, esclera, córnea, conjuntiva e cristalino, além da avaliação da motilidade extra ocular e oftalmoscopia indireta para avaliação do fundo de olho sob midríase. Foi feita uma análise descritiva e da prevalência das alterações oculares encontradas, analisando quais delas trariam comprometimento ao desenvolvimento visual e necessitariam de acompanhamento oftalmológico até resolução total do quadro. Além disso, quais dessas alterações não seriam detectadas apenas com o exame de rastreio disponível atualmente, o TRV. A refração, apesar de ter sido realizada durante a avaliação dos lactentes, não foi analisada. A partir das análises realizadas, foi feita uma avaliação dos aspectos críticos para o cuidado das alterações encontradas. Resultados: Foram avaliados 561 lactentes entre 09/03/2017 e 27/02/2019. A mediana de idade dos lactentes foi 1 mês (IQR 25-75: 1-2 meses). A prevalência de alterações oculares encontradas ao exame oftalmológico nos lactentes foi 5,7% (32/561), sendo 1,6% (9/561) passíveis de identificação pelo TRV. Todas as anormalidades posteriores e as que demandam a dilatação das pupilas para o seu diagnóstico não foram detectadas pelo TRV. Estas correspondem a 72% (23/32) de todas as alterações oculares encontradas. E foram elas: sinéquia posterior de íris, hipoplasia de nervo óptico, relação escavação/disco óptico aumentada, palidez de disco óptico bilateral, hemorragia retiniana, atenuação vascular, anormalidades da mácula e retinopatia da prematuridade. Noventa e quatro por cento (30/32) dos lactentes que apresentaram alteração ao exame precisaram de encaminhamento para acompanhamento oftalmológico. Conclusão: O TRV não identifica as alterações do segmento posterior do olho, que representam a maioria das anormalidades encontradas e que, apesar de não necessitarem de cirurgia, precisam de acompanhamento.

Purpose: To analyze the prevalence of ocular abnormalities in a group of infants, to describe those that would not be detected by the red reflex test (RRT) and to analyze the critical aspects for the care of eye abnormalities. Introduction: Global data regarding the prevalence and causes of ocular alterations are scarce, due to the difficulty of carrying out population-based studies. It is estimated that there are currently around 1.4 million children with visual impairment worldwide and that half of the cases are attributed to causes that are preventable or treatable. Visual impairment in childhood has a direct impact on all aspects of child development. RRT is a method of tracking changes in the transparency of ocular means implemented in the state of Rio de Janeiro since 2002. It has helped to prevent visual impairment in childhood, through the early detection of changes in the transparency of ocular means. Methods: A cross-sectional study was carried out within a prospective cohort study that evaluated pregnant women and their newborns (ZIP Study- International Cohort Study of Children Born to Women Infected with Zika Virus During Pregnancy). The pregnant women in the original study were recruited from 8 "Clínicas da Família" in the city of Rio de Janeiro and their newborns underwent an eye examination in the first year of life. An external examination was performed to assess the eyelids, sclera, cornea, conjunctiva and lens, in addition to the evaluation of extraocular motility and indirect ophthalmoscopy to evaluate the fundus of the eye under pupillary dilation. From the collected data, a descriptive analysis was made and t prevalence of ocular abnormalities found in the infants who participated in the study, analyzing which ones would compromise the visual development and would need ophthalmological follow-up until full resolution of the condition. Furthermore, which of these abnormalities would not be detected only by the screening test currently available, the RRT. Despite having being performed, the refraction was not analized. From the analyzes carried out, an assessment of the critical aspects for the care of the abnormalities found was carried out. Results: 561 infants were evaluated between 03/09/2017 to 02/27/2019. The infants' median age was 1 month (IQR 25-75: 1-2 months) and the prevalence of ocular abnormalities found on ophthalmological examination was 5.7% (32/561). The prevalence of ocular abnormalities detected by RRT in the study was 1.6% (9/561). All posterior abnormalities and those that require pupil dilation for diagnosis were not detected by the RRT. These correspond to 72% (23/32) of all ocular abnormalities. These were: posterior iris synechia, optic nerve hypoplasia, increased cup/optic disc ratio, bilateral optic disc pallor, retinal hemorrhage, vascular attenuation, macular abnormalities, and retinopathy of prematurity. Most ocular abnormalities, even transient ones with a potential for benignity, need ophthalmological follow-up until the complete resolution of the condition. In the study, 94% (30/32) of the infants who presented abnormalities on the exam needed to be referred for ophthalmological follow-up.

[Joubert syndrome: incidence and clinicoradiological description of a genotyped series of seven cases]. / Síndrome de Joubert: incidencia y descripción clinicorradiológica de una serie genotipada de siete casos.

INTRODUCTION: Joubert syndrome is produced by an alteration of the ciliary proteins essential for the structure and function of neurons and organs such as the kidneys, liver, sight, and hearing. Some 34 mutations are currently known. OBJECTIVE: Calculate the incidence / prevalence, describe the phenotype / genotype and radiological alterations of this ciliopathy in our health area. PATIENTS AND METHODS: We reviewed the medical records with a diagnosis of Joubert Syndrome in the last 10 years to collect phenotype, radiological characteristics, and extra-neurological manifestations in relation to the genetic alteration detected. RESULTS: 7 cases were included: 5 children (6 -17 years). They had 6 different mutations. Hypotonia, thin / long fingers and delayed psychomotor development were constant. They presented dysmorphic features, mental retardation, ocular apraxia, and nystagmus indistinctly in 3/7; Neonatal apnea/hyperpnea 2/7; hypoplasia of vermis 7/7; Molar syndrome was evident in 6/7 and in 2/7 there was elongation-thinning of cerebellar peduncles. Pontomesencephalic junction tightness 6/7; fastigium of the IV ventricle high in 4/7. Among the somatic complications, retinopathy 2/7, retinal coloboma 1/7, liver fibrosis 1/7, nephronoptysis 1/7 and renal cyst 1/7. CONCLUSIONS: The incidence of Joubert syndrome was at least 1 / 20,000 newborns / year. The pontomesencephalic and peduncular radiological alterations were constant. Hypotonia, psychomotor retardation, and thin / long fingers affected all cases.

TITLE: Síndrome de Joubert: incidencia y descripción clinicorradiológica de una serie genotipada de siete casos.Introducción. El síndrome de Joubert se produce por una alteración de las proteínas ciliares esenciales para la estructura y la función de neuronas y órganos como los riñones, el hígado, la retina y el oído. Se conocen unas 34 mutaciones en la actualidad. Objetivo. Calcular la incidencia/prevalencia y describir el fenotipo/genotipo y las alteraciones clinicorradiológicas de esta ciliopatía en nuestra área de salud. Pacientes y métodos. Revisamos las historias clínicas con diagnóstico de síndrome de Joubert en los últimos 10 años para recoger el fenotipo, las características radiológicas y las manifestaciones extraneurológicas en relación con la alteración genética detectada. Resultados. Se incluyeron siete casos, de los cuales cinco eran varones (6-17 años). Presentaban seis mutaciones diferentes. Fue constante la hipotonía, los dedos finos/largos y el retraso en el desarrollo psicomotor. Presentaban rasgos dismórficos, retraso mental, apraxia ocular y nistagmo indistintamente, 3/7; apnea/hiperpnea neonatal, 2/7; hipoplasia de vermis, 7/7; síndrome del molar, 6/7; elongación-adelgazamiento de los pedúnculos cerebelosos, 2/7; estrechez en la unión pontomesencefálica, 6/7, y fastigio del IV ventrículo alto, 4/7. Entre las complicaciones somáticas había: retinopatía, 2/7; coloboma retiniano, 1/7; fibrosis hepática, 1/7; nefronoptisis, 1/7, y quiste renal 1/7. Conclusiones. La incidencia del síndrome de Joubert fue de al menos 1/20.000 recién nacidos/año. Las alteraciones radiológicas pontomesencefálicas y pedunculares fueron constantes. La hipotonía, el retraso psicomotor y los dedos finos/largos afectaron a todos los casos.

A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome.

Bartsocas-Papas syndrome (BPS) is a rare autosomal recessive disorder characterized by popliteal pterygia, syndactyly, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and genital malformations. Most of the BPS cases reported to date are fatal either in the prenatal or neonatal period. Causative genetic defects of BPS were mapped on the RIPK4 gene encoding receptor-interacting serine/threonine kinase 4, which is critical for epidermal differentiation and development. RIPK4 variants are associated with a wide range of clinical features ranging from milder ectodermal dysplasia to severe BPS. Here, we evaluated a consanguineous Turkish family, who had two pregnancies with severe multiple malformations compatible with BPS phenotype. In order to identify the underlying genetic defect, direct sequencing of the coding region and exon-intron boundaries of RIPK4 was carried out. A homozygous transversion (c.481G>C) that leads to the substitution of a conserved aspartic acid to histidine (p.Asp161His) in the kinase domain of the protein was detected. Pathogenicity predictions, molecular modeling, and cell-based functional assays showed that Asp161 residue is required for the kinase activity of the protein, which indicates that the identified variant is responsible for the severe BPS phenotype in the family.

Early detection of ocular abnormalities in a Chinese multicentre neonatal eye screening programme-1-year result.

PURPOSE: Early detection of ocular abnormalities in newborns is essential for timely diagnosis and treatment. This study aimed to assess the 1-year result of a multicentre prospective neonatal eye examination programme with wide-field digital imaging system in China. METHODS: A multicentre collaborative prospective study group for neonatal eye screening was established in nine hospitals, including eight Maternal and Children's Hospitals, and one general hospital across China from July 2016 to June 2017. Ocular examinations were performed on newborns within 28 days after birth using a wide-field digital imaging system. Data were reviewed and analysed. The primary outcome was the prevalence of ocular abnormalities in neonates. RESULTS: We detected 13 514 (20.91%) abnormal cases in 64 632 newborns. The most frequent abnormality was retinal haemorrhage (RH; 11.83%). Most of mild RH resolved spontaneously. Among those who were beyond retinopathy of prematurity (ROP) screening criteria of China (gestational age ≥32 w and birthweight ≥2000 g), the total number of neonates with ocular abnormality was 12 218/62 799(19.45%). 59.44% of neonatal ocular abnormalities detected (accounting for 11.56% of all the screened population) needed further interference or observation. Among them, 258 patients (0.41% of all the screened population) needed immediate or timely intervention, including congenital cataract, retinal detachment, retinoblastoma and other ocular abnormalities. One thousand and ninety-eight patients (1.75% of all the screened neonates) should be followed up closely and needed further diagnosis or intervention if necessary, such as ROP or ROP-like retinopathy, familial exudative vitreoretinopathy and persistent hyperplasia of primary vitreous. Five thousand nine hundred and six patients (9.4%) with minor clinical significance needed short-term follow-up. CONCLUSIONS: This prospective multicentre study of newborn ocular examination showed a relatively high prevalence of ocular abnormalities. There are a relatively high percentage of congenital eye pathology that required further referral and treatment in those neonates who were not screened routinely. According to the benefits and risks associated with neonatal eye examinations, neonatal ocular screening programme can detect ocular abnormalities at the very early stage and may play a positive role in promoting paediatric eye health.

Epidemiology, Clinical Features, and Use of Early Supportive Measures in PHACE Syndrome: A European Multinational Observational Study.

BACKGROUND: PHACE syndrome is a rare inborn condition characterized by large facial hemangiomas and variable malformations of the arterial system, heart, central nervous system, and eyes. According to Orphanet estimates, the prevalence is <1.0 per million. Data from Europe are limited to small case series, and there are no population-based data available. OBJECTIVES: We conducted the present study to provide population-based estimates of the disease prevalence of PHACE syndrome in children in Germany, Switzerland, and Austria. We compared these first systematic data on PHACE syndrome from Europe to published data from the PHACE Syndrome International Clinical Registry and Genetic Repository (USA). Clinical features in our cohort with PHACE syndrome were assessed in detail, including the need for early supportive measures. METHODS: We used a population-based approach by means of a previously well-established network of child neurologists from Germany, Switzerland, and Austria ("ESNEK") to identify potential patients. The patients' guardians and child neurologists were asked to fill in questionnaires developed in collaboration with the International PHACE Registry. RESULTS: We identified 19 patients with PHACE syndrome. Estimated prevalence rates were 6.5 per million in Switzerland, 0.59 per million in Germany, and 0.65 per million in Austria. A subset of 10 patients from Germany and Switzerland participated in our study, providing detailed clinical assessment (median age: 2.5 years; 9 females, 1 male). Cerebrovascular involvement was frequent (80%). Facial hemangioma extent correlated significantly with the number of organs involved (p = 0.011). In 9 out of 10 patients, facial hemangiomas were treated successfully with oral propranolol. Baseline demographic data as well as the rate of cerebrovascular and cardiovascular anomalies were in line with those from the US International PHACE Registry and other published PHACE cohorts. CONCLUSIONS: Our study provides population-based estimates for PHACE syndrome in 3 German-speaking countries. The data from Switzerland indicate that PHACE syndrome may be more prevalent than demonstrated by previous reports. Underreporting of PHACE syndrome in Germany and Austria likely accounts for the differences in prevalence rates. The clinical observation of a potential association between the size of facial hemangioma and extent of organ involvement warrants further investigation.

Age and sex prevalence estimate of Joubert syndrome in Italy.

OBJECTIVE: To estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort. METHODS: We enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available. RESULTS: We identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41-0.53), 0.41 (95% CI 0.32-0.49), and 0.53 (95% CI 0.45-0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49-1.97), 1.62 (95% CI 1.31-1.99), and 1.80 (95% CI 1.49-2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age (r 2 = 0.79; p < 0.001). CONCLUSIONS: We estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients' genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.

Healthcare recommendations for Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

[Treatment of congenital ptosis in a low-income country: polypropylene frontalis sling at the African Institute of Tropical Ophthalmology]. / Traitement du ptosis congénital dans un pays à faible revenu : suspension du releveur au muscle frontal par le polypropylène à l'Institut d'Ophtalmologie tropicale de l'Afrique (IOTA).

INTRODUCTION: Treatment of congenital ptosis is exclusively surgical; the frontalis sling method is most appropriate when the ptosis is severe, with no upper eyelid levator function. This surgery typically utilizes various materials (autologous fascia lata, silicone, nylon, or polypropylene bands, etc.). MATERIALS AND METHODS: This was a retrospective descriptive study of 22 children under 16 years of age, treated for congenital ptosis by frontalis suspension of the levator muscle of the upper eyelid using the polypropylene technique, between January 1, 2014 and June 30, 2017 at the African Institute of Tropical Ophthalmology teaching hospital. RESULTS: In our study, the surgical result (prior to correction of recurrences) was satisfactory in 81.82 % of cases, with a recurrence rate of 13.64 %. The mean follow-up was 14 months, ranging from 4 to 25 months. DISCUSSION: The use of polypropylene provides encouraging results in ptosis surgery, while also offering the advantage of being low cost and more available. Its use in developing countries deserves special attention.

Childhood-onset cerebellar ataxia in Japan: A questionnaire-based survey.

OBJECTIVE: The diagnosis of childhood-onset cerebellar ataxia (CA) is often challenging due to variations in symptoms and etiologies. Despite the known regional differences in the prevalence of etiologies underlying CA, the frequency and characteristics of CA in Japan remain unclear. We conducted a questionnaire-based survey to identify the clinical characteristics of childhood-onset CA in the Japanese population. MATERIALS AND METHODS: Questionnaires were sent to 1,103 board-certified pediatric neurologists in Japan from 2016 to 2017. The primary survey requested the number of patients with CA under care, and the follow-up secondary questionnaire requested additional clinical characteristics of the patients. RESULTS: The primary survey obtained 578 responses (response rate, 52.4%) on 385 patients with CA, including 171 diagnosed and 214 undiagnosed cases (diagnostic rate, 44.4%). The most frequent etiology was dentatorubropallidoluysian atrophy (DRPLA), followed by mitochondrial disorders and encephalitis. The secondary survey obtained the clinical characteristics of 252 cases (119 diagnosed and 133 undiagnosed cases). Multiple logistic regression analysis revealed that a younger age at onset, hearing issues, and short stature were associated with a higher risk of remaining undiagnosed with CA in Japan. CONCLUSIONS: The diagnostic rate of childhood-onset CA in the current study was comparable to those reported in other countries. The high prevalence of autosomal dominant ataxia, especially DRPLA, was a signature of CA in Japan. These data offer insights into the characteristics of childhood-onset CA in the Japanese population.

Surgical outcomes after unilateral horizontal rectus surgery in children with infantile esotropia for the correction of A or V pattern.

PURPOSE: The management of A or V pattern deviation associated with esotropia can be challenging since the horizontal deviation changes with position of gaze. This study aimed to assess the effect of unilateral horizontal rectus surgery for the correction of horizontal deviation associated with A or V pattern in children with non-comitant infantile esotropia. METHODS: Twenty-seven children with infantile esotropia and A-V pattern, more than 10 and 15 prism diopters respectively, were included in this retrospective observational single-center study. Horizontal rectus surgery was performed on the most deviated eye under general anesthesia. The patients were divided into two groups: A pattern and V pattern. The outcome measures were change in the amount of pattern and rate of regression after surgery. The amount of pattern was characterized by the difference in esodeviation between upgaze and downgaze. RESULTS: Horizontal deviation at distance and near fixation decreased significantly (P<0.0001). Vertical gaze esotropia disparity decreased significantly (P=0.01 and P=0.0002 for A and V patterns respectively). A pattern esotropia was reported in only 2 (7%) cases after surgery compared to 9 (33%) before surgery. The number of subjects with V pattern esotropia decreased from 18 (67%) to 3 (11%) after surgery. CONCLUSIONS: The mechanisms involved in the pathophysiology of A and V patterns may not always be related to oblique muscle dysfunction. These findings suggest that unilateral horizontal rectus surgery may be an effective procedure to correct both horizontal deviation and A-V pattern in non-comitant infantile esotropia.

Ocular Complications in PHACE Syndrome: A True Association or a Coincidence?

OBJECTIVE: To characterize the risk for ocular complications in patients with PHACE syndrome. STUDY DESIGN: This study included consecutive patients with PHACE syndrome who were seen at Lurie Children's Hospital of Chicago from January 2000 through May 2017. A complete ophthalmic examination was performed in all patients, with extra attention for findings typically associated with PHACE syndrome. RESULTS: Thirty patients (67% female, median age of onset 0.08 months) were included: 38 (93%) demonstrated a segmental infantile hemangioma distribution. Twenty-one (70%) cases had a periocular involvement, and 47% had an infantile hemangioma with a deep component. Among 21 patients with periocular distribution, 9 had ocular complications secondary to the periocular location (mainly ptosis, nasolacrimal duct obstruction, and refractive errors), and one had an ocular complication specifically associated with PHACE syndrome (Horner syndrome). None of the patients without periocular distribution had an ocular complication. CONCLUSIONS: In patients with PHACE syndrome who have a periocular infantile hemangioma, a complete eye examination is recommended. Although specific ocular anomalies related to PHACE syndrome are rare, serious ocular complications secondary to the location of the hemangioma may be present. Eye examination in patients with PHACE syndrome without a periocular infantile hemangioma distribution is likely of low yield.

Universal ocular screening of 481 infants using wide-field digital imaging system.

BACKGROUND: Universal ocular screening of infants is not a standard procedure in children's health care system in China. This pilot study investigated prevalence of ocular abnormalities of 6 weeks-age infants using wide-field digital imaging system. METHODS: Infants aged 6 weeks around were consecutively enrolled in a public hospital between April 2015 and August 2016. All the infants who were enrolled in the study underwent vision assessment, eye position examination, external eye check, pupillary light reflex, red reflex examination, anterior and posterior ocular segments were examined using flashlight, ophthalmoscope, and wide-field digital imaging system. RESULTS: A total of 481 infants at 45.1 ± 6.1 days after birth were enrolled in the study. 198 infants had abnormal findings (41.2%). Retinal white spots and retinal white areas were the most common findings (42.9% of abnormalities and 17.7% of all infants screened). The second major finding was retinal hemorrhage (16.2% of abnormalities and 6.7% of all infants screened). Other abnormal findings include retinal pigmentation, concomitant exotropia, neonatal dacryocystitis, retinopathy of prematurity, 'albinism-like fundus', congenital nasolacrimal duct obstruction, familial exudative vitreoretinopathy, immature retina, corneal dermoid tumor, large physiologic cupping of optic disc, congenital persistent pupillary membrane, entropion trichiasis, subconjunctival hemorrhage, congenital cataract, vitreous hemorrhage, ptosis and choroidal nevus. Intervention of any form was required in 22 infants, which accounted for 11.1% of abnormalities detected and 4.6% of all infants screened. CONCLUSION: Universal ocular screening is not only necessary for preterm infants but also for full-term infants. Addition of red reflex examination with wide-field digital imaging system can enhance the sensitivity of screening for ocular fundus abnormities. Further study with a long-term follow-up is needed in the future.

Molecular characterization of Axenfeld-Rieger spectrum and other anterior segment dysgeneses in a sample of Mexican patients.

BACKGROUND: Anterior segment dysgenesis (ASD) and Axenfeld-Rieger spectrum (ARS) are mainly due to PITX2 and FOXC1 defects, but it is difficult in some patients to differentiate among PITX2-, FOXC1-, PAX6- and CYP1B1-related disorders. Here, we set out to characterize the pathogenic variants (PV) in PITX2, FOXC1, CYP1B1 and PAX6 in nine unrelated Mexican ARS/ASD patients and in their available affected/unaffected relatives. MATERIALS AND METHODS: Automated Sanger sequencing of PITX2, FOXC1, PAX6 and CYP1B1 was performed; those patients without a PV were subsequently analyzed by Multiplex Ligation-dependent Probe Amplification (MLPA) for PITX2, FOXC1 and PAX6. Missense variants were evaluated with the MutPred, Provean, PMUT, SIFT, PolyPhen-2, CUPSAT and HOPE programs. RESULTS: We identified three novel PV in PITX2 (NM_153427.2:c.217G>A, c.233T>C and c.279del) and two in FOXC1 [NM_001453.2:c.274C>T (novel) and c.454T>A] in five ARS patients. The previously reported FOXC1 c.367C>T or p.(Gln123*) variant was identified in a patient with ASD. The ocular phenotype related to FOXC1 included aniridia, corneal opacity and early onset glaucoma, while an asymmetric ocular phenotype and aniridia were associated with PITX2. No gene rearrangements were documented by MLPA analysis, nor were any PV identified in PAX6 or CYP1B1. CONCLUSIONS: Heterozygous PV in the PITX2 and FOXC1 genes accounted for 66% (6/9) of the ARS/ASD cases. The absence of PAX6 or CYP1B1 abnormalities could reflect our small sample size, although their analysis could be justified in ARS/ASD patients that present with congenital glaucoma or aniridia.

Optic Disc Pit Maculopathy: A Two-Year Nationwide Prospective Population-based Study.

PURPOSE: To identify the incidence, presenting features, treatment, and clinical course of optic disc pit maculopathy (ODPM) in the United Kingdom (UK). DESIGN: A 2-year nationwide prospective population-based study. SUBJECTS: All new incident cases of ODPM presenting to UK ophthalmologists using the British Ophthalmic Surveillance Unit monthly reporting system. METHODS: All reporting ophthalmologists were sent an initial questionnaire requesting data on previous medical and ophthalmic history, presentation details, investigation findings, and management. A further questionnaire was sent at 12 months post diagnosis to ascertain further outcome data. MAIN OUTCOME MEASURES: Visual acuity at initial presentation, at 1 year, and after any intervention. Foveal involvement and optical coherence tomography (OCT) findings, including retinal layers affected, and the location and size of the optic disc pit. Management, including observation, vitrectomy, and associated procedures. RESULTS: There were 74 confirmed new cases, giving an annual incidence of approximately 1 per 2 million. Complete data were available on 70 patients (70 eyes) at baseline and 68 after 1 year. There were 35 (50%) female patients with a mean age of 35 years (range, 3-82 years). Visual acuity at baseline ranged from 6/5 to hand movements. In 43 patients (61%) subretinal fluid (SRF) was present, whereas 27 (39%) had intraretinal fluid only. The presence of SRF was associated with worse vision and foveal involvement. Of the 53 eyes initially observed with 1-year follow-up, 10 (19%) deteriorated and 9 (16%) improved on OCT; eyes with SRF were more likely to worsen and those without SRF were more likely to improve. Fifteen of the 70 patients (21%) at baseline had primary surgery and a further 10 had deferred surgery within 1 year of presentation; 19 of these 25 eyes (76%) showed anatomic success with a dry fovea at 1 year of follow-up, and 15 (60%) had a greater than 0.1 logMAR improvement in visual acuity. CONCLUSION: The incidence and presenting features of ODPM were defined. Patients with SRF had worse vision and were more likely to deteriorate than patients with intraretinal fluid only. Surgery was anatomically successful in 75% of cases. Patients without SRF tended to remain stable with observation.

Prevalence of Congenital Ocular Anomalies among Children with Genetic Disorders: An Egyptian Study.

PURPOSE: To assess the pattern and frequency of occurrence of ocular anomalies among other genetic disorders in Egypt. METHODS: This is a cross-sectional study of 2500 cases presenting with genetic disorders. Cases were recruited from the clinical genetics department of the National Research Centre (NRC) over a four-year period between January 2011 and December 2014. Ophthalmological examination of the cases was performed in the pediatric ophthalmology department of Cairo University Hospitals. RESULTS: Out of 2500 cases with congenital disorders, 2.4% suffered one or more ocular anomalies with a male to female ratio of 1.7:1. Consanguinity was reported in 76.7% and family history was positive in 35% of ocular cases. The most common ocular anomalies were congenital cataract, retinal dystrophies, glaucoma, and retinoblastoma in order of frequency. Chromosomal aberrations were detected in two retinoblastoma cases and in one case of charge association with cataract and iris coloboma. A truncating mutation in exon 8 of OCRL1 was reported in a case of Lowe syndrome with cataract. A total of 51.7% of ocular cases were non-isolated (associated with other genetic disorders). CONCLUSION: In Egypt, ocular genetic disorders are not uncommon among other genetic disorders. Consanguinity is high, suggesting high incidence of autosomal recessive inheritance of genetic disorders with an ocular component. Proper systemic assessment of all cases with ocular anomalies is a necessity due to the high percentage of non-isolated ocular anomalies. Genetic counseling of parents would help in reducing recurrence rates through prenatal diagnosis whenever possible.

Full-Term Neonatal Ophthalmic Screening in China: A Review of 4-Year Outcomes.

BACKGROUND AND OBJECTIVE: To report the 4-year outcomes of a neonatal ophthalmic screening program in the Kunming Maternity and Child Care Hospital of Kunming City, Kunming, China. PATIENTS AND METHODS: This was a retrospective, observational case series study. Newborns who underwent neonatal eye screening using the RetCam system (Clarity Medical Systems, Pleasanton, CA) at the authors' hospital from March 2010 to February 2014 were included. RESULTS: Of the 15,284 full-term infants who participated in the program, 21% (3,171 of 15,284) had some ocular abnormalities. Among these abnormalities, retinal hemorrhage was the most frequent finding, accounting for 19% (2,899 of 15,284) of all cases. Other anomalies were found in 2% (272 of 15,284) of the cases. No major ocular or systemic complications were found to be associated with the screening process. CONCLUSION: Overall, 21% of the newborns who underwent the eye screening program were found to have an abnormality. The use of the RetCam for the screening program was both efficient and safe in identifying ocular anomalies. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:983-992.].