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.

Eye Abnormalities in Children with Fetal Alcohol Spectrum Disorders: A Systematic Review.

PURPOSE: Although eye abnormalities are reported in fetal alcohol spectrum disorders (FASD), no systematic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines has been undertaken. Our aim was to document the range and prevalence of eye abnormalities reported in children with prenatal alcohol exposure (PAE) and/or FASD. METHODS: Searches of electronic databases and manual searches. Eligible articles were observational studies in children with PAE and/or FASD; peer reviewed journal articles in the English language; and studies reporting quantitative or frequency data on functional/structural eye abnormalities. Pooled prevalence, odds ratio, and mean differences were calculated. RESULTS: Of the 1,068 retrieved articles 36 were eligible, including articles on children with diagnosed fetal alcohol syndrome/FASD (N = 31); PAE (N = 3); and FASD or PAE without FASD (N = 2). Structural and functional eye abnormalities were identified, the most prevalent being short palpebral fissure length (66.1%), visual impairment (55.5%), epicanthus (53.5%), subnormal stereoacuity (53.0%), abnormal retinal tortuosity (50.5%), impaired fixation ability (33.3%), telecanthus (31.7%), optic nerve hypoplasia (30.2%), and small optic discs (27.0%). Compared to non-exposed controls, strabismus, subnormal vision, ptosis, short palpebral fissure length, microphthalmos, smaller optic disc area, and retinal vessel tortuosity were more prevalent in children with FASD. CONCLUSIONS: Examination of eyes and vision should be considered in children with PAE and suspected or diagnosed FASD to enable early identification and optimal management. This first comprehensive, systematic literature review demonstrates the variety and frequency of eye abnormalities reported in PAE/FASD.

Prevalence of individual brain and eye defects potentially related to Zika virus in pregnancy in 22 U.S. states and territories, January 2016 to June 2017.

During the Centers for Disease Control and Prevention's Zika Virus Response, birth defects surveillance programs adapted to monitor birth defects potentially related to Zika virus (ZIKV) infection during pregnancy. Pregnancy outcomes occurring during January 2016 to June 2017 in 22 U.S. states and territories were used to estimate the prevalence of those brain and eye defects potentially related to ZIKV. Jurisdictions were divided into three groups: areas with widespread ZIKV transmission, areas with limited local ZIKV transmission, and areas without local ZIKV transmission. Prevalence estimates for selected brain and eye defects and microcephaly per 10,000 live births were estimated. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated using Poisson regression for areas with widespread and limited ZIKV transmission compared with areas without local ZIKV transmission. Defects with significantly higher prevalence in areas of widespread transmission were pooled, and PRs were calculated by quarter, comparing subsequent quarters to the first quarter (January-March 2016). Nine defects had significantly higher prevalence in areas of widespread transmission. The highest PRs were seen in intracranial calcifications (PR = 12.6, 95% CI [7.4, 21.3]), chorioretinal abnormalities (12.5 [7.1, 22.3]), brainstem abnormalities (9.3 [4.7, 18.4]), and cerebral/cortical atrophy (6.7 [4.2, 10.8]). The PR of the nine pooled defects was significantly higher in three quarters in areas with widespread transmission. The largest difference in prevalence was observed for defects consistently reported in infants with congenital ZIKV infection. Birth defects surveillance programs could consider monitoring a subset of birth defects potentially related to ZIKV in pregnancy.

The prevalance of congenital optic disc anomalies in Turkey: a hospital-based study.

PURPOSE: The aim of this study was to investigate the prevalence of congenital optic disc anomalies in Turkey. METHODS: The 11,123 eyes of 5570 patients were screened for optic disc anomalies. All patients were underwent a complete ophthalmic examination including best corrected visual acuity, refraction, spherical equivalent, slit lamp biomicroscopy, intraocular pressure measurements, dilated stereoscopic fundus examination. Data analyses were performed by using SPSS for Windows, version 22.0 (SPSS Inc., Chicago, IL, United States). RESULTS: 11,123 eyes of 5570 participants were screened. Of the 5570 participants who underwent optic disc examination, 246 eyes of 174 patients (3.12%, 95% CIs 2.66-3.58%) had optic disc anormalies. 92 (52.9%) were female, 82 (47.1%) were male and the mean of age was 44.25 ± 15.67 years. 72 (41.4%) patients were bilateral, 102 (58.6%) patients were unilateral involvement. The tilted disc was the most common anomaly and was found at least one eye in 46 patients (75 eyes) and 0.83% of all screened patients. Peripapillary myelinated nerve fibers was the second common anomaly and was found at least one eye in 31 subjects (35 eyes) and 0.56% of all screened subjects. Peripapillary atrophy was the third common anomaly, and was found in at least one eye in 24 patients (37 eyes) and 0.43% of all screened subjects. CONCLUSION: To our knowledge, this is the first study that the prevalences of all congenital optic disc anomalies from Turkey. The prevalence of congenital optic disc anomalies is higher than in other countries.

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.

Clinical patterns of congenital ocular anomalies in the pediatric age group (0 to 5 years) and its association with various demographic parameters.

PURPOSE: Congenital ocular anomalies are rare but important cause of childhood blindness. This study aimed to observe the clinical patterns of congenital ocular anomalies in the pediatric age group (0 to 5 years) and its association with various demographic parameters. METHODS: Hospital-based cross-sectional study done on all pediatric patients in the 0-to-5-year age group presenting with congenital ocular anomalies to the Ophthalmology department of a tertiary care hospital in Eastern India between October 2018 and October 2020. Thorough clinical history was obtained, and comprehensive ocular examination was done in each case. RESULTS: A total of 5686 patients in the 0 to 5 years age group attended the eye OPD during the study period. Congenital ocular anomalies were seen in 140 patients. The prevalence of ocular anomalies was 2.46%. Average age of patients was 3.32 ± 1.42 years. There were 74 (52.9%) males and 66 (47.1%) females. Unilateral and bilateral involvement was seen in 100 (71.45%) and 40 (28.6%) cases, respectively. Antenatal period was uneventful in 92.14% cases. Decreased vision was the most common presentation (40%). Congenital nasolacrimal duct obstruction was the most common anomaly seen in 29 (20.71%) cases followed by congenital cataract in 21 (15%) cases. CONCLUSION: Few of the congenital ocular anomalies can be prevented by increasing community awareness. Findings of the study can act as a reference guide for clinicians and health professionals for counseling and health planning.

Zika-Associated Birth Defects Reported in Pregnancies with Laboratory Evidence of Confirmed or Possible Zika Virus Infection - U.S. Zika Pregnancy and Infant Registry, December 1, 2015-March 31, 2018.

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities (1,2). The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate (3,4). This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015-March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

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.

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

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.(AU)

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.(AU)

[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.

[Congenital ocular anomalies at the University Hospital Campus in Lomé, Togo]. / Les anomalies congénitales oculaires au Centre Hospitalier Universitaire-Campus de Lomé, Togo.

INTRODUCTION: congenital ocular anomalies are rare clinical entities. The purpose of this study is to describe the epidemiological and clinical features of congenital ocular anomalies at the University Hospital Campus in Lomé. METHODS: we conducted a retrospective study at the Department of Ophthalmology of the University Hospital Campus in Lomé, over a 3-year period, from January 2016 to December 2018. It involved children with congenital ocular anomalies. The study variables were: sex; age at diagnosis; type of congenital ocular anomalies; laterality. RESULTS: out of 2621 children assessed during the study period, 103 (3.9%) had congenital ocular anomalies. Of these, 60 (58.2%) were boys and 43 (41.8%) girls. The average age at diagnosis was 16 ± 5.2 months (ranging from 1 months to 5 years). The most common congenital ocular anomaly was cataract (53.4%). Unilateral alterations were predominant (56.3%). Congenital ocular anomalies were isolated (82.5%); associated with systemic anomalies (11.7%); associated with each other (5.8%). CONCLUSION: these results show that the epidemiological and clinical features of congenital ocular anomalies are similar to those reported in the literature. However, in our Hospital, the frequency of congenital ocular anomalies and patients' age at diagnosis are high. Early diagnosis is essential to ensure adequate management and preserve visual function.

Plasma lipidome profiling of newborns with antenatal exposure to Zika virus.

The 2015-2016 Zika virus (ZIKV) outbreak in Brazil was remarkably linked to the incidence of microcephaly and other deleterious clinical manifestations, including eye abnormalities, in newborns. It is known that ZIKV targets the placenta, triggering an inflammatory profile that may cause placental insufficiency. Transplacental lipid transport is delicately regulated during pregnancy and deficiency on the delivery of lipids such as arachidonic and docosahexaenoic acids may lead to deficits in both brain and retina during fetal development. Here, plasma lipidome profiles of ZIKV exposed microcephalic and normocephalic newborns were compared to non-infected controls. Our results reveal major alterations in circulating lipids from both ZIKV exposed newborns with and without microcephaly relative to controls. In newborns with microcephaly, the plasma concentrations of hydroxyoctadecadienoic acid (HODE), primarily as 13-HODE isomer, derived from linoleic acid were higher as compared to normocephalic ZIKV exposed newborns and controls. Total HODE concentrations were also positively associated with levels of other oxidized lipids and several circulating free fatty acids in newborns, indicating a possible plasma lipidome signature of microcephaly. Moreover, higher concentrations of lysophosphatidylcholine in ZIKV exposed normocephalic newborns relative to controls suggest a potential disruption of polyunsaturated fatty acids transport across the blood-brain barrier of fetuses. The latter data is particularly important given the neurocognitive and neurodevelopmental abnormalities observed in follow-up studies involving children with antenatal ZIKV exposure, but normocephalic at birth. Taken together, our data reveal that plasma lipidome alterations associated with antenatal exposure to ZIKV could contribute to identification and monitoring of the wide spectrum of clinical phenotypes at birth and further, during childhood.

More than meets the eye: Expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome.

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype- and phenotype-oriented literature overview of all (n = 85) reported patients with ZNF469 (n = 53) and PRDM5 (n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.

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.

Analysis of genotype-phenotype correlations in PAX6-associated aniridia.

BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher's exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini-Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3'-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.

Adult Chinese twins with Kenny-Caffey syndrome type 2: A potential age-dependent phenotype and review of literature.

Kenny-Caffey syndrome (KCS) type 2 (OMIM 127000) is a rare syndromic cause of hypoparathyroidism which is characterized by proportionate short stature, long bone abnormalities, delayed closure of anterior fontanelle, eye abnormalities, and normal intelligence. It is caused by variants in FAM111A (NM_001942519.1). In this review, we reported the first Chinese patients, a pair of monozygotic twins, with genetically confirmed KCS type 2 with over 20 years follow-up. We summarized the clinical features of 14 previously reported and genetically confirmed KCS type 2 patients; our twin patients exhibited a unique spinal manifestation which could be an important age-dependent feature of KCS type 2. In this review, over 60% KCS type 2 patients had dental problem and over 80% suffered from refractive errors or structural eye abnormalities. Therefore, early dental, ophthalmological, and orthopedic assessments are warranted for KCS type 2 patients. Micro-orchidism, previously reported in KCS type 2 patients, was also detected in our patients. The possibility of subfertility should be considered in male KCS type 2 patients. A multidisciplinary management approach for this rare syndrome is recommended.

Gene-specific facial dysmorphism in Axenfeld-Rieger syndrome caused by FOXC1 and PITX2 variants.

Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld-Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty-four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

Congenital ocular malformations in dogs and cats: 123 cases.

OBJECTIVE: Provide epidemiological data regarding the prevalence of congenital ocular malformations in dogs and cats. ANIMALS STUDIED: A population of 32 974 dogs and 13 977 cats that presented for consultation at the veterinary teaching hospital. PROCEDURES: Medical records from 2011 to 2018 were reviewed. A retrospective and prospective epidemiological clinical study addressing congenital ocular malformations was conducted. Signalment, medical history, reason for presentation, clinical findings, vision impairment, and treatment options were analyzed. RESULTS: From the total of cases analyzed, 103 dogs (0.3%) and 20 cats (0.1%) met the inclusion criteria. The majority of dogs were mixed breed, the most common breed being the French Bulldog, while the majority of cats were European domestic shorthair. The median age of diagnosis was 12 months for dogs and 6 months for cats. Sex predisposition was not found. The most frequently identified abnormalities were as follows: congenital cataract (dogs: 31.1%; cats: 30.0%), microphthalmia (dogs: 35.0%, cats: 25.0%), and persistent pupillary membrane (dogs: 27.2%, cats: 40.0%). Some of the concurrently observed malformations were significantly associated. A statistically significant association was found between ocular dermoids and the French Bulldog breed (P < .001). CONCLUSIONS: Even though congenital ocular malformations are uncommon, knowledge about their prevalence is important, since they can cause vision impairment or even blindness. Moreover, some human ocular disease phenotypes are similar to the ones presented by dogs and cats, so they can be used as models to investigate pathophysiology and therapeutic approaches.