Visual Function and Ophthalmological Findings in CHARGE Syndrome: Revision of Literature, Definition of a New Clinical Spectrum and Genotype Phenotype Correlation.

CHARGE syndrome (CS) is a rare genetic disease causing multiple anatomical defects and sensory impairment. Visual function is usually reported by caregivers and has never been described with a structured behavioral assessment. Our primary objective was to describe ocular abnormalities, visual function and genotype-ocular-phenotype correlation in CS. A prospective monocentric cohort study was performed on 14 children with CS carrying pathogenic CHD7 variants. All children underwent ophthalmological evaluation and structured behavioral assessment of visual function. The VISIOCHARGE questionnaire was administered to parents. Colobomas were present in 93% of patients. Genotype-phenotype correlation documented mitigated features in a subset of patients with intronic pathogenic variants predicted to affect transcript processing, and severe features in patients with frameshift/nonsense variants predicting protein truncation at the N-terminus. Abnormal visual function was present in all subjects, with different degrees of impairment. A significant correlation was found between visual function and age at assessment (p-value = 0.025). The present data are the first to characterize visual function in CS patients. They suggest that hypomorphic variants might be associated with milder features, and that visual function appears to be related to age. While studies with larger cohorts are required for confirmation, our data indicate that experience appears to influence everyday use of visual function more than ocular abnormalities do.

Bilateral congenital macular coloboma and cataract: A case report.

RATIONALE: The case with congenital macular coloboma and cataract was rarely reported, and the pathogenic gene of the disease is still not clear. Moreover, it is difficult to improve the visual acuity of the eye with this disease. PATIENT CONCERNS: An 11-year-old boy presented low visual acuity and horizontal nystagmus in both eyes. Ophthalmologic examination showed the patient with bilateral congenital coloboma and cataract. The visual acuity of the patient improved slightly after cataract surgery. Heterozygous mutations of frizzled-4 (FZD4) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) were identified by next-generation sequencing in this case. DIAGNOSIS: Congenital macular coloboma and cataract of both eyes. INTERVENTIONS: We performed the standard phacoemulsification and intraocular lens implantation on both eyes of the patient for the treatment of congenital cataract, and then followed up the fundus lesions regularly. OUTCOMES: Cataract surgery may improve the visual acuity of the eyes with congenital macular coloboma and cataract at some degree, but the vision of this patient was still very poor postoperatively. Furthermore, the heterozygous mutations of FZD4 and NOD2 were found in this patient. LESSONS: Cataract surgery may improve the visual acuity of the eyes with congenital macular coloboma and cataract at some degree, and heterozygous mutations of FZD4 and NOD2 may be involved in the occurrence of congenital macular coloboma and cataract.

Functional vision and quality of life in children with microphthalmia/anophthalmia/coloboma-a cross-sectional study.

PURPOSE: To determine the child's and parental perception of functional visual ability (FVA), vision-related and health-related quality of life (VR-QoL, HR-QoL) in children with microphthalmia/anophthalmia/coloboma (MAC). METHODS: Between June 25, 2014, and June 3, 2015, we carried out a cross-sectional observational study at Moorfields Eye Hospital, London, UK, enrolling 45 children 2-16 years of age with MAC attending our clinics, and their parents. To assess FVA, VR-QoL, and HR-QoL we asked participants to complete three validated tools, the Cardiff Visual Ability Questionnaire for Children (CVAQC), the Impact of Vision Impairment for Children (IVI-C) instrument, and the PedsQL V 4.0. The main outcome measures were the FVA, VR-QoL, and HR-QoL scores, reported by children and parents. RESULTS: In children with MAC, FVA is moderately reduced, with a median CVAQC score of -1.4 (IQR, -2.4 to 0.4; range, -3.0 [higher FVA] to +2.8 [lower FVA]). VR-QoL and HR-QoL are greatly reduced, with an IVI-C median score of 63 (IQR, 52-66; normal VR-QoL, 96), a median self-reported PedsQL score of 77 (IQR, 71-90; normal HR-QoL, 100) and parental score of 79 (IQR, 61-93), and a family impact score of 81 (67-93). Psychosocial well-being scores are lower than physical well-being scores. Parents and children have a different perception of the impact of the condition on the child's HR-QoL. CONCLUSIONS: MAC has a significant impact on a child's FVA and QoL, similar to that described by children with acute lymphoblastic leukaemia and chronic systemic conditions. Children and families may benefit from psychosocial support.

Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases.

OBJECTIVE: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. PATIENTS AND METHODS: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. RESULTS: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. CONCLUSION: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome.

Alu-mediated deletion of PIGL in a Patient with CHIME syndrome.

CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event. Analysis of PIGL genomic sequences for repetitive elements demonstrated that Alu repeats represent ∼34% of its intronic sequence, suggesting that the genomic architecture may predispose the gene to disease-causing copynumber changes. Taken together, these findings indicate that patients with a clinical diagnosis of CHIME syndrome and a single identifiable mutation in PIGL warrant further investigation for copynumber changes involving PIGL.

Desprendimiento seroso macular asociado a foseta papilar congénita y coloboma de papila: ¿Qué opciones terapéuticas tenemos? / Macular serous detachment associated to congenital papillary pit and papillary coloboma: What treatment options do we have?

La foseta papilar es una rara anomalía congénita que forma parte del espectro de las anormalidades congénitas del disco óptico. Se trata de invaginaciones intrapapilares que suelen localizarse en el margen del disco óptico. La mayoría se localiza a nivel temporal; en torno al 20 por ciento son de localización central seguidas por las fosetas superiores, inferiores o nasales. La bilateralidad se estima en un 10-15 por ciento y su incidencia se ha establecido en torno al 0,19 por ciento. Suelen ser asintomáticas, aunque en aproximadamente el 50 por ciento de los casos se produce afectación macular por el paso de fluido procedente desde la foseta papilar hacia las diferentes capas retinianas, lo que afecta secundariamente la agudeza visual y es, por tanto, el motivo de consulta. Hasta el momento se han descrito múltiples alternativas terapéuticas para el tratamiento de los desprendimientos de retina serosos asociados a foseta de papila, pero ninguna de estas alternativas se ha impuesto sobre el resto. El tratamiento de esta enfermedad consiste en cerrar la comunicación entre la foseta y el espacio subretiniano con diversas opciones terapéuticas como: la fotocoagulación láser, la neumoretinopexia, la indentación escleral posterior, la fenestración del nervio óptico, la vitrectomía o alguna combinación de las anteriores. La actual revisión bibliográfica se propone profundizar en el tema, sobre la base de pacientes en consulta con dicha afección retiniana(AU)

Papillary pit is a rare congenital anomaly that is part of the congenital optic disc anomaly spectrum. It deals with intrapapillary invaginations that may be located at the border of the optic disc. Most of them is located at temporal level, around 20 percent are located centrally followed by upper, lower and nasal pits. Bilateral pits are estimated to be 10-15 percent and their incidence has been set at 0.19 percent. They are asymptomatic although 50 percent of cases suffer macular damage due to the passing of fluid from the papillary pit to the different retinal layers, which affecgs in a secondary way the visual acuity and thus it is the reason to go to the ophthalmologist. Multiple therapeutic alternatives for the treatment of papillary pit-associated serous retinal detachments have been described but none of them has predominated over the others. The treatment of this disease consists of closing the communication between the pit and the subretinal space with several therapeutic options such as laser photocoagulation, pneumoretinopexia, posterior scleral indentation, optic nerve fenestration, vitrectomy or any combination of the above-mentioned methods(AU)

Exome sequencing identifies a de novo frameshift mutation in the imprinted gene ZDBF2 in a sporadic patient with Nasopalpebral Lipoma-coloboma syndrome.

Nasopalpebral lipoma-coloboma syndrome (NPLCS, OMIM%167730) is an uncommon malformation entity with autosomal dominant inheritance characterized by the combination of nasopalpebral lipoma, colobomas in upper and lower eyelids, telecanthus, and maxillary hypoplasia. To date, no genetic defects have been associated with familial or sporadic NPLCS cases and the etiology of the disease remains unknown. In this work, the results of whole exome sequencing in a sporadic NPLCS patient are presented. Exome sequencing identified a de novo heterozygous frameshift dinucleotide insertion c.6245_6246 insTT (p.His2082fs*67) in ZDBF2 (zinc finger, DBF-type containing 2), a gene located at 2q33.3. This variant was absent in parental DNA, in a set of 300 ethnically matched controls, and in public exome variant databases. This is the first genetic variant identified in a NPLCS patient and evidence supporting the pathogenicity of the identified mutation is discussed. © 2016 Wiley Periodicals, Inc.

Achondroplasia and Macular Coloboma.

Achondroplasia is an autosomal dominant congenital disorder of enchondral ossification. It is clinically characterized by low stature, craniofacial deformity, and vertebral malformation. Associated ophthalmic features include telecanthus, exotropia, angle anomalies, and cone-rod dystrophy. A 24-year-old male presented with decreased vision bilaterally and typical achondroplasia. The best corrected visual acuity was 20/70 in both eyes. Anterior segment examination was normal. Fundus examination revealed a well-demarcated circular paramacular lesion in both eyes. As macular coloboma and achondroplasia are developmental disorders, the funduscopic examination is required in patients with achondroplasia.

Bilateral isolated lens coloboma associated with bicuspid aortic valve / Coloboma de cristalino bilateral isolado associado à valva aórtica bicúspide

ABSTRACT A 27-year-old woman presented with a history of long-standing poor vision in both eyes. Ophthalmologic examination after pupillary dilatation revealed bilateral lens coloboma situated in the inferotemporal quadrant. No associated ocular abnormalities were seen, except amblyopia. A bicuspid aortic valve was observed during echocardiography during systemic evaluation. Lens coloboma usually occurs unilaterally; however, bilateral lens coloboma which is isolated or associated with other ocular malformations is also encountered. This is the first description of bilateral isolated lenticular coloboma associated with bicuspid aortic valve. Although the association between bicuspid aortic valve and lens coloboma may be an incidental finding, they may be components of an unknown syndrome.

RESUMO Uma mulher de 27 anos apresentou-se com uma história de longa data de deficiência visual em ambos os olhos. O exame oftalmológico após dilatação pupilar revelou coloboma de cristalino bilateral localizado no quadrante temporal inferior. Nenhuma outra alteração ocular associadas foi observada, exceto ambliopia. A valva aórtica bicúspide foi diagnosticada no exame de ecocardiograma durante a avaliação sistêmica. Coloboma cristaliniano ocorre geralmente de forma unilateral, no entanto já foi descrito bilateralmente, associado a outras malformações oculares ou isolado. Esta é a primeira descrição de coloboma cristaliniano isolado bilateral associado à valva aórtica bicúspide. Embora a associação de valva aórtica bicúspide e coloboma cristaliniano no nosso caso pode ter sido um achado incidental, eles podem ser componentes de uma síndrome desconhecida.

Lens coloboma treated with lens surgery.

A 5-year-old boy was referred to our clinic due to an abnormal visual acuity test at school. His corrected visual acuity was counting fingers in the left eye. A nasal side deficiency of the lens substituted by a membrane was found. Lens coloboma was diagnosed. After making a 3 mm limbal incision, the colobomatous lens was removed by anterior continuous curvilinear capsulorhexis and lens aspiration. Posterior capsulorhexis and anterior vitrectomy on the side of the lens was performed to prevent posterior capsular or anterior hyaloid opacity. As the defect in the lens was very large, intracapsular placement of an intraocular lens was not feasible. A three-piece acrylic soft intraocular lens was placed in the ciliary sulcus. Since amblyopia was diagnosed by poor corrected visual acuity as 20/800 1 month after the operation, occlusion therapy with correcting eyeglasses was started at 6 h a day on the contralateral eye. The patient's corrected visual acuity improved to 20/125 7 months after the operation.

Clinical and Echographic Features of Retinochoroidal and Optic Nerve Colobomas.

PURPOSE: We reported the clinical and echographic features of colobomas, prevalence of retinal detachment, and associated visual acuity in these patients. METHODS: The study is a nonrandomized consecutive case series of 140 colobomatous eyes in 98 patients (age range, 0-83 years). Coloboma depth, width, volume, and relative coloboma excavation (coloboma depth/axial length) were measured using standardized echographic images. The presence of structural and other ocular abnormalities was noted. The clinical and echographic findings present were correlated with visual acuity of the patient. In addition, these features were correlated with the presence or absence of retinal detachment. RESULTS: Increased relative coloboma excavation was significantly associated with an increased risk of retinal detachment. A relative coloboma excavation (ratio of coloboma depth to axial length) greater than 0.15 was associated with an increased risk of retinal detachment (52%), compared to those with a relative coloboma excavation less than 0.15 (23%, P = 0.014). The presence of any structural abnormality and the presence of a retrobulbar cyst were associated with increased risk of retinal detachment and severe visual impairment (worse than 20/200). Increased coloboma depth, width, volume, and relative coloboma excavation were not associated with increased risk of severe visual impairment. CONCLUSIONS: Clinical and echographic features of colobomas may be used in predicting the risk of retinal detachment. Measuring relative coloboma excavation upon presentation may alter follow-up and assist in the diagnosis of retinal detachment.

A paraganglioma in a hypertensive patient with unilateral renal hypoplasia.

We report the case of a 46-year-old hypertensive Japanese female with renal insufficiency related to unilateral renal hypoplasia. The patient was found to have developed paraganglioma in the retroperitoneal space over a 5-year period. Catecholamine-producing tumors are not usually recognized as conditions associated with renal hypoplasia. Our long-term observation of the patient eventually led us to the diagnosis of paraganglioma. In hypertensive patients with chronic kidney disease, not only the renin-angiotensin-aldosterone system but also catecholamine activity may be involved, particularly in the patients whose cases are complicated with unilateral renal hypoplasia.

Otodental syndrome: a case presentation in a 6-year old child.

BACKGROUND: Otodental syndrome is a rare condition characterised by globodontia, and sensorineural high frequency hearing loss. To date, only 20 cases of otodental syndrome have been reported. CASE REPORT: A 6 year-old girl presented with a chief complaint of delay in the eruption of primary canines. Following clinical, radiographic and audiologic evaluations, the patient was diagnosed with otodental syndrome. CONCLUSION: Globodontia is a diagnostic feature of the otodental syndrome, which often provides the path to discovery of the associated hearing loss. Missing teeth, arch-size discrepancies, chewing problems and teething disturbances are the other major complications.

The Dkk1 dose is critical for eye development.

During mammalian ocular development, several signaling pathways control the spatiotemporal highly defined realization of the three-dimensional eye architecture. Given the complexity of these inductive signals, the developing eye is a sensitive organ for several diseases. In this study, we investigated a Dkk1+/- haploinsufficiency during eye development, resulting in coloboma and anterior eye defects, two common developmental eye disorders. Dkk1 impacts eye development from a defined developmental time point on, and is critical for lens separation from the surface ectoderm via ß-catenin mediated Pdgfrα and E-cadherin expression. Dkk1 does not impact the dorso ventral retina patterning in general but is critical for Shh dependent Pax2 extension into the midline region. The described results also indicate that the retinal Dkk1 dose is critical for important steps during eye development, such as optic fissure closure and cornea formation. Further analysis of the relationship between Dkk1 and Shh signaling revealed that Dkk1 and Shh coordinatively control anterior head formation and eye induction. During eye development itself, retinal Dkk1 activation is depending on cilia mediated Gli3 regulation. Therefore, our data essentially improve the knowledge of coloboma and anterior eye defects, which are common human eye developmental defects.

Long-term anatomical and visual outcome of vitreous surgery for retinal detachment with choroidal coloboma.

CONTEXT: Vitreous surgery has been advocated as an alternative treatment of selected retinal detachments with choroidal colobomas. AIM: To study the long term anatomical and visual outcome of choroidal coloboma with retinal detachment managed by pars plana vitrectomy with silicone oil tamponade. SETTING AND DESIGN: Retrospective study conducted in a tertiary eye care hospital. MATERIALS AND METHODS: Fourty two eyes of 40 patients with retinal detachments related to coloboma of the choroid without any peripheral breaks were analyzed. All eyes underwent pars plana vitrectomy with internal tamponade using silicone oil. Endolaser was performed along the coloboma border. Silicone oil was removed in 50% of patients. The main outcome measures were retinal reattachment and visual recovery. SPSS (Statistical Package for the Social Science), version 10.0 was used for analysis. RESULTS: The retina in all cases (100%) undergoing vitrectomy were completely reattached intra-operatively. After a mean follow-up of 14 months, 37 (88.1%) eyes had attached retina. The best corrected visual acuity was 10/200 or better in 33 (78.4%) eyes. The best corrected visual acuity improved from a preoperative median of counting fingers (range 20/40 to perception of light) to median best corrected visual acuity of 20/200 (range 20/40 to perception of light) at the end of 6 months. Of the 50% (21) cases that underwent silicone oil removal, two eyes had re-detachment of retina. CONCLUSION: Pars plana vitrectomy along with silicone oil tamponade for retinal detachment related to choroidal coloboma improves the long-term anatomical and visual outcome.

CHARGE syndrome: relations between behavioral characteristics and medical conditions.

The behaviors and medical problems in 27 persons with CHARGE syndrome were studied, because it was hypothesized that their behavior might be partly dependent on the heterogeneous medical status. With the exception of more tics, cardiac surgery was associated with positive behaviors: less withdrawn behavior, better mood, and a more easy temperament. Tube feeding was also related to positive behavior, since participants with a history of tube feeding showed less intense behavior. Cerebral deficits were associated with three problem behaviors: more intense and withdrawn behavior and a worse mood. Deaf-blindness was associated with developmental delays in expressive and overall communication level, and recurrent middle ear infections correlated with delays in written language. Of all medical conditions, only the presence or absence of heart defects and cardiac surgery could differentiate between the participants with regard to the number of behavioral problems. Participants with heart surgery especially, had less behavior problems. The number of operations and hospitalizations was not associated with behavior, but the total length of the hospitalizations was. Long hospital stays were associated with less problem behavior, especially internalizing behaviors. Cerebral and heart problems did not result in longer hospital stays, whereas esophageal reflux did. Age effects were reflected in older participants, who showed more internalizing problems. Heart surgery and hospitalization may be protective factors, but the protection might not be the actual surgery or hospital stay, as there may be other variables that are the actual cause, such as reduced vitality or altered parent child interactions after heart surgery. The study could not confirm a significant association between medical conditions and autism found in previous studies.

[Does amblyopia therapy make sense in eyes with severe organic defects?]. / Ist eine Amblyopietherapie bei schwerer organischer Augenerkrankung sinnlos?

BACKGROUND: In eyes with severe organic defects the question arises if amblyopia therapy makes sense. PATIENTS AND METHODS: Three children are presented in whom despite severe organic eye diseases amblyopia therapy was tried. The first child had a unilateral large macular scar secondary to retinoblastoma treatment, the second a unilateral severe optic nerve atrophy secondary to an orbital hemangioma, and the third a unilateral large optic nerve coloboma. RESULTS: In the first case a reading visual acuity of 0.9 was achieved by occlusion therapy and in the second a reading visual acuity of 0.5. In the third case occlusion lead to alternation of the divergent strabismus (child too strongly retarded for reliable visual acuity measurements). CONCLUSIONS: During the sensitive phase, amblyopia therapy is also indicated in eyes with severe organic defects since good visual acuities can be achieved.

Ocular and systemic findings associated with optic disc colobomas.

PURPOSE: To determine the ocular and systemic anomalies associated with optic disc colobomas. PATIENTS AND METHODS: The records of patients with a diagnosis of isolated optic disc coloboma and chorioretinal coloboma with optic disc involvement were retrospectively reviewed. RESULTS: Fifteen patients were included in the study. Of the 30 eyes, the optic disc and choroid were involved in 18, an isolated disc coloboma was present in 5, a normal optic disc was present in 4, and the optic disc could not be identified because of extreme microphthalmia in 1. Of the optic discs outside the fundus colobomas, 1 had an abnormal shape and 1 had optic atrophy and hypoplasia. Eight patients had bilateral but asymmetric involvement of the optic nerve with the coloboma. Fourteen eyes of 9 patients were microphthalmic. Nine eyes of 6 patients had microcornea. One patient had a nonrhegmatogenous retinal detachment at the time of diagnosis. One eye had a retrobulbar cyst with microphthalmia. Eight (53%) of the patients had sensory strabismus. Two patients had unilateral cortical lens opacities. Associated systemic findings were present in 6 (40%) of the 15 patients. CONCLUSIONS: Optic disc colobomas have a wide variety of presentations. Poor visual acuity was observed mostly in eyes with macular involvement and microphthalmia.

Early prognostic factors for intellectual outcome in CHARGE syndrome.

CHARGE syndrome (coloboma, heart disease, atresia of the choanae, retarded growth and mental development, genital anomalies, and ear malformations and hearing loss) is a heterogeneous condition for which early prediction of intellectual outcome is important but difficult. The psychomotor milestones and intellectual outcome of a consecutive series of children with CHARGE syndrome who were observed by the same team from the neonatal period to the time of study were analyzed retrospectively. Twenty-one children (11 males and 10 females, aged from 5 to 12 years, mean 8 years 7 months, SD 2 years 5 months) were included. The influence of 19 early identifiable parameters that could be considered as deleterious for intellectual outcome was recorded. Generally, the main psychomotor milestones (0 to 4 years) were severely delayed, although intellectual outcome (at primary-school age) was satisfactory for half the children in this series. We show that extensive bilateral coloboma resulting in low vision, microcephaly, and brain malformation were the only three parameters that were predictive of poor intellectual outcome. Conversely, severe neonatal medical conditions, such as tracheotomy, conditions requiring long stays in hospital, or cardiac surgery were not predictive of poor intellectual outcome. Severe hearing loss was not found to be negatively correlated with intellectual outcome once coloboma had been taken into account.