Ubiquitous Chromatin Modifiers in Congenital Retinal Diseases: Implications for Disease Modeling and Regenerative Medicine.

Retinal congenital malformations known as microphthalmia, anophthalmia, and coloboma (MAC) are associated with alterations in genes encoding epigenetic proteins that modify chromatin. We review newly discovered functions of such chromatin modifiers in retinal development and discuss the role of epigenetics in MAC in humans and animal models. Further, we highlight how advances in epigenomic technologies provide foundational and regenerative medicine-related insights into blinding disorders. Combining knowledge of epigenetics and pluripotent stem cells (PSCs) is a promising avenue because epigenetic factors cooperate with eye field transcription factors (EFTFs) to direct PSC fate - a foundation for congenital retinal disease modeling and cell therapy.

[Congenital abnormalities of the optic disc]. / Anomalies congénitales de la papille.

Congenital abnormalities of the optic disc are not uncommon in clinical practice and should be recognized. Size abnormalities of the optic disc include optic disc aplasia, hypoplasia, megalopapilla, and optic disc cupping in prematurity. Among congenital excavations of the optic disc head, morning glory disc anomaly and optic disc pit can be complicated by serous retinal detachment; the papillorenal disc is an association of bilateral optic disc cupping and renal hypoplasia which should be ruled out; optic disc coloboma is caused by an abnormal closure of the embryonic fissure and can be complicated by choroidal neovascularization and retinal detachment. Other abnormalities that will be discussed are congenital tilted disc syndrome, duplicity of the optic disc head, congenital pigmentation of the optic disc head and myelinated retinal nerve fibers. All of these abnormalities can be associated with syndromes and neurological diseases, as well as other potentially blinding ophthalmological defects which can be secondarily complicated by amblyopia, strabismus and nystagmus. Thus, they should be recognized in order to plan for appropriate follow-up.

Síndrome de Michaelis-Manz. A propósito de un caso clínico / Michaelis-Manz syndrome. A case report

El síndrome de Michaelis-Manz es una tubulopatia de herencia autosómica recesiva asociada a mutaciones en las proteínas claudina 16 y 19 que se encuentran en el túbulo contorneado distal y asa de Henle en el riñón. La claudina 19 también se encuentra en el epitelio pigmentario de la retina. Clínicamente, el cuadro provoca hipomagnesemia, hipercalciuria y nefrocalcinosis que puede dar lugar a insuficiencia renal. Oftalmológicamente presentan colobomas maculares, estafilomas por miopía magna y nistagmo. Presentamos el caso de un varón de 18 años afectado de hipomagnesemia familiar con hipercalciuria y nefrocalcinosis, o síndrome de Michaelis-Manz, asociado a un coloboma macular con una agudeza visual estable

Michaelis-Manz syndrome is an autosomal recessive hereditary tubulopathy associated with mutations in the tight-junction proteins claudin-16 and claudin-19, which are present in the distal convoluted tubule and the loop of Henle in the kidney. Claudin-19 is also expressed in the retinal pigmentary epithelium. The clinical picture causes hypomagnesemia, hypercalciuria and nephrocalcinosis that can lead to renal failure, which is the condition that marks the prognosis of the disease. Ophthalmologically patients can present macular coloboma, myopic staphyloma and nystagmus. We present the case report of an 18-year-old man suffering from hereditary hypomagnesemia, hypercalciuria and nephrocalcinosis, or Michaelis-Manz syndrome, with macular coloboma and stable visual acuities

Isquemia retiniana y proliferación fibrovascular tardía asociada a coloboma de nervio óptico / Retinal ischaemia and delayed fibrovascular proliferation associated with an optic nerve coloboma

CASO CLÍNICO: Paciente con coloboma de nervio óptico izquierdo, que desarrolla tardíamente (a los 15 años de edad) proliferación fibrovascular vitreorretiniana y desprendimiento de retina traccional (DRT). Se realiza fotocoagulación retiniana sectorial con regresión del tejido proliferativo y la exudación asociada. DISCUSIÓN: Las anomalías congénitas del nervio óptico pueden asociar avascularidad e isquemia retiniana significativa y proliferación fibrovascular de aparición tardía. El tratamiento láser es efectivo para obtener la regresión del tejido neovascular y prevenir la progresión del DRT

CASE REPORT: A patient with a left optic nerve coloboma with late development (at 15 years of age) of vitreoretinal fibrovascular proliferation and tractional retinal detachment (TRD). Sectorial retinal photocoagulation was performed with regression of the proliferative tissue and exudation. DISCUSSION: Congenital optic nerve anomalies may be associated with significant retinal avascularity, ischaemia and late fibrovascular proliferation. Laser is effective for regression of the neovascular tissue and preventing TRD progression

Coloboma ocular como hallazgo incidental. Reporte de caso / Ocular coloboma as incidental finding. A case report

El coloboma ocular es una entidad infrecuente provocada por el cierre incompleto de la fisura embrionaria entre la quinta y la séptima semana de gestación. Se presenta el caso de una paciente de 6 años admitida por urgencias por presentar trauma contundente en el ojo derecho, es valorada por oftalmología, que encuentra en la ecografía ocular bilateral, compromiso de ojo derecho con ectasia y herniación secundaria del humor vítreo hacia la pared posterior del globo ocular y desarrollo anormal de la retina, coroides y esclera. Se decide realizar procedimiento quirúrgico que se lleva a cabo sin complicaciones. Patología reporta, cambios de metaplasia del contenido "Uveo-retiniano", formando cartílago, musculo y tejido adiposo, que se dispone de forma desordenada en un estroma fibroso, realizando diagnóstico de Coloboma Uveal.

Ocular coloboma is an uncommon condition caused by an incomplete closure of the embryonic fissure between the fifth and the seventh week of gestation. We reported a case of a 6 year old patient who was evaluated by ophthalmology service at emergency room after blunt trauma in the right eye. Patient was evalutated bilaterally with ocular ultrasound which showed, commitment ectasia right eye and vitreous herniation secondary to posterior wall eyeball and abnormal development of the retina, choroid and sclera. Was decided to perform a surgical procedure is performed without complications. Pathology reports, content metaplastic changes "uveo-retinal" forming cartilage, muscle and adipose tissue, which is arranged in a disorderly manner in a fibrous stroma, making diagnosis of Uveal Coloboma.

Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation.

BACKGROUND: Renal coloboma syndrome (RCS) is a highly variable syndrome characterized by renal and ocular abnormalities. It is associated in about 50 % of cases with mutations of PAX2, a gene encoding a transcription factor required during development. CASE-DIAGNOSIS/TREATMENT: The case study involves two monozygotic twin sisters with RCS showing highly discordant phenotypes. Twin 1 was antenatally diagnosed with multiple cysts in the right kidney. She had complicated vacuum-assisted delivery with acute renal failure. She developed proteinuria at age 4 years, followed by a progressive rise in serum creatinine requiring renal replacement therapy at age 22. No ocular abnormalities have been detected. Twin 2 experienced rapidly reversible acute renal failure without renal morphological abnormalities at birth. At age 2 years, complete visual acuity loss of the left eye secondary to an optic disc coloboma was diagnosed. No significant events occurred until the age of 20, when clinical proteinuria was detected. Proteinuria remission was obtained by multidrug treatment. In both patients, a novel de novo mutation of PAX2 was detected, which leads to the substitution of a highly conserved cysteine (p.C52Y). CONCLUSIONS: The patients described provide an extreme example of clinical variability in RCS. The role of environmental, genetic, and epigenetic factors is discussed.

Anophthalmos, microphthalmos, and Coloboma in the United kingdom: clinical features, results of investigations, and early management.

PURPOSE: To describe the clinical features of children with anophthalmos, microphthalmos, and typical coloboma (AMC). DESIGN: Descriptive, observational, cross-sectional study of the United Kingdom. PARTICIPANTS: A total of 135 children with AMC newly diagnosed over an 18-month period beginning in October 2006. METHODS: Cases were identified using active surveillance through an established ophthalmic surveillance system. Eligible cases were followed up 6 months after first notification. MAIN OUTCOME MEASURES: Phenotypic characteristics, both ocular and systemic, clinical investigations, causes, and interventions. RESULTS: A total of 210 eyes (of 135 children) were affected by AMC, of which 153 had isolated coloboma or coloboma with microphthalmos. The most common colobomatous anomaly was a chorioretinal defect present in 109 eyes (71.2%). Some 44% of children were bilaterally visually impaired. Systemic abnormalities were present in 59.7% of children, with craniofacial anomalies being the most common. Children with bilateral disease had a 2.7 times higher odds (95% confidence interval, 1.3-5.5, P = 0.006) of having systemic involvement than unilaterally affected children. Neurologic imaging was the most frequent investigation (58.5%) performed. Less than one third (30.3%) of the children with microphthalmos had ocular axial lengths measured. Eight children had confirmed genetic mutations. Approximately half (49.2%) of the children required ocular intervention. CONCLUSIONS: Colobomatous defects were the most common phenotype within this spectrum of anomalies in the United Kingdom. The high frequency of posterior segment colobomatous involvement means that a dilated fundal examination should be made in all cases. The significant visual and systemic morbidity in affected children underlines the importance of a multidisciplinary approach to management.

[Long-term results of the treatment of optic disc pit associated with serous macular detachment: a review of 20 cases]. / Résultats à long terme du traitement des fossettes colobomateuses de la papille compliquées de décollement séreux rétinien maculaire : à propos de 20 cas.

INTRODUCTION: The pathogenesis of the macular serous retinal detachment (SRD) associated with congenital optic disc pit remains controversial. The treatment is also discussed. Through this study, which includes the majority of the techniques available, we report our experiment in the treatment of this pathology. PATIENTS AND METHODS: This was a retrospective single-centre study of 20 patients who presented with macular SRD associated with optic disc pit between 1983 and 2009. Various treatments were provided. At the beginning of the study, patients were treated only by juxtapapillary laser photocoagulation. After laser failure then as first-line treatment, laser photocoagulation was associated with intravitreal gas (C3F8) injection with postoperative facedown positioning for 2 weeks. During the past few years, all patients have been systematically treated with vitrectomy with or without internal limiting membrane (ILM) peeling, laser, and gas (C2F6) tamponade. RESULTS: This series consisted of 20 patients: nine men and 11 women. The patients' mean age at presentation was 29 years (range, 9-60 years). The mean time between the onset of the decrease in visual acuity (VA) and treatment was 6.1 months. None of these patients had a posterior vitreous detachment at the time of diagnosis. Six patients were treated by laser photocoagulation alone, which was successful only in two cases. Eleven patients (with laser treatment failure in three) were treated by laser and intravitreal gas injection, with a 72% success rate. We performed vitrectomy with posterior hyaloid dissection, laser, and gas tamponade in eight cases (with laser-gas treatment failure in two) with 87% success rate and no recurrence. Five of these patients had ILM peeling during the vitrectomy. The mean follow-up period was 60 months (range, 2 months to 17 years). CONCLUSION: This study shows that early treatment of macular SRD associated with optic disc pit by vitrectomy, ILM peeling, juxtapapillary photocoagulation, and gas tamponade is followed by good anatomical and functional results. This treatment is superior to the other less invasive procedures. Optical coherence tomography is an important exam for diagnosis and postoperative follow-up of patients.

Successful airway management with use of a laryngeal mask airway in a patient with CHARGE syndrome.

CHARGE syndrome refers to an autosomal dominant disorder in patients with coloboma (C) of the eye, heart disease (H), atresia of choanae (A), retarded growth (R), genital hypoplasia (G), and ear anomalies (E). In addition to these typical features, airway abnormalities, including retrognathia, glossoptosis, and laryngeal paralysis, have been reported in patients with this syndrome. This report describes a case of CHARGE syndrome observed in a 6-year-old male patient with a difficult airway, in whom anesthesia was managed successfully using a laryngeal mask airway.

Update on the morning glory disc anomaly.

The morning glory disc anomaly has distinctive clinical characteristics and is important to diagnose correctly so that associated central nervous system and vascular abnormalities are promptly identified and treated. This review covers the ophthalmic findings, clinical features, and histopathologic findings in patients with this rare developmental abnormality. The most common systemic associations are described and reviewed.

Unrelated partially matched lymphocyte infusions in a patient with complete DiGeorge/CHARGE syndrome.

We present an infant with cDGS overlapping with CHARGE syndrome, who suffered from T-cell deficiency treated with screened healthy DLI from an unrelated donor (8/10 match). The first dose of DLI (1.1 x 10(6) CD3+/kg) was administered at the age of six months, the second one (0.9 x 10(6) CD3+/kg) 36 days later. No conditioning was employed, GvHD prophylaxis consisting of CsA was used only during the second infusion. Since day+10 after the first DLI, split chimerism showing T-cell engraftment has been documented. Proliferative response to PHA was detected on day+145. The treatment was complicated by severe acute GvHD (grade II-III) after the first DLI and prolonged chronic liver cholestatic GvHD developing after the second DLI. Vigorous EBV proliferation four wk after the second DLI was accompanied by peripheral expansion of CD8+ donor cells. The patient, 26-months old, is clinically well and has slowly started to gain his developmental milestones. We believe that infusions of small doses of DLI from an unrelated donor represent a potentially helpful therapeutic option in patients with cDGS/CHARGE phenotype.

Otodental syndrome.

The otodental syndrome also named otodental dysplasia, is characterised by a striking dental phenotype known as globodontia, associated with sensorineural high frequency hearing loss and eye coloboma. Globodontia occurs in both primary and permanent dentition, affecting canine and molar teeth (i.e. enlarged bulbous malformed posterior teeth with almost no discernable cusps or grooves). The condition appears to be inherited in an autosomal dominant mode, although sporadic cases have been reported. It is a rare disease, a few families have been described in the literature. In the British family, the locus for oculo-oto-dental syndrome was mapped to 20q13.1 within a 12-cM critical chromosomal region. Dental management is complex, interdisciplinary and will include regular follow up, scheduled teeth extraction and orthodontic treatment. Hearing checks and, if necessary, hearing aids are mandatory, as well as eye examination and ad hoc treatment if necessary.

Requirements for optical services in children with microphthalmos, coloboma and microcornea in southern India.

PURPOSE: The aim of the study was (1) to determine the need for spectacles in children in Southern India with coloboma, microphthalmos and microcornea, (2) to describe their refractive errors and (3) to assess their needs for low vision aids (LVAs). METHODS: Children with congenital eye anomalies were recruited from special education for the blind, schools for the mentally handicapped, community-based rehabilitation programmes and hospital records in Andhra Pradesh, India. All those with at least light perception vision (PL) in one eye and who had navigational vision were refracted. Those whose distance vision in their better eye improved with refraction were prescribed spectacles. Those unable to read N10 were assessed for LVAs for near. Those with distance visual acuity of < 6/18 in the better eye were assessed for telescopes to aid distance vision. RESULTS: Ninety-nine children with coloboma, microcornea or microphthalmos had functional vision. Eight unilateral cases were excluded. Ninety-one bilateral cases were refracted and assessed for LVAs. The vision in 52 children (57%) improved in the better-seeing eye by 1 or more lines of Snellen acuity with spectacles. Spectacles were prescribed most frequently for myopia associated with choroidal coloboma. After refraction, all 19 children with a visual acuity of 6/18 or better could read N10, and 43 of the 72 children (60%) with a visual acuity of < 6/18 to PL with functional vision could read N10 unaided, or with distance correction. A further 6 (8%) reached this level with magnifiers. Thirteen children (18%) were given telescopes. CONCLUSION: Children with congenital anomalies of the eye and functional vision benefit from refraction and low vision services.

The CHARGE association: the role of tracheotomy.

OBJECTIVES: To evaluate the need for a tracheotomy and its timing during the evolution of an association of malformations, including coloboma, heart defects, choanal atresia, developmental and growth retardation, genitourinary malformation, and ear anomalies (CHARGE association). DESIGN: Retrospective study from January 1988 through December 1997. SETTING: Four academic tertiary care centers. PATIENTS AND METHODS: Forty-five patients with CHARGE association having at least 3 cardinal malformations (growth retardation excluded) and review of the malformations and respiratory manifestations encountered. All the patients underwent endoscopic exploration on several occasions. We reviewed the nature and the timing of therapeutic interventions performed on the airway. RESULTS: Two patients died (one patient of septicemia, the other of unknown causes). Abnormalities of blood gas levels and/or sleep were found in 30 patients (67%), were responsible for cardiorespiratory arrest in 9 (20%), and required admission to the intensive care unit in 21 (47%). Pharyngolaryngeal anomalies leading to dyspnea (discoordinate pharyngolaryngomalacia, glossoptosis, retrognathia, laryngeal paralysis, cleft, stenosis, and difficult intubation) were found in 26 patients (58%). Tracheobronchial anomalies (esophagotracheal fistula, esophageal atresia, and tracheomalacia) were present in 18 patients (40%). Resection of the aryepiglottic folds was attempted 3 times, but without success. Tracheotomy was necessary in 13 patients (29%) at a median age of 2.4 months (mean duration, 25 months). Among these infants, the posterior nasal choanae were patent in 10 patients at the time of tracheotomy. Gastroesophageal reflux was encountered in 36 patients (80%). Prolonged enteral feeding was necessary in 21 patients (47%), with gastrostomy in 16 (of whom 9 needed a tracheotomy). These feeding difficulties and airway problems were highly correlated. CONCLUSIONS: We encountered multiple, complicated airway abnormalities. Resection of aryepiglottic folds was inadequate. Often, a tracheotomy could not be avoided in these patients, regardless of choanal patency. Tracheotomy needs to be performed early to avoid hypoxic events. In some selected patients, ventilation using bilevel positive airway pressure may be an alternative.

[Management of congenital microphthalmos and anophthalmos]. / Prise en charge des microphtalmies et anophtalmies congénitales.

PURPOSE: To better characterize congenital anophthalmos and microphthalmos in order to distinguish which patients need surgical treatment. MATERIALS AND METHODS: A retrospective study of 42 cases with congenital anophthalmos and microphthalmos over a 16 years period was performed. Seven anophthalmos, 20 microphthalmic globes with no associated colobomatous orbital cyst and 15 microphthalmic globes associated with colobomatous orbital cyst were observed. Complete history, pediatrical and ophthalmological examination, electrophysiological feature, oculo-cerebral imagery and karyotype on each of the patients were reviewed. RESULTS: Among all patients, lack of development of the lids was observed in 45% of cases. In our group of anophthalmos, 100% had micro-orbit. In our group of microphthalmic globes with no associated colobomatous orbital cyst, 30% had micro-orbit and in our group of microphthalmic globes associated with colobomatous orbital cyst, 6% had micro-orbit. 75% of patients had ocular anomalies and 39% had systemic anomalies, mostly on the face. Aetiology were found in 36% of cases. Visual evoked potentials and retinal electric feature were useful to better determine visual function. CONCLUSION: Expandable orbital prosthesis would appear to be the most effective therapy for certain cases of anophthalmos and microphthalmos with micro-orbit.