Complex balanced intrachromosomal rearrangement involving PITX2 identified as a cause of Axenfeld-Rieger Syndrome.

Axenfeld-Rieger Syndrome (ARS) type 1 is a rare autosomal dominant condition characterized by anterior chamber anomalies, umbilical defects, dental hypoplasia, and craniofacial anomalies, with Meckel's diverticulum in some individuals. Here, we describe a clinically ascertained female of childbearing age with ARS for whom clinical targeted sequencing and deletion/duplication analysis followed by clinical exome and genome sequencing resulted in no pathogenic variants or variants of unknown significance in PITX2 or FOXC1. Advanced bioinformatic analysis of the genome data identified a complex, balanced rearrangement disrupting PITX2. This case is the first reported intrachromosomal rearrangement leading to ARS, illustrating that for patients with compelling clinical phenotypes but negative genomic testing, additional bioinformatic analysis are essential to identify subtle genomic abnormalities in target genes.

Novel compound heterozygous variants in ARL13B lead to Joubert syndrome.

Joubert syndrome (JBTS) is a systematic developmental disorder mainly characterized by a pathognomonic mid-hindbrain malformation. All known JBTS-associated genes encode proteins involved in the function of antenna-like cellular organelle, primary cilium, which plays essential roles in cellular signal transduction and development. Here, we identified four unreported variants in ARL13B in two patients with the classical features of JBTS. ARL13B is a member of the Ras GTPase family and functions in ciliogenesis and cilia-related signaling. The two missense variants in ARL13B harbored the substitutions of amino acids at evolutionarily conserved positions. Using model cell lines, we found that the accumulations of the missense variants in cilia were impaired and the variants showed attenuated functions in ciliogenesis or the trafficking of INPP5E. Overall, these findings expanded the ARL13B pathogenetic variant spectrum of JBTS.

Deep learning-based optic disc classification is affected by optic-disc tilt.

We aimed to determine the effect of optic disc tilt on deep learning-based optic disc classification. A total of 2507 fundus photographs were acquired from 2236 eyes of 1809 subjects (mean age of 46 years; 53% men). Among all photographs, 1010 (40.3%) had tilted optic discs. Image annotation was performed to label pathologic changes of the optic disc (normal, glaucomatous optic disc changes, disc swelling, and disc pallor). Deep learning-based classification modeling was implemented to develop optic-disc appearance classification models with the photographs of all subjects and those with and without tilted optic discs. Regardless of deep learning algorithms, the classification models showed better overall performance when developed based on data from subjects with non-tilted discs (AUC, 0.988 ± 0.002, 0.991 ± 0.003, and 0.986 ± 0.003 for VGG16, VGG19, and DenseNet121, respectively) than when developed based on data with tilted discs (AUC, 0.924 ± 0.046, 0.928 ± 0.017, and 0.935 ± 0.008). In classification of each pathologic change, non-tilted disc models had better sensitivity and specificity than the tilted disc models. The optic disc appearance classification models developed based all-subject data demonstrated lower accuracy in patients with the appearance of tilted discs than in those with non-tilted discs. Our findings suggested the need to identify and adjust for the effect of optic disc tilt on the optic disc classification algorithm in future development.

Evaluation of the efficacy and safety of pars plana vitrectomy with irido-zonulo-hyaloidotomy for malignant glaucoma.

PURPOSE: To assess the efficacy and safety of pars plana vitrectomy with irido-zonulo-hyaloidotomy (IZH) for fluid misdirection syndrome (FMS) in pseudophakic eyes. METHODS: This was a retrospective case series study of patients treated with pars plana vitrectomy with IZH for FMS between February 2017 and March 2020. Complete success was defined as central anterior chamber (AC) deepening with an intraocular pressure (IOP) of 21mmHg or less (on 2 consecutive visits at least 1 week apart) without topical or systemic glaucoma medications. Qualified success was defined as central AC deepening with an IOP of 21mmHg or less (on 2 consecutive visits at least 1 week apart) with topical or systemic glaucoma medications. RESULTS: Twelve eyes of 12 patients with a diagnosis of FMS were included. The mean age of the population was 73.6±15.4 years [39-90] with a majority of women (58.3%). Prior surgeries at the time of FMS diagnosis were trabeculectomy (4 eyes) and non-perforating deep sclerectomy (2 eyes). At presentation, mean IOP was 38.2±9.8mmHg, which decreased to 17.9±7.7mmHg (P<0.0001) at final follow-up (mean follow-up of 4.9±4.3 months). Complete success was achieved in 6 eyes (50%) and qualified success in 10 eyes (83%), with two eyes failing treatment. There was no statistical significant relationship between demographic data and clinical success (P > 0.05). CONCLUSION: Pars plana vitrectomy combined with IZH appears to be a safe and effective technique for the treatment of FMS in pseudophakic patients.

A case of Joubert syndrome caused by novel compound heterozygous variants in the TMEM67 gene.

Joubert syndrome (JS) is a recessive disorder that is characterized by midbrain-hindbrain malformation and shows the "molar tooth sign" on magnetic resonance imaging. Mutations in 40 genes, including Abelson helper integration site 1 (AHI1), inositol polyphosphate-5-phosphatase (INPP5E), coiled-coil and c2 domain-containing protein 2A (CC2D2A), and ARL2-like protein 1 (ARL13B), can cause JS. Classic JS is a part of a group of diseases associated with JS, and its manifestations include various neurological signs such as skeletal abnormalities, ocular coloboma, renal disease, and hepatic fibrosis. Here, we present a proband with the molar tooth sign, ataxia, and developmental and psychomotor delays in a Dagestan family from Russia. Molecular genetic testing revealed two novel heterozygous variants, c.2924G>A (p.Arg975His) in exon 28 and c.1241C>G (p.Pro414Arg) in exon 12 of the transmembrane protein 67 (TMEM67) gene. These TMEM67 gene variants significantly affected the development of JS type 6. This case highlights the importance of whole exome sequencing for a proper clinical diagnosis of children with complex motor and psycho-language delays. This case also expands the clinical phenotype and genotype of TMEM67-associated diseases.

Observation of the effect of posterior scleral reinforcement combined with orthokeratology and 0.01% atropine in the treatment of congenital myopia: a case report.

BACKGROUND: Myopia has recently emerged as a significant threat to global public health. The high and pathological myopia in children and adolescents could result in irreversible damage to eye tissues and severe impairment of visual function without timely control. Posterior scleral reinforcement (PSR) can effectively control the progression of high myopia by limiting posterior scleral expansion, improving retrobulbar vascular perfusion, thereby stabilizing the axial length and refraction of the eye. Moreover, orthokeratology and low concentrations of atropine are also effective in slowing myopia progression. CASE PRESENTATION: A female child was diagnosed with binocular congenital myopia and amblyopia at the age of 3 and the patient's vision had never been rectified with spectacles at the first consultation. The patient's ophthalmological findings suggested, high refractive error with low best corrected visual acuity, longer axial length beyond the standard level of her age, and fundus examination suggesting posterior scleral staphyloma with weakened hemodynamics of the posterior ciliary artery. Thereby, PSR was performed to improve fundus health and the combination of orthokeratology and 0.01% atropine were performed to control the development of myopia. Following up to 8 years of clinical treatment and observations, the progression of myopia could be well controlled and fundus health was stable. CONCLUSION: In this report, 8-year of clinical observation indicated that PSR could improve choroidal thickness and hemodynamic parameters of the retrobulbar vessels, postoperative orthokeratology combined with 0.01% atropine treatment strategy may be a good choice for myopia control effectively.

Novel mutation in RPGRIP1L gene causing Joubert syndrome: A case report.

INTRODUCTION: Joubert syndrome is a rare disease of genetic origin with autosomal recessive inheritance and extreme genetic heterogeneity with more than 40 causative genes. Joubert syndrome 7 is caused by mutations in the RPGRIP1L gene. PATIENT CONCERNS: Our report describes a pediatric patient with clinical features compatible with JS type 7 such as hypotonia, developmental delay and aplasia of the cerebellar vermis. DIAGNOSIS: The clinical features and the MRI of the head and neck which showed alterations at the level of the posterior fossa, with absence of the vermis and horizontal disposition of the cerebellar peduncles, were compatible with Joubert syndrome. Whole exome sequencing detected the variants RPGRIP1L (NM_015272.2) c.697A > T (p. Lys233Ter) and RPGRIP1L (NM_015272.2) c.3545 del (p.Pro1182LeufsTer25). INTERVENTIONS: Resection was performed to correct the polydactyly. At age 2 years umbilical hernia, adenoid surgery and ventilatory tubes surgery were performed. Renal biopsy confirmed interstitial fibrosis and focally accentuated mild tubular atrophy with focal tubular hypertrophy, compatible with the clinical suspicion of Joubert syndrome. Congenital hip dislocation surgery was performed. The patient underwent surgery for correction of concomitant divergent strabismus and continued with glasses for astigmatism and hyperopia. OUTCOMES: Sanger sequencing confirmed the patient´s results and the father was found to be a carrier of RPGRIP1L (NM_015272.2) c.697A > T (p. Lys233Ter) and the mother and maternal grandmother as carriers of RPGRIP1L (NM_015272.2) c.3545del (p.Pro1182LeufsTer25). RPGRIP1L:c.3545del novel variant is a deletion which changes the reading frame, altering the RPGR1_C terminal domain and giving rise to an incomplete protein whose functions will be altered. CONCLUSION: This is the first genetically confirmed case of JS in Colombia, the first carrier of biallelic RPGRIP1L gene mutations with hip dislocation and incomplete glottic closure and the first report of the novel c.3545del likely pathogenic variant causing JS.

Alternative Genetic Diagnoses in Axenfeld-Rieger Syndrome Spectrum.

Axenfeld-Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. PITX2 and FOXC1 variants explain the majority of individuals with Axenfeld-Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with ARA/ARS or similar phenotypes affecting five different genes/regions. USP9X and JAG1 explained three families each. USP9X was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy-Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with FOXC1-ARS. Anterior segment anomalies are not currently associated with USP9X, yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of JAG1 variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in CDK13, BCOR, and an X chromosome deletion encompassing HCCS and AMELX (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for PITX2/FOXC1 sequencing and copy number analysis, with attention to the described genes/regions.

PHACE(S) SYNDROME - EARLY DIAGNOSTICS IN THE MAXILLOFACIAL AREA.

OBJECTIVE: The aim: To determine the minimum criteria for early diagnosing PHACE(S) syndrome in neonates and infants with infantile hemangioma (IH) in the max¬illofacial area. PATIENTS AND METHODS: Materials and methods: A total of 26 asymptomatic children from 20 days to six months of aged with IH of more than 5 cm² in the maxillofacial area were included in this study. A medical record of patients clinical examination, Holter monitoring, echocardiographic ultrasound and magnetic resonance imaging (MRI) were analysed. The IH treatment with ß-blockers was carried out. RESULTS: Results: IH localization was diagnosed: 62% with a lesion of a part facial segment, 23% in one segment, 15% in several segments (p=0.018), and 12% with other parts of the body lesion (p=1.000). The patent foramen ovale was diagnosed in 35% of children. Central nervous system disorders were observed in 12% over two years of age. The indices of Holter monitoring and blood glucose changed in age norm range during treatment. Cardiovascular (the aortic coarctation (p=0.003) and brain (the Dandy-Walker malformation) (p=0.031) abnormalities were determined in two cases (8%) according to the MRI only. We diagnosed PHACE(S) syndrome in both these cases of children, only aged 12 months and 2.5 years old. CONCLUSION: Conclusions: Early diagnosis of PHACE(S) syndrome is possible on a contrast-enhanced MRI performed in asymptomatic neonates and infants with the facial several segmental IH with / without ulceration (p=0.018, p=0.046; p < 0.05) for recognition of presymptomatic cardiovascular and brain abnormalities.

Exploration on surgery of malignant glaucoma with prolonged absence of the anterior chamber: a retrospective consecutive case series.

OBJECTIVE: To evaluate the surgical outcomes of anterior chamber restoration in patients with malignant glaucoma and a prolonged absence of the anterior chamber. METHODS: Five patients with malignant glaucoma and a long-term absence of the anterior chamber underwent a combination of anterior pars plana vitrectomy (aPPV), phacoemulsification cataract excision, intraocular lens implantation, peripheral iridotomy (PI), goniosynechialysis (GSL) (referred to aPPV + P + I + PI + GSL) at Beijing Tongren Hospital from October 2018 to June 2021. The study compared the changes in their visual acuity, intraocular pressure (IOP) and medication requirements between the pre-surgery period and their most recent follow-up visit. RESULTS: The five patients did not report any discomfort, such as pain, tearing, swelling, etc., in their affected eyes, and maintained a stable restoration of the anterior chamber. Among the affected eyes, only one eye demonstrated improved vision during the follow-up visit, while the remaining four eyes did not show any significant improvement. One eye underwent transscleral cyclophotocoagulation as an additional procedure, while the other four eyes did not require any further surgical intervention. In all cases, the intraocular pressure (IOP) was successfully controlled below 30 mmHg. Post-surgery, four eyes still required cycloplegia treatment, and three eyes continued to rely on eye drops to manage their IOP. CONCLUSION: Despite minimal improvement in vision, surgical intervention successfully restored the anterior chamber in malignant glaucoma patients with a prolonged absence of anterior chamber. This restoration contributed to alleviating subjective complaints of discomfort and delaying eyeball atrophy.

Non-syndromic Retinal Degeneration Caused by Pathogenic Variants in Joubert Syndrome Genes.

Inherited retinal degenerations (IRDs) are a group of genetic disorders characterized by progressive dysfunction and loss of photoreceptors. IRDs are classified as non-syndromic or syndromic, depending on whether retinal degeneration manifests alone or in combination with other associated symptoms. Joubert syndrome (JBTS) is a genetically and clinically heterogeneous disorder affecting the central nervous system and other organs and tissues, including the neuroretina. To date, 39 genes have been associated with JBTS, a majority of which encode structural or functional components of the primary cilium, a specialized sensory organelle present in most post-mitotic cells, including photoreceptors. The use of whole exome and IRD panel next-generation sequencing in routine diagnostics of non-syndromic IRD cases led to the discovery of pathogenic variants in JBTS genes that cause photoreceptor loss without other syndromic features. Here, we recapitulate these findings, describing the JBTS gene defects leading to non-syndromic IRDs.

Joubert syndrome: a case report of neonatal presentation and early diagnosis.

BACKGROUND: Joubert syndrome is a rare genetic condition with a prevalence of 1:80,000-1:100,000. In most cases, it shows an autosomal autosomal recessive hereditary pattern, although X-linked and autosomal dominant cases have been described. The distinctive characteristic of this syndrome is the malformation at cerebral and cerebellar levels, known as the "molar tooth sign," hypotonia, and delayed neurodevelopment. CASE REPORT: We describe the case of a newborn with transient tachypnea. However, during hospital stay, he showed other clinical signs not corresponding to the admission diagnosis, such as bradycardia, apneas, hypotonia, and alteration in swallowing mechanics. To rule out etiologies of central origin, we conducted a magnetic resonance of the brain and identified the "molar tooth sign," where the pathognomonic sign of Joubert syndrome. CONCLUSIONS: Rare genetic diseases may manifest as early as the neonatal period with non-specific signs. The early diagnosis of Joubert syndrome is reflected in better pediatric follow-up, which impacts its prognosis and the possibility of improving the patient's quality of life with a multidisciplinary management and genetic counseling.

INTRODUCCIÓN: El síndrome de Joubert es una rara condición genética con una prevalencia de 1:80,000 a 1:100,000. En la mayoría de los casos se presenta con un patrón de herencia autosómica recesiva, aunque se han reporatdo casos ligados al cromosoma X y autosómicos dominantes. La característica distintiva de este síndrome es la malformación a nivel cerebral y del cerebelo conocido como el "signo del molar", hipotonía y retraso en el neurodesarrollo. CASO CLÍNICO: Se describe el caso de un recién nacido con taquipnea transitoria del recién nacido; sin embargo, durante su estancia manifestó otros signos que no correspondían con el diagnóstico de ingreso, como bradicardia, apneas, hipotonía y alteración en la mecánica de la deglución. Para descartar etiologías de origen central, se realizó una resonancia magnética cerebral en la que se detectó el "signo del molar", patognomónico del síndrome de Joubert. CONCLUSIONES: Las enfermedades genéticas raras pueden manifestarse desde el periodo neonatal con signos muy inespecíficos. El diagnóstico precoz del Síndrome de Joubert permite un mejor seguimiento pediátrico que impacta en su pronóstico y en la posibilidad de mejorar la calidad de vida del paciente con un manejo multidisciplinario, así como brindar asesoramiento genético.

The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued.

BACKGROUND: The term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti-Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient. RESULTS: Using a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI. CONCLUSIONS: Our findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA.

Long-term follow-up of patients with extensive segmental infantile hemangioma of the cervical or facial region: A French single-center prospective study.

BACKGROUND: Infantile hemangiomas (IHs) can be part of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies) syndrome when they are segmental, extensive, and located on the face or neck. The initial assessment is codified and well known, but there are no recommendations for the follow-up of these patients. The aim of this study was to assess the long-term prevalence of different associated abnormalities. METHODS: Patients with a history of large segmental IHs of the face or neck. diagnosed between 2011 and 2016 were included in the study. Each patient underwent an ophthalmological, dental, ENT (ear, nose, and throat), dermatological, neuro-pediatric, and radiological assessment at inclusion. Eight patients including five with PHACE syndrome were prospectively evaluated. RESULTS: After a mean follow-up of 8.5 years, three patients presented with an angiomatous aspect of the oral mucosa, two with hearing loss, and two with otoscopic abnormalities. No patients developed ophthalmological abnormalities. The neurological examination was altered in three cases. Brain magnetic resonance imaging follow-up was unchanged in three out four patients and revealed atrophy of the cerebellar vermis in 1 patient. Neurodevelopmental disorders were found in five of the patients and learning difficulties were observed in five patients. The S1 location appears to be associated with a higher risk of neurodevelopmental disorders and cerebellar malformations, while the S3 location was associated with more progressive complications, including neurovascular, cardiovascular, and ENT abnormalities. CONCLUSION: Our study reported late complications in patients with a large segmental IH of the face or neck, whether associated with PHACE syndrome or not, and we proposed an algorithm to optimize the long-term follow-up.

Using in vivo cerebellar electroporation to study neuronal cell proliferation and differentiation in a Joubert syndrome mouse model.

Joubert syndrome (JS) is an autosomal recessive ciliopathy that mainly affects the morphogenesis of the cerebellum and brain stem. To date, mutations in at least 39 genes have been identified in JS; all these gene-encoding proteins are involved in the biogenesis of the primary cilium and centrioles. Recent studies using the mouse model carrying deleted or mutated JS-related genes exhibited cerebellar hypoplasia with a reduction in neurogenesis; however, investigating specific neuronal behaviors during their development in vivo remains challenging. Here, we describe an in vivo cerebellar electroporation technique that can be used to deliver plasmids carrying GFP and/or shRNAs into the major cerebellar cell type, granule neurons, from their progenitor state to their maturation in a spatiotemporal-specific manner. By combining this method with cerebellar immunostaining and EdU incorporation, these approaches enable the investigation of the cell-autonomous effect of JS-related genes in granule neuron progenitors, including the pathogenesis of ectopic neurons and the defects in neuronal differentiation. This approach provides information toward understanding the multifaceted roles of JS-related genes during cerebellar development in vivo.

Clinico-radiologic characteristics of lacrimal sac area swellings misdiagnosed as dacryocystocele or mucocele.

PURPOSE: Several non-lacrimal lesions can present with lacrimal sac area swelling mimicking a dacryocystocele or mucocele with a possibility of misdiagnosis. This study investigates the clinic-radiologic characteristics of the mimicking conditions compared to true lacrimal sac distension. DESIGN: Retrospective, comparative, interventional case series. PARTICIPANTS: Patients referred by primary care ophthalmologists between January 2015 and October 2021 with a misdiagnosis of dacryocystocele or lacrimal sac mucocele (n = 39) and an age-matched group of proven true lacrimal sac swelling (TLS group, n = 44). METHODS: Data collected included demographics, presenting features, investigations, management, histopathology, and outcomes. Both groups were statistically compared for several clinical and radiological variables. RESULTS: Final diagnoses in the mimicking group were skin/subcutaneous swellings (14/39, 35.9%), vascular malformations (10/39, 25.6%), inferomedial anterior orbital cysts (7/39, 17.9%), sino-orbital masses (5/39, 12.8%). Female gender (<0.001), epiphora (p = 0.001), and discharge (p < 0.001) were significantly more frequent in the TLS group. The mimicking group was more likely to be associated with a longer swelling duration (p < 0.001), a swelling extending beyond the lacrimal sac area (p <0.001), orbital signs (p <0.001), and periorbital abnormality. Non-patent lacrimal irrigation (p < 0.001) was significantly more frequent in the TLS group. On imaging, all swellings in the mimicking group were separate from the lacrimal pathway and 94.9% (37/39) extended beyond the lacrimal sac fossa. CONCLUSION: Various cutaneous, subcutaneous, vascular, inferomedial orbital cystic, and sinonasal pathologies can present with lacrimal sac area swelling and mimic a TLS. A high index of suspicion, a thorough clinical evaluation and proper imaging are essential to avoid a misdiagnosis.

New insights into CC2D2A-related Joubert syndrome.

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Cardiac anomalies in Axenfeld-Rieger syndrome.

Axenfeld-Rieger syndrome is a rare multi-system disorder associated with cardiac anomalies. All patients with a diagnosis of Axenfeld-Rieger syndrome were identified from our electronic medical record. Chart review was performed to document the presence and types of CHD. Out of 58 patients, 14 (24.1%) had CHD and a wide variety of cardiac lesions were identified.

Axenfeld-Rieger syndrome: a novel histopathologic finding associated with corneal abnormalities.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is a rare kind of anterior segment dysgenesis (ASD). The most common ocular features of ARS are posterior embryotoxon and iris hypoplasia, while some patients may manifest as corneal opacity and edema. However, the current understanding of how ARS affects the cornea is still incomplete. This study reports a novel histopathological finding of ARS, complicating corneal abnormalities, including congenital corneal opacity and irreversible endothelial decompensation. METHODS: This retrospective study included 6 eyes of 3 ARS patients, 5 of which underwent keratoplasty for irreversible endothelial decompensation from May 2016 to January 2019. No eye had a history of surgery. We reviewed the data of epidemiology, clinical manifestations and histopathologic examinations. RESULTS: Five eyes developed irreversible endothelial decompensation, among which 4 were born with corneal opacity. One eye exhibited transparent cornea but showed a continuous loss of endothelial cells in the absence of surgery and elevated intraocular pressure thereafter. Anterior segment optical coherence tomography photographs showed that anterior synechia existed in the area with corneal opacities, where we found the interlayer splitting of the Descemet membrane inserted by hypoplastic iris and a basement membrane-like structure under a light microscope. CONCLUSION: Anterior synechia might be associated with corneal abnormalities in ARS patients. The novel histopathologic finding revealed the internal relation between anterior segment dysgenesis and would help explore the inner mechanism of corneal abnormalities in ARS.