Caroline Thaung

A Dominant-Negative Mutation of Mouse Lmx1b Causes Glaucoma and Is Semi-lethal via LBD1-Mediated Dimerisation

Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice.

Isolated Diffuse Episcleral Neurofibroma

Abstract Aims: To report a rare case of isolated diffuse episcleral neurofibroma and to discuss possible differential diagnoses. Case report: A 37 year old Caucasian female was found to have an epibulbar tumour arising from the superior aspect of her left eye. Clinical examination revealed a 12 mm × 8 mm “salmon pink” coloured lesion. Results: A biopsy was performed and histopathologic examination and subsequent systemic evaluation showed it to be a rare case of isolated diffuse episcleral neurofibroma. Conclusion: There are many differential diagnoses for an epibulbar lesion and neurofibroma should be added to these. Even though a small risk of malignant transformation exists, we recommend a conservative approach for slow growing lesions.

Detection of extrascleral extension in uveal melanoma with histopathological correlation

ABSTRACT Purpose: Uveal melanoma is the most common primary intraocular malignancy. Extrascleral extension (ESE) is rare, but associated with an increased rate of orbital recurrence and an overall poor prognosis. Clinical studies show low rates when compared with histological studies. Due to the prognostic importance of ESE, we sought to compare our clinical, intraoperative, and histological detection rates. Design: A retrospective cross-sectional case series. Methods: A list of eyes enucleated for uveal melanoma was compiled from the admissions records of the London Ocular Oncology Service during the 28-month period, i.e. January 2010–April 2012. The surgical and clinical notes of patients with histopathology proven ESE were reviewed to determine when it was first diagnosed or suspected. The subsequent management of these cases is discussed. Results: A total of 16 out of 174 (9%) eyes had histologically proven ESE. Eight of 16 cases were detected preoperatively at clinical examination, including the use of ocular ultrasound, 3 of 16 were discovered intra-operatively, and 5 of 16 deemed microscopic ESE, were first detected on histological examination. Seven of 7 (100%) of cases with anterior ESE were detected clinically by slit lamp biomicroscopy, while only 1 out of 9 (11%) of cases with posterior ESE was detected preoperatively with ultrasound. Conclusions: Slit lamp biomicroscopy is sensitive for detecting anterior ESE. Most posterior ESE is microscopic, but macroscopic posterior ESE may also be missed by B-scan ocular ultrasound. Orbital surgeons should be suspicious of clinically undetected posterior ESE, and consider adjuvant orbital radiotherapy in cases with macroscopic ESE.

Longitudinal changes in corneal leucocyte density in vivo following transplantation

Aims To prospectively evaluate the changes in corneal leucocyte density with in vivo confocal microscopy (IVCM) following transplantation and to determine if leucocyte density post-transplant is an indicator of graft rejection risk. Methods IVCM imaging of cornea pre-transplant and post-transplant at 1 week, 1, 3 and 12 months. The changes in leucocyte density associated with diagnosis, vascularisation, type of keratoplasty, topical steroid and immunosuppression treatment, allograft rejection and failure within 4 years post-transplant were analysed. Results Sub-basal nerve plexus total central leucocyte density (SBNP-TCLD) varied with diagnosis (p<0.001), interval post-transplant (p<0.001), degree of vascularisation (p=0.001) and rejection episodes in eyes off topical steroid (p=0.01). The highest SBNP-TCLD was found in eyes with inflammation pre-transplant. Mean 12-month SBNP-TCLD in eyes which had rejection episodes was almost double that in eyes which did not (79.0 and 39.8 cells/mm2, respectively). SBNP-TCLD >63.5 cells/mm2 was associated with a higher risk of rejection within 1 year (p=0.04) and 4 years (p=0.007). Changes in leucocyte density on the donor endothelium significantly differed between penetrating keratoplasty and deep anterior lamellar keratoplasty grafts (p<0.01) and in those in which rejection episodes were observed (p<0.001). Conclusions Leucocyte density varies with corneal diagnosis, extent of vascularisation and interval post-transplant. Topical steroid treatment is associated with reduced leucocyte density and risk of graft rejection. Higher endothelium leucocyte density correlates significantly with previous or subsequent rejection episodes. Leucocyte density measurement by IVCM may be useful in identifying transplants at risk of rejection.

Nonteratoid Medulloepithelioma Presenting in a 78-Year-Old Male

Background: Medulloepithelioma is a rare congenital neoplasm derived from precursors of the nonpigmented ciliary epithelium of the ciliary body. The average patient age at clinical presentation is 3.8 years. Case Presentation: We present the case of a 78-year-old male with progressive lens subluxation and ocular hypertension who was found to have a ciliary body mass. After enucleation for presumed ciliary body melanoma, histopathology showed a nonteratoid medulloepithelioma. Cytogenetic analysis revealed abnormalities in chromosomes 3 and 8. Conclusion: Medulloepithelioma is often initially misdiagnosed. Though congenital in nature, it can exhibit rapid growth, have chromosomal abnormalities, and must be considered in all age groups.

Classification of Retinal and Retinal Pigment Epithelium Tumors

Tumor classification is important as it creates a common terminology that allows clinicians and researchers to accurately communicate, thus facilitating diagnosis by helping the clinician to include all conditions that are relevant in a differential diagnosis. Classification allows us to draw historical, international, or multicenter clinical and biological comparisons, thus improving our ability to understand the natural course of tumors and facilitate research into new treatments. In this chapter, the term “tumor” is used in its broadest sense as a mass without implication to its pathogenesis or its neoplastic or malignant properties.