Phacoemulsification in anterior megalophthalmos: rhexis fixation technique for intraocular lens centration.

We describe phacoemulsification in both eyes of a patient with anterior megalophthalmos. Surgery in such cases can be challenging because of a deep anterior chamber, enlarged ciliary ring, weakened zonules, and large capsular bag. Phacoemulsification performed through a scleral tunnel resulted in a stable wound. We report the use of anterior optic capture technique (optic within the capsulorhexis margin, haptics in the sulcus) for successful intraocular lens implant centration.

Amniotic bands as a cause of congenital anterior staphyloma.

BACKGROUND: Congenital anterior staphyloma is a rare, complex malformation syndrome of the anterior segment. Only a few reports on associated systemic malformations have been published. We herein present a rare manifestation of congenital anterior staphyloma (CAS) combined with amniotic band disruption syndrome (ABS). PATIENT AND METHODS: Shortly after birth, a massive enlargement of the left eye was observed in a female child. Furthermore, an extensive bilateral congenital cleft lip and cleft alveolar ridge with oblique facial cleft extending into the left medial canthal region, coloboma(s) of the left eyelids, extensive adhesions between lids and eye bulb, as well as circumferential grooves, clubfeet, and terminal transverse defects in both hands and feet were present. Due to severe progression of eye bulb protrusion with thinning of the sclera, enucleation of the left eye was performed at the age of 3 years in order to prevent complications including perforation of the globe and with the aim of improving cosmetic aspects. RESULTS: Histopathological examination of the enucleated eye disclosed findings typical of congenital anterior staphyloma, including massive corneal staphylomatic deformation with superficial vascularization and elapsed corneoscleral margin, destruction of Bowman's layer, absence of Descemet's layer, corneal endothelium, and angle structures. The lens was only partially formed, and had mainly dissolved. The neural retina appeared normal. The optic nerve disc revealed a pronounced excavation. Facial clefts, lid colobomas, congenital constriction bands, and amputation of distal limbs match ABS. This malformation complex develops in early pregnancy, probably prior to 35 days post conception. CONCLUSION: This is the first report on an association of these two rare complex congenital malformations, congenital anterior staphyloma and amniotic band syndrome. The anterior staphyloma was unilateral, and related to facial clefts and lid coloboma in the area adjacent to the anterior staphyloma. Furthermore, the systemic deformities are clearly due to the amniotic bands, and the timing of the development of both complex malformations seems to be similar. All findings suggest that the presence of amniotic bands is a causative factor for all observed abnormalities including anterior staphyloma.

Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome.

Rieger syndrome (RIEG) is an autosomal-dominant human disorder that includes anomalies of the anterior chamber of the eye, dental hypoplasia and a protuberant umbilicus. We report the human cDNA and genomic characterization of a new homeobox gene, RIEG, causing this disorder. Six mutations in RIEG were found in individuals with the disorder. The cDNA sequence of Rieg, the murine homologue of RIEG, has also been isolated and shows strong homology with the human sequence. In mouse embryos Rieg mRNA localized in the periocular mesenchyme, maxillary and mandibular epithelia, and umbilicus, all consistent with RIEG abnormalities. The gene is also expressed in Rathke's pouch, vitelline vessels and the limb mesenchyme. RIEG characterization provides opportunities for understanding ocular, dental and umbilical development and the pleiotropic interactions of pituitary and limb morphogenesis.

Maternal treatment with opioid analgesics and risk for birth defects.

OBJECTIVE: We examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with birth defects. STUDY DESIGN: The National Birth Defects Prevention Study (1997 through 2005) is an ongoing population-based case-control study. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIS) for birth defects categories with at least 200 case infants or at least 4 exposed case infants. RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects (OR, 2.7; 95% CI, 1.1-6.3), atrioventricular septal defects (OR, 2.0; 95% CI, 1.2-3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4-4.1), spina bifida (OR, 2.0; 95% CI, 1.3-3.2), or gastroschisis (OR, 1.8; 95% CI, 1.1-2.9) in infants. CONCLUSION: Consistent with some previous investigations, our study shows an association between early pregnancy maternal opioid analgesic treatment and certain birth defects. This information should be considered by women and their physicians who are making treatment decisions during pregnancy.

FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A.

Mutations in the human FOXC1 transcription factor gene underlie Axenfeld-Rieger (AR) syndrome, a disorder characterized by anterior segment malformations in the eye and glaucoma. Through the use of an inducible FOXC1 protein, along with an intermediate protein synthesis blocker, we have determined direct targets of FOXC1 transcriptional regulation. FOXC1 regulates the expression of FOXO1A and binds to a conserved element in the FOXO1A promoter in vivo. The zebrafish foxO1a orthologs exhibit a robust expression pattern in the periocular mesenchyme. Furthermore, FOXO1A expression is reduced in cultured human trabecular meshwork (TM) cells and in the zebrafish developing eye when FOXC1 expression is knocked down by siRNAs and morpholino antisense oliognucleotides, respectively. We also demonstrate that reduced FOXC1 expression increases cell death in cultured TM cells in response to oxidative stress, and increases cell death in the developing zebrafish eye. These studies have uncovered a novel role for FOXC1 as an essential mediator of cellular homeostasis in the eye and indicate that a decreased resistance to oxidative stress may underlie AR-glaucoma pathogenesis. Given that FOXO1A influences cellular homeostasis when positively or negatively regulated; the dysregulation of FOXO1A activities in the eye through FOXC1 loss of function mutations and FOXC1 gene duplications provides an explanation into how seemingly similar human disorders can arise from both increases and decreases in FOXC1 gene dose.

Arginine to Glutamine Variant in Olfactomedin Like 3 (OLFML3) Is a Candidate for Severe Goniodysgenesis and Glaucoma in the Border Collie Dog Breed.

Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (Canis lupus familiaris), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and have subsequently been found in this breed in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine single nucleotide variant genotyping chip was used to identify a candidate genetic region. There was a highly significant peak of association over chromosome 17, with a p-value of 2 × 10-13 Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Whole genome sequences of three dogs with glaucoma, three severely affected by goniodysgenesis and three unaffected dogs identified a missense variant in the olfactomedin like 3 (OLFML3) gene in all six affected animals. This was homozygous for the risk allele in all nine cases with glaucoma and 12 of 14 other severely affected animals. Of 67 reportedly unaffected animals, only one was homozygous for this variant (offspring of parents both with goniodysgenesis who were also homozygous for the variant). Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. The identification of a candidate genetic region and putative causative variant will aid breeders to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population.

Factors influencing pupil behaviour during femtosecond laser assisted cataract surgery.

AIM: Femtosecond laser assisted cataract surgery is associated with pupillary constriction. This study aims to look at patient and surgical factors predisposing to abnormal pupil behaviour during FLACS. METHODS: This prospective observational study included all patients undergoing FLACS in the Princess of Wales Hospital, Bridgend, UK between February and June 2017. Pupils were measured at three time points; immediately before and after laser pre-treatment, and at the start of surgery. Pupil behaviour during surgery was noted in descriptive terms, patient demographic, co-morbidities, eye measurements, suction on time, shifting time and laser energy levels were recorded. RESULTS: Seventy-three eyes were included. Average patient age was 74.84 ±â€¯9.1 years. Mean horizontal pupil sizes immediately before and after femto pre-treatment were 7.87 ±â€¯0.87 mm and 7.7 ±â€¯0.89 mm respectively (P < 0.0005). Mean horizontal pupil size at the start of surgery was 6.83 ±â€¯1.43 mm (P < 0.0005). Short capsulotomy-pupil distance (P = 0.01), shallower anterior chamber (P = 0.0012), smaller pre-operative pupil size (P = 0.045) and longer suction on time (P = 0.0019) were significantly associated with intra-operative miosis during FLACS. Sustained mydriasis was observed in eyes in whom topical diclofenac was used within 2 h of surgery. CONCLUSIONS: FLACS can result in significant pupil miosis. Eyes particularly at risk are ones with smaller pre-operative pupils and shallower anterior chambers and those subjected to longer suction on time. Well-timed NSAIDs application could be protective against this phenomenon.

Iridogoniodysgenesis: A Challenging Case.

Iridogoniodysgenesis is a rare autosomal dominant disorder affecting anterior segment of the eye. Fifty percent cases of iridogoniodysgenesis have glaucoma, which is particularly difficult to manage. We report here a case of 40 years old man with this rare disorder, presenting to our glaucoma department. It was characterised by iris hypoplasia and juvenile glaucoma. To stop fluctuation in his intraocular pressure (IOP) and to save his vision from glaucomatous damage, our team had to do three different surgical procedures, i.e. trabeculectomy with F5U, diode laser cycloablation and aqueous shunt procedure, over a period of 10 months. This case report discusses management of glaucoma in this particular patient and challenges faced during the treatment. Regular follow-up and timely intervention can save such patients from complete blindness. To authors' knowledge, this is the first reported case of iridogoniodysgenesis in Pakistan.

Perinatal ablation of the mouse lens causes multiple anterior chamber defects.

PURPOSE: The purpose of this study was to reassess the role of the lens as an "embryonic organizer" of ocular tissues. METHODS: We ablated the lens in mice by lens-specific expression of an attenuated version of diphtheria toxin A subunit(Tox176) driven by a modified crystallin promoter. Alterations in the differentiation programs of ocular tissues were examined by hematoxylin and eosin staining, in situ hybridization, and immunohistochemistry. RESULTS: Transgenic mice in the family OVE1757 exhibited severe microphakia. Apoptotic lens fibers were seen by embryonic day 15 (E15) and the lenses were completely ablated by post natal day 8. Multiple defects were seen in the anterior chamber. Corneal endothelial cells did not differentiate properly. The mesenchymal cells that would normally give rise to the endothelial layer were found to express N-cadherin, but they failed to form tight junctions and undergo a mesenchymal-to-epithelial transition. Although early specification of the presumptive ciliary body and iris was detected, subsequent differentiation of the iris was blocked. No dramatic changes were seen in the development of the retina. CONCLUSIONS: These results support the hypothesis that an intact lens is essential for proper differentiation of both the corneal endothelium and the iris and that the lens "organizes" the development of tissues in the anterior chamber.

Abnormal iris processes may be a marker of glaucoma gene carrier status in some cases of primary infantile glaucoma.

PURPOSE: To report the presence of dense and abnormal iris processes in the unaffected parents and sibling of a non consanguineous family where 3 children out of 4 suffer from primary infantile glaucoma (PIG). METHODS: A descriptive case report. All family members were clinically characterized. Candidate gene screening and chromosome analysis were also performed. RESULTS: The 3 children with PIG displayed a spectrum of anterior chamber angle anomalies with the absence of posterior embryotoxon and iridotrabeculodysgenesis abnormalities. Unaffected family members had dense and abnormal iris processes but no features of glaucoma. Candidate gene screening and chromosome analysis were normal. CONCLUSION: Iris processes indicate angle maldevelopment and may signify carrier status of an autosomal recessive glaucoma gene. Identification of iris processes in relatives of PIG children is a useful clinical sign that may be of benefit for genetic counseling and risk stratification purposes.

Cataract surgery and anterior megalophthalmos: custom intraocular lens and special considerations.

We report a patient who presented with anterior megalophthalmos: corneal diameter of nearly 17.0 mm, anterior chamber depth of 7.0 mm, mild lens subluxation, and nuclear sclerotic cataract. Surgical management consisted of a scleral tunnel incision, capsule staining, a predetermined capsulorhexis size, microcoaxial phacoemulsification with torsional ultrasound, and implantation of a custom IOL to ensure endocapsular fixation. Special consideration must be given to the patient with a very large anterior segment.

Bilateral prominent schwalbe ring in the anterior chamber in a patient with axenfeld-rieger syndrome and megalocornea.

PURPOSE: To report the unusual presentation of bilateral Schwalbe rings suspended in the anterior chambers of a patient with Axenfeld-Rieger syndrome. METHODS: A 37-year-old man with bilateral decreasing visual acuity underwent slit-lamp examination, dark room gonioscopy, and photographic documentation. RESULTS: Prominent bilateral Schwalbe rings and peripheral iridocorneal strands were observed in both anterior chambers. No systemic abnormalities were found. CONCLUSIONS: The position of the Schwalbe ring in patients with Axenfeld-Rieger syndrome can vary in appearance from almost normal to displaced markedly. It remains to be seen whether these variations reflect genetic differences.

Familial ectopia lentis with Axenfeld-Rieger anomaly.

Three siblings with ectopia lentis were examined for associated abnormalities. Case 1 had Axenfeld-Rieger anomaly and retinal detachment. Case 2 had Axenfeld-Rieger anomaly, ciliary staphyloma, and glaucoma. Case 3 had no associated ocular abnormality. The parents had normal eyesight. This is the first report of ectopia lentis associated with Axenfeld-Rieger anomaly. The mode of inheritance is likely autosomal recessive.

A rare case of cleft number nine associated with atypical cleft number two.

The incidence of the craniofacial cleft is rare ranging between 1.43 and 4.85/100,000 births. Tessier number nine cleft being the rarest, there are a few reports of detailed ophthalmologic examinations performed in them. In this study, 1-day-old female neonate delivered by normal vaginal delivery at term, weighing 1480 g presented with right eye dystopia, cleft extending through the lateral third of the upper eyelid, brow ending at the temporal region, conjunctival congestion, clear cornea 10 mm in diameter, normal anterior chamber, pupil 2 mm reactive to light, clear lens, and normal fundus. Cleft extended downward from the right medial canthus involving the nasal ala and left forearm had an oblique-crease with camptodactyly. We thus report a case of anterior segment abnormality with an oblique craniofacial cleft. The cause of which is unclear, amniotic band syndrome being a possible cause.

Identification of four new PITX2 gene mutations in patients with Axenfeld-Rieger syndrome.

PURPOSE: Axenfeld Rieger syndrome (ARS) is an autosomal dominant inherited disorder affecting development of the ocular anterior chamber, abdomen, teeth and facial structures. The PITX2 gene is a major gene encoding a major transcription factor associated with ARS. METHODS: ARS patients were collected from six unrelated families. Patients and their families were ophthalmologically phenotyped and their blood was collected for DNA extraction. We screened the coding region of human PITX2 gene by direct sequencing. The consequences of the mutations described were investigated by generating crystallographic representations of the amino acid changes. In order to better understand the occurrence of glaucoma in ARS patients, we studied the PITX2 gene expression in human embryonic and fetal ocular tissue sections. RESULTS: We identified four novel PITX2 genetic alterations in four unrelated families with ARS. These mutations included two nonsense mutations (E55X and Y121X), an eight nucleotides insertion (1251 ins CGACTCCT) and a substitution (F58L), in familial and sporadic cases of ARS. We also showed for the first time that PITX2 is expressed at early stages of the human embryonic and fetal periocular mesenchyme, as well as at later stages of human development in the fetal ciliary body, ciliary processes, irido corneal angle and corneal endothelium. The human fetal eye PITX2 gene expression pattern reported here for the first time provides a strong basis for explaining the frequent occurrence of glaucoma in patients affected by PITX2 gene mutations. CONCLUSIONS: Two mutations identified affect the homeodomain (E55X and F58L). The E55X nonsense mutation is likely to alter dramatically the DNA-binding capabilities of the PITX2 homeodomain. Furthermore, there is a complete loss of the carboxy-terminal part of the PITX2 protein beyond the site of the mutation. The phenylalanine F58 is known to contribute to the hydrophobic network of the homeodomain. The crystallographic representations of the mutation F58L show that this mutation may change the conformation of the helical core. The F58L mutation is very likely to modify the homeodomain conformation and probably alters the DNA binding properties of PITX2. The other mutations (Y121X and the eight-nucleotide insertion (1251 ins CGA CTC CT) CGA CTC CT, at position 224 in PITX2A) result in partial loss of the C-terminal domain of PITX2. Pitx2 synergistically transactivates the prolactin promoter in the presence of the POU homeodomain protein Pit-1. Pitx2 activity is regulated by its own C-terminal tail. This region contains a highly conserved 14-amino-acid element involved in protein-protein interactions. The C-terminal 39-amino-acid tail represses DNA binding activity and is required for Pitx2 interactions with other transcription factors, for Pitx2-Pit-1 interaction and Pit-1synergism. Pit-1 interaction with the Pitx2 C terminus masks the inhibitory effect and promotes increased DNA binding activity. Thus, the partial or complete loss of the C terminus tail can lead to decreased or absent DNA binding activity and trigger severe ARS phenotypes. Our in situ hybridization results obtained on human embryonic and fetal ocular tissue sections constitute the first molecular histological data providing an explanation for the occurrence of precocious glaucoma in human patients affected by ARS caused by PITX2 mutations. Further structural and biochemical studies are needed for understanding the wide spectrum of clinical phenotypes caused by the increasing number of new PITX2 mutations found in ARS affected patients.

Genotype and phenotype correlations in congenital glaucoma: CYP1B1 mutations, goniodysgenesis, and clinical characteristics.

PURPOSE: To determine whether there is a correlation among mutations in the cytochrome P4501B1 gene (CYP1B1), the degree of angle dysgenesis observed histologically, and disease severity in congenital glaucoma. DESIGN: Interventional case series. METHODS: Direct DNA sequencing was used to screen six unrelated children with congenital glaucoma, each set of parents, and all siblings for CYP1B1 mutations. Specimens of the anterior chamber angle obtained at trabeculectomy were examined histologically to identify abnormalities of the aqueous outflow pathway. CYP1B1 mutations were correlated with both the degree of angle dysgenesis and the patients' disease severity (age at diagnosis, difficulty in achieving intraocular pressure [IOP]) control. RESULTS: Four (66.7%) of the six patients were compound heterozygotes for mutations in the CYP1B1 gene. Seven of the eight CYP1B1 mutations were identified, including two novel mutations (R117P, C209R) and five others previously described (G61E, R368H, R390H, E229K, 4340delG). The cases were divided on the basis of histological phenotype into categories of (1) severe goniodysgenesis highlighted by the agenesis of the canal of Schlemm (two patients), (2) moderate goniodysgenesis characterized by the presence of a band of collagenous tissue (CT) in the trabecular meshwork (TM) and/or the juxtacanalicular tissues (JXT) (three patients), and (3) mild goniodysgenesis with deposition of a mucopolysaccharide material in the JXT (one patient). CYP1B1 mutations were identified in both cases of severe angle dysgenesis and two of three cases of moderate dysgenesis. Disease severity closely correlated with the degree of angle dysgenesis. CONCLUSIONS: Most patients in our cohort had compound heterozygous CYP1B1 mutations. Specific CYP1B1 mutations may be associated with severe or moderate angle abnormalities.

Congenital hypothyroidism in Peters plus syndrome.

Peters plus syndrome is a multiple malformation syndrome characterized by a combination of Peters anomaly of the eye and other extraocular defects, including short-limb dwarfism, a thin upper lip, hypoplastic columella, and a round face. Two unrelated children with the typical features of Peters plus syndrome and hypothyroidism have been previously reported in medical literature. Herein, we report a male patient who exhibited the Peters plus syndrome phenotype as well as hypothyroidism and provide further evidence that hypothyroidism may represent an under-recognized feature of Peters plus syndrome. The consanguinity of the parents in the present case supports, but does not confirm, the notion that a homozygous defect in a single autosomal recessive gene might be responsible for the normal morphogenesis of both the anterior chamber and the thyroid gland.

Peters anomaly in association with multiple midline anomalies and a familial chromosome 4 inversion.

We describe the clinical presentation of a boy with Peters anomaly and a cataract of the left eye in association with multiple midline defects. His extraocular developmental abnormalities include cleft lip and palate, cardiac anomalies, an atretic cranial meningocele, as well as malformation of the left ear with chronic otitis media. Genetic analysis revealed a balanced paracentric inversion of chromosome 4, inv(4)(q12q13.3), also present in his asymptomatic father and siblings. His normal stature and cognitive development distinguish this case from the Peters Plus syndrome. The presence of a cranial meningocele represents a new association with Peters anomaly.

Phacoemulsification in anterior megalophthalmos.

This case outlines the phacoemulsification technique used to overcome the challenge of the hyperdeep anterior chamber, weak zonules, abnormal anterior capsule, and large capsular bag. Key steps included trypan blue staining of the anterior capsule, a large capsulorhexis, prolapse of the nucleus into the anterior chamber with phacoemulsification anterior to the capsulorhexis, and a posterior chamber-placed iris-clip intraocular lens. Successful visual rehabilitation is achievable in these anatomically challenging eyes.

Strabismus and amblyopia in bilateral Peters anomaly.

BACKGROUND: Peters anomaly is a rare form of anterior segment dysgenesis in which abnormal cleavage of the anterior chamber occurs at the end of the third week of gestation. We examined the prevalence of strabismus and amblyopia and analyzed predictive factors for their development, as well as the visual outcome and associated anomalies in patients with bilateral Peters anomaly. METHODS: Using a retrospective review, we identified 25 consecutive patients with bilateral Peters anomaly who were observed between August 1995 and February 2005. Ocular structural and systemic anomalies, amblyopia therapy, visual acuity, and binocular alignment at last visit were recorded. Fisher's exact test was used to identify any association between defined predictive factors and the development of strabismus. RESULTS: Mean follow-up time was 5.1 year (range, 0.5-21 years). Median age at presentation was 2.5 months (range, 1 day to 13 years). Penetrating keratoplasties were performed on 34 eyes in 20 patients. Final best-corrected visual acuity ranged from 20/25 to no light perception. Thirteen of 18 patients with recorded motility (72%) developed strabismus: esotropia (n = 7), exotropia (n = 5), and variable (n = 1); one also had dissociated vertical deviation. Patients with equal vision were either orthophoric (n = 4) or had intermittent esotropia (n = 1), whereas strabismus occurred in 100% of patients whose vision was asymmetric by more than 1.5 octaves. Asymmetric vision was the only statistically significant predictive factor for the development of strabismus (P = 0.002). Amblyopia treatment resulted in improved vision in 3 of 5 patients. CONCLUSION: Strabismus occurs frequently in bilateral Peters anomaly. Asymmetric vision, (because of ocular structural anomalies) postoperative complications, and amblyopia may predispose to strabismus. Despite ocular structural limitations, amblyopia therapy is recommended in the aggressive rehabilitation of these eyes.