Novel prenatally diagnosed compound heterozygous PXDN variants in fetal congenital primary aphakia and blepharophimosis.

OBJECTIVE: To precision survey a fetal congenital primary aphakia molecular etiology. CASE REPORT: A case of 42 years old pregnancy woman prenatal diagnostic examination by amniocentesis conducted at 17 weeks' gestation and demonstrated a normal female karyotype. Trio studies based on chromosome microarray analysis (CMA) and Sanger's genetic analysis did not detect a pathologic variant of the FOXE3 gene. Fetal congenital primary aphakia accompanied with microphthalmia detected by sonography in the second trimester (22 weeks). MRI indicated bilateral absence of the lenses, consistent with primary congenital aphakia. Due to the poor prognosis of congenital aphakia, the parents decided to terminate the fetus and provided consent for an autopsy. Pathological analysis revealed dysplasia of the anterior segment of both eyes. However, post fetal mortem extended trio whole exon sequencing (WES) and Sanger's genetic analysis identified compound heterozygous variants in the chromosomal location 2p25.3 in the PXDN gene. CONCLUSION: Extended whole exon sequencing is an important tool to study primary congenital aphakia.

Congenital primary aphakia.

PURPOSE: To describe the natural history, management, and visual outcome in children with congenital primary aphakia (CPA). METHODS: This is a multicenter retrospective consecutive case series from five academic centers in England and North America. RESULTS: A total of 27 eyes of 14 patients were included (male:female, 1.7:1). Thirteen patients had bilateral CPA, and 1 patient had unilateral CPA. Mean age at diagnosis was 18 months (median, 21; range, 0.5-144). Of 11 patients who underwent genetic testing, 9 had FOXE3 pathogenic variants. In all patients, visual acuity at presentation was not better than fixing and following light. Typical findings included silvery appearance of the cornea with vascularization (96%), glaucoma (81%), iridocorneal adhesions (74%), optic nerve coloboma (55%), abnormal vitreous (33%), retinal detachment (30%), and aniridia with hypoplasia of ciliary body (19%). Surgical interventions in select patients included penetrating keratoplasty (PKP), glaucoma drainage device implantation, and cyclophotocoagulation (CPC). CONCLUSIONS: Eyes with corneal ectasia and a silvery appearance of the cornea with vascularization should alert the physician to the possibility of CPA. Glaucoma causes globe enlargement and may increase the risk of corneal perforation, but glaucoma is often refractory to medical treatment, and the threshold for surgical treatment should be low. PKP outcomes are very poor.

Anterior segment alterations in congenital primary aphakia-a clinicopathologic report of five cases.

Purpose: To report the clinicopathological features of corneal buttons in patients with congenital primary aphakia. Methods: Five corneal specimens of five patients with congenital primary aphakia who underwent penetrating keratoplasty (PKP) were studied by light microscopy, and immunohistochemistry with anti-smooth muscle (SMA) antibody. Results: All patients were born from consanguineous parents. Of the five, two patients were identical twins. All eyes were microphthalmic. In four patients, congenital primary aphakia was bilateral and in one patient (Patient 3), it was unilateral. PKP failed in all eyes due to hypotony. Histologically, Bowman's layer was absent in all specimens. The corneal stroma was thin; however, the stromal collagen showed thick and irregularly arranged fibers with neovascularization in all eyes. Descemet's membrane and the corneal endothelium were absent in all specimens. In three specimens, atrophic iris tissue without dilator muscle was adherent to the posterior corneal surface. In addition, anteriorly displaced hypoplastic ciliary body and/or pigmented and non-pigmented ciliary epithelium were attached to the posterior corneal surface in three of the five specimens. SMA staining demonstrated disorganized ciliary muscle in one case. SMA-positive stromal keratocytes demonstrated their myofibroblast nature. Conclusion: The corneal findings in congenital primary aphakia are similar to that seen in other causes of congenital corneal opacification. The anteriorly displaced hypoplastic ciliary body that was partially excised during keratoplasty explains the ocular hypotony in these eyes.

[Assessment of visual acuity in aphakia patient after bilateral cataract removal]. / Ocena ostrosci wzroku u chorej bezsoczewkowej po obustronnym usunieciu zacmy wrodzonej.

Congenital cataracts are lens opacities that are already present at birth or are developing in the first years of life. Treatment consists of the surgical removal of the lens. Bilateral cataract deeply impairs vision, preventing the development of physiological reflex fixation and causes the development of nystagmus about 3 months of age. This nystagmus persists even after the surgical removal of cataracts without allowing often >0,1 visual acuity despite adequate aperture correction. Intraocular lens implants in children under the age of 1 are subject to discussion. Presents the patient's current visual acuity, in which an artificial intraocular lens was not implanted after a congenital cataract removal, retinal detachment, high myopia, glaucoma and persistent nystagmus. The whole treatment and adaptation mechanisms of the patient allowed to obtain surprising visual acuity for near vision without additional eyeglass correction.

Lack of FOXE3 coding mutation in a case of congenital aphakia.

PURPOSE: To report the findings in a patient with congenital primary aphakia, a rare disease known to be caused by mutations in the FOXE3 gene. METHODS: The clinical appearances and visual functions of the patient were determined from the medical records. Genetic analyses were performed to search for mutations in the FOXE3 gene by Sanger sequencing and whole exome sequencing. RESULTS: The 2-month-old male patient first presented with bilateral congenital aphakia associated with microphthalmia, corneal opacity, and dysplasia of the anterior segment. At the age of 2-years, his visual acuity in the left eye was 20/1000 at 30 cm, he was able to discriminate red, blue, and yellow light stimuli, and a b-wave was recorded by scotopic combined rod-cone electroretinograms. The right eye became blind during the follow-up period. No mutation in the FOXE3 gene was detected. CONCLUSION: Although congenital aphakia is known to be caused by mutations in the FOXE3 gene, the results of lack of coding mutation in this patient suggests a possible genetic heterogeneity of the disease.

Congenital anterior staphyloma associated with Peters' anomaly and aphakia in a Holstein calf.

A Holstein calf was born with a large protruding right eye and a central corneal opacity. Enucleation was the first choice of treatment. The calf had a good prognosis and was raised for milking purposes. Macroscopically, the enucleated eye was characterized by the protruded cornea, adherence of the iris to the central posterior cornea and aphakia. Microscopically, central corneal thickening and a defect in the endothelium and Descemet's membrane were observed. These data suggest that this represents a case of unilateral anterior segment dysgenesis consistent with congenital corneal staphyloma with Peters' anomaly and aphakia. Neither a mutation of the WFDC1 gene in multiple ocular defects nor any other identifiable cause for ocular anomalies was detected.

Secondary congenital aphakia.

UNLABELLED: Abstract PURPOSE: We present the clinical, paraclinical and therapeutic features in a patient with secondary congenital aphakia. METHODS: A 2-year-old patient, diagnosed with congenital rubella syndrome including sensorineural deafness, congenital heart disease, intellectual disability, microcephaly, microphthalmia, and congenital cataract, presented to our clinic for the surgical treatment of cataract. RESULTS: During the surgery, the absence of the lens' cortex was observed, hence, the final diagnose was of secondary congenital aphakia. Surgery was then continued with a posterior capsulorhexis and an anterior vitrectomy, deciding to postpone the implantation of the posterior chamber intraocular lens.

Motor skills of children with unilateral visual impairment in the Infant Aphakia Treatment Study.

AIM: To assess motor functioning in children aged 4 years 6 months enrolled in the Infant Aphakia Treatment Study, and to determine contributions of visual acuity and stereopsis to measured motor skills. METHOD: One hundred and four children (53% female) with unilateral aphakia randomized to intraocular lens or contact lens treatment were evaluated at 4 years 6 months (age range 4y 6mo-4y 11mo) for monocular recognition visual acuity, motor skills, and stereopsis by a traveling examiner masked to treatment condition. Motor skills were assessed with the Movement Assessment Battery for Children--Second Edition (MABC-2). Visual acuity was operationalized as log10 of the minimum angle of resolution (logMAR) value for treated eye, best logMAR value for either eye, and intraocular logMAR difference. RESULTS: Student's t-tests showed no significant differences in MABC-2 scores between the intraocular lens and contact lens groups. The mean total score was low (6.43; 18th centile) compared with the normative reference group. Motor functioning was not related to visual acuity in the treated eye or to intraocular logMAR difference, but was predicted in a regression model by the better visual acuity of either eye (usually the fellow eye), even after accounting for the influence of age at surgery, examiner, orthotropic ocular alignment, and stereopsis. INTERPRETATION: Children with unilateral congenital cataract may have delayed motor functioning at 4 years 6 months, which may adversely affect their social and academic functioning.

Dynamic tube movement after reimplantation of Ahmed glaucoma valve in a child with glaucoma in aphakia.

A 10-year-old girl underwent an Ahmed glaucoma valve (AGV) implantation as a primary procedure for glaucoma in aphakia due to congenital cataract surgery. Following an unintended accidental excision of AGV tube during bleb revision for hypertensive phase, AGV was explanted and a second AGV was implanted in the same quadrant after 2 weeks. This resulted in a rare complication of dynamic tube movement in the anterior chamber with tube corneal touch and localised corneal oedema. Excision of the offending unstable tube and placement of a paediatric AGV in a different quadrant led to resolution of this complication, stable vision and well-controlled intraocular pressure. This case highlights the possible causes of dynamic tube, related complications and its management. This case also highlights the importance of understanding the various physiological phases after glaucoma drainage device implantation and their appropriate management.

Comparison of contact lens and intraocular lens correction of monocular aphakia during infancy: a randomized clinical trial of HOTV optotype acuity at age 4.5 years and clinical findings at age 5 years.

IMPORTANCE: The efficacy and safety of primary intraocular lens (IOL) implantation during early infancy is unknown. OBJECTIVE: To compare the visual outcomes of patients optically corrected with contact lenses vs IOLs following unilateral cataract surgery during early infancy. DESIGN, SETTING, AND PARTICIPANTS: The Infant Aphakia Treatment Study is a randomized clinical trial with 5 years of follow-up that involved 114 infants with unilateral congenital cataracts at 12 sites. A traveling examiner assessed visual acuity at age 4.5 years. INTERVENTIONS: Cataract surgery with or without primary IOL implantation. Contact lenses were used to correct aphakia in patients who did not receive IOLs. Treatment was determined through random assignment. MAIN OUTCOMES AND MEASURES: HOTV optotype visual acuity at 4.5 years of age. RESULTS: The median logMAR visual acuity was not significantly different between the treated eyes in the 2 treatment groups (both, 0.90 [20/159]; P = .54). About 50% of treated eyes in both groups had visual acuity less than or equal to 20/200. Significantly more patients in the IOL group had at least 1 adverse event after cataract surgery (contact lens, 56%; IOL, 81%; P = .02). The most common adverse events in the IOL group were lens reproliferation into the visual axis, pupillary membranes, and corectopia. Glaucoma/glaucoma suspect occurred in 35% of treated eyes in the contact lens group vs 28% of eyes in the IOL group (P = .55). Since the initial cataract surgery, significantly more patients in the IOL group have had at least 1 additional intraocular surgery (contact lens, 21%; IOL, 72%; P < .001). CONCLUSIONS AND RELEVANCE: There was no significant difference between the median visual acuity of operated eyes in children who underwent primary IOL implantation and those left aphakic. However, there were significantly more adverse events and additional intraoperative procedures in the IOL group. When operating on an infant younger than 7 months of age with a unilateral cataract, we recommend leaving the eye aphakic and focusing the eye with a contact lens. Primary IOL implantation should be reserved for those infants where, in the opinion of the surgeon, the cost and handling of a contact lens would be so burdensome as to result in significant periods of uncorrected aphakia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00212134

A case of 22q11.2 deletion syndrome with right microphthalmia and left corneal staphyloma.

UNLABELLED: Abstract Background: A microdeletion in the chromosome 22q11.2 (DiGeorge or velocardiofacial syndrome) is the most common human deletion syndrome. Patients with 22q11.2 deletion may have a wide range of ocular findings but severe ocular involvement is uncommon. Here, we describe a 2-year-old boy who had growth retardation, developmental delay, right renal agenesis, ventricular septal defect and severe bilateral ocular anomalies. MATERIALS AND METHODS: The systemic and ocular findings and cranial magnetic resonance imaging study results were reviewed. Fluorescence in situ hybridization analysis was performed on his peripheral blood. RESULTS: The patient presented with the oculodigital sign. On examination, he had severe right microphthalmia with no light perception and his left eye could not fix and follow. The left eye had anterior segment dysgenesis, mild sclerocornea, corneal staphyloma and congenital aphakia. Systemic findings included growth deficiency, microcephaly, micrognathia, ventricular septal defect, atrial septal defect and right renal agenesis. Fluorescence in situ hybridization analysis of this patient was significant for a heterozygous deletion covering DiGeorge critical region 2 and spanning a 250 kb region in the 22q11.2 locus. CONCLUSION: The 22q11.2 deletion syndrome may be associated with severe bilateral ocular malformations including microphthalmia, sclerocornea, corneal staphyloma, anterior segment dysgenesis and congenital aphakia. Corneal staphyloma might have resulted from the oculodigital phenomenon or increased intraocular pressure.

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.

Lens induction requires attenuation of ERK signaling by Nf1.

Aphakia (lack of lens) is a rare human congenital disorder with its genetic etiology largely unknown. Even in model organisms, very few mutations are known to result in such a drastic ocular defect. In this study, we have shown that homozygous deletion of Nf1, the Ras GTPase gene underlying human neurofibromatosis type 1 syndrome, causes lens dysgenesis in mouse. Although early lens specification proceeded normally in Nf1 mutants, lens induction was disrupted due to deficient cell proliferation. Further analysis showed that extracellular signal-regulated kinase (ERK) signaling was initially elevated in the invaginating lens placode, but by the lens vesicle stage, ERK phosphorylation was significantly reduced. Only after intraperitoneal treatment of U0126, an inhibitor of ERK phosphorylation, was lens development restored in Nf1 mutants. Hyperactive Ras-mitogen-activated protein kinase (MAPK) signaling is known to cause neuro-cardiofacial-cutaneous (NCFC) syndromes in humans. As a member of NCFC family genes, Nf1 represents the first example that attenuation of Ras-MAPK kinase signaling pathway is essential for normal lens development.

A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family.

PURPOSE: Aphakia is the complete absence of any lens in the eye, either due to surgical removal of the lens as a result of a perforating wound or ulcer, or due to a congenital anomaly. The purpose of this study was to elucidate the molecular genetics for a large consanguineous Pakistani family with a clear aphakia phenotype. METHODS: The initial homozygosity screening of the family was extended to all the known autosomal recessive cataract loci in order to exclude the possibility of surgical cataract removal leading to aphakia. The screening was performed using polymorphic nucleotide repeat markers, followed by DNA sequencing of a possible candidate gene, the forkhead box protein E3 gene (FOXE3). The identified mutation was counter-checked by a diagnostic restriction enzyme digest of all the family members, and an analysis of the normal population. RESULTS: The initial homozygosity screening of 13 known autosomal recessive loci resulted in negative LOD (logarithm of odds) scores. The aphakia phenotype suggested a mutation in FOXE3 close to the AR-locus 1p34.3-p32.2, and sequence analyses revealed the nonsense mutation c.720C>A, changing cysteine 240 to a stop codon. Segregation in the family was shown by diagnostic restriction enzyme digest, and marker analysis of another aphakia family from Madagascar carrying the same mutation excluded the presence of a founder mutation. Clinical re-examination of the family was not possible due to the escalating security concerns and internal displacement of the population in this region of Pakistan which has prevailed for many months. CONCLUSIONS: FOXE3 is responsible for the early developmental arrest of the lens placode, and the complete loss of a functional FOXE3 protein results in primary aphakia. It can also be deduced that this mutation is quite primitive in origin since the same mutation is responsible for the same phenotypic outcome in two families of geographically different descent.

Aniridia associated with congenital aphakia and secondary glaucoma.

We report a case of aniridia associated with congenital aphakia and secondary glaucoma. A 35-year-old male presented with aniridia, congenital aphakia and secondary glaucoma in both eyes. After an unsuccessful medical management, he underwent trabeculectomy with mitomycin C and anterior vitrectomy under local anesthesia in his left eye. Postoperatively, at the end of six months, intraocular pressure (IOP) in his left eye was controlled without medications. This case highlights the rare association of aniridia with congenital aphakia and secondary glaucoma.