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Aniridia syndrome
Introduction
Aniridia syndrome (OMIM 106210) is a rare multisystem disorder with a prevalence of 1:40,000 to 1:72,000. It is inherited in an autosomal dominant manner in about two-thirds of cases, with the remainder being sporadic. The condition is caused by heterozygous loss-of-function mutations or deletions in the PAX6 gene or in nearby regulatory elements that control PAX6 expression. Patients are often diagnosed in early infancy because of the associated pan-ocular anomalies such as iris hypoplasia (aniridia), nystagmus, foveal hypoplasia, ptosis, and visual impairment. Due to the progressive nature of ocular disease, the associated systemic abnormalities and frequent complications, the management of this condition requires a multidisciplinary approach involving pediatricians, ophthalmologists, and medical geneticists. Despite the wide phenotypic spectrum, even within the same family, an achievable goal for each patient is to maximize and maintain their visual capacity as much as possible.
Clinical presentation
Aniridia syndrome typically presents at birth or in early infancy with variable iris hypoplasia, and nystagmus becomes apparent by 6 weeks of age in about 83%–95% of cases. Foveal hypoplasia, observed by a reduced foveal reflex, is seen in about 80% of cases. Secondary to either foveal hypoplasia or optic nerve hypoplasia, best-corrected visual acuity ranges from 20/100 to 20/200. Other ocular abnormalities include dry eye (53%) and strabismic amblyopia (31%). In the majority of cases progressive vision loss occurs primarily due to cataracts (65%–85%), glaucoma (46%), and keratopathy (20%–45%) with progressive corneal opacification. In some patients systemic abnormalities have been observed, including brain anomalies, olfactory defects, hearing defects, obesity, and diabetes. Aniridia also presents with a number of different syndromes, including WAGR syndrome (Wilms tumour, aniridia, genitourinary malformations, and mental retardation), WAGRO syndrome (WAGR plus obesity), and Gillespie syndrome (atypical aniridia, cerebellar-ataxia, and mental-retardation).
Iris abnormalities
Iris hypoplasia is the distinguishing feature ranging from minor iris pigment defects to almost complete absence of iris tissue ( Fig. 38.1 ). In the most severe cases there is only residual iris root tissue observed by gonioscopy or anterior segment optical coherence tomography (OCT). However, in milder cases the pupil may look normal sized with only transillumination defects. 15 Some patients present with pupillary defects such as partial iris coloboma, eccentric or misshapen pupils, or iris ectropion.
Foveal architecture
Foveal hypoplasia ( Fig. 38.2 ) is a very common finding associated with reduced visual acuity and nystagmus. On fundoscopy, there is a decreased or absent foveal reflex and in some cases blood vessels cross into the foveal avascular zone. A grading system has been developed based on the morphologic findings observed by spectral-domain OCT, which relates to the stage at which development of the foveal region was arrested.
Lens opacity
Small lens opacities are often found in infancy; however, most patients develop significant dense cataracts in early adulthood. Based on histopathology, the anterior lens capsule tends to be thin and fragile, and this is often combined with poor zonular stability, making cataract surgery a challenge. In some patients a persistent pupillary membrane is present, or vascularization of the anterior lens capsule is observed. An uncommon finding is ectopia lentis or lens subluxation (see Fig. 38.1 ).
Increased intraocular pressure
Increased intraocular pressure generally develops in late childhood or early adulthood, although it can be present in infancy if there is an underdeveloped Schlemm’s canal or goniodysgenesis. During infancy the anterior chamber angle appears to be open, however over time synechiae form connections between the iris stroma and the angle wall. This abnormal tissue obscures the trabecular meshwork and blocks the aqueous outflow resulting in angle closure glaucoma.
Keratopathy
Although aniridia-associated keratopathy (AAK) occurs in up to 45% of patients, ocular surface abnormalities are found in up to 90% of patients. Limbal stem cell deficiency, abnormal cellular adhesion, impaired healing response and infiltration of conjunctival cells result in progressive corneal defects. In addition, an abnormal tear film coupled with meibomian gland dysfunction causes chronic dry eyes. A ring of avascular fibrous pannus in the peripheral corneal epithelium over time becomes vascularized and advances into the central cornea until the whole cornea is affected (see Fig. 38.1B ). Increased corneal thickness has also been documented and may result in incorrect estimates of intraocular pressure. Patients with AAK experience redness, dryness, recurrent corneal erosions, ulceration, and blurred vision that is often chronic. Eventually, in most patients, the keratopathy causes stromal scarring with corneal decompensation and opacification.
Optic nerve
The optic nerve is affected in about 10% of patients either as optic nerve hypoplasia, where the optic nerve head is smaller than normal, or as an optic disc coloboma, where the optic disc is malformed. Most commonly, optic disc cupping is seen due to associated glaucoma.
Aniridia fibrosis syndrome
Aniridia fibrosis syndrome is a complication of intraocular surgery thought to occur when intraocular devices such as intraocular lenses or drainage tubes come into contact with immature vasculature on the abnormal iris root seen in aniridia. It is most common after cataract surgery. Biomicroscopy reveals fibrovascular sheets extending from the iris root to cover the anterior and posterior lens epithelium. This can result in intraocular lens migration forward to touch the corneal endothelium. In more advanced cases fibrovascular membranes can be seen to cover the back of the cornea. Corneal decompensation is common in advanced cases. The fibrotic membranes can also spread over the ciliary body resulting in hypotony and also over the peripheral retina resulting in traction retinal detachment ( Fig. 38.3 ). Untreated aniridic fibrosis syndrome can result in phthisis.
Systemic features
Aniridia can occur with many systemic, non-ocular features. Developmental abnormalities of the CNS include absence or hypoplasia of the anterior commissure, anterior cingulate cortex, cerebellum, temporal and occipital lobes, pineal gland, corpus callosum, and olfactory bulb ( Fig. 38.4 ). These abnormalities can cause sleep disturbances due to lack of melatonin from the pineal gland, hearing difficulties due to auditory processing defects because of abnormal interhemispheric transfer, reduced olfaction, reduced cognition, behavioral problems, and developmental delay. Increased average body mass index, obesity, and hyperphagia are also common findings. A subset of aniridia patients have mild glucose intolerance with impaired insulin secretion; this is related to the pancreatic requirement for PAX6 to function throughout life.
WAGR syndrome (OMIM 194072)
Approximately 30% of patients diagnosed with sporadic aniridia have WAGR syndrome. This phenotype is caused by large chromosome 11p13 deletions encompassing all or part of PAX6 , WT1 , and other nearby genes. Patients with WAGR are at a high risk (50%–70%) of developing Wilms tumor and exhibit genitourinary abnormalities (60%), intellectual disability/behavioral disorders (70%), neurological abnormalities (30%), and obesity (WAGRO syndrome).
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