Young woman presents with iris cyst
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A 26-year-old woman was referred to the New England Eye Center Cornea Department for evaluation of a cystic iris lesion noted on routine exam. She was asymptomatic at the time of the visit.
The patient had a medical history of migraines, vertigo, borderline sensorineural hearing loss in both ears, a single kidney and microdontia.
Source: William Warr Binotti, MD, and Helen K. Wu, MD
Examination
Best corrected visual acuity was 20/25 in the right eye and 20/20 in the left eye. IOP was 14 mm Hg in the right eye and 15 mm Hg in the left eye. The patient had telecanthus on external exam. Anterior segment exam showed corectopia with temporal displacement of the pupil in the right eye (Figure 1a). Posterior embryotoxon, iris hypoplasia and iridocorneal bands were also noted in the right eye (Figures 1a and 1b). There was also a 1-mm posterior iris cyst at 9 o’clock that was mildly pigmented but transilluminated on slit lamp exam (Figure 1c). The left eye showed posterior embryotoxon and iris hypoplasia (Figure 2). Besides the area of the cyst in the right eye, a 360° embryotoxon with iris processes was visible on gonioscopy of both eyes. Dilated fundus exam showed 0.1 cup-to-disc ratio, inferior scleral crescent and preserved optic nerve rims of both eyes with no macular or peripheral changes.
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Iris lesion
One should always consider iris melanoma on the differential for an iris lesion, as many are asymptomatic. Iris melanomas are typically pigmented (tan or dark brown); signs such as prominent intralesional vessels, large size, pupillary peaking and/or hyphema should raise suspicion for malignancy. However, in our case, the lesion was small and cystic with transillumination, despite the mild pigmentation noted on the slit lamp.
The differential diagnosis for an iris cyst is broad and can include iris cyst (pigment epithelium or stroma), iris nevus, iris nodules secondary to iridocorneal endothelial (ICE) syndrome and metastatic primary extraocular cancer. The patient was young and otherwise healthy and thus had a low risk for extraocular primary tumor. In addition, clinical features of the lesion were not consistent with an iris nevus or melanoma. Stromal iris cysts are frequently congenital, benign and transilluminate on slit lamp exam, consistent with our patient’s findings.
Axenfeld-Rieger syndrome (ARS) is often confused with ICE syndrome and Peters anomaly due to their overlapping features involving anterior segment structures. Some consider ARS and Peters anomaly a spectrum of the same disease as reports have documented patients with Peters anomaly to have mutations in genes known to cause ARS. A distinguishing clinical feature in Peters anomaly is corneal opacity at varying degrees (secondary to posterior stromal defects), which was not observed in our patient. In patients with ICE syndrome, distinguishing features are the “beaten metal” appearance of the corneal endothelium, iris nodules and posterior angle synechia with angle closure, as opposed to the iris processes seen in our case.
Our patient had bilateral posterior embryotoxon, iridocorneal processes and iris hypoplasia without corneal opacity, endothelial involvement or posterior angle synechiae. The patient also had sensorineural hearing loss, microdontia and a single kidney. The constellation of bilateral ocular findings, specifically posterior embryotoxon (a key feature of ARS), and her systemic findings are most consistent with ARS.
Management
Upon further questioning, the patient reported that a doctor had previously diagnosed her with presumed ARS, but the patient chose not to pursue genetic testing at that time. Ultrasound biomicroscopy was performed and revealed two adjacent iris cysts separated by a septation (Figure 3). The cysts measured 2.76 mm and 0.89 mm in diameter, respectively. There was a small and focal narrowing of the anterior chamber angle (1 clock hour) but no signs of intraocular complications from the lesion.
Based on the patient’s history, systemic findings and ophthalmologic findings, she was diagnosed with presumed ARS and incidental iris stromal cysts. The patient was advised to follow up with a geneticist for genetic confirmation and yearly follow-up with ophthalmology to monitor for glaucoma and iris cyst growth.
Discussion
ARS is a rare autosomal dominant disorder in which anterior segment structures derived from neural crest cells do not fully develop. The prevalence of ARS is estimated to be one in 50,000 to 100,000 newborns. Historically, several terms have been used to describe these features, such as Axenfeld anomaly, Rieger anomaly, Rieger syndrome and Axenfeld syndrome. Most recently, these conditions have been combined under the term ARS and subclassified as type 1, 2 and 3, based on molecular genetic testing. The major genes associated with disease are mutations in PITX2 or FOXC1. The most common non-ocular findings include microdontia, hypodontia, maxillary hypoplasia, prominent lower lip, sensorineural hearing loss, cardiac septal and valvular defects, kidney abnormalities, redundant periumbilical skin, hypospadias, empty sella syndrome and intellectual disability.
Although patients can be diagnosed clinically, genetic testing allows for not only confirmation, but also classification and phenotyping of the disease. In general, patients with associated systemic findings of umbilical and dental abnormalities have the PITX2 gene mutation. Patients with isolated ocular findings or systemic findings such as heart abnormalities and hearing loss are more often associated with FOXC1 mutations. Glaucoma prevalence is similar in both genes. However, patients with FOXC1 mutations tend to have an earlier onset of glaucoma compared with patients with PITX2. mutations. It is important to highlight that the phenotypes are variable in both mutations and that mutations in these two genes are present in only 40% of patients with ARS. Thus, in 60% of patients with ARS, the underlying genetic mutation is unknown. This implies that additional unidentified genes and environmental factors may be involved in its pathogenesis; hence, better molecular testing is required. Genetic counseling is recommended in ARS as the patient’s offspring has a 50% chance of inheriting the trait, and up to 70% of diagnosed patients have de novo mutations.
The ocular malformations are usually bilateral and involve the iris, cornea and anterior chamber angle at varying degrees. Posterior embryotoxon, which describes the anterior displacement of Schwalbe’s line, is the hallmark ocular presentation. It can be a partial or complete circumference involving the cornea. A large prevalence report noted that while this finding was not seen on the slit lamp in some patients, it was always visualized on gonioscopy, highlighting the importance of performing this exam. Other ocular findings include strabismus, iris hypoplasia, corectopia and, rarely, polycoria. Iridocorneal strands or iris process adhesions can be seen on gonioscopy. These strands normally do not narrow or obstruct the anterior chamber angle, which distinguishes them from posterior synechiae. Other less common ocular findings include nerve hypoplasia, retinal degeneration, chorioretinal colobomas and limbal dermoid.
Historically, patients with ARS have a 50% chance of developing glaucoma, which is the most serious ocular complication. The main pathogenesis is blockage or malformation of Schlemm’s canal, leading to increased IOP, retinal ganglion cell death, nerve fiber loss and eventual blindness if left untreated. The age of onset may vary, but affected patients usually develop glaucoma in their teens and 20s. Recent cohorts alarmingly indicate a higher prevalence of glaucoma (70% to 75%). Of those who develop glaucoma, up to 86% will ultimately require surgical intervention. Given the high prevalence and morbidity, close monitoring of IOP and the optic nerve via OCT are warranted in ARS. In our case, it was also important to assess the burden of the cyst on the aqueous humor drainage system, as it could further increase the risk for developing glaucoma.
Notably, iris cysts have not been reported to be associated with ARS. In our case, the iris cyst is likely unrelated to the disease pathology. Iris cysts can occur in children or adults, and they usually arise from the iris pigment epithelium or the iris stroma. Congenital cysts most commonly arise from the stroma, present before 10 years of age and often require treatment. In contrast, acquired iris cysts present later in life and seldomly require any intervention. Most affected patients are asymptomatic, and the cysts remain stable and indolent. Complications can occur from cyst enlargement, including obscuration of the visual axis, angle closure, corneal decompensation, and rupture resulting in intraocular inflammation or bleeding. For progressive cases, the treatment options include fine needle aspiration, intracystic injection of absolute alcohol or antimitotic agents, laser or surgery. Most iris cysts have an indolent course in which observation is the main management. Ultrasound biomicroscopy is the ideal monitoring modality as it has a higher resolution than ultrasound and a higher tissue penetration compared with anterior segment OCT.
- References:
- Boese EA, et al. Axenfeld-Rieger syndrome. In: Cornea Fundamentals, Diagnosis and Management. 5th ed. Elsevier; 2022:551-557.
- Georgalas I, et al. Surv Ophthalmol. 2018;doi:10.1016/j.survophthal.2017.08.009.
- Giaconi JA, et al. Ultrasound biomicroscopy. https://eyewiki.org/Ultrasound_Biomicroscopy. Updated Sept. 13, 2022. Accessed Oct. 21, 2022.
- Honkanen RA, et al. Am J Ophthalmol. 2003;doi:10.1016/s0002-9394(02)02061-5.
- Reis LM, et al. J Med Genet. 2022;doi:10.1136/jmg-2022-108646.
- Seifi M, et al. Clin Genet. 2018;doi:10.1111/cge.13148.
- For more information:
- William Warr Binotti, MD, and Helen K. Wu, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Yi Ling Dai, MD, and Teresa P. Horan, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 800 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.