As you can probably tell, I'm starting to skip around a little bit while I put together these OKAP review articles. I have a fairly large list of topics to cover, but hopefully these will all be helpful pieces of information. I decided to skip to aniridia, because it is one of those conditions that seems to be very popular in practice questions.
As the figure states, aniridia refers to the absence of the iris. In most cases, there can be a residual stump or only partial aniridia; complete absence of the iris is actually less common.
Inheritance and Genetics
- PAX6: PAX6 is a transcription factor for eye development. It is inherited in an autosomal dominant pattern, and its disruption is the most common cause of aniridia.
- PAX6 gene mutations are an example of haploinsufficiency - for some proteins, both genes need to be functioning normally to produce a normal result.
- In rare cases, aniridia can also be inherited in a sporadic or autosomal recessive fashion. De novo mutations are associated with Wilms tumor (see below).
There are many different eye problems that can arise with PAX6 gene mutations. Because tests questions can arise in many permutations, here is an extensive list of those mutations. A mnemonic to help remember those eye manifestations is FAVE PC SONG*:
- Foveal hypoplasia
- Visual acuity subnormal
- Ectopia lentis
- Corneal pannus/limbal stem cell deficiency
- Optic nerve hypoplasia
Gillespie syndrome is an autosomal recessive condition in which aniridia can manifest. Gillespie syndrome is associated with the following features:
- Partial aniridia
- Congenital cataract
- Cerebellar ataxia
- Mental retardation
One of the major implications of aniridia is related to WAGR syndrome, a gene-deletion syndrome involving the 11p13 locus.
- It typically arises de novo (sporadic inheritance); any case of aniridia in which the parents are unaffected should be screened for WAGR syndrome.
- WAGR is an abbreviation for the following features:
- Wilms tumor
- GU abnormalities
- Mental Retardation
Here is the recommended workup for aniridia:
- Examine parents for any evidence of aniridia
- Females: consider a high-resolution banded chromosomal analysis
- Males and older children: baseline IV pyelogram and periodic urinalysis (to look for microscopic hematuria)
Sample Questions (answers at the bottom of the page)
- A parent brings their 4-year-old son into clinic because his eyes "look funny." On examination you notice the following anterior segment finding. Which of the following diagnostic tests may be helpful?
A. Complete blood count
B. Urinary catecholamines
C. Abdominal ultrasound
D. Serum protein electrophoresis
- What is the pathophysiology for corneal haze in this finding?
A. Corneal endothelial dysfunction
B. Limbal stem cell deficiency
C. Incomplete closure of the embryonic fissure
D. Traumatic rupture of Descemet's membrane
- Which of the following findings is NOT associated with mutations of the PAX6 gene?
C. Optic nerve hypoplasia
D. Persistent fetal vasculature
- Which of the following statements is TRUE?
A. Aniridia is associated with mutations on chromosome 13.
B. Aniridia is most commonly inherited in an autosomal recessive pattern.
C. Aniridia results from a disruption in organogenesis.
D. Aniridia is typically asymptomatic.
- Treatment of PAX6-associated ocular complications is likely to include all of the following EXCEPT:
A. Penetrating keratoplasty
B. Anterior vitrectomy
C. Glaucoma shunt
D. Kestenbaum-Anderson procedure
Sample Question Answers
- C. Sporadic mutations of the 11p13 gene may be associated with WAGR syndrome, which consists of Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation. Workup should include an abdominal ultrasound or CT to look for a Wilms tumor, and periodic urinalysis to look for microhematuria. An IV pyelogram or chromosomal analysis may also be helpful for diagnosis. Image from: University of Arizona.
- B. Corneal haze in aniridia is a result of limbal stem cell deficiency. Corneal endothelial dysfunction is the pathophysiology of corneal haze associated with CHED. Incomplete closure of the embryonic fissure results in colobomas. Traumatic rupture of Descemet's membrane does not affect the iris. Image from: University of Iowa.
- D. PAX6 mutations are associated with foveal and optic nerve hypoplasia, strabismus, glaucoma, nystagmus, cataracts, corneal pannus/haze and limbal stem cell deficiency, ectopia lentis, and decreased vision. Persistent fetal vasculature is not associated with PAX6 mutations.
- C. PAX6 is a transcription factor responsible for the organogenesis of the eye. It is found on chromosome 11. Mutations in PAX6 are inherited in an autosomal dominant fashion. Patients with PAX6-associated aniridia will often have decreased vision.
- A. Treatments for PAX6-associated ocular manifestations may include cataract surgery (including anterior vitrectomy and scleral-fixated IOL), glaucoma surgery, and strabismus surgery. The Kestenbaum-Anderson procedure is a strabismus surgery for treating nystagmus, essentially moving the null point of nystagmus to primary gaze (if possible). Corneal tattooing or contact lenses may be helpful in cases where the cornea is clear but there is significant light sensitivity due to the aniridia. Penetrating keratoplasty is less likely to be performed for corneal haze due to the limbal stem cell deficiency causing the corneal haze. In extreme cases, a keratoprosthesis may be necessary to improve vision from corneal haze.
References and Additional Reading
- Basic and Clinical Science Course, Section 2: Fundamentals and Principles of Ophthalmology. American Academy of Ophthalmology, 2015.
- Basic and Clinical Science Course, Section 4: Ophthalmic Pathology and Intraocular Tumors. American Academy of Ophthalmology, 2015.
- Basic and Clinical Science Course, Section 6: Pediatric Ophthalmology and Strabismus. American Academy of Ophthalmology, 2015.
Do you have any suggestions on what else might be important to remember about PAX6 mutations or aniridia that may show up on the OKAP? Do you have any tips for helping to remember all of this information? Do you have any requests for specific topics to cover? Leave a comment or contact us!
*Special thanks to Derrick Fung, M.D. for teaching me the mnemonic, and giving me permission to use the mnemonic on the website!