Jennifer Rossen, MD, a pediatric ophthalmologist at Lurie Children’s Hospital in Chicago, talks about how pediatric cataracts can be the first symptom of an underlying inherited syndrome that needs your attention.
Question:
Can you talk about how pediatric cataracts can be connected to underlying, often unknown, medical conditions?
Jennifer Rossen, MD:
While pediatric cataracts may develop from medication or diseases like diabetes, they can sometimes be inherited. Sometimes inherited cataracts are seen in isolation, meaning without any other medical issues, but other times, cataracts can be the first symptom of an underlying inherited syndrome. There are over 300 genes that are associated with pediatric cataracts, with at least some literature support, and almost 240 of those genes are associated with other medical issues.
Question:
Specifically, can you talk about the link between pediatric cataracts and cerebrotendinous xanthomatosis?
Jennifer Rossen, MD:
Definitely. Cerebrotendinous xanthomatosis or CTX is a condition caused by 2 biallelic variants in CYP27A1, which means that an abnormal copy of CYP27A1 is passed down from both parents. While the first symptom of CTX is often diarrhea in infancy, this often resolves spontaneously. The first identified symptom of CTX is usually pediatric cataracts. Other common symptoms of CTX include other neurologic and developmental issues such as developmental delays, psychiatric disorders, and neurologic symptoms such as ataxia, neuralgia, and spastic paraplegia. The neurologic symptoms tend to be progressive and can get more and more and worse and worse as patients grow into young adulthood. But there are medications for CTX, when initiated early, can even prevent a lot of these devastating neurologic complications. Since the cataracts often present before the neurologic symptoms, that is usually a time for us to try and identify CTX early before these problems happen. But unfortunately, the average age of diagnosis of CTX right now is almost 34 years old with an average delay of almost 25 years from symptom onset to diagnosis.
Question:
Can you talk about the importance of genetic testing to help clinicians and families identify rare genetic conditions?
Jennifer Rossen, MD:
I think while CTX is a rare condition, I think it’s really undiagnosed and the true frequency is unknown because we’re not testing early enough. Now the genetic testing is becoming more and more available for patients, which hadn’t been for a very long time. We have a unique opportunity now as ophthalmologists to try and identify patients with CTX and other underlying diseases associated with early onset cataracts.
I think cataracts happen in all adults, but they don’t happen in most children. I think as clinicians and ophthalmologists, we have to think carefully when a patient is diagnosed with a cataract early on, whether or not it needs surgery. Sometimes the cataracts associated with CTX are very small and don’t need to be removed. But when a child has cataracts, I think it’s important to think about family history, other medical problems, and, when in doubt, offer the family genetic testing because there are free to the patient options for genetic testing for patients with cataracts right now that are early onset. Just so that the family knows, there’s a possibility that this may be related to an underlying medical disease that may need treatment. I think families should be aware of that option and be given it.
Question:
You are chair of the Pediatric Cataract Variant Curation Expert Panel at ClinGen. Can you talk about the work you’re doing and the goals of this program?
Jennifer Rossen, MD:
Yeah, definitely. I can talk a bit about ClinGen first. ClinGen, briefly, is an NIH-affiliated organization with the goal of standardizing genetic testing analysis for patients across all different types of conditions and working groups score the strength of both gene disease relationships through the Gene Curation Expert Panels or the GCEPs, and then develop rule specifications for varying classifications and classify variants for gene disease pairs through the Variant Curation Expert Panels or the VCEPs. Our Pediatric Cataract VCEP is focusing on pediatric cataract genes, and the first one we’re looking at is CYP27A1, and its association with CTX. What we’re trying to do is improve how labs classify variants, so changes in the gene CYP27A1 to determine if that change in the gene can cause CTX or not.
That’s important one, for kids with pediatric cataracts or other symptoms of CTX but it’s also becoming even more important now because CYP27A1 was just added to the list of secondary findings by ACMG. Meaning all patients that are getting whole genome or whole exome sequencing, their gene CYP27A1 will be evaluated to see if there’s any potential causes of CTX because some patients may have it and not know yet because they’re pretty symptomatic.
In addition, the CTX Alliance, which is the patient advocacy group for CTX, is working on adding CTX to the newborn screening across the US. They’ve been successful in New York, which is great. This all means that more and more patients are going to have their gene CYP27A1 evaluated. Our goal is to try and help the labs consistently and accurately analyze the changes in 27A1 to determine if those changes can cause CTX or not, because not all changes in the gene can cause disease. We want to just help identify patients earlier.
Related Content
