Researchers Pinpoint Causes of Foveal Hypoplasia

Laird Harrison

April 14, 2022

Newly published insights into the causes of foveal hypoplasia may allow clinicians to make quicker and more accurate diagnoses of the underlying conditions, in some cases preventing complications.

Using genetic tests and optical coherence tomography (OCT), ophthalmologists may be the first to identify a genetic disorder, such as albinism, said Mervyn Thomas, FRCOphth, PhD, an academic clinical lecturer in ophthalmology and genetic medicine at the University of Leicester, United Kingdom.

"Often the first presenting sign in these children is the nystagmus, or wobbly eyes," he told Medscape Medical News.

In Ophthalmology, Thomas and his colleagues published an analysis of how genetic variants relate to the structure and function of foveal hypoplasia.

Because foveal hypoplasia is rare, a collaboration of 12 centers in nine countries pooled their data, and researchers drew other cases from published literature, to create a database of 907 cases.

Each of those patients had both a molecular diagnosis and OCT scans of the fovea. Their average age was 22.7 years.

The advent of handheld OCT scanners has facilitated the research and diagnosis of foveal disorders in children who can't easily hold their chins steady on a chinrest for a standard OCT scan, Thomas said. "In Leicester, we've been one of the pioneers to use a handheld device, which looks like a hairdryer. We can take images in children and even in infants really looking at the structure of the fovea," he explained.

The researchers used the Leicester Grading System, which Thomas and colleagues developed. The system divides foveal hypoplasia into two types: typical and atypical. Typical foveal hypoplasia is characterized by the progressive loss of inner retinal layers posterior to the fovea. Atypical foveal hypoplasia is associated with photoreceptor degeneration.

The grading system itself can help predict the future visual acuity of preverbal children with nystagmus, Thomas said. And by linking the grading system to genetic variants, the researchers can make a prognosis based on genetic testing.

"Let's say, in some center they can't actually have access to specialized optical coherence tomography," said Thomas. "In reality, you don't need that. You can actually just do a saliva swab or a buccal swab. And from the saliva sample itself, we can sequence the known genes that we've characterized in this study."

This approach can spare children from more invasive testing such as MRI, which may require general anesthesia.

Although no treatment is yet available, a better prognosis can still help the patient. For example, if a child's visual acuity is worse than predicted, clinicians know to look for some other causes, such as a refractive error. Correcting such an error early on can prevent amblyopia, Thomas said.

Other diagnoses can lead to concerns outside the eye. "As soon as someone's diagnosed with albinism, they get referred not only to the ophthalmologist, but in addition to that to a dermatologist to ensure that they have adequate skin protection," Thomas said.

People with Hermansky-Pudlak syndrome may also benefit from care of other specialists, he added.

Furthermore, the findings open up the possibility for more practical research, Thomas said. "This lays the foundation that allows us to think about treatments and start moving forward in that direction," he noted.

Raj K. Maturi, MD, an associate professor of ophthalmology at Indiana University in Indianapolis, who was not involved in the study, said it will help diagnose diseases that can appear very similar. "You have a symphony of data that puts together information, starting from the molecule all the way to the phenotype, in a completely logical, understandable, stepwise fashion," said Maturi, a spokesperson for the American Academy of Ophthalmology, in an interview with Medscape Medical News.

In this study, the most common genetic etiology for typical foveal hypoplasia was albinism (affecting 67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). In 67.4% of achromatopsia cases, the researchers found atypical foveal hypoplasia.

Patients with atypical foveal hypoplasia had significantly worse visual acuity compared to typical foveal hypoplasia (P < .0001).

The FRMD7 cohort had the best visual acuity. This variant was associated with grade 1 (normal) morphology, and was suggestive of developmental arrest at a later time point.

Albinism, SLC38A8, and PAX6 gene variants were associated with worse visual acuity, possibly because they mostly fell into grades 3 and 4 of foveal hypoplasia.

Within albinism, the researchers categorized the ocular albinism and Hermansky-Pudlak syndrome as grades 3 and 4, and the oculocutaneous albinism as across a spectrum of grades.

They identified a narrow spectrum of foveal hypoplasia in SLC38A8 variants (grade 3-4).

The study was funded by the UK Medical Research Council, Fight for Sight, Nystagmus Network, Ulverscroft Foundation, Wellcome Trust, Korea Centers for Diseases Control and Prevention, and the National Research Foundation of Korea. Neither Thomas nor Maturi reported any relevant financial interests.

Ophthalmology. Published online February 11, 2022. Full text

Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio, and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at or follow him on Twitter: @LairdH

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