Congenital aniridia has long been recognized as more than just an iris disorder. Driven most commonly by PAX6 haploinsufficiency, the condition encompasses foveal hypoplasia, cataract, glaucoma, and the progressive ocular surface disease known as aniridia-associated keratopathy (AAK). Structural studies have shown reduced corneal nerve density in these patients – but a comprehensive functional evaluation of corneal nerves has been lacking.
Now, a new clinical investigation published in Cornea provides the first systematic assessment of corneal sensory nerve function in congenital aniridia, revealing that nerve dysfunction is not only present, but worsens with age and disease severity.
“To date, research on congenital aniridia corneal sensory innervation has focused on structural nerve alterations, leaving sensory functionality and reflex evocations largely unexamined,” explains lead author, María Carmen Acosta. “Due to our experience in corneal neurobiology, we partnered with Dr. Szentmáry’s clinical team to investigate these functional deficits in aniridia patients for the first time.”
In the study, 14 genetically confirmed PAX6-aniridia patients (aged 9-60 years) underwent detailed sensory testing. Mechanical sensitivity was assessed using a non-contact gas esthesiometer, and cold sensitivity was measured with 4°C saline drops. Basal blinking, basal tearing, and CO₂-evoked reflex tearing were also recorded, with results being compared to healthy controls and stratified by age, AAK grade, and mutation type.
Adult patients demonstrated significantly reduced mechanical sensitivity to higher-intensity stimuli compared with controls, and cold sensitivity was also diminished, particularly in older patients and in those with more advanced AAK. Importantly, both mechanical and cold sensitivity showed negative correlations with age.
In contrast, children with aniridia exhibited only mild impairment, suggesting that corneal sensory dysfunction progresses over time rather than being fully congenital. Given that age-related sensory decline in healthy individuals typically becomes evident after 60, the deficits observed in middle-aged aniridia patients appear disease-driven rather than physiological.
While basal tear production and spontaneous blinking were largely preserved, reflex tearing told a different story. Although variable, reflex tearing trended lower in patients. More strikingly, tearing reserve (reflex minus basal tearing) was significantly reduced in adults with aniridia.
The reduction suggests impaired polymodal nociceptor function and possibly reduced lacrimal gland responsiveness. Clinically, a low tearing reserve may signal subclinical neurotrophic dysfunction – even when baseline tear volume appears adequate.
As well as age, patients were also grouped according to mutation type: loss-of-function (LOF) variants versus milder reduced-expression (REX) variants. Although the REX cohort was small, LOF mutations showed a trend toward greater sensory impairment and significantly higher AAK grades. Multivariable modeling identified age and AAK severity – rather than mutation type alone – as the strongest predictors of reduced sensory function. Cold sensitivity, in particular, declined with increasing keratopathy severity, consistent with inflammatory influences on thermoreceptor activity.
The findings suggest that corneal nerve dysfunction in aniridia is progressive and multifactorial. Reduced sensitivity across all receptor types may compromise protective reflexes long before overt neurotrophic keratopathy develops. “Our findings demonstrate that all classes of corneal sensory neurons – mechano-nociceptors, polymodal nociceptors, and cold thermoreceptors – exhibit functional dysfunction,” says Acosta, “which progressively worsens with age.”
Acosta continues: “The observation that corneal nerve function remains largely intact in children, followed by a progressive decline with age, underscores the critical need for early clinical intervention. These findings suggest that monitoring and treating the ocular surface from early childhood is essential to potentially halt or delay the functional deterioration of corneal sensory innervation.”
For clinicians, this raises important considerations. Monitoring corneal sensitivity and tearing reserve could help to identify these patients at risk of surface breakdown. Moreover, emerging biologic therapies – including recombinant nerve growth factor, autologous serum, and platelet-rich plasma – may offer opportunities to support corneal innervation in these early years before irreversible damage occurs.
Aniridia may begin with the iris, but this clinical study makes one thing clear: over time, the corneal nerves fall increasingly silent.
