Work

Novel compound heterozygous POLR3A variation: expanding 4H syndrome with progressive keratoconus

Year: 2026

Type: article

Abstract: POLR3A-related leukodystrophy is a multisystem disorder classically defined by hypomyelination, hypodontia, and hypogonadotropic hypogonadism (4H syndrome). While neurological and endocrine features are well-defined, the ocular phenotypic spectrum remains incomplete. We present a 15.9-year-old female with a classic 4H phenotype and compound heterozygosity for 2 novel variants (NM_007055.4:c.2102G > T [p.(Gly701Val)] and NM_007055.4:c.2989C > T [p.(Pro997Ser)]). The patient exhibited advanced, rapidly progressive bilateral keratoconus, with a maximum keratometry (K-max) reaching an extreme 75.9 diopter (D). K-max of 75.9 D (approximately 40-47 D in children and adolescents) represents extreme corneal ectasia. Longitudinal follow-up documented progressive ectasia, treated with penetrating keratoplasty in the left eye and corneal collagen cross-linking in the right eye. On the postoperative Pentacam examination at age 22, right-eye K-max was 70.7 D (66.7 D at age 10), and the thinnest location was 304 µm; left-eye values were unreliable owing to automated quality alerts. This case highlights progressive keratoconus as a potential clinical component of POLR3A-related disorders. We propose that ribonucleic acid polymerase III is essential for corneal proteostasis. Our findings position keratoconus as a potential early clinical sentinel for 4H syndrome, necessitating mandatory corneal topography in suspected cases to ensure timely, vision-saving intervention.

Source: JCEM Case Reports

DOI: 10.1210/jcemcr/luag333

Authors: Enver Simsek, Tulay Simsek, Oguz Cilingir, Eray Atalay

Institution: Eskişehir Osmangazi University

Language: English

Topic: Corneal surgery and disorders

Subfield: Ophthalmology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $930