Skip to content
DraconiticResearch
Search Sources API
203,234 studies31 sourcesUpdated 26 min ago
Peer-reviewedCC BYJCEM case reports

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

  • Enver Simsek1
  • Tulay Simsek2
  • Oguz Cilingir3
  • Eray Atalay2
  1. 1Division of Pediatric Endocrinology, Department of Pediatrics, Eskişehir Osmangazi University School of Medicine, Eskişehir 26040, Türkiye.
  2. 2Department of Ophthalmology, Eskişehir Osmangazi University School of Medicine, Eskişehir 26040, Türkiye.
  3. 3Department of Medical Genetics, Eskişehir Osmangazi University School of Medicine, Eskişehir 26040, Türkiye.
Read full textPDFDOICite

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.

Related

  1. Congenital hyperinsulinism as part of a multisystem disease caused by a compound heterozygous variant in the YARS1 gene
    JCEM case reportsPeer-reviewedCC BY-NC-NDFull textEndocrinology & metabolismEurope PMC
  2. A case of renal hypouricemia type 1 associated with compound heterozygous URAT1/SLC22A12 variants A209V and F379L: clinical evidence for their pathogenic significance
    Naoyuki Otani, Marie Yamamoto, Tomoaki Takata +10
    CEN case reportsPeer-reviewedCC BYFull textGeneral medicineEurope PMC
  3. Familial Hypomagnesemia With Hypercalciuria and Nephrocalcinosis: A Case Report of Compound Heterozygous Variants in the CLDN16 Gene Inherited From Symptomatic Heterozygous Carriers
    Monica Ceol, Elena Sgrò, Franca Anglani +6
    Case Reports in Nephrology and DialysisPeer-reviewedCC BY 4.0Full textGeneral medicinePMC
  4. Case Report: Neonatal ultra-severe hemolytic anemia complicated by pulmonary hypertension induced by compound heterozygous variants in the KLF1 gene and literature review
    Yunzhi Liu, Dejian Yuan, Yanxing Lv +3
    Frontiers in PediatricsPeer-reviewedCC BY 4.0Full textHuman geneticsPMC
  5. Comprehensive Transcriptomic and Proteomic Profiling of CILD40 with Novel Compound Heterozygous Mutations of DNAH9.
    Siming Kong, Mingshuo Wang, Xuedong Wang +8
    Phenomics (Cham, Switzerland)Peer-reviewedCC BYFull textGeneral medicineEurope PMC

Cite

BibTeXRIS
BibTeX
@article{simsek2026novel,
  title = {{Novel compound heterozygous POLR3A variation: expanding 4H syndrome with progressive keratoconus.}},
  author = {Enver Simsek and Tulay Simsek and Oguz Cilingir and Eray Atalay},
  journal = {JCEM case reports},
  year = {2026},
  month = nov,
  doi = {10.1210/jcemcr/luag333},
  url = {https://europepmc.org/article/MED/42996498},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Novel compound heterozygous POLR3A variation: expanding 4H syndrome with progressive keratoconus.
AU  - Enver Simsek
AU  - Tulay Simsek
AU  - Oguz Cilingir
AU  - Eray Atalay
PY  - 2026
DA  - 2026/11/06
JO  - JCEM case reports
DO  - 10.1210/jcemcr/luag333
UR  - https://europepmc.org/article/MED/42996498
AB  - 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.
SN  - 2755-1520
ER  -