Phenotypic criteria for early-onset glaucoma in patients with anterior segment mesenchymal dysgenesis

Anterior segment mesenchymal dysgenesis comprises a broad group of phenotypically and genetically heterogeneous diseases that are frequently associated with the development of glaucoma in early childhood. One of the most common conditions within this group is Frank – Kamenetsky syndrome, which has an X-linked mode of inheritance and is characterized by distinctive abnormalities of the anterior segment of the eye, including features of goniodysgenesis. Identification of biological markers of the onset and manifestation of hydrodynamic disturbances remains an important challenge in ophthalmology.

PURPOSE. To identify phenotypic criteria for early-onset glaucoma in Frank – Kamenetsky syndrome.

METHODS. A comparative retrospective analysis of phenotypic features of Frank – Kamenetsky syndrome was performed in patients from two groups stratified according to the timing of glaucoma manifestation. Group 1 included 22 patients in whom elevated intraocular pressure (IOP) and the first signs of glaucoma were documented at the age of 5–10 years. Group 2 comprised 14 patients in whom persistent IOP elevation and signs of glaucomatous optic neuropathy were diagnosed after the age of 20 years.

RESULTS. Phenotypic criteria associated with early-onset glaucoma in patients with Frank – Kamenetsky syndrome included congenital non-progressive megalocornea (corneal diameter >12 mm), grade II–III goniodysgenesis, and iris stromal thickness <50 μm, indicating a combination of defects in the embryonic development of all mesenchymal tissue derivatives.

CONCLUSION. The abnormal phenotype of Frank – Kamenetsky syndrome can be readily distinguished from normal anatomy by the presence of specific and characteristic alterations of the iris and the anterior segment as a whole. At the same time, this disease demonstrates marked variability in the severity and range of clinical manifestations, as well as in the time of glaucoma onset. Differences in phenotypic expression of the abnormal genotype may lead to difficulties in interpreting the diagnosis and delayed identification of hydrodynamic disturbances and glaucomatous optic neuropathy.

1. Shchuko A.G., Veselov A.A., Iureva T.N., et al. Epigenetics and methods of its implementation. Siberian Scientific Medical Journal 2017; 37(4):26-36.

2. Alward WL. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Ophthalmol 2000; 130(1):107-115. https://doi.org/10.1016/s0002-9394(00)00525-0.

3. Beck AD. Diagnosis and management of pediatric glaucoma. Ophthalmol Clin North Am 2001; 14(3):501-512. https://doi.org/10.1016/s0896-1549(05)70248-0.

4. Berry FB, Lines MA, Oas JM, Footz T, Underhill DA, Gage PJ, Walter MA. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet 2006; 15(6):905-919. https://doi.org/10.1093/hmg/ddl008.

5. Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior segment dysgeneses. Surv Ophthalmol 2006; 51(3):213-231. https://doi.org/10.1016/j.survophthal.2006.02.006.

6. Rieger H. Beiträge zur Kenntnis seltener Mißbildungen der Iris: II. Über Hypoplasie des Irisvorderblattes mit Verlagerung und Entrundung der Pupille. v. Graefes Arch Klin Exp Ophthal 1935; 133:602-635.

7. Tümer Z, Bach-Holm D. Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations. Eur J Hum Genet 2009; 17(12):1527-1539. https://doi.org/10.1038/ejhg.2009.93.

8. Bhandari R, Ferri S, Whittaker B, Liu M, Lazzaro DR. Peters anomaly: review of the literature. Cornea 2011; 30(8):939-944. https://doi.org/10.1097/ICO.0b013e31820156a9.

9. Shigeyasu C, Yamada M, Mizuno Y, Yokoi T, Nishina S, Azuma N. Clinical features of anterior segment dysgenesis associated with congenital corneal opacities. Cornea 2012; 31(3):293-298. https://doi.org/10.1097/ICO.0b013e31820cd2ab.

10. Shchuko A.G., Iureva T.N., Chekmareva L.T., Malyshev V.V. Glaukoma i patologiya raduzhki [Glaucoma and iris pathology]. Moscow, 2009. 165 p.

11. Shchuko A.G., Chekmareva L.T., Iureva T.N. Frank-Kamenetsky glaucoma. RMJ Clinical ophthalmology 2002; 3(1):25.

12. Redkie formy glaukomy [Rare forms of glaucoma] edited by A.G. Shchuko, T.N. Iureva. 2nd ed., suppl. Irkutsk, Irkutsk Branch of Fyodorov Eye Microsurgery Complex, 2021. 217 p.