Donnai‑Barrow syndrome (DBS) is an ultra-rare autosomal recessive disorder with fewer than 100 reported cases. Affected individuals have biallelic LRP2 (megalin) loss‑of‑function variants and varying clinical features that can include craniofacial anomalies, sensorineural hearing loss, renal tubular dysfunction, and distinctive ocular features. This article reviews the genetic and developmental basis of the syndrome and outlines its key ophthalmic manifestations of high myopia, retinal detachment, oculofacial findings of hypertelorism and iris coloboma, and optic nerve head anomalies. Additionally, this article describes diagnostic strategies including prenatal imaging and molecular testing and summarizes currently available management approaches drawn largely from case reports given the condition's rarity. By consolidating the limited literature and illustrative clinical examples, this review offers practicing ophthalmologists a concise reference for early recognition and multidisciplinary care of these patients.

To report a rare case of bilateral giant retinal tear (GRT)-related retinal detachments in a 24-month-old male with Donnai-Barrow syndrome (DBS) and to review the current literature on this disorder. Clinical information was obtained from the medical records of a patient with Donnai-Barrow syndrome seen at the Children's Hospital of Philadelphia. A literature review was conducted to identify all published cases of genetically or clinically diagnosed Donnai-Barrow syndrome. We report a case of a 24-month-old male with a history of DBS presenting with sudden loss of vision in both eyes. Ophthalmic examination revealed bilateral retinal detachments with GRT, complicated by grade C proliferative vitreoretinopathy (PVR) in the right eye. The patient underwent sequential scleral buckling, pars plana vitrectomy, membrane peeling, perfluoron, endolaser, fluid air exchange, and silicone oil placement in both eyes. Both eyes developed re-detachment, requiring repeat pars plana vitrectomy. Literature review revealed 10 reported cases of retinal detachments out of 38 DBS patients who survived past 1 year (26.3%). This case highlights the early presentation and complexity of GRT-related retinal detachment in DBS patients. Early, aggressive management using prophylactic laser retinopexy or scleral buckling may be essential in improving visual outcomes in DBS patients.

Megalin (low-density lipoprotein receptor-related protein 2) is a giant glycoprotein of about 600 kDa, mediating the endocytosis of more than 60 ligands, including those of proteins, peptides, and drug compounds [S. Goto, M. Hosojima, H. Kabasawa, A. Saito, Int. J. Biochem. Cell Biol. 157, 106393 (2023)]. It is expressed predominantly in renal proximal tubule epithelial cells, as well as in the brain, lungs, eyes, inner ear, thyroid gland, and placenta. Megalin is also known to mediate the endocytosis of toxic compounds, particularly those that cause renal and hearing disorders [Y. Hori et al., J. Am. Soc. Nephrol. 28, 1783-1791 (2017)]. Genetic megalin deficiency causes Donnai-Barrow syndrome/facio-oculo-acoustico-renal syndrome in humans. However, it is not known how megalin interacts with such a wide variety of ligands and plays pathological roles in various organs. In this study, we elucidated the dimeric architecture of megalin, purified from rat kidneys, using cryoelectron microscopy. The maps revealed the densities of endogenous ligands bound to various regions throughout the dimer, elucidating the multiligand receptor nature of megalin. We also determined the structure of megalin in complex with receptor-associated protein, a molecular chaperone for megalin. The results will facilitate further studies on the pathophysiology of megalin-dependent multiligand endocytic pathways in multiple organs and will also be useful for the development of megalin-targeted drugs for renal and hearing disorders, Alzheimer's disease [B. V. Zlokovic et al., Proc. Natl. Acad. Sci. U.S.A. 93, 4229-4234 (1996)], and other illnesses.