Case Report: Acute keratoconus as the presenting feature in undiagnosed Norrie disease: hypothesis from a novel NDP...

Norrie disease is a rare X-linked recessive disorder characterized by congenital blindness, with approximately one-third of patients developing progressive sensorineural hearing loss and neurodevelopmental abnormalities. While over 200 pathogenic variants in the NDP gene have been identified, the phenotypic spectrum continues to expand.

We report a 33-year-old Chinese male who presented with acute hydrops of the right cornea as the initial clinical manifestation leading to the diagnosis of Norrie disease. Comprehensive ophthalmological examination revealed bilateral keratoconus (right eye with acute Descemet's membrane rupture), spherophakia, shallow anterior chambers, and characteristic grayish-white fibrovascular masses in the vitreous cavity. Whole-genome sequencing identified a novel hemizygous mutation in NDP (NM_000266.4: c.140_144delinsTTTTA), resulting in p. Ser47_Ile48delinsPheLeu. This mutation affects highly conserved residues adjacent to the cysteine knot domain critical for Norrin protein function. The proband's mother was a heterozygous carrier with normal phenotype, confirming X-linked recessive inheritance. In silico analysis using multiple prediction algorithms uniformly indicated pathogenicity.

This represents, to our knowledge, the first report of Norrie disease presenting with acute keratoconus (hydrops) as the initial diagnostic manifestation in an undiagnosed adult. The novel p. Ser47_Ile48delinsPheLeu mutation expands both the mutational spectrum of NDP and the phenotypic presentation of Norrie disease. These findings emphasize the importance of genetic testing in patients with complex anterior segment abnormalities and provide crucial information for genetic counseling and clinical management.