Norrie disease (ND) is an X-linked recessive genetic disorder caused by mutations in the NDP gene (Xp11.4-p11.3). It presents with bilateral retinal dysplasia at or shortly after birth, usually leading to blindness. About 30% of cases are complicated by hearing loss and intellectual disability.
In 1961, Danish ophthalmologist Mette Warburg first reported it as a syndrome. It is named after Danish ophthalmologist Gordon Norrie (1855–1941).
Norrie disease is the most severe phenotype among “NDP-related retinopathies.” This spectrum includes the following diseases 1).
The exact prevalence is unknown, but over 400 cases have been reported. There is no association with specific ethnicities or races. Penetrance is 100% in affected males. More than 75 pathogenic mutations in the NDP gene are known.
Due to X-linked recessive inheritance, it occurs almost exclusively in males. Females are carriers but usually asymptomatic. Rarely, females with mild ocular findings or partial hearing loss have been reported due to non-random X-chromosome inactivation or consanguinity.
Most patients are congenitally blind or lose vision early in life. It is often discovered at 2–3 months of age due to poor fixation or leukocoria.
Ocular findings in Norrie disease are usually bilateral and symmetric. Various findings appear as the disease progresses.
Early to Active Stage
Leukocoria (pseudoglioma): A grayish-yellow raised mass behind the lens, consisting of immature retinal cell aggregates.
Retinal detachment: Partial to complete detachment progresses within the first few months of life.
Microphthalmos: May be present at birth.
Iris atrophy and synechiae: May present with anterior and posterior synechiae, leading to a shallow anterior chamber.
End Stage
Cataract: Progressive lens opacification.
Shallow anterior chamber and glaucoma: The anterior chamber collapses when the lens is pushed from behind, leading to secondary glaucoma.
Corneal opacity and band keratopathy: The cornea becomes milky white.
Phthisis bulbi: The eye shrinks and sinks into the orbit.
A shallow anterior chamber is a sign of impending glaucoma and corneal opacity, and regular examinations are necessary.
Many patients are born with normal hearing, but progressive sensorineural hearing loss begins in adolescence (median age 12 years). Initially, it is mild high-frequency hearing loss, and although long plateaus or partial recovery may occur, it becomes severe and involves all frequencies by age 35.
Norrie disease is caused by mutations in the NDP gene. There are no known risk factors other than genetics.
The NDP gene encodes the Norrin protein, which is involved in molecular signaling essential for the normal development of retinal and inner ear blood vessels (see Pathophysiology section for details).
There are over 75 pathogenic mutations in the NDP gene. The severity of the disease varies depending on the type of mutation.
Even within families with the same gene mutation, there is variability in phenotype, and differences between the left and right eyes of the same individual have been reported. Interactions between genes and environmental factors are suspected to be involved.
Norrie disease should be suspected in infants with the following ocular findings:
If the anterior segment findings do not reveal the intraocular condition, B-mode ultrasound can confirm retinal detachment or subretinal hemorrhage. CT is useful for differentiating from retinoblastoma.
Definitive diagnosis is made by molecular genetic testing of the NDP gene. Pathogenic variants can be identified in approximately 95% of affected males.
If the causative mutation has been identified in the family, prenatal genetic testing via chorionic villus sampling is possible 2). There are also reports of detecting retinal detachment in utero by fetal ultrasound 2).
The main differential diagnoses for leukocoria are listed below.
| Differential Diagnosis | Key Differentiating Features |
|---|---|
| Retinoblastoma | Calcium detected on ultrasound |
| FEVR | Mild form also associated with NDP mutations |
| Persistent Hyperplastic Primary Vitreous | Usually unilateral |
In addition, differentiation from retinopathy of prematurity, Coats disease, uveitis, trisomy 13, and Walker-Warburg syndrome is necessary.
The following imaging findings have been reported in Norrie disease:
Jokela et al. (2022) reported gadolinium enhancement of multiple cranial nerves in a 45-year-old Finnish man with Norrie disease4). Elevated cerebrospinal fluid protein (1,066 mg/L; reference range 150–450 mg/L) was also noted.
The visual prognosis for Norrie disease is generally poor, and no curative treatment has been established.
A shallow anterior chamber is a sign of impending glaucoma and corneal opacity, and regular examinations are necessary to determine the timing of intervention. Once the cornea becomes opaque, there is no effective treatment.
Justin et al. (2024) reported a case of a fetus with positive genetic testing in whom transabdominal ultrasound at 32 weeks detected bilateral total retinal detachment in utero2). After early delivery at 37 weeks, examination under anesthesia revealed inoperable bilateral total retinal detachment.
On the other hand, a previous report described a case where planned preterm delivery at 34 weeks combined with laser photocoagulation and intravitreal anti-VEGF injection resulted in visual acuity of 20/80 in both eyes after 8 years2). Another report achieved 20/100 in both eyes with laser photocoagulation at birth2).
In typical Norrie disease, visual prognosis is poor. However, in cases combining planned early delivery based on prenatal diagnosis and immediate postnatal laser photocoagulation of the retina, preservation of vision of 20/80 to 20/100 has been reported 2). Intervention is difficult if retinal detachment is already complete in utero.
The NDP gene is a 28 kb gene encoding the Norrin protein, which consists of 133 amino acids. Norrin comprises two main domains: an N-terminal signal peptide and a highly conserved cystine knot motif 1).
Mutations in the cystine knot region cause more severe retinal dysplasia (Norrie disease). In contrast, mutations outside the knot are often found in FEVR, where the retina is present but vascularization is incomplete 1).
Norrin binds to the Frizzled-4 receptor (FZD4) and, together with the co-receptors TSPAN-12 and LRP-5, activates the Norrin Wnt-β-catenin signaling pathway 1)3). This pathway is essential for the following processes:
The core of this disease is impaired retinal vascular development. This secondarily leads to intraocular fibrovascular proliferation, causing leukocoria and retinal detachment due to proliferative tissue on the posterior lens surface. When the lens is compressed from behind, the anterior chamber collapses, leading to glaucoma. Eventually, corneal opacification occurs, resulting in vision loss.
The stria vascularis of the cochlea depends on Norrin-FZD4-Wnt signaling to maintain its vascular structure. In mouse models, the stria vascularis is normal at birth, but thereafter progressively dilated abnormal capillaries appear, leading to cell loss, enlargement of the interstitial space, and eventually almost complete regression 3). Degeneration of the stria vascularis is accompanied by a decrease in outer hair cells, and later, spiral ganglion neurons and inner hair cells also degenerate 3). Vestibular function is not affected 3).
Both are included in the spectrum of NDP-related retinopathy caused by NDP gene mutations 1). Norrie disease is often associated with mutations in the cystine knot motif and is the most severe form, presenting with retinal dysplasia and blindness. FEVR is often associated with mutations outside the knot, where the retina is present but peripheral vascularization is incomplete. FEVR often does not involve systemic symptoms.
Pauzuolyte et al. (2023) reported successful restoration of microvascular formation in the neural retina and cochlea after intravenous administration of adeno-associated virus vector 9 (AAV9) in Ndp knockout mice1).
This study suggests that restoring norrin function may treat vascular lesions in both the retina and inner ear. Clinical trials for human application have not yet been conducted.
In a mouse model of oxygen-induced retinopathy, a single intravitreal injection of norrin protein promoted vascular regrowth and reduced neuronal loss in the inner retina1). In a diabetic retinopathy model, exogenous norrin has been reported to restore retinal endothelial cell junctions via the Wnt signaling pathway and repair blood-retinal barrier breakdown1).
Barkovich et al. (2025) reported bilateral cochlear enhancement on MRI in a 3-year-old child with Norrie disease who had normal hearing3). They suggest that this finding precedes sensorineural hearing loss and may serve as a biomarker for candidate selection and treatment monitoring in gene therapy.
