Clinical Description
NDP-related ocular phenotypes typically involve bilateral and symmetric fibrovascular changes of the retina that are evident at birth and usually progress through childhood or adolescence to cause varying degrees of visual impairment. The NDP-related ocular phenotypes appear to be a continuum with considerable overlap: Norrie disease, NDP-related persistent fetal vasculature (PFV), NDP-related familial exudative vitreoretinopathy (FEVR), NDP-related advanced retinopathy of prematurity (ROP), and NDP-related Coats disease [Black et al 1999, Dickinson et al 2006] (Table 2).
Norrie Disease
Ocular findings. The ocular findings in Norrie disease are the first described and best characterized eye findings of the NDP-related retinopathies.
In newborns and infants, the classic finding is a grayish-yellow, glistening, elevated retrolental mass composed of immature retinal cells that is usually visible through a clear lens in both eyes. These masses are referred to as "pseudogliomas" because they resemble tumors such as retinoblastoma. There is retinal dysplasia and incomplete foveal development in all cases. Partial or complete retinal detachments are often present at birth in both eyes. If not present at birth, retinal detachments may evolve over the first few months of life.
Nystagmus is common secondary to profound, bilateral vision loss [Smith et al 2012].
The irides, anterior chambers, and corneal diameter may be abnormal in size and appearance as a result of anterior segment dysgenesis.
The size of the globe may be normal, smaller (microphthalmia), or enlarged (buphthalmos).
Intraocular pressure is often normal at birth but can become elevated (i.e., secondary glaucoma) as a result of malformations of the anterior chamber and angle resulting in impaired outflow through the trabecular meshwork. Other consequences of impaired outflow include buphthalmos, pain, and further progression of vision loss.
From infancy through childhood, progressive changes typically include opacification of the lens (cataract) and cornea, atrophy or hypoplasia of the iris with adhesions forming between the lens and the iris (posterior synechiae) and between the iris and the cornea (anterior synechiae), and shallowing of the anterior chamber. Hemorrhagic necrosis of the undifferentiated retinal masses can occur.
These changes are followed by corneal opacification (e.g., band keratopathy), loss of intraocular pressure (hypotony), and shrinkage of the globe (phthisis bulbi) usually within the first decade of life. In the end stage of the Norrie disease ocular phenotype, the corneas appear milky and opacified, and the globes appear small and sunken in the orbits [Drenser et al 2007].
The majority of affected males lose all light perception during the first year of life.
Extraocular findings
Cognitive disability. In a large series, 14 of 51 of males with the Norrie disease
phenotype had developmental delay / intellectual disability [
Smith et al 2012].
Mental health and behavior. While most affected individuals are cognitively normal and develop healthy relationships, nearly all report a period of depression coincident with the onset of hearing loss. For individuals who are blind, becoming deaf-blind results in increased social isolation. Autism spectrum disorder has been reported in one third of affected individuals. Emotional lability has been reported in up to one fourth of affected individuals. In one large series, only one individual was reported with mental illness [
Smith et al 2012].
Seizures have been reported in 16 of 56 individuals with Norrie disease. Spontaneous resolution of seizures was reported in 50% [
Smith et al 2012].
Auditory findings. Hearing initially waxes and wanes, followed by slow deterioration over time. By the late teenage years, 42 of 56 males with Norrie disease in one report had hearing loss, with an increase to 80%-90% by their late 20s () [
Smith et al 2012].
In a report of six affected males, onset of hearing loss ranged between ages three and 35 years [
Bryant et al 2022]. Audiograms showed significant fluctuation: one individual had an abnormal audiogram at age eight years, a normal audiogram at age nine years, and subsequently abnormal audiograms at age 10 years and thereafter.
Hearing loss typically progresses over time. Three individuals whose hearing loss progressed over time reported significantly improved quality of life after cochlear implantation [
Smith et al 2012,
Bryant et al 2022].
Varicosities in the lower extremities followed by development of stasis ulcers have been reported in nearly half of all affected males more than 16 years old.
Erectile dysfunction has been reported in 14 of 20 adults.
Life span may be shortened by general risks associated with intellectual disability, blindness, and/or hearing loss, such as increased risk of trauma, complications related to a seizure disorder, and peripheral vascular disease.
Hearing loss by age group in a subset of affected males enrolled in the Norrie Disease Registry (n=56) [Smith et al 2012]
Peripheral vascular disease by age group in a subset of affected males enrolled in the Norrie Disease Registry (n=56) [Smith et al 2012]
Heterozygous Females
Clinical manifestations in heterozygous females are rare and usually presumed to be secondary to non-random (unfavorable) X-chromosome inactivation. NDP-related ocular manifestations in heterozygous females have included:
Extraocular findings that include mild sensorineural hearing loss [
Halpin et al 2005].
Phenotypic expression has also been reported in two women with an X-autosome translocation [Meire et al 1998].
Intrafamilial variability may be observed among heterozygous female family members. In one family segregating an NDP pathogenic variant, the maternal grandmother had Norrie disease with bilateral congenital blindness and progressive hearing loss, whereas a daughter heterozygous for the same NDP pathogenic variant was unaffected [Shastry et al 1999].
Nomenclature
The term "Norrie disease" used in the literature typically refers to the classic Norrie disease ocular phenotype occurring with or without extraocular features.
Outdated names for Norrie disease include Anderson-Warburg syndrome, atrophia bulborum hereditarian, Episkopi blindness, Norrie-Warburg syndrome, and pseudoglioma congenita.
Persistent fetal vasculature (PFV) was formerly referred to as persistent hyperplastic primary vitreous (PHPV).
NDP-related familial exudative vitreoretinopathy may also be referred to as X-linked familial exudative vitreoretinopathy.
Prevalence
No incidence or prevalence figures for NDP-related retinopathies are available.
In one academic institution with a large pediatric retina practice, 109 individuals with vitreoretinopathies were enrolled in a three-year prospective study. Eleven of the 109 individuals had NDP pathogenic variants: five with NDP-related Norrie disease, one with bilateral NDP-related PFV, four with NDP-related FEVR, and one with NDP-related advanced ROP [Wu et al 2007].
Norrie disease has been reported in many populations, including northern and central European, American of European descent, African American, French Canadian, Hispanic, Chinese, Iranian [Talebi et al 2018], Indian [Ghosh et al 2012, Sudha et al 2018], and Japanese.