Norrie disease …

Developmental Malformations

Updated 08.11.2024
Released 11.19.2001
Expires For CME 08.11.2027

Norrie disease

Authors: Adam Friedant DO, Aparna M Prabhu MD MRCP

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Editor: Ganeshwaran H Mochida MD

Norrie disease

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Introduction

Overview

Norrie disease is a rare, congenital X-linked recessive disorder of the eyes, particularly the retina of affected males, resulting in congenital blindness or progressive visual loss through childhood. Mutations in the NDP (Norrin Cysteine knot growth factor protein coding) gene and absence of the NDP protein norrin are associated with a spectrum of diseases featuring altered retinal vasculature development. Additional complications of Norrie disease, the most severe form of NDP-related retinopathy, are sensorineural deafness, intellectual deficits, psychosis, or other behavioral problems. Information continues to be gained concerning the clinical variability, genetics, and pathogenetic mechanisms of this disease. Vitrectomy with or without lensectomy has benefited some patients.

Key points

	• Norrie disease is a rare, congenital X-linked recessive disorder of the eyes, particularly the retina, of affected males, resulting in congenital blindness or progressive visual loss through childhood.
	• Mutations in the NDP gene, of which there are likely more than 200 pathogenic variants, and an absence of the NDP protein norrin are associated with altered retinal vasculature development.
	• Information continues to be gained concerning the phenotypic variability, genetics, and pathogenetic mechanisms of this disease.
	• Additional complications are sensorineural deafness, seizures, intellectual deficits, autism, and psychosis or other behavioral problems. Other anomalies, particularly involving the CNS, have been reported.
	• Vitrectomy with or without lensectomy has benefited some patients.

Historical note and terminology

In 1961, Warburg identified seven patients from seven generations of a Danish family as well as an additional 48 patients from nine families described in the literature; she suggested the name Norrie disease to reflect Norrie's earlier publication in 1933 (66; 112). The term “Episkopi blindness” derived from a study of a large Greek family (16 males in five generations) in Episkopi, Cyprus (104). Some early cases were labeled “pseudotumors” or “pseudoglioma,” but these are nonspecific terms reserved for conditions resembling retinoblastoma and are no longer considered appropriate diagnoses for this condition (70). Two conditions (persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy) are part of the spectrum of NDP-related retinopathies, of which Norrie disease is the most severe. Berger and colleagues and Chen and colleagues isolated a candidate gene for Norrie disease (06; 15). In the following years, the NDP gene and a variety of mutations have been identified as causative (123; 73).

Clinical manifestations

Presentation and course

Norrie disease is a congenital X-linked recessive disorder involving the eyes, particularly the retina, of affected males and resulting in congenital blindness or progressive visual loss through childhood (90). A patient's condition can be placed within the spectrum of Norrie disease if several findings are identified: normal size of eyes at birth, normal anterior chamber, clear lenses, additional (bilateral) changes including fibrovascular alterations of retina and vitreous characterized by hemorrhage, and membrane formation or attachment to retina (95). At least one-third of patients have sensorineural deafness, and one-half have intellectual deficits, which appear after 3 years after birth and are sometimes complicated by psychosis or other abnormal behavior (71; 95). Patients may manifest depression (2%), anxiety (6%), attention difficulties (8%), labile affect (25%), or autism (27%) (99). Infantile spasms (EEG-demonstrated hypsarrhythmia) have been noted in a profoundly retarded male with congenital blindness (54). The disease is clinically heterogeneous; however, presentations may vary, even within families (123).

The eyes may be normal at birth but, within a few months, develop a variety of fibrous and vascular changes. These changes range in severity from masses involving the retina, resulting in complete loss of vision, to less severe fibrotic stalks extending from the optic disc to the lens (persistent hyperplastic primary vitreous) or retinal vascular changes with or without fibrosis (familial exudative vitreoretinopathy or FEVR). A 2022 systematic review article suggests the severity of the retinopathy is associated with the type of mutations in the NDP gene and depends on the protein region affected (114). The combination of dense stalks, globular dystrophy, and peripheral avascularity of the retina, accompanied by pigmentary changes, may be pathognomonic for Norrie disease (23). By about 10 years, eyes are end-stage and shrunken (phthisis bulbis), with milky corneas, shallow anterior chambers, opaque corneas, leukocoria, dilated pupils with no light reflex, and hypoplastic irides with posterior synechiae.

These changes need not develop late, however, and the finding of leukocoria with microphthalmia in early infancy can lead to a diagnosis of Norrie disease (76). Additionally, a case report in 2019 discussed ocular abnormalities on prenatal ultrasound, which prompted genetic analysis and subsequent diagnosis of Norrie disease during the third trimester. These ultrasound abnormalities included hyperechogenic opacities behind the lenses; MRI showed primary vitreous hyperplasia and hypertrophied, irregular, and hypointense lenses (25). Glaucoma can occur secondary to shape changes that produce increased intraocular pressure. Rarely, carrier females and even noncarrier females have ocular changes (retinal detachment or abnormal peripheral retinal vasculature, phthisis bulbi; dragged maculae) or loss of vision (13; 96; 60; 119; 55). Explanations for this occurrence in females include X inactivation or other adverse effects of the mutant allele on the retina during early development.

Additional extraocular changes are recognized, though incompletely. Central nervous dysfunction with seizures, growth retardation, and immunodeficiency become apparent in later stages in about one-third of cases (08). Because norrin is important to angiogenesis, several defects in the vascular system may occur, including peripheral vascular disease (ie, varicose veins, venous stasis ulcers, and erectile dysfunction) (99). Cerebroretinal microangiopathy is associated with calcifications and cysts involving terminal arteriolar zones (eg, basal ganglia) and deep gray nuclei (85). Chronic seizures occur in about 10% of patients (99) and may be refractory (10). In one study, epilepsy developed from discharges in the occipital areas of three brothers (69).

Hearing loss can progress subtly and does not seem to affect speech. The inner ear (cochlea) appears to be involved, and retrocochlear and brain auditory system function is normal. One study of the inner ears of a 77-year-old patient revealed marked atrophy of the stria vascularis, severe degeneration of hair cells and cochlear neurons, and connective tissue proliferation in the spiral ganglion, osseous spiral lamina, and walls of the membranous vestibular labyrinth (64). In a mouse model for Norrie disease, the primary change was abnormal or decreased vessels of the stria vascularis, in which the cochlear vasculature is located (81). In Ndp knockout mice, cochlear function decreased with age due to progressive loss of transcription factors, Pou4f3 and Gfi1, which are key in hair cell maturation; there was also progressive loss of Myo7a, a specialized myosin required for normal function of HC stereocilia (37).

If deletions of the Norrie disease gene involve adjacent monoamine oxidase genes (MAOA, MAOB), phenotypic and physiologic changes are more severe, including hypogonadism, hypertensive crises, disorganized REM sleep, myoclonus or other involuntary movements, and variable degrees of intellectual deficits (18; 108; 102). Additional anomalies associated with these deletions continue to be uncovered, including short stature, hypotonia, and autism (88).

Prognosis and complications

In severe Norrie disease, visual impairment is congenital, complete or progressive, and irreversible. For patients with Norrie disease and persistent fetal vasculature syndrome, early vitrectomy has been performed, with or without lensectomy, with maintenance or restoration of light perception vision in a majority of cases; most patients experienced no phthisis bulbi postoperatively (109; 110). In less severe forms, vision may be mildly impaired or even normal. Deafness and intellectual deficits are complications in some 50% of cases (82). Hearing loss is bilateral and progressive but responsive to hearing aids; with care, preservation of word recognition is possible (35). Additionally, a 2022 review suggested the utility of multidisciplinary dual sensory clinics as part of the follow-up for these patients with visual and hearing impairment (100).

The less severe form of the condition may be progressive and treatable. Growth retardation, epilepsy, and behavioral and sleep disturbances are other complications (72; 71; 119). One patient with Norrie disease, complicated by paroxysms of deafness, slurred speech, and somnolence, was successfully treated with beta-blockers (47). Pancreatic exocrine insufficiency and microvillus inclusion disease have been observed in a newborn male (74). One affected adult has been reported with chronic peripheral venous insufficiency, requiring surgery for varicose veins (61). Two patients with microdeletions in the NDP region have been diagnosed with pulmonary hypertension or progressive, eventually fatal dyspnea (101). Parental counseling, with a goal of combating depression, may help improve the long-term developmental outlook of patients (31).

Biological basis

Etiology and pathogenesis

Because Norrie disease is X-linked recessive, affected males inherit the disorder from carrier mothers or acquire it sporadically through a new mutation in the Norrie disease gene, NDP (“Norrie Disease Pseudoglioma”), located at Xp11.4-p11.3 (14). Affected males transmit the (recessive) mutation via the X chromosome, thus affecting their daughters but not their sons. Carrier females have a 50% chance of transmitting the mutation to either male or female children (the former will have Norrie disease, and the latter will be carriers).

Four loci have been named EVR1 to EVR4 and mapped to 11p, 11q, and Xp (106). It is likely other loci also exist (48). To date, a number of variants of two genes (LRP5 and FZD4) have been found to cause familial exudative vitreoretinopathy (65); FZD4 may be mutated in some cases of both unilateral and bilateral forms of persistent hyperplastic primary vitreous as well (91). High levels of aqueous VEGF-A in one enucleated eye with retinal dysplasia consistent with Norrie disease suggest this cytokine may also be involved in pathogenesis (45). The mutational spectrum of Norrie disease continues to be expanded and can suggest a founder effect (77). Contiguous deletions involving NDP give rise to diverse findings, depending on the exact nature of the deletion (46). Additional literature has suggested at least 201 unique pathogenic variants in the NDP gene (114).

Forms of Norrie disease. At least three major phenotypic varieties of Norrie disease are distinguished (95):

Classic form. In the classic and most severe form, gray-yellow masses of fibrovascular tissue replace the retina; these have sometimes been described as pseudotumors or pseudoglioma. This change is associated with severe or total loss of vision. With time, various additional changes may occur, including the formation of cataracts or synechiae, opacified cornea, atrophic iris, altered shape of globe or individual chambers, or band keratopathy.

Persistent hyperplastic primary vitreous form. In persistent hyperplastic primary vitreous form, a fibrotic white stalk containing hyaloid vessels connects the optic disc and posterior lens capsule; the lens is variably opacified, and the retina is variably folded or detached. This change is apparent at birth, and the extent of progression is unknown; the degree of visual loss is variable. An apparently rare, novel nonsense mutation of the Norrie disease gene has been identified in a family with two sons affected by persistent hyperplastic primary vitreous (36).

Familial exudative vitreoretinopathy. Familial exudative vitreoretinopathy is manifested by peripheral zones of retinal avascularity, sometimes with retinal folds, which can cause dragging and displacement of the macula (macular ectopia), or fibrous tissue bands, which are apparent at birth. These changes are associated with normal or reduced vision and can progress throughout the first 2 decades of life, causing eventual retinal detachment. Neonatal retinal folds or vitreoretinal traction can be signs of Norrie disease or other retinopathy (19). Retinal detachment may also occur in fetal life or infancy (115; 29). The term “exudative” derives from the exudation of serous fluid from capillaries in the (abnormal) retinal vasculature. Microscopically, the retina appears immature and dysplastic, with little or no normal structure; the retinal vasculature is also underdeveloped (26; 107). These changes are thought to arise early in development, possibly from changes in cells of the inner optic cup wall (71).

Defects in the Wnt signaling pathway are found in patients with familial exudative vitreoretinopathy and Norrie disease (113; 41). The Wnt pathway plays multiple roles in embryonic development, including regulation of ocular growth and development (52; 38). The exact pathogenesis is complex and continues to be elucidated.

The NDP protein (norrin) binds to at least three proteins and serves as an antagonist to BMP and activates the Wnt pathway (20). Norrin also has a function in progenitor proliferation in the retina that is independent of its function in the developing vasculature of the retina (59). A further complication is that the same mutation may be responsible for different phenotypes (82). Regardless, vascularization is abnormal in the peripheral retina of all forms of Norrie disease (93) and norrin, the protein product of NDP, appears to be part of a signaling system important to vascular development in the eye and ear (117). It has been suggested that aberrations in normal apoptosis play a role (91) and that the proliferation of endothelial cells in the retinal vascular plexus is reduced (124). The endothelial cell-specific protein PLVAP (plasmalemma vesicle-associated protein) is involved in vascular permeability, leukocyte migration, and angiogenesis; it is upregulated in Norrie disease and, thus, may be a target for future therapy (32). Mouse models have suggested Plvap mutations may influence vascular permeability as early as the 1-month mark (09).

Norrin is also important to extraocular angiogenesis (80; 61; 122). Homologies with known proteins and other modeling data suggest that mutations also alter the regulation of cell interaction, differentiation, or proliferation (12; 05). In approximately 70% of patients, single base pair changes are found; in about 24%, partial or complete deletions are identified. More than 100 sequence variations, including intragenic deletions, nucleotide substitutions, or splicing variants, cause the disease (87; 61). Most are unique and confined to single patients and families. Phenotypes can vary among family members carrying the same mutation or be misdiagnosed, given the wide variation in allelic variants. It has been suggested that milder mutations in the Norrie disease gene are associated with less severe retinal disease or that deletions may be associated with more severe forms (49; 83). Certain mutations result in significant phenotypic heterogeneity (01). This latter observation suggests that phenotypic definitions of Norrie disease variants may not be the most appropriate nomenclature.

A mouse knockout model will be helpful in understanding disease progression (53). In the model, numerous photoreceptor cell-specific gene transcripts are absent or down-regulated in older (ie, 2 years) but not younger (ie, 1 year) animals. Without the Norrie disease gene product, photoreceptor cells cannot survive in this model. Such animals manifest a failure of retinal angiogenesis, with a lack of deep capillary layers of the retina and blindness (67). This has been confirmed in studies wherein the role of norrin in retinal vascular development continues to be elucidated (89). The gene product also influences the regression of hyaloid vessels that otherwise are a component of retrolental membranes in knockout mice (68). Vessel density (but not cell number) is also reduced in the cerebellum of knockout mice (58). It seems that reproductive tissues can also be affected, for female mice homozygous for the Norrie disease pseudoglioma homolog (Ndph) are almost uniformly infertile; heterozygous females and hemizygous males are not (57). The role of hypoxia and reduced induction of vascular endothelial growth factor (VEGF) on retinal vascularity has been investigated in one experimental model (78).

Differential diagnosis

Associated or underlying disorders

Norrie disease manifests as a spectrum, with several phenotypes that overlap considerably (85). These include Norrie disease, Coats, Coats plus, leukoencephalopathy with calcifications and cysts, and cerebroretinal microangiopathy with calcifications and cysts. Some cases of retinoblastoma may prove to be Norrie disease or related phenotypes (02). Diagnosis is facilitated by identifying intraocular changes and mutations in the Norrie disease gene. Some workers have held that patients (3% of advanced cases in one study) labeled as having retinopathy of prematurity, in fact, have Norrie disease, the diagnosis of which can be substantiated by clinical and molecular means (92; 34; 42). Evidence is mounting that the presence of certain mutations in the Norrie disease gene may predispose some patients to severe retinopathy of prematurity (103; 33). In one study, six of 54 (11%) infants with severe retinopathy of prematurity had polymorphisms in the Norrie disease gene (NDP) (43). However, other investigators have failed to identify mutations in their patients (50). It is also possible that X-linked primary retinal dysplasia is part of this spectrum, although studies to date have been incomplete (79). Coats disease (exudative retinopathy) and congenital or juvenile retinoschisis can be differentiated by clinical and molecular means (07; 40; 39). The affected proteins of Norrie disease (NDP) and retinoschisis (RS1) are thought to be indirectly linked by FZD4 protein interactome via PLIN2, as well as the MAP kinase signaling pathway. One patient with Coats disease, Turner syndrome, and type 1 von Willebrand disease was negative for mutations in NDP (21). Mutations involving the Norrie disease gene and contiguous genes may result in more complex phenotypes (84; 88).

Diagnostic workup

Diagnosis is achieved through clinical (chiefly ophthalmologic and otolaryngologic) workup and identification of a mutation in the Norrie disease gene at Xp11. Identification of the mutation has been possible in approximately 70% of affected males (95). The presence of retinal changes is not helpful in identifying carrier patients (48). Prenatal diagnosis is valuable to confirm the presence of disease, counsel families, and prepare for possible postnatal therapy (16; 73; 97; 25). It is especially sought in cases of recurrent familial disease and has been successful as early as 11 weeks’ gestation, using chorionic villus sampling (30). Preimplantation genetic diagnosis is also possible for parents using in vitro fertilization (118). Ocular anomalies can also be identified ultrasonographically, which can be especially helpful when corneal opacity precludes more traditional examination (62). Persistent hyperplastic primary vitreous has been diagnosed in the early third trimester by ultrasound (27; 25). Large vitreous cavity opacities and retinal detachment have been visualized in a fetus at 36 weeks, with Norrie disease subsequently confirmed by Sanger sequencing (115). Molecular analysis of affected pedigree members is, of course, fundamental to understanding familial disease (22), and such workups may reveal adults that have been carried for years with incorrect diagnoses (11). The use of microarray technology to study retinopathies in large populations shows great promise (86). Copy number analysis is successful as well (03). Given the clinical variability within families, it is likely that additional genetic and environmental factors remain to be discovered (28).

Genetic factors are involved in some 50% of cases of profound hearing loss, including Norrie disease (04). To assess hearing loss, brainstem-evoked responses can be measured and electrocochleography performed.

The identification of cerebellar atrophy and motor or mental disorders in three affected members of a Chinese family is indication for additional imaging workup (56).

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Authors

Adam Friedant DO

Dr. Friedant of Jefferson Einstein Medical Center has no relevant financial relationships to disclose.
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Aparna M Prabhu MD MRCP

Dr. Prabhu of Thomas Jefferson University and Jefferson Einstein Medical Center has no relevant financial relationships to disclose.
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Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
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Former Authors

Joseph R Siebert PhD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: males more frequently affected (x-linked disease)
Heredity: heredity typical

heredity may be a factor

X-linked recessive
Population groups selectively affected: none
Occupation groups selectively affected: none

ICD & OMIM codes

ICD-10: Other specified congenital malformations of eye: Q15.8
ICD-11: Other specified syndromes with eye anomalies as a major feature: LD21.Y
OMIM: Norrie disease: #310600

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Norrie disease

Associated Disorders

Glaucoma
Intellectual deficits
Retinopathy of prematurity
Sensorineural deafness

Differential Diagnosis

retinopathy of prematurity
x-linked primary retinal dysplasia
Coats disease
Coats plus
congenital retinoschisis
- juvenile retinoschisis

Norrie disease …

Norrie disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

Dysplastic gangliocytoma of the cerebellum

Norrie disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vein of Galen malformations

Epileptic lesions due to malformation of cortical development

Agenesis of the corpus callosum

Epidermal nevus syndromes: neurologic phenotypes

Aqueductal stenosis

Klippel-Feil syndrome

Cerebellar hypoplasia, dysplasia, and enlargement

Dysplastic gangliocytoma of the cerebellum

This is an article preview.
Start a Free Account
to access the full version.