Clinical characteristics.

NDP-related retinopathies are characterized by a spectrum of fibrous and vascular changes of the retina at birth that progress through childhood or adolescence to cause varying degrees of visual impairment. The most severe phenotype is described as Norrie disease (ND), characterized by grayish-yellow fibrovascular masses (pseudogliomas) secondary to retinal vascular dysgenesis and detachment. Congenital blindness is almost always present. Approximately 30%-50% of males with ND have developmental delay / intellectual disability, behavioral abnormalities, or psychotic-like features. The majority of males with ND develop sensorineural hearing loss. Less severe phenotypes include: persistent hyperplastic primary vitreous (PHPV), characterized by a fibrotic white stalk from the optic disk to the lens; X-linked familial exudative vitreoretinopathy (XL-FEVR), characterized by peripheral retinal vascular anomalies with or without fibrotic changes and retinal detachment; retinopathy of prematurity (ROP); and Coats disease, an exudative proliferative vasculopathy. Phenotypes can vary within families.

Diagnosis/testing.

The diagnosis of NDP-related retinopathies relies on a combination of clinical findings and molecular genetic testing of NDP, which identifies pathogenic variants in approximately 95% of affected males.

Management.

Treatment of manifestations: Treatment for less than complete retinal detachment includes surgery and/or laser therapy with the potential for improved outcomes if done at an early age. Surgery may be required for increased intraocular pressure. Rarely, enucleation of the eye is required to control pain. Treatment for hearing loss may include hearing aids and cochlear implantation. Behavioral issues and/or cognitive impairment involve supportive intervention and therapy.

Surveillance: Routine monitoring of vision and hearing.

Genetic counseling.

NDP-related retinopathies are inherited in an X-linked manner. Affected males transmit the pathogenic variant to all their daughters, who will be carriers, and none of their sons. Carrier females have a 50% chance of transmitting the pathogenic variant to each child; males who inherit the pathogenic variant will be affected, and females who inherit the pathogenic variant will be carriers and will generally not be affected. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant has been identified in the family.

Suggestive Findings

An NDP-related retinopathy should be suspected in individuals with the following ocular findings:

• Congenital visual failure / blindness
• Bilateral, often symmetric involvement of the eyes
• Persistent hyperplastic primary vitreous, hyaloid vessels, shallow anterior chamber, and vitreoretinal hemorrhages. Microopthalmia and cataracts may be present.
• Presence of retrolental fibrous and vascular retinal changes at birth (leukokoria) with progressive changes through childhood or adolescence

Pathogenic variants in NDP are associated with a spectrum of characterized retinal findings ranging from classic Norrie disease (ND) to X-linked familial exudative vitreoretinopathy (FEVR), some cases of persistent hyperplastic primary vitreous (PHPV), Coats disease, and advanced retinopathy of prematurity (ROP). These phenotypes appear to be a continuum of retinal findings with considerable overlap (Table 1).

Establishing the Diagnosis

The diagnosis of an NDP-related retinopathy is established in a proband with the identification of a pathogenic variant in NDP (see Table 2).

• One genetic testing strategy is molecular genetic testing of NDP. Sequence analysis is performed first and followed by deletion/duplication analysis if no pathogenic variant is found.
• An alternative genetic testing strategy is use of a multigene panel that includes NDP and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Linkage analysis. In the very infrequent cases where a known NDP pathogenic variant is not identified, linkage analysis can be considered in families with more than one affected family member. Linkage studies are based on accurate clinical diagnosis of NDP-related retinopathies in the affected family members and accurate understanding of the genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of family members to be tested. The markers used for NDP linkage are highly informative and very tightly linked to the NDP locus; thus, they can be used in many families with NDP-related retinopathies with greater than 95% accuracy. In informative families, linkage analysis can be used to determine the carrier status of an at-risk female.

Clinical Description

The ocular findings in males with an NDP pathogenic variant are usually bilateral and symmetric. They are present at birth and are usually progressive. The classic ND phenotype after which the disorder is named was the first described eye finding and is the best characterized of the ocular manifestations. With the discovery of NDP and the advent of clinically available molecular genetic testing, it has become evident that the ocular phenotypes observed in NDP-related retinopathies include Norrie disease (ND), persistent hyperplastic primary vitreous (PHPV), and X-linked familial exudative vitreoretinopathy (XL-FEVR), [Riveiro-Alvarez et al 2005, Dickinson et al 2006, Kondo et al 2007] (Table 1).

The ocular phenotype can vary even within a family [Berger & Ropers 2001, Allen et al 2006]. In one family, the spectrum of ocular phenotypes in nine affected males ranged from unilateral subtotal retinal detachment at ages three to four years that slowly progressed to a tractional detachment (at the severe end) to peripheral retinal pigmentary changes in a male age 79 years (at the mild end) [Allen et al 2006].

Norrie disease

• Ocular findings. At birth, the irises, anterior chambers, cornea, intraocular pressure, and size of the globe may be normal. In newborns and infants, the classic finding is a grayish-yellow, glistening, elevated mass that replaces the retina and is visible through a clear lens. These masses are referred to as "pseudogliomas" because they resemble tumors. Partial or complete retinal detachment evolves over the first few months.
  From infancy throughout childhood, progressive changes typically include: opacification of the lens (cataract), atrophy of the iris with adhesions forming between the lens and the iris (posterior synechiae) and between the iris and the cornea (anterior synechiae), and development of a shallow anterior chamber with occlusion of the outflow tracts, which may result in increased intraocular pressure and pain.
  These changes are followed by corneal opacification and band keratopathy, loss of intraocular pressure, and shrinkage of the globe (phthisis bulbi). In the end stage of ND, the corneas appear milky and opacified, and the globes appear small and sunken in the orbits [Drenser et al 2007].
• Cognitive/behavioral findings. Approximately 30%-50% of males with the ND phenotype have developmental delay / intellectual disability and may show poorly characterized behavioral abnormalities or psychotic-like features. Intra- and interfamilial variability in the appearance and expression of the cognitive and behavioral difficulties is common. A severe neurologic phenotype including infantile spasms has been reported [Lev et al 2007].
• Auditory findings. The majority of males with the ND phenotype develop progressive sensorineural hearing loss starting in early childhood (Figure 1). Onset of hearing loss can be insidious.
  Audiologic data suggest that the pathology resides in the cochlea (specifically, the stria vascularis) and that retrocochlear and brain auditory system function is normal. Early hearing loss is sensorineural, mild, and asymmetric. High-frequency hearing loss appears by adolescence. By age 35 years, hearing loss is severe, symmetric, and broad-spectrum. Speech discrimination is relatively well preserved even when the threshold loss is severe [Halpin et al 2005, Halpin & Sims 2008].
  For most affected individuals, adaptation to the congenital blindness may be less problematic than adjustment to the later-onset, slowly progressive hearing loss.
• Other. Peripheral vascular disease (Figure 2) appears to be an associated clinical finding in a number of affected males [Smith et al 2012].
  Pulmonary hypertension has been described.
  General health is normal. Life span may be shortened by general risks associated with intellectual disability, blindness, and/or hearing loss, such as increased risk of trauma, aspiration pneumonia, and complications of seizure disorder.

Figure 1.

Hearing loss in males with Norrie disease. A subset of males enrolled in the Norrie Disease Registry (n=56) by age group with hearing loss [Smith et al 2012]

Figure 2.

Peripheral vascular disease in males with Norrie disease. Peripheral vascular disease by age group in a subset of patients enrolled in the Norrie Disease Registry (n=56) [Smith et al 2012]

PHPV is characterized by a fibrotic white stalk with vessels extending from the optic disk to the temporal posterior lens capsule. The retina may be in folds or detached; the lens may or may not be clear. Although progression to complete retinal detachment has been described, it is not clear if such progression always occurs [Wu et al 2007]. PHPV is usually unilateral; therefore, bilateral presentation should suggest an NDP-related retinopathy.

X-linked FEVR is characterized by premature arrest of vascularization of the retina resulting in an avascular zone in the peripheral retina. This avascular zone may be the only retinal finding, or congenital falciform retinal folds or retinal detachment may be present. When falciform folds are present, the macula may be dragged temporally (so-called macular ectopia).

These eye findings may progress to retinal detachment either through increasing traction on the retina from progressive fibrovascular changes in the temporal retinal periphery or through exudation of serous fluid by the fragile capillaries in the abnormal peripheral retinal vasculature. Retinal detachment is usually accompanied by a decrease in central visual acuity because of macular involvement.

Advanced retinopathy of prematurity (ROP; Stage 4B/5) involves retinal changes similar to those found in FEVR. Pathogenic variants in NDP were identified in four of 16 premature infants with advanced ROP [Hiraoka et al 2001a], raising the question of whether NDP pathogenic variants may predispose to the ND ocular phenotype in some premature infants. More recently in 17 infants with advanced ROP, one was identified with an NDP pathogenic variant in the 5'UTR [Hiraoka et al 2010]. A study of 102 Kuwaiti Arab premature infants, however, identified only polymorphisms and no phenotype-associated NDP pathogenic variants [Haider et al 2001]. Hutcheson et al [2005] studied 54 infants with severe ROP (Stage ≥3) of different ethnic backgrounds and identified five sequence variations in untranslated regions (UTR) of NDP. No clear role for these NDP polymorphisms in the pathogenesis of ROP was established.

Coats disease (exudative retinitis) is an exudative proliferative vasculopathy with onset typically before age 20 years, and usually in infancy or childhood. Male-to-female ratio is 10:1. Retinal vascular changes include telangiectasias, venous and capillary fusiform dilatation, and microaneurysms. Subretinal lipid exudate and retinal hemorrhage are observed, usually in the macula and/or supertemporal regions. Exudative retinal detachment and decreased retinal capillary perfusion may occur. Other complications can include iridocyclitis, cataract, or neovascular glaucoma. More than 90% of reported cases appear to be unilateral.

Genotype-Phenotype Correlations

Phenotypic variability, both intra- and interfamilial, has been noted in retinal phenotype [Wu et al 2007] and in the non-retinal clinical characteristics [Khan et al 2004, Allen et al 2006]. Intellectual disability can be variably expressed as was noted in one of two brothers with a deletion involving the NDP start codon [Zhang et al 2013], although in other reported cases, multiple brothers evidenced classic NDP retinal features and all had intellectual disability [Arai et al 2014]. A more extended phenotype including cerebellar atrophy, movement disorder, and intellectual disability was described in three brothers and supports the hypothesis that other epigenetic factors beyond the NDP pathogenic variant may affect clinical phenotypic expression [Liu et al 2010].

Males with NDP deletions exhibit a more severe phenotype than those with non-deletion pathogenic variants [Suárez-Merino et al 2001, Wu et al 2007, Yang et al 2012, Arai et al 2014]. In addition to the ocular manifestations of ND, individuals with a deletion may have microcephaly, severe-to-profound intellectual disability, seizures, myoclonus, somatic growth failure, and/or delayed puberty.

Pathogenic variants disrupting the cysteine-knot motif appear to correspond to severe retinal dysgenesis [Wu et al 2007]. Unique single-nucleotide variants, identified in four individuals with severe retinal dysplasia, affected a cysteine residue and presumably altered important structural aspects of the protein [Drenser et al 2007].

Although it has been suggested that pathogenic missense variants in the C-terminus region may be associated with the milder FEVR phenotype [Allen et al 2006], a number of individuals with severe ocular phenotypes with or without intellectual disability have had pathogenic variants in the C-terminus region [Sims, unpublished].

No specific correlations have been identified between single-base-pair pathogenic variants and cognitive dysfunction or hearing impairment. However, one individual with a single nucleotide variant (c.134T>A) has been reported with a severe neurologic phenotype including profound intellectual disability and infantile spasms [Lev et al 2007].

Contiguous gene syndromes with more extended and variable phenotypes have been described with NDP+ deletion cases [Sims et al 1989, Rodriguez-Revenga et al 2007]. Familial idiopathic pulmonary hypertension was reported in a family with a Xp11.3-11.4 microdeletion including NDP [Staropoli et al 2010].

A more extended phenotype in the affected son (cerebroretinal microangiopathy with calcifications and cysts) of a mother diagnosed with unilateral atypical Coats disease was described in association with an NDP pathogenic missense variant and compound heterozygous pathogenic variants in CTCI (conserved telomere maintenance component 1) gene [Romaniello et al 2013] previously associated with a small-vessel obliterative microangiopathy in Coats plus [Anderson et al 2012] and in cerebroretinal microangiopathy with calcifications [Polvi et al 2012]. This importantly raises the question of possible pathway interactions between these two genes leading to a severe and extended phenotype both in male probands and in carrier mothers.

Penetrance

Penetrance is complete in affected males.

Rarely, a partial or mild ocular phenotype occurs in carrier females, presumably secondary to non-random X-chromosome inactivation.

Nomenclature

The following are outdated terms for Norrie disease:

• Atrophia bulborum hereditaria
• Pseudoglioma
• Episkopi blindness

Prevalence

No incidence or prevalence figures are available. NDP pathogenic variants were identified in 11/109 individuals with diverse pediatric vitroretinopathies [Wu et al 2007].

Norrie disease has been reported in all ethnic groups, including northern and central European, Americans of European descent, African American, French-Canadian, Hispanic, Chinese, and Japanese. Although no ethnic group appears to predominate, most of the individuals reported in the first decades after the original description of Norrie disease were from Scandinavia.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NDP-related retinopathies, the following evaluations are recommended:

• Complete ophthalmologic examination
• Baseline audiologic evaluation
• Neurodevelopmental assessment in early childhood if developmental milestones are not met
• Behavioral evaluation as needed
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Ocular manifestations

• The majority of males with the classic Norrie disease (ND) phenotype have complete retinal detachment at the time of birth; therefore, interventional therapy may not offer much with regard to preservation of sight. Ophthalmologic evaluation is warranted.
• Individuals without complete retinal detachment may benefit from surgery and/or laser therapy with the potential for improved outcomes if done at an early age.
  • A report by Chow et al [2010] described successful laser photocoagulation at birth (37 weeks' gestation) of a male with ND in which Teller visual acuity was measured at 20/100 O.D. at 23 months of life.
  • Retrospective medical record review of all patients seen in a tertiary care pediatric retinal clinical practice (1988-2008) of 14 males with ND documented maintenance of light perception in at least one eye (7/14 cases) with early vitrectomy done by age 12 months (median 4.5 months) [Walsh et al 2010].
• In the progressive stage of the Norrie disease phenotype, development of increased intraocular pressure may require surgery. Rarely, enucleation of the eye is required to control pain.

Sensorineural hearing loss

• Hearing aid augmentation is usually successful well into middle or late adulthood.
• Cochlear implantation should be considered when hearing-assisted audiologic function is significantly impaired.

Behavioral issues are a lifelong challenge to many individuals with Norrie disease and to their guardians/caretakers, whether or not intellectual disability or cognitive impairment is present. Intervention and therapy are supportive and aimed at maximizing educational opportunities.

An empiric trial of psychotropic medications may be warranted, although no studies have addressed or supported the use of specific medications for treatment of Norrie disease.

Surveillance

The following are recommended:

• Routine follow up with an ophthalmologist in all individuals with an NDP-related retinopathy, even when vision is severely reduced
• Given that most individuals with the NDP-related spectrum of retinopathies are blind, routine monitoring of hearing so that hearing loss can be detected early and managed appropriately
• Observation for clinical evidence of venous stasis or ulcer disease

Agents/Circumstances to Avoid

Given the increased risk of hearing loss, exposure to loud noises should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Pregnancy Management

A planned delivery at 34 weeks' gestation of a male with an established NDP pathogenic variant (in whom retinal detachment was excluded following fetal ultrasonography at 28 and 33 weeks) was reported [Sisk et al 2014]. Authors describe treatment at two days of life with laser ablation of the avascular retina in both eyes and ten-month follow up that showed the retina to remain completely attached in both eyes [Sisk et al 2014].

Therapies Under Investigation

Ohlmann et al [2005] have elaborated in the mouse knockout a failure of retinal angiogenesis and documented correction of the ocular-vascular phenotype by transgenic ectopic lens expression of norrin. These authors also noted a potential effect of norrin on retinal ganglion cell proliferation.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

NDP-related retinopathies are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of a male proband is neither affected nor a carrier.
• The majority of mothers of a male proband are carriers of an NDP pathogenic variant, even when the family history is negative.
• Rarely, affected males have a de novo pathogenic variant. Women who are carriers may have an inherited or de novo pathogenic variant.
• Women who have an affected child and one other affected relative are obligate heterozygotes (carriers).

Sibs of a male proband. The risk to sibs depends on the carrier status of the mother:

• If the mother of the proband has an NDP pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will generally not be affected.
• If the pathogenic variant has not been identified in DNA extracted from the mother's leukocytes, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a male proband. Males with an NDP-related retinopathy will pass the NDP pathogenic variant to all of their daughters, who will be carriers, and to none of their sons.

Other family members of a male proband. The proband's maternal aunts may be at risk of being carriers of an NDP pathogenic variant and the aunts' offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier (Heterozygote) Detection

Identification of female carriers requires one of the following:

• Prior identification of the NDP pathogenic variant in the family
• If an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no NDP pathogenic variant is identified, then by deletion/duplication analysis (see Table 2)
• Linkage analysis if:
  • Sequence analysis and deletion analysis do not identify a pathogenic variant;
    AND
  • The family structure is appropriate for linkage studies;
    AND
  • The necessary family members are available for testing.

Note: Carriers are heterozygotes for this X-linked disorder and rarely develop clinical findings related to the disorder; however, individuals with manifestations have been described [Lin et al 2010, Romaniello et al 2013, Parzefall et al 2014] and caution should be maintained when discussing carrier risk in the context of genetic and prenatal counseling.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the NDP pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for an NDP-related retinopathy are possible.

Molecular Pathogenesis

Mouse model studies have documented that norrin deficiency plays a critical role in the retinal and cochlear vasculopathy [Xu et al 2004, Hendrickx & Leyns 2008] and presumably the same pathobiologic failure of normal angiogenesis underlies the visual failure and risk of hearing loss and/or intellectual disability in human ND. Studies in the knockout mouse (Ndp y/-) have shown failure of retinal angiogenesis with complete lack of the deep capillary layers of the retina and progressive loss of vessels in the stria vascularis of the cochlea [Rehm et al 2002]. This failed retinal vascularization presumably leads to retinal hypoxia and fatal retinal injury [Luhmann et al 2005].

Norrin binds to the Fzd4 CRD [Smallwood et al 2007]. Norrin-Fzd4 signaling [Ye et al 2010], with subsequent activation of the classic Wnt pathway, plays a central role in retinal vascular development [Xu et al 2004, Warden et al 2007, Parmalee & Kitajewski 2008, Ohlmann & Tamm 2012] including effect on endothelial cell proliferation, migration and retinal invasion, arterial and venous topography, and stability of the BBB and BRB through regulation of transcription factors, cell surface receptors, and cell junction proteins [Paes et al 2011, Wang et al 2012]. Norrin also has significant neuroprotective properties through activation of Wnt/beta-catenin signaling [Seitz et al 2010] and induction of neuroprotective growth factor synthesis in Muller cells [Ohlmann & Tamm 2012]. Norrin is expressed widely in brain astrocytes and cerebellar Bergmann glia [Ye et al 2011], suggesting an as-yet unclarified phenotypic role in these CNS systems.

The role that norrin plays in intellectual disability remains unclear. Recently, NDP expression was shown to be initiated in retinal progenitors in response to Hedgehog (Hh) signaling through induction of Gli2 binding to the NDP promoter [McNeill et al 2013]. The authors hypothesized a possible role for Ndp in more global neural function, given the identification of Ndp function in neural progenitor proliferation apart from its function in the retinal vasculature.

Gene structure. NDP spans 28 kb of genomic DNA. The cDNA comprises three exons, and the coding portion spans the latter half of exon 2 and the first portion of exon 3 yielding a mRNA of 2.1 kb. Exon 1 is untranslated and may function as a promoter region for gene transcription. ND-associated pathogenic variants have been identified in exon 1 [Schuback et al 1995, Kenyon & Craig 1999], although their functional significance remains controversial. A cysteine-rich region, presumed critical to secondary protein structure, exists in the carboxyl terminus of exon 3. It is here that the majority of pathogenic variants have been identified, although such variants are widely dispersed throughout the coding region. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. The possibility remains that single-nucleotide variants (SNVs) may play a role in ND clinical phenotypic expression or modulation. Both insertion and deletion variants in exon 1, associated with advanced ROP, have been described [Hiraoka et al 2001a, Dickinson et al 2006, Wu et al 2007]. Exon 1 insertions and deletions have been seen in a number of controls [Sims, unpublished data], suggesting that these may be benign. It remains, however, a possibility that these exon 1 variants predispose to a clinical vascular phenotype in certain at-risk cohorts.

Pathogenic variants. More than 100 NDP pathogenic variants (missense, null, splice, deletions) have been described [Ye et al 2010]. The majority of pathogenic variants are single-base-pair changes identified in the coding region of NDP [Schuback et al 1995, Shastry 1998, Zaremba et al 1998, Black et al 1999, Hiraoka et al 2001b, Yamada et al 2001, Dickinson et al 2006, Drenser et al 2007, Kondo et al 2007, Lev et al 2007, Wu et al 2007, Khan et al 2008, Yang et al 2012].

More than 20 DNA rearrangements have been noted including intragenic (small) deletions, or submicroscopic ("NDP plus") deletions and account for approximately 15% of pathogenic variants [Berger & Ropers 2001; Rodriguez-Revenga et al 2007; Staropoli et al 2010; Sims, unpublished data]. Affected individuals with insertions [Hiraoka et al 2001a], complex rearrangements [Schuback et al 1995], and X;autosome translocations [Meire et al 1998] have been documented. A few of these individuals have deletions that have been identified as extending beyond the NDP locus. These individuals have more complex phenotypes suggestive of contiguous gene syndromes [Sims et al 1989, Suárez-Merino et al 2001, Rodriguez-Revenga et al 2007, Staropoli et al 2010].

Ke et al [2013] characterized five categories of pathogenic variant based on crystalline structure of NDP: (1) cysteine residue, (2) dimer interface, (3) hydrophobic core, (4) Fzd4 binding site, and (5) Lrp5/6 binding site variants. Fzd4 cysteine-rich domain (CRD) variants had previously been shown to affect Norrin binding and signaling [Zhang et al 2011].

Most pathogenic variants are unique and have been identified in single individuals/families; a few pathogenic variants have been seen in multiple, apparently unrelated families. Founder variants have not been identified. The pathogenic missense variants all predict significant amino acid change and often affect one of the many cysteine residues immediately adjacent to a cysteine. These cysteine residues are presumed important for the maintenance of protein structure, and pathogenic variants in these residues would be potentially deleterious to protein function.

Normal gene product. Norrin [NM_000266; NP_000257] is a secreted protein comprising 133 amino acids; it has a cysteine-knot motif (highly conserved in many growth factors). Crystal structure analysis indicates that norrin exists as a homodimer and that dimer formation is required for binding to Frizzled-4 (Fzd4) receptors [Ke et al 2013]. This binding activates the canonical Wnt/beta-catenin signaling pathway and is enhanced by Tspan12 [Junge et al 2009]. Norrin is critical in CNS vascular development as norrin is required for angiogenesis in the eye, ear, and brain; maintains the blood-brain-barrier (BBB) and the blood-retinal-barrier (BRB); and exhibits neuro-protective properties for retinal neurons.

Messenger RNA localization by in situ hybridization to the outer nuclear layer, inner nuclear layer, and ganglion cell layer of the retina (mice, rabbit, human) early on suggested a role in retinal development [Hartzer et al 1999]. Later and ongoing animal model studies (see Abnormal gene product) have continued to support a role for norrin in cellular or tissue differentiation and maintenance of cellular phenotype and in intercellular communication, critical to normal retinal, CNS, and cochlear development.

Abnormal gene product. The phenotype of the norrin-deficient mouse models (Ndp y/-) shows impaired retinal vascular development with inadequate capillary outgrowth into the retinal surface and attendant loss of all intraretinal capillaries [Richter et al 1998, Rehm et al 2002, Luhmann et al 2005, Ohlmann et al 2005], as well as abnormal persistence of the hyaloid vasculature. Late-onset hearing loss was seen associated with cochlear degeneration [Berger 1998], and abnormal vessels in the inner ear were described [Rehm et al 2002, Ohlmann et al 2005]. Differential gene expression in Ndp knockout mice provides further evidence of a role for norrin in retinal vascular development [Schäfer et al 2009, Ye et al 2011, Lee et al 2013].

Exogenous norrin has been shown to restore the normal retinal vascular network [Ohlmann et al 2005], suppress vascular loss and pathologic neovascularization in a mouse model of ROP [Ohlmann et al 2010], and rescue the retinal vasculature in a mouse model of oxygen-induced retinopathy [Tokunaga et al 2013]. Overexpression of norrin activates the Wnt/beta-catenin and endothelin-2 signaling and protects photoreceptors from light damage [Braunger et al 2013].

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Author Notes

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Revision History

• 3 September 2020 (ma) Chapter retired: outdated; qualified authors not available for update
• 18 September 2014 (me) Comprehensive update posted live
• 23 July 2009 (me) Comprehensive update posted live
• 8 August 2006 (me) Comprehensive update posted live
• 14 May 2004 (me) Comprehensive update posted live
• 11 June 2002 (me) Comprehensive update posted live
• 30 July 1999 (me) Review posted live
• 10 February 1999 (ks) Original submission