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NDP-Related Retinopathies

, MD
Director, Developmental Neurogenetics Clinic
Director, Neurogenetics DNA Diagnostic Lab
Professor, Neurology
Massachusetts General Hospital / Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Update: September 18, 2014.

Summary

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 greyish 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.

GeneReview Scope

NDP-Related Retinopathies: Included Phenotypes 1
  • Norrie disease (ND)
  • Persistent hyperplastic primary vitreous (PHPV)
  • X-linked familial exudative vitreoretinopathy (X-linked FEVR)
  • NDP-related retinopathy of prematurity (ROP)
  • Coats disease

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

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).

Table 1.

Classification of Ocular Phenotypes Observed in Individuals with an NDP Pathogenic Variant

PhenotypeOcular Findings /
Age
Progression /
Age
Vision
Norrie disease (ND)Greyish-yellow fibrovascular masses ("pseudoglioma") behind the lens (i.e., retrolental), retinal detachment (frequently) /
Birth – 3 mos
Cataract, posterior synechiae (iris to lens), anterior synechiae (iris to cornea), iris atrophy, shallowing of anterior chamber, corneal opacification, band keratopathy, loss of intraocular pressure, shrinking of the globe (phthisis bulbi) /
3 mos to 8-10 yrs
Light perception impaired or non-existent
Persistent hyperplastic primary vitreous (PHPV) 1Fibrotic white stalk with hyaloid vessels extending from optic disk to posterior lens capsule /
Birth
Unknown /
Unknown
Varying impairment
X-linked familial exudative vitreoretinopathy (FEVR) 2Peripheral temporal retinal avascular zone ± congenital retinal folds, macular ectopia, fibrous tissue band at ora serrate /
Birth
± Retinal detachment (tractional and/or exudative; may be unilateral) /
≤ age 20 yrs
Normal to impaired
Retinopathy of prematurity (ROP) stage 4B/5 3Retinal neovascularization, fibrous proliferation, end-stage retrolental fibroplasia /
Premature birth
Partial or complete retinal detachmentImpaired to blind
Coats disease 4Unilateral retinal telangiectasia, exudative fibrosisProgressive vascular leakage, subretinal exudation and fibrosis, retinal detachmentNormal to impaired
1.

NDP pathogenic variants in PHPV [Shastry 2009a]

2.

NDP pathogenic variants not infrequent in clinically identified X-linked FEVR [Nikopoulos et al 2010a, Nikopoulos et al 2010b, Poulter et al 2010, Walsh et al 2011, Yang et al 2012].

3.

Rare NDP pathogenic variants have been seen in those with an ROP phenotype [Shastry et al 1997]. Subsequent studies have identified DNA changes outside of the coding region that may be polymorphisms and/or possible modifiers of NDP gene expression [Kenyon & Craig 1999, Hiraoka et al 2001a, Talks et al 2001, Haider et al 2002, Hutcheson et al 2005, Shastry 2009b].

4.

In a family with an NDP pathogenic variant, a female carrier had a mosaic phenotype (Coats disease); and her sons had classic ocular findings of ND [Black et al 1999].

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).

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.

Table 2.

Summary of Molecular Genetic Testing Used in NDP-Related Retinopathies

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
Affected MalesCarrier Females
NDPSequence analysis 295% 3, 480% 5
Deletion/duplication analysis 615% 715% 7
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.

4.

Includes the 15% of pathogenic variants that are submicroscopic deletions involving all or part of NDP and adjacent genomic segments [Berger & Ropers 2001; Sims, unpublished].

5.

Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

6.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7.

Submicroscopic deletions involving all or part of NDP and adjacent genomic segments [Berger & Ropers 2001; Sims, unpublished].

Clinical Characteristics

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 greyish-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.

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.

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.

Histopathology

A retinal vasculopathy appears to be the primary pathophysiologic ocular change underlying the secondary, fibrotic reaction and associated vitreous hemorrhage. Retinal ganglion cell loss may also occur.

Abnormalities of retinal vasculature have been described in the mouse model [Richter et al 1998, Schäfer et al 2009]. In the ND mouse model, Rehm et al [2002] documented a progressive loss of vessels in the stria vascularis of the cochlea and an associated hearing loss. A differential gene expression study has identified candidate genes for retinal (photoreceptor) phenotype in the Ndp knockout mouse [Lenzner et al 2002]. Cerebellar vascular changes have also been documented in the Ndph knockout mouse [Luhmann et al 2008].

Heterozygotes

In rare instances, females who are carriers may have retinal findings (retinal detachment, abnormal retinal vasculature) [Lin et al 2010, Parzefall et al 2014] and have been described with associated vision loss [Yamada et al 2001]. A severe ocular phenotype has been described in multiple females in one family [Khan et al 2008].

Some carrier females may show a mild sensorineural hearing loss [Halpin et al 2005; Sims, unpublished data].

Phenotypic expression has been reported in two females with an X;autosome translocation [Meire et al 1998]; however, carrier expression is usually presumed to be secondary to non-random X-chromosome inactivation and is rare.

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.

Differential Diagnosis

Retinoblastoma (RB) is often considered in index cases of Norrie disease (ND) if the ocular pathology is predominantly that of unilateral pseudoglioma. Because the usual presentation of ND is bilateral, diagnosis of RB is not usually a consideration. Fundoscopic examination by an ophthalmologist familiar with retinal diseases can distinguish between the two disorders.

Retinal findings of ND can mimic PHPV and retinopathy of prematurity (ROP) (which occurs in preterm low birth-weight infants who have been treated with supplemental oxygen) [Shastry 2009a].

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is another consideration. NDP is a frizzled-4 (Fzd-4) ligand and activates the canonical Wnt signaling pathway [Xu et al 2004, Hendrickx & Leyns 2008]. Pathogenic variants in FZD4 [Robitaille et al 2002], LRP5 [Jiao et al 2004, Toomes et al 2004], and TSPAN12 [Nikopoulos et al 2010b, Poulter et al 2010, Yang et al 2011] have been identified in autosomal dominant FEVR. Because the phenotype of FEVR may overlap with that of ND, FZD4, LRP5, and TSPAN12 pathogenic variants may underlie some instances of ND in which the mode of inheritance is not clear.

Retinal dysplasia with PHPV-type changes can be associated with lissencephaly in Walker-Warburg syndrome, an autosomal recessive form of congenital muscular dystrophy, and with multiple anomalies in trisomy 13. However, neither of these should be confused clinically with Norrie disease.

ND is not considered in the differential diagnosis of intellectual disability and/or progressive sensorineural hearing loss (see Deafness and Hereditary Hearing Loss Overview) in the absence of the characteristic ocular features.

Management

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
  • Clinical genetics consultation

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 which 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 for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

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 Detection

Identification of female carriers requires:

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 and preimplantation genetic diagnosis for a pregnancy at increased risk for an NDP-related retinopathy are possible options.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Norrie Disease Association (NDA)
    PO Box 3244
    Munster IN 46321
    Email: joinnda@gmail.com
  • American Council of the Blind (ACB)
    2200 Wilson Boulevard
    Suite 650
    Arlington VA 22201
    Phone: 800-424-8666 (toll-free); 202-467-5081
    Fax: 202-467-5085
    Email: info@acb.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jernigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • Norrie Disease Registry
    Massachusetts General Hospital
    185 Cambridge Street
    CRP Building North, 5th Floor, Suite 5300
    Boston MA 02114
    Phone: 617-726-5718
    Fax: 617-724-9620
    Email: ksims@mgh.harvard.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

NDP-Related Retinopathies: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for NDP-Related Retinopathies (View All in OMIM)

300216COATS DISEASE
300658NDP GENE; NDP
305390EXUDATIVE VITREORETINOPATHY 2, X-LINKED; EVR2
310600NORRIE DISEASE; ND

Molecular Genetic 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 allelic 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 allelic 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 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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  • Ye X, Wang Y, Nathans J. The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med. 2010;16:417–25. [PMC free article: PMC2963063] [PubMed: 20688566]
  • Zaremba J, Feil S, Juszko J, Myga W, van Duijnhoven G, Berger W. Intrafamilial variability of the ocular phenotype in a Polish family with a missense mutation (A63D) in the Norrie disease gene. Ophthalmic Genet. 1998;19:157–64. [PubMed: 9810571]
  • Zhang K, Harada Y, Wei X, Shukla D, Rajendran A, Tawansy K, Bedell M, Lim S, Shaw PX, He X, Yang Z. An essential role of the cysteine-rich domain of FZD4 in Norrin/Wnt signaling and familial exudative vitreoretinopathy. J Biol Chem. 2011;286:10210–5. [PMC free article: PMC3060474] [PubMed: 21177847]
  • Zhang XY, Jiang WY, Chen LM, Chen SQ. A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family. Int J Ophthalmol. 2013;6:739–43. [PMC free article: PMC3874509] [PubMed: 24392318]

Suggested Reading

  • Berger W, Ropers HH. Norrie disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 239. McGraw-Hill. Available online. Accessed 5-11-16.

Chapter Notes

Author Notes

Web: www.DNAlab.org

Revision History

  • 18 September 2014 (me) Comprehensive update posted live
  • 23 July 2009 (me) Comprehensive update posted live
  • 8 August 2006 (me) Comprehensive update posted to live Web site
  • 14 May 2004 (me) Comprehensive update posted to live Web site
  • 11 June 2002 (me) Comprehensive update posted to live Web site
  • 30 July 1999 (me) Review posted to live Web site
  • 10 February 1999 (ks) Original submission
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