Norrie Disease

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Article initiated by:
Mario Carranza Casas, MD
All contributors:
Felix Y. Chau, MD, Leo A. Kim, MD, PhD, Koushik Tripathy, MD (AIIMS), Mario Carranza Casas, MD, Mary Elizabeth Hartnett, MD, Jennifer I Lim MD, Marcus M. Marcet, MD, Michael Murri, MD, Gabriel Velez, MD, PhD, Brittni A. Scruggs, MD, PhD
Assigned editor:
Brittni A. Scruggs, MD, PhD
Review:
Assigned status Update Pending
 by Mary Elizabeth Hartnett, MD on January 7, 2024.


Norrie Disease
DiseasesDB
31165
OMIM
310600
MeSH
C537849


Norrie disease is a rare genetic disorder that primarily affects the retina, usually leading to blindness. In addition to the congenital ocular symptoms, patients may suffer from other systemic symptoms, including childhood-onset progressive hearing loss, abnormal sleep wake cycles,[1] peripheral vascular disease and learning or behavioral problems.

Patients with Norrie disease may develop retinal detachment, cataracts, leukocoria, iris atrophy as well as other developmental issues in the eye. Patients may experience psychotic-like features and poor coordination of movements.

Most patients are born with normal hearing with onset of hearing loss commonly seen in the second decade of life. Apart from retinal disease, there is significant variance in additional symptoms with only 15% of patients estimated to develop all the features of the disease.

The disease affects almost only male infants, owing to its X-linked recessive inheritance, although females have been reported to show some milder features of the disease.

Disease Entity

Norrie disease (ND; OMIM 310600) is a rare X-linked recessive disorder resulting from a mutation in the the Norrin cystine knot growth factor gene also referred to as Norrie Disease Pseudoglioma (NDP) gene that is involved in retinal cell development and blood flow to the inner ear and retina. It is characterized by retinopathy leading to blindness in male infants at birth or soon afterwards.[2] Variable systemic features include growth and developmental delays with cognitive impairment and/or behavioral disorders, peripheral vascular disease as well as sensorineural hearing loss.

Disease

Norrie disease is the most severe phenotype in the spectrum of NDP-Related Retinopathies,[3][4] a group that includes: Persistent fetal vasculature (PFV), X-linked familial exudative vitreoretinopathy (X-linked FEVR), NDP-related retinopathy of prematurity (ROP), and has been reported with some forms of Coats disease or diseases with Coats-like manifestations[5][6][7][8][9].

NDP-related retinopathies are genetically determined diseases inherited in an X-linked manner and caused by mutations in the NDP gene. They are characterized by fibrous and vascular changes of the retina at birth that progress through childhood and adolescence and cause different degrees of visual impairment. Most of these also include diverse systemic features that can vary throughout and within families.[10]

Other names for this disease include:

  • Anderson-Warburg syndrome,
  • Norrie-Warburg syndrome,
  • Whitnall-Norman syndrome,
  • Atrophic bulborum hereditaria,
  • Episkopi blindness:[11] The disease was described in a family of a village of Cyprus, named Episkopi.
  • Fetal iritis syndrome,
  • Congenital progressive oculo-acoustico-cerebral degeneration,
  • Oligophrenia microphthalmos, and
  • Pseudoglioma congenita.

Etiology

Norrie disease is a genetically inherited, X-linked recessive disorder that results from mutations in the NDP gene (Xp11.4-p11.3; GeneID: 4693) encoding the Norrin protein, involved in the vascular development of the retina and inner ear. [12][13][14] Pathogenic variants that disrupt normal protein formation cause retinal dysgenesis that in turn results in disorganized retinal tissue development with fibrovascular changes.[15] Since Norrin is also expressed in other systems of the body, the effects of the disorder are pleiotropic.

There are more than 75 pathogenic variants of the NDP gene (including deletions) that cause Norrie disease with many novel mutations as might be expected for a disorder that leads to a reduction in reproductive fitness. [3] [16] While penetrance is complete (100%) in affected males, carrier females are usually unaffected or asymptommatic, except in rare cases with partial hearing loss or mild ocular phenotype. These cases are secondary to non-random X-chromosome inactivation or a mutation on both X chromosomes seen in consanguineous families or spontaneous somatic mutations. [17] In a recent study, 12 carrier females were found to exhibit clinical features of FEVR, including peripheral vascular changes telangiectatic endings, anomalous circumferential vessels, supernumerary vascular branching, fluorescein leakage, avascular retinal areas, retina folds, and peripheral straightening of retinal vessels.[18]

Epidemiology

Norrie disease is a rare disorder; its exact incidence and prevalence are unknown, but more than 400 cases have been described. Affected patients are almost always male, while females are carriers. [19] It is not associated with any specific race or ethnicity, and has been reported in the following groups: northern and central European, American 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 original descriptions of Norrie disease were of Scandinavian (Denmark) descent. [20] [21]

Risk Factors

Currently there are no known risk factors or racial predisposition for this disease apart from genetic inheritance.

General Pathology

A retinal vasculopathy appears to be the primary pathologic ocular change underlying the secondary, fibrotic reaction and associated vitreous hemorrhage. Retinal ganglion cell loss may also occur. [15] Histology shows hemorrhagic necrosis of an undifferentiated glial mass.  The primary defect seems to lie in the neurosensory retina with absence of the ganglion cells and dysplasia of the remaining layers. If allowed to progress, many eyes become phthisical. [22]

Pathophysiology

The NDP gene is a 28 kb gene used to synthesize the 133 amino acid protein Norrin[23], which plays a role in molecular signaling pathways that affect tissue development. Studies suggest that Norrin may play a role in Wnt signaling, which is important for cell division, adhesion, migration, and many other cellular activities. [24] Norrin is one of many ligands that can bind to cell membrane receptors referred to as frizzled receptors. Norrin binds with the receptor frizzled-4 (produced from the FZD4 gene) and initiates a genetic regulatory process. [14] This pathway is believed to affect molecular processes that are crucial for normal development of the eye and other body systems. In particular, Norrin seems to play critical roles in the specialization of cells in the retina (with high expression of NDP in Müller cells),[23] the establishment of blood supply to the retina and the inner ear, [25] [26] and the maturation of cochlear hair cells.[27]

As a result of these mutations, masses of immature retinal cells accumulate in the vitreous chamber. Disruption in the establishment of blood vessels supplying the eye also causes retinal tissue breakdown leading to a retrolental mass of disorganized tissue. [28]

Dysfunction of Norrin protein depends on the type and location of the NDP gene mutation. Nonsense mutations that delete portions of the NDP gene prevent full production of Norrin and result in more severe disease.[10] Missense mutations that delete or change single amino acids but do no cut short full protein production usually result in less widespread effects. This leads to a gradient of severity in systemic issues including intellectual disability, seizures, behavioral problems, peripheral vascular disease, and delayed development. [22]

In general, there can be great variability between genotype and phenotype.[29] Variability exists within families that have the same genetic mutation and has been reported within the same individual between eyes. In addition, individuals with different genotypes can have similar phenotypes. Part of the reason for this may be gene-gene interactions, gene-environment interactions, as well as the involvement of later pathophysiologic processes. An example can be an early retinal detachment that progresses to become a fold involving the fovea.  

Diagnosis

Norrie disease and other NDP related diseases are diagnosed with the combination of the characteristic clinical ocular findings and confirmation by molecular genetic testing. [4] These tests can identify pathogenic variants in approximately 95% of affected males. No biochemical or functional assays are available for diagnosis.

Molecular genetic testing can be used for more than a confirmatory diagnosis. Currently it is also used for testing possible carrier females, for prenatal diagnosis, and preimplantation genetic diagnosis. There are three types of clinical molecular genetic tests. In approximately 85% of males, missense and splice mutations of the NDP gene and partial or whole deletions are detected using sequence analysis. In addition, deletion/duplication analysis can be used to detect the remaining 15% submicroscopic deletions that cannot be tested with sequence analysis. Sequence analysis is also used to test carrier females. The last test used is linkage analysis, which is done when the first two options are unavailable. Linkage analysis is also recommended for those families who have more than one family member affected by the disease. [4] Prenatal testing for at-risk pregnancies is available if the disease-causing mutation has been identified in the family. [30] Prenatal ultrasound has also been used to diagnose Norrie disease, albeit infrequently.[31]

History

Norrie disease was first described by Mette Warburg, a Danish ophthalmologist, as a defined hereditary syndrome in Acta Ophtalmologica in 1961.[20] She reported the disease in a 12 month old boy from a family with seven cases of a hereditary retinal degeneration in which five of the seven cases developed deafness later in life and four of the seven had abnormal mental capacity. In the literature, Warburg discovered 48 similar cases which she believed were caused by this disease as well. She named the disease after a fellow Danish ophthalmologist, Gordon Norrie (1855–1941), who was a highly recognized surgeon and mentor in the Danish Institute for the Blind for 35 years.

Norrie had in fact described several familial cases of congenital blindness in 1927, although he did not recognize them as a clinical syndrome.[21] Other physicians before Warburg, including Taylor (1959 in Episkopi, Greece), [11] Roberts (1937), [32] Whitnall, Norman (1940) [33] and Stephens (1947) [34] reported families with similar symptoms that were later assumed to be cases of Norrie disease. Warburg was credited with expanding the clinical description to include hearing loss and intellectual disability, noting the X-linked recessive heritability of the disease, and further defining the characteristics of the disease.

Physical examination

On external examination, Norrie disease often presents at birth or soon after with leukocoria from the abnormal retrolental tissue. Microphthalmia is another possible initial presentation. [10] On slit lamp biomicroscopy the iris, anterior chamber, cornea, intraocular pressure, and size of the globe may be normal at birth, although iris atrophy, cataracts, a shallow anterior chamber, and synechiae may be noted. An important distinction of this disease is its predisposition for bilateral and symmetric manifestations. [19][22][35]

On fundoscopy the classic finding is a greyish-yellow, glistening, elevated mass that replaces the retina and is visible through a clear lens. These masses have been referred to as "pseudogliomas" due to their appearance. [36] Partial or complete retinal detachment evolves over the first few months. The mass consists of immature retinal cells and may be apparent a few days after birth but may not be noted until weeks or months later. Norrie disease is an important consideration in the possible differential diagnosis for any case of leukocoria (especially bilateral cases).[37]

Signs and Symptoms

The ocular findings in males with Norrie disease are varied, but usually bilateral and symmetric. They are often present at birth and are mostly progressive, from infancy throughout childhood. [38]

The main disorder is retinal degeneration which occurs in utero and results in blindness at birth or early infancy. [19] This visual failure is caused by the abnormal development of the retina. As retinal detachment develops, a grayish-yellow mass can be seen in the back of eye. Other ocular signs include opacification of the lens (cataract), atrophy of the iris, anterior and/or posterior synechiae, and development of a shallow anterior chamber with occlusion of the outflow tracts which may result in increased intraocular pressure and glaucoma. [22] As the tissue dysplasia progresses, these changes can be followed by corneal opacification, calcific band keratopathy, loss of intraocular pressure, and shrinkage of the globe (phthisis bulbi). In the end stages of Norrie disease, the corneas appear milky and opacified; the globes appear small and sunken in the orbital cavity. [4]

Microphthalmia may be present at birth, and the pupils may be dilated with hypoplastic irides. Most patients are either blind from birth or develop poor vision during the course of the disease[10] Cognitive/behavioral findings: Approximately 30%-50% of males with the Norrie disease phenotype have poorly characterized behavioral disturbances or developmental delay/intellectual disability and may show psychotic-like features. Abnormalities include autism or autism-like behavior (27%), depression, and labile affect (25%). [22] Intra- and interfamilial variability in the expression of the cognitive and behavioral difficulties is common. Severe neurologic phenotype, including infantile spasms and chronic seizures, have been reported in up to 9% of patients[39] Dementia is rare but may occur in late adulthood.

Auditory findings: Most males with Norrie disease develop insidious and progressive sensorineural hearing loss starting during adolescence with a median age of 12 years, although the range of presentation of this loss can be between 5–48 years. [19] Audiologic data suggest the abnormality resides in the cochlea (specifically, the stria vascularis) and that retrocochlear and brain auditory system function is normal. [40][41] Early hearing loss is sensorineural, mild, and asymmetric. The description of hearing loss is homogenous, with most patients describing episodic hearing loss, initially of high frequencies, of variable severity, with a slow deterioration over time and tinnitus present for much of that duration. Many describe long plateaus and at times partial recovery of some hearing. By age 35 years, hearing loss is severe, symmetric, and broad-spectrum frequency. Speech discrimination is relatively well preserved even when the threshold loss is severe . [42]

Vascular findings: Peripheral vascular disease appears to be an associated clinical finding in a subset of affected males. Patients have been reported with venous stasis ulcers, varicose veins, and erectile dysfunction (ED). [22][43] These findings are present in nearly all male cases over the age of 50 years, perhaps the result of small vessel angiopathy. Of note, a significant amount of Norrie disease patients experience ED at an early age (between ages 16 and 30).[19][41]

In more complex molecular genetic cases (NDP deletion), other clinical features may include severe growth failure, endocrine abnormalities, or severe mental retardation.

Clinical diagnosis

The classic presentation of Norrie disease includes congenital blindness, progressive hearing loss and cognitive-psychosocial disturbances. [4] Norrie disease (or any 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 fetal vasculature, hyaloid vessels, shallow anterior chamber, and vitreoretinal hemorrhages
  • Microphthalmia and cataracts
  • Presence of retrolental fibrous and vascular retinal changes at birth (leukocoria) with progressive changes through childhood or adolescence


A significant amount of clinical variability exists. Other clinical manifestations can be progressive, post-lingual, sensorineural hearing loss and cognitive impairments or behavioral disturbance.

Pathogenic variants in NDP-Related Retinopathies, range from classic Norrie disease (ND) to X-linked familial exudative vitreoretinopathy (FEVR), some cases of persistent fetal vasculature (PFV), Coats disease, and advanced retinopathy of prematurity (ROP).[5][6][7][8] These phenotypes appear to be a continuum of retinal findings with considerable overlap.

Diagnostic procedures

Once the clinical suspicion is established, to further characterize this disease the following evaluations are recommended: Complete ophthalmologic examination Baseline audiologic evaluation Neurodevelopmental assessment (if developmental milestones are not met) Behavioral evaluation (as needed) Clinical genetics consultation

The definitive diagnosis of an NDP-related retinopathy (including ND) is established in a proband with the identification of a pathogenic variant in the NDP gene by genetic testing. [4]

One genetic testing strategy is molecular testing of NDP. Sequence analysis is performed first, [44] followed by deletion/duplication analysis if no pathogenic variant is found.
An alternative genetic testing strategy is the use of a multi-gene panel that includes NDP and other genes of interest. Specific genes included and the methods used in multi-gene panels vary by laboratory and over time.

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. Importantly 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 also be used to determine the carrier status of an at-risk female. [4]

Laboratory test

No biochemical or functional assays are available.

Differential diagnosis

  1. Retinoblastoma
  2. Retinopathy of prematurity
  3. Persistent fetal vasculature
  4. Familial exudative vitreoretinopathy (X-linked or autosomal dominant)
  5. Coats Disease
  6. Walker-Warburg Syndrome
  7. Trisomy 13


Differential diagnosis may include retinoblastoma (RB), which is considered in any case of leukocoria. [10] Fundoscopic examination can often distinguish between the two disorders and ultrasonography to detect calcium in cases of RB. Other disorders related to NDP mutations such as retinopathy of prematurity in later stages, persistent fetal vasculature, X-linked familial exudative vitreoretinopathy and Coats disease can also be considered.[5][6][7][8] The retinal dysplasia that occurs in Norrie disease can be clinically indistinguishable from the dysplasia found in trisomy 13 and Walker–Warburg syndrome (in the latter associated with lissencephaly) and must be distinguished through genetic testing.

Norrie disease is not considered in the differential diagnosis of intellectual disability and/or progressive sensorineural hearing loss in the absence of the characteristic ocular features. [4]

Management

The treatment of Norrie disease requires the coordinated efforts of a team of specialists. Ophthalmologists, pediatricians, audiologists, and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.

General treatment

The treatment of individuals with Norrie disease is directed toward the specific symptoms that are apparent in each patient. Surgery may be necessary to remove cataracts and treat retinal detachment. These efforts may prevent phthisis bulbi, but often will not correct the underlying cause of poor retinal development. Early laser photocoagulation, as well as early vitrectomy have been reported as possible treatments to preserve vision, but are not yet standardized.[45][46][47][48] Hearing assistive devices may be of benefit for individuals with hearing loss and can provide benefit into middle or late adulthood. When hearing becomes significantly impaired, a cochlear implant can be of aid. Other treatment is symptomatic and supportive. [42]

Early intervention and appropriate specialized education are important in ensuring that children with Norrie disease reach their highest potential. Services that may be beneficial include special remedial or personalized education in conjunction with adaptive medical, social, and/or vocational services. Genetic counseling is important for genetic risk assessment in family members. [22]

Medical therapy

At present there is no medical therapy useful for the ocular manifestations of the disease. Behavioral issues are a lifelong challenge to many individuals with Norrie disease and to their guardians/caretakers, in the presence or absence of intellectual disability or cognitive impairment. 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 behavioral aspects of Norrie disease. [22]

Medical follow up

Routine monitoring of vision and hearing are recommended, including:

  • Routine follow up with an ophthalmologist in all individuals with an NDP-related retinopathy, even when vision is severely reduced.
  • Routine monitoring of hearing to detect changes early and manage them appropriately
  • Observation for clinical evidence of venous stasis or other signs of vascular disease.
  • Follow up on developmental and behavioral abnormalities by appropriate behavioral specialists.


Follow up timing is decided on an individual basis, depending on the severity and manifestations of each patient.

Surgery

The majority of males with the classic Norrie disease phenotype have complete retinal detachment at birth; therefore, surgery is often targeted toward prevention of further complications. Treatment for partial retinal detachment includes pars plicata/plana vitrectomy or limbal lensectomy/vitrectomy, laser therapy and/or cryotherapy with the potential for improved outcomes if done at an early stage.[19]

Planned preterm delivery and intervention in the vaso-proliferative stage of Norrie disease has been reported in a single case. Laser ablation of the avascular retina and intravitreal bevacizumab injections were performed at 34 weeks gestational age following induced delivery. [49][50] Long term follow-up of this patient demonstrated that his retinas remained attached at 8 years-of-age and BCVA was 20/80 OU without the need for further intervention after infancy.[51] Although preterm delivery offers an opportunity for early intervention in Norrie disease, it carries the risk of permanent morbidity and mortality. More study is needed before this type of procedure would be uniformly considered at this point in time.

Some reports have described successful laser photocoagulation at birth, helping preserve some degree of visual function. [45][46][47] Other reports mention that early vitrectomy (done by age 12 months) can help with maintenance of light perception vision in at least one eye.[48] There have been no systematic clinical studies indicating a preferred method of surgical treatment that can be used on all patients, especially regarding the variability of the disease. Each patient should be studied individually to determine if surgery is a possibility, and to find the best treatment options.

In the progressive stages of Norrie disease, development of increased intraocular pressure may also require glaucoma surgery. Rarely, in the most severe cases, enucleation of the eye is required to control ocular pain.

Cochlear implantation should be considered when hearing-assisted audiologic function is significantly impaired. [40][42]

Genetic Counseling

Genetic counseling should be offered to all affected families.

Norrie disease and other NDP-related retinopathies are inherited in an X-linked recessive manner (though in rare instances de novo mutations can occur). 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. [4][30]

Risk to Family Members [4]

Parents of a male proband:

  • The father of a male proband is neither affected nor is he a carrier.
  • Many 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).


Siblings of a male proband (The risk 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 siblings who inherit the pathogenic variant will be affected; female siblings 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 siblings 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 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 [4]

Identification of female carriers requires:

  • Prior identification of the NDP pathogenic variant in the family.

OR

  • 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.

OR

  • Linkage analysis if sequence analysis and deletion analysis do not identify a pathogenic variant, the family structure is appropriate for linkage studies and the necessary family members are available for testing.


Family planning [4]

  • 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.

Prognosis

Ocular prognosis is poor, and most patients develop blindness in the course of the disease. Planned preterm delivery and early laser appears to offer an option for vision, although this strategy poses risk to the infant and mother. Overall health in systems not mentioned previously is normal. Life span may be shortened by general risks associated with peripheral vascular disease, intellectual disability, blindness, and/or hearing loss, such as increased risk of trauma, aspiration pneumonia, and complications of seizure disorder. [19]

Additional Resources

References

  1. ↑ Parkes. Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome. Journal of Sleep Research. 1999;8(S1):14-22. doi:10.1046/j.1365-2869.1999.00004. x.
  2. ↑ Holmes, L. B. Norrie's disease--an X-linked syndrome of retinal malformation, mental retardation and deafness. New Eng. J. Med. 284: 367-368, 1971.
  3. ↑ 3.0 3.1 Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat. 2010 Jun;31(6):656-66.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 Sims KB. Updated:July 23,2009 . NDP-Related Retinopathies. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org.
  5. ↑ 5.0 5.1 5.2 Chamney S, McLoone E, Willoughby CE. A mutation in the Norrie disease gene (NDP) associated with familial exudative vitreoretinopathy. Eye (Lond). 2011 Dec;25(12):1658.
  6. ↑ 6.0 6.1 6.2 Walsh MK, Drenser KA, Capone A Jr, Trese MT. Norrie disease vs familial exudative vitreoretinopathy. Arch Ophthalmol. 2011 Jun;129(6):819-20.
  7. ↑ 7.0 7.1 7.2 Dickinson JL, Sale MM, Passmore A, FitzGerald LM, Wheatley CM, Burdon KP, Craig JE, Tengtrisorn S, Carden SM, Maclean H, Mackey DA (2006). "Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity". Clin Experiment Ophthalmol. 34 (7): 682–8.
  8. ↑ 8.0 8.1 8.2 Black GC, Perveen R, Bonshek R, Cahill M, Clayton-Smith J, Lloyd IC, McLeod D. Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet. 1999;8:2031–5.
  9. ↑ Liu HY, Huang J, Wang RL, et al. A novel missense mutation of NDP in a Chinese family with X-linked familial exudative vitreoretinopathy. Journal of the Chinese Medical Association. 2016;79(11):633-638. doi: 10.1016/j.jcma.2016.08.002.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 Donnai, D., Mountford, R. C., Read, A. P. Norrie disease resulting from a gene deletion: clinical features and DNA studies. J. Med. Genet. 25: 73-78.
  11. ↑ 11.0 11.1 Taylor, P. J., Coates, T., Newhouse, M. L. Episkopi blindness: hereditary blindness in a Greek Cypriot family. Brit. J. Ophthal. 43: 340-344, 1959.
  12. ↑ Chen ZY, Hendriks RW, Jobling MA, et al. Isolation and characterization of a candidate gene for Norrie disease. Nat Genet. 1992 Jun;1(3):204-8.
  13. ↑ Berger W, Meindl A, van de Pol TJ, et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet. 1992;: 199-203.
  14. ↑ 14.0 14.1 Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004 Mar 19;116(6):883-95.
  15. ↑ 15.0 15.1 Drenser KA, Fecko A, Dailey W, Trese MT. A characteristic phenotypic retinal appearance in Norrie disease. Retina. 2007;27:243–6.
  16. ↑ Schuback DE, Chen ZY, Craig IW, Breakefield XO, Sims KB. Mutations in the Norrie disease gene. Hum Mutat. 1995;5(4):285-92.
  17. ↑ Sims KB, Irvine AR, Good WV. Norrie disease in a family with a manifesting female carrier. Arch Ophthalmol. 1997;115:517-519.
  18. ↑ Huang L, Sun L, Li X, Li S, Zhang T, Zhang Z, Ding X. NDP-related retinopathies: clinical phenotype of female carriers. Br J Ophthalmol. 2022 Mar 31:bjophthalmol-2021-320084. doi: 10.1136/bjophthalmol-2021-320084. Epub ahead of print. PMID: 35361573.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 19.6 Roche O. Norrie disease. Orphanet encyclopedia, July 2005. Available at: http://www.orpha.net
  20. ↑ 20.0 20.1 Warburg, M. Norrie's disease: a new hereditary bilateral pseudotumour of the retina. Acta Ophthal. (Copenh) 39: 757-772, 1961.
  21. ↑ 21.0 21.1 Norrie, G. Nogle Blindhedsaarsager: en oversigt. Hospitalstidende 76: 141-147, 1933.
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 22.7 Smith SE, Mullen TE, Graham D, Sims KB, Rehm HL. Norrie disease: Extraocular clinical manifestations in 56 patients. Am J Med Genet A. 2012 Jul 11.
  23. ↑ 23.0 23.1 De Silva SR, Arno G, Robson AG, et al. The x-linked retinopathies: Physiological insights, pathogenic mechanisms, phenotypic features and novel therapies. Progress in Retinal and Eye Research. 2020:100898. doi: 10.1016/j.preteyeres.2020.100898.
  24. ↑ Clevers H. Wnt signaling: Ig-norrin the dogma. Curr Biol. 2004 Jun 8;14(11):R436-7.
  25. ↑ Ye X, Smallwood P, Nathans J. Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain. Gene Expr Patterns. 2011 Jan-Feb;11(1-2):151-5.
  26. ↑ Lenzner S, Prietz S, Feil S, Nuber UA, Ropers HH, Berger W. Global gene expression analysis in a mouse model for Norrie disease: late involvement of photoreceptor cells. Invest Ophthalmol Vis Sci. 2002 Sep;43(9):2825-33.
  27. ↑ Hayashi Y, Chiang H, Tian C, Indzhykulian AA, Edge ASB. Norrie disease protein is essential for cochlear hair cell maturation. Proc Natl Acad Sci U S A. 2021 Sep 28;118(39):e2106369118. doi: 10.1073/pnas.2106369118. PMID: 34544869; PMCID: PMC8488680.
  28. ↑ Paes KT, Wang E, Henze K, Vogel P, Read R, Suwanichkul A, Kirkpatrick LL, Potter D, Newhouse MM, Rice DS. Frizzled 4 is required for retinal angiogenesis and maintenance of the blood-retina barrier. Invest Ophthalmol Vis Sci. 2011;52:6452–61.
  29. ↑ Wawrzynski J, Patel A, Badran A, Dowell I, Henderson R, Sowden JC. Spectrum of Mutations in NDP Resulting in Ocular Disease; a Systematic Review. Front Genet. 2022 May 16;13:884722. doi: 10.3389/fgene.2022.884722. PMID: 35651932; PMCID: PMC9149367.
  30. ↑ 30.0 30.1 Gal, A., Uhlhaas, S., Glaser, D., Grimm, T. Prenatal exclusion of Norrie disease with flanking DNA markers. Am. J. Med. Genet. 31: 449-453, 1988.
  31. ↑ Dubucs C, Merveille M, Kessler S, Sevely A, Chassaing N, Calvas P. Prenatal diagnosis of Norrie disease based on ultrasound findings. Ultrasound in Obstetrics & Gynecology. 2019;54(1):138-139. doi:10.1002/uog.20097.
  32. ↑ Roberts, J. A. F. Sex-linked microphthalmia sometimes associated with mental defect. Brit. Med. J. 2: 1213-1216, 1937
  33. ↑ Whitnall, S. E., Norman, R. M. Microphthalmia and the visual pathways: a case associated with blindness and imbecility, and sex-linked. Brit. J. Ophthal. 24: 229-244, 1940.
  34. ↑ Stephens, F. E. A case of sex-linked microphthalmia. J. Hered. 38: 307-310, 1947.
  35. ↑ McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:310600; Last Update:3/3/10. Available at: http://omim.org/entry/310600.
  36. ↑ Duke-Elder, J. R. Pseudoglioma in children: aspects of clinical and pathological diagnosis.Sth. Med. J. 51: 754-759, 1958.
  37. ↑ Kanukollu VM, Tripathy K. Leukocoria. [Updated 2023 Aug 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560794/
  38. ↑ Lewis RA. Norrie Disease. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:655-656.
  39. ↑ Lev, D., Weigl, Y., Hasan, M., Gak, E., Davidovich, M., Vinkler, C., Leshinsky-Silver, E., Lerman-Sagie, T., Watemberg, N. A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms. Am. J. Med. Genet. 143A: 921-924, 2007.
  40. ↑ 40.0 40.1 Haplin C, Owen G, Gutierrez-Espeleta GA, Sims K, Rehm HL. Audiologic features of Norrie disease. Ann Oto Rhinol Laryngol. 2005;114:533-538.
  41. ↑ 41.0 41.1 Rehm HL, Zhang DS, Brown MC, Burgess B, Halpin C, Berger W, Morton CC, Corey DP, Chen ZY. Vascular defects and sensorineural deafness in a mouse model of Norrie disease. J Neurosci. 2002 Jun 1;22(11):4286-92.
  42. ↑ 42.0 42.1 42.2 Halpin C, Sims K. Twenty years of audiology in a patient with Norrie disease. Int J Pediatr Otorhinolaryngol. 2008;72:1705–10.
  43. ↑ Michaelides M, Luthert PJ, Cooling R, Firth H, Moore AT. Norrie disease and peripheral venous insufficiency. Br J Ophthalmol. 2004 Nov;88(11):1475. Erratum in: Br J Ophthalmol. 2005 May;89(5):645.
  44. ↑ Suárez-Merino B, Bye J, McDowall J, Ross M, Craig IW. Sequence analysis and transcript identification within 1.5 MB of DNA deleted together with the NDP and MAO genes in atypical Norrie disease patients presenting with a profound phenotype. Hum Mutat. 2001 Jun;17(6):523.
  45. ↑ 45.0 45.1 Drenser KA, Walsh MK, Capone A Jr, Trese MT, Luo CK. Preterm treatment of Norrie disease. Ophthalmology. 2011 Aug;118(8):1694-5.
  46. ↑ 46.0 46.1 Kiernan DF, Blair MP, Shapiro MJ. In utero diagnosis of Norrie disease and early laser preserves visual acuity. Arch Ophthalmol. 2010 Oct;128(10):1382.
  47. ↑ 47.0 47.1 39.0 39.1 Chow CC, Kiernan DF, Chau FY, Blair MP, Ticho BH, Galasso JM, Shapiro MJ. Laser photocoagulation at birth prevents blindness in Norrie’s disease diagnosed using amniocentesis. Ophthalmology. 2010 Dec;117(12):2402-6.
  48. ↑ 48.0 48.1 Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol. 2010 Apr;128(4):456-60.
  49. ↑ Sisk RA, Miraldi-Utz V, Schwartz TL, Hufnagel RB, Ahmed ZM. Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease. Ophthalmic Surg Lasers Imaging Retina. 2022 Aug;53(8):464-467. doi: 10.3928/23258160-20220706-01. Epub 2022 Aug 1. PMID: 35951720.
  50. ↑ Sisk RA, Hufnagel RB, Bandi S, Polzin WJ, Ahmed ZM. Planned preterm delivery and treatment of retinal neovascularization in Norrie disease. Ophthalmology. 2014 Jun;121(6):1312-3. doi: 10.1016/j.ophtha.2014.01.001. Epub 2014 Feb 14. PMID: 24529712; PMCID: PMC9126609.
  51. ↑ Sisk RA, Miraldi-Utz V, Schwartz TL, Hufnagel RB, Ahmed ZM. Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease. Ophthalmic Surg Lasers Imaging Retina. 2022 Aug;53(8):464-467. doi: 10.3928/23258160-20220706-01. Epub 2022 Aug 1. PMID: 35951720.
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