Developmental Malformations
Basilar impression
May. 06, 2023
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Norrie disease …
- Updated 06.01.2020
- Released 11.19.2001
- Expires For CME 06.01.2023
Norrie disease
Introduction
This article includes discussion of Norrie disease, atrophia bulborum hereditaria, Episkopi blindness, hereditary oculo-acoustic-cerebral degeneration, oculo-acousticocerebral degeneration, persistent hyperplastic primary vitreous, pseudoglioma, and X-linked familial exudative vitreoretinopathy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Overview
Norrie disease is a rare, congenital X-linked recessive disorder of the eyes, particularly the retina of affected males, resulting in congenital blindness or progressive visual loss through childhood. Mutations in the NDP gene and absence of the NDP protein norrin are associated with altered development of retinal vasculature. Additional complications are sensorineural deafness, intellectual deficits, and psychosis or other behavioral problems. Information continues to be gained concerning the clinical variability, genetics, and pathogenetic mechanisms of this disease. Vitrectomy with or without lensectomy has benefited some patients.
Key points
• Norrie disease is a rare, congenital X-linked recessive disorder of the eyes, particularly the retina, of affected males, resulting in congenital blindness or progressive visual loss through childhood. | |
• Mutations in the NDP gene and absence of the NDP protein norrin are associated with altered development of retinal vasculature. Information continues to be gained concerning the phenotypic variability, genetics, and pathogenetic mechanisms of this disease. | |
• Additional complications are sensorineural deafness, seizures, intellectual deficits, autism, and psychosis or other behavioral problems. Other anomalies, particularly involving the CNS, have been reported. | |
• Vitrectomy with or without lensectomy has benefited some patients. |
Historical note and terminology
In 1961 Warburg identified 7 patients from 7 generations of a Danish family as well as an additional 48 patients from 9 families described in the literature; she suggested the name Norrie disease, to reflect Norrie's earlier publication in 1933 (63; 106). The term “Episkopi blindness” derived from a study of a large Greek family (16 males in 5 generations) in Episkopi, Cyprus (98). Some early cases were labeled “pseudotumors” or “pseudoglioma,” but these are nonspecific terms reserved for conditions resembling retinoblastoma and are no longer considered appropriate diagnoses for this condition (67). Two conditions (persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy) are part of the spectrum of Norrie disease. Berger and colleagues and Chen and colleagues isolated a candidate gene for Norrie disease (06; 14). In the following years, the NDP gene and a variety of mutations have been identified as causative (116; 70).
Clinical manifestations
Presentation and course
Norrie disease is a congenital X-linked recessive disorder involving the eyes, particularly the retina, of affected males and resulting in congenital blindness or progressive visual loss through childhood. A patient's condition can be placed within the spectrum of Norrie disease if several findings are identified: normal size of eye at birth, normal anterior chamber, clear lenses, additional (bilateral) changes including fibrovascular alterations of retina and vitreous characterized by hemorrhage, and membrane formation or attachment to retina (90). At least one-third of patients have sensorineural deafness and one-half have intellectual deficits, which appear after 3 years and is sometimes complicated by psychosis or other abnormal behavior (68; 90). Patients may manifest depression (2%), anxiety (6%), attention difficulties (8%), labile affect (25%), or autism (27%) (94). Infantile spasms (EEG-demonstrated hypsarrhythmia) have been noted in a profoundly retarded male with congenital blindness (51). The disease is clinically heterogeneous; however, presentations may vary, even within families (116).
The eyes may be normal at birth but within a few months develop a variety of fibrous and vascular changes. These changes range in severity from masses involving the retina, and resulting in complete loss of vision to less severe fibrotic stalks extending from the optic disc to the lens (persistent hyperplastic primary vitreous), or retinal vascular changes with or without fibrosis (familial exudative vitreoretinopathy). The combination of dense stalks, globular dystrophy, and peripheral avascularity of the retina, accompanied by pigmentary changes, may be pathognomonic for Norrie disease (22). By about 10 years, eyes are end-stage and shrunken (phthisis bulbis), with milky corneas, shallow anterior chambers, opaque corneas, leukocoria, dilated pupils with no light reflex, and hypoplastic irides with posterior synechiae. These changes need not develop late, however, and the finding of leukocoria with microphthalmia in early infancy can lead to a diagnosis of Norrie disease (72). Glaucoma can occur secondary to shape changes that produce increased intraocular pressure. Rarely, carrier females and even noncarrier females have ocular changes (retinal detachment or abnormal peripheral retinal vasculature, phthisis bulbi; dragged maculae) or loss of vision (12; 91; 57; 112; 52). Explanations for this occurrence in females include X inactivation or other adverse effects of the mutant allele on the retina during early development.
Additional extraocular changes are recognized, though incompletely. Central nervous dysfunction with seizures, growth retardation, and immunodeficiency become apparent in later stages in about one-third of cases (08). Because norrin is important to angiogenesis, a number of defects in the vascular system may occur, including peripheral vascular disease (ie, varicose veins, venous stasis ulcers, and erectile dysfunction) (94). Cerebroretinal microangiopathy is associated with calcifications and cysts involving terminal arteriolar zones (eg, basal ganglia) and deep gray nuclei (81). Chronic seizures occur in about 10% of patients (94) and may be refractory (09). In 1 study, epilepsy developed from discharges in the occipital areas of 3 brothers (66).
Hearing loss can progress subtly and does not seem to affect speech. The inner ear (cochlea) appears to be involved, and retrocochlear and brain auditory system function is normal. One study of the inner ears of a 77-year-old patient revealed marked atrophy of the stria vascularis, severe degeneration of hair cells and cochlear neurons, and connective tissue proliferation in the spiral ganglion, osseous spiral lamina, and walls of the membranous vestibular labyrinth (61). In a mouse model for Norrie disease, the primary change was abnormal or decreased vessels of the stria vascularis, in which the cochlear vasculature is located (77).
If deletions of the Norrie disease gene involve adjacent monoamine oxidase genes (MAOA, MAOB), phenotypic and physiologic changes are more severe, including hypogonadism, hypertensive crises, disorganized REM sleep, myoclonus or other involuntary movements, and variable degrees of intellectual deficits (17; 102; 96). Additional anomalies associated with these deletions continue to be uncovered, including short stature, hypotonia, and autism (84).
Prognosis and complications
In severe Norrie disease, visual impairment is congenital, complete or progressive, and irreversible. For patients with Norrie disease and persistent fetal vasculature syndrome, early vitrectomy has been performed, with or without lensectomy, with maintenance or restoration of light perception vision in a majority of cases; most patients experienced no phthisis bulbi postoperatively (103; 104). In less severe forms, vision may be mildly impaired or even normal. Deafness and intellectual deficits are complications in some 50% of cases (78). Hearing loss is bilateral and progressive but responsive to hearing aids; with care, preservation of word recognition is possible (33). The less severe form of the condition may be progressive and treatable. Growth retardation, epilepsy, and behavioral and sleep disturbances are other complications (69; 68; 112). One patient with Norrie disease, complicated by paroxysms of deafness, slurred speech and somnolence, was successfully treated with beta blockers (44). Pancreatic exocrine insufficiency and microvillus inclusion disease have been observed in 1 newborn male (71). One affected adult has been reported with chronic peripheral venous insufficiency, requiring surgery for varicose veins (58). Two patients with microdeletions in the NDP region have been diagnosed with pulmonary hypertension or progressive, eventually fatal dyspnea (95). Parental counseling, with a goal of combating depression, may help improve the long-term developmental outlook of patients (29).
Biological basis
Etiology and pathogenesis
Because Norrie disease is X-linked recessive, affected males inherit the disorder from carrier mothers or acquire it sporadically through a new mutation in the Norrie disease gene, NDP (“Norrie Disease Pseudoglioma”), located at Xp11.4-p11.3 (13). Affected males transmit the (recessive) mutation via the X chromosome, thus affecting their daughters but not their sons. Carrier females have a 50% chance of transmitting the mutation to either male or female children (the former will have Norrie disease, and the latter will be carriers). Four loci have been named EVR1 to EVR4, and mapped to 11p, 11q, and Xp (100). It is likely other loci exist as well (45). To date, a number of variants of 2 genes (LRP5 and FZD4) have been found to cause familial exudative vitreoretinopathy (62); FZD4 may be mutated in some cases of both unilateral and bilateral forms of persistent hyperplastic primary vitreous as well (86). High levels of aqueous VEGF-A in 1 enucleated eye with retinal dysplasia consistent with Norrie disease suggest this cytokine may be involved in pathogenesis as well (42). The mutational spectrum of Norrie disease continues to be expanded and can be suggestive of a founder effect (73). Contiguous deletions involving NDP give rise to diverse findings, depending upon the exact nature of the deletion (43).
At least 3 major phenotypic varieties of Norrie disease are distinguished (90). In the classic and most severe form, gray-yellow masses of fibrovascular tissue replace the retina; these have sometimes been described as pseudotumors or pseudoglioma. This change is associated with severe or total loss of vision. With time, a variety of additional changes may occur, including formation of cataracts or synechiae, opacified cornea, atrophic iris, altered shape of globe or individual chambers, or band keratopathy. In persistent hyperplastic primary vitreous, a fibrotic white stalk containing hyaloid vessels connects the optic disc and posterior lens capsule; the lens is variably opacified and the retina variably folded or detached. This change is apparent at birth, and the extent of progression is unknown; the degree of visual loss is variable. An apparently rare, novel nonsense mutation of the Norrie disease gene has been identified in 1 family with 2 sons affected by persistent hyperplastic primary vitreous (34). Familial exudative vitreoretinopathy is manifested by peripheral zones of retinal avascularity, sometimes with retinal folds, which can cause dragging and displacement of the macula (macular ectopia), or fibrous tissue bands, which are apparent at birth. These changes are associated with normal or reduced vision and can progress throughout the first 2 decades of life, causing eventual retinal detachment. Neonatal retinal folds and/or vitreoretinal traction can be signs of Norrie disease or other retinopathy (18). Retinal detachment may also occur in fetal life or infancy (108; 27). The term “exudative” derives from the exudation of serous fluid from capillaries in the (abnormal) retinal vasculature. Microscopically, the retina appears immature and dysplastic, with little or no normal structure; the retinal vasculature is underdeveloped as well (24; 101). These changes are thought to arise early in development, possibly from changes in cells of the inner optic cup wall (68).
Defects in the Wnt signaling pathway are found in patients with familial exudative vitreoretinopathy and Norrie disease (107; 38). The Wnt pathway plays multiple roles in embryonic development, including regulation of ocular growth and development (49; 35). The exact pathogenesis is complex and continues to be elucidated. The NDP protein (norrin) binds to at least 3 proteins and serves as an antagonist to BMP as well as activating the Wnt pathway (19). Norrin also has a function in progenitor proliferation in the retina that is independent of its function in the developing vasculature of the retina (56). A further complication is that the same mutation may be responsible for different phenotypes (78). Regardless, vascularization is abnormal in the peripheral retina of all forms of Norrie disease (88) and norrin, the protein product of NDP, appears to be part of a signaling system important to vascular development in the eye and ear (110). It has been suggested that aberrations in normal apoptosis play a role (86) and that the proliferation of endothelial cells in the retinal vascular plexus is reduced (117). The endothelial cell-specific protein PLVAP (plasmalemma vesicle-associated protein) is involved in vascular permeability, leukocyte migration, and angiogenesis; it is upregulated in Norrie disease and thus may be a target for future therapy (30).
Norrin is also important to extraocular angiogenesis (76; 58; 115). Homologies with known proteins and other modeling data suggest that mutations also alter the regulation of cell interaction, differentiation, or proliferation (11; 05). In approximately 70% of patients, single base pair changes are found; in about 24%, partial or complete deletions are identified. More than 100 sequence variations, including intragenic deletions, nucleotide substitutions, or splicing variants, cause the disease (83; 58). Most are unique and confined to single patients and families. Phenotypes can vary among family members carrying the same mutation or be misdiagnosed, given the wide variation in allelic variants. It has been suggested that milder mutations in the Norrie disease gene are associated with less severe retinal disease, or that deletions may be associated with more severe forms (46; 79). Certain mutations result in significant phenotypic heterogeneity (01). This latter observation suggests that phenotypic definitions of Norrie disease variants may not be the most appropriate nomenclature.
A mouse knockout model will be helpful in understanding disease progression (50). In the model, numerous photoreceptor cell-specific gene transcripts are absent or down-regulated in older (ie, 2 years), but not younger (ie, 1 year), animals. Without the Norrie disease gene product, photoreceptor cells cannot survive in this model. Such animals manifest a failure of retinal angiogenesis, with lack of deep capillary layers of the retina and blindness (64). This has been confirmed in studies, wherein the role of norrin in retinal vascular development continues to be elucidated (85). The gene product also influences the regression of hyaloid vessels that otherwise are a component of retrolental membranes in knockout mice (65). Vessel density (but not cell number) is also reduced in the cerebellum of knockout mice (55). It seems that reproductive tissues can also be affected, for female mice homozygous for the Norrie disease pseudoglioma homolog (Ndph) are almost uniformly infertile; heterozygous females and hemizygous males are not (54). The role of hypoxia and reduced induction of vascular endothelial growth factor (VEGF) on retinal vascularity has been investigated in one experimental model (74).
Epidemiology
The disease is rare, with 150 to 200 cases reported. In 1 study of 109 pediatric patients with vitreoretinopathy, 11 (10%) were proven by molecular means to have Norrie disease (109). In another review of familial exudative vitreoretinopathy, 6% of patients carried mutations in the Norrie disease gene (48). Over time, the genetic details of specific patient populations are becoming known. A study of 44 patients from China, for example, demonstrated the population differences in prevalence of NDP mutations (113). Several novel mutations in NDP have been recognized in a sample of Indian patients with familial exudative vitreoretinopathy (60).
Prevention
Avoidance of pregnancy by carrier females is the only way to prevent the disorder. De novo mutations cannot be predicted or prevented.
Differential diagnosis
Norrie disease manifests as a spectrum, with several phenotypes that overlap considerably (81). These include Norrie disease, Coats, Coats plus, leukoencephalopathy with calcifications and cysts, and cerebroretinal microangiopathy with calcifications and cysts. Some cases of retinoblastoma may prove to be Norrie disease or related phenotypes (02). Diagnosis is facilitated by identifying intraocular changes and by identifying mutations in the Norrie disease gene. Some workers have held that patients (3% of advanced cases in 1 study) labeled as having retinopathy of prematurity in fact have Norrie disease, the diagnosis of which can be substantiated by clinical and molecular means (87; 32; 39). Evidence is mounting that the presence of certain mutations in the Norrie disease gene may predispose some patients to severe retinopathy of prematurity (97; 31). In 1 study, 6 of 54 (11%) infants with severe retinopathy of prematurity had polymorphisms in Norrie disease gene (NDP) (40). However, other investigators have failed to identify mutations in their patients (47). It is also possible that X-linked primary retinal dysplasia is part of this spectrum, although studies to date have been incomplete (75). Coats disease (exudative retinopathy) and congenital or juvenile retinoschisis can be differentiated by clinical and molecular means (07; 37; 36). One patient with Coats disease, Turner syndrome, and type 1 von Willebrand disease was negative for mutations in NDP (20). Mutations involving the Norrie disease gene and contiguous genes may result in more complex phenotypes (80; 84).
Diagnostic workup
Diagnosis is achieved through clinical (chiefly ophthalmologic and otolaryngologic) workup and identification of a mutation in the Norrie disease gene at Xp11. Identification of the mutation has been possible in approximately 70% of affected males (90). The presence of retinal changes is not helpful in identifying carrier patients (45). Prenatal diagnosis is valuable to confirm the presence of disease, counsel families, and prepare for possible postnatal therapy (15; 70; 92). It is especially sought in cases of recurrent familial disease and has been successful as early as 11 weeks’ gestation, using chorionic villus sampling (28). Preimplantation genetic diagnosis is also possible for parents using in vitro fertilization (111). Ocular anomalies can also be identified ultrasonographically, which can be especially helpful when corneal opacity precludes more traditional examination (59). Persistent hyperplastic primary vitreous has been diagnosed in the early third trimester by ultrasound (25). Large vitreous cavity opacities and retinal detachment have been visualized in a fetus at 36 weeks, with Norrie disease subsequently confirmed by Sanger sequencing (108). Molecular analysis of members of affected pedigrees is, of course, fundamental to understanding familial disease (21), and such workups may reveal adults that have been carried for years with incorrect diagnoses (10). The use of microarray technology to study retinopathies in large populations shows great promise (82). Copy number analysis is successful as well (03). Given the clinical variability within families, it is likely that additional genetic and environmental factors remain to be discovered (26).
Genetic factors are involved in some 50% of cases of profound hearing loss, including Norrie disease (04). To assess hearing loss, brainstem-evoked responses can be measured and electrocochleography performed.
The identification of cerebellar atrophy and motor or mental disorders in 3 affected members a Chinese family is indication for additional imaging workup (53).
Management
Treatment by ophthalmologists, otolaryngologists, and pediatricians is necessary. Medical geneticists will be helpful in discerning the hereditary status of the disorder and with family counseling. Ophthalmologic surgery is more often palliative than curative but may be performed for cataracts, detached retina, or drainage of vitreous (vitrectomy), which may prevent shrinkage of the eyes but does not improve vision. Newer surgical techniques hold promise (89) and appear to be especially valuable when instituted early, even in the newborn period (103; 104; 105; 23; 99). Vitrectomy and laser photocoagulation of avascular retinal tissue are examples (16; 103; 104). Anti-VEGF injections have been used in cases of familial exudative vitreoretinopathy (93). Cochlear implants have proven successful in patients with Norrie disease prior to the onset of total deafness (41).
Special considerations
Anesthesia
Surgical procedures can be performed on both eyes during a single operation, with the goal of minimizing patient discomfort and exposure to anesthesia (114).
References
- 01
- Allen RC, Russell SR, Streb LM, Alsheikheh A, Stone EM. Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein. Eye 2006;20(2):234-41. PMID 15776010
- 02
- Aponte EP, Pulido JS, Ellison JW, Quiram PA, Mohney BG. A novel NDP mutation in an infant with unilateral persistent fetal vasculature and retinal vasculopathy. Ophthalmic Genet 2009;30:99-102. PMID 19373682
- 03
- Arai E, Fujimaki T, Yanagawa A, et al. Familial cases of Norrie disease detected by copy number analysis. Jpn J Ophthalmol 2015;58(5):448-54. PMID 25023092
- 04
- Bayazit YA, Yilmaz M. An overview of hereditary hearing loss. ORL J Otorhinolaryngol Relat Spec 2006;68(2):57-63. PMID 16428895
- 05
- Berger W. Molecular dissection of Norrie disease. Acta Anat (Basel) 1998;162:95-100. PMID 9831755
- 06
- Berger W, van de Pol D, Warburg M. Mutations in the candidate gene for Norrie disease. Hum Mol Genet 1992;1:461-5. PMID 1307245
- 07
- Berinstein DM, Hiraoka M, Trese MT, Shastry BS. Coats’ disease and congenital retinoschisis in a single eye: a case report and DNA analysis. Ophthalmologica 2001;215(2):132-5. PMID 11244345
- 08
- Black GC, Perveen R, Bonshek R, et al. 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(11):2031-5. PMID 10484772
- 09
- Cação G, Garrido C, Miranda V, Pinto-Basto J, Chaves J, Chorão R. Refractory epilepsy in Norrie disease. Neurol Sci 2018;39(9):1631-3. PMID 29725776
- 10
- Callaway NF, Berrocal AM. Wnt-spectrum vitreoretinopathy masquerading as congenital toxoplasmosis. Ophthalmic Surg Lasers Imaging Retina 2018;49(6):446-50. PMID 29927473
- 11
- Chen ZY, Battinelli EM, Hendriks RW, et al. Norrie disease gene: characterization of deletions and possible function. Genomics 1993b;16:533-5. PMID 8314592
- 12
- Chen ZY, Battinelli EM, Woodruff G, et al. Characterization of a mutation within the NDP gene in a family with a manifesting female carrier. Hum Mol Genet 1993a;2:1727-9. PMID 8268931
- 13
- Chen ZY, Denney RM, Breakefield XO. Norrie disease and MAO genes: nearest neighbors. Hum Mol Genet 1995;4:1729-37. PMID 8541872
- 14
- Chen ZY, Hendriks RW, Jobling MA, et al. Isolation and characterization of a candidate gene for Norrie disease. Nature Genet 1992;1:204-8. PMID 1303236
- 15
- Chini V, Stambouli D, Nedelea FM, et al. Utilization of gene mapping and candidate gene mutation screening for diagnosing clinically equivalent conditions: a Norrie disease case study. Eye Sci 2014;29(2):104-7. PMID 26011961
- 16
- Chow CC, Kiernan DF, Chau FY, et al. Laser photocoagulation at birth prevents blindness in Norrie’s disease diagnosed using amniocentesis. Ophthalmology 2010;117:2402-6. PMID 20619898
- 17
- Collins FA, Murphy DL, Reiss AL, et al. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie gene locus and monoamine oxidase (MAOA and MAOB). Am J Med Genet 1992;42:127-34. PMID 1308352
- 18
- Coussa RG, Zhao Y, DeBenedictis MJ, Babiuch A, Sears J, Traboulsi EI. Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature. Ophthalmic Genet 2020;41(1):63-8. PMID 32039639
- 19
- Deng C, Reddy P, Cheng Y, Luo CW, Hsiao CL, Hsueh AJ. Multi-functional norrin is a ligand for the LGR4 receptor. J Cell Sci 2013;126(Pt 9):2060-8. PMID 23444378
- 20
- Desai RU, Saffra NA, Krishna RP, Rosenberg SE. Coats’ Disease, Turner Syndrome, and von Willebrand Disease in a Patient with Wildtype Norrie Disease Pseudoglioma. J Pediatr Ophthalmol Strabismus 2010:1-3. PMID 20411871
- 21
- Dhingra S, Shears DJ, Blake V, Stewart H, Patel CK. Advanced bilateral persistent fetal vasculature associated with a novel mutation in the Norrie gene. Br J Ophthalmol 2006;90(10):1324-5. PMID 16980647
- 22
- Drenser KA, Fecko A, Dailey W, Trese MT. A characteristic phenotypic retinal appearance in Norrie disease. Retina 2007;27(2):243-6. PMID 17290208
- 23
- Drenser KA, Walsh MK, Capone A, et al. Preterm treatment of Norrie disease. Ophthalmology 2011;118:1694-5. PMID 21813101
- 24
- Enyedi LB, de Juan E Jr, Gaitan A. Ultrastructural study of Norrie’s disease. Am J Opthalmol 1991;111(4):439-45. PMID 1781818
- 25
- Esmer AC, Sivrikoz TS, Gulec EY, et al. Prenatal diagnosis of persistent hyperplastic primary vitreous: report of 2 cases and review of the literature. J Ultrasound Med 2016;35(10):2285-91. PMID 27582535
- 26
- Gal M, Levanon EY, Hujeirat Y, Khayat M, Pe’er J, Shalev S. Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability. Am J Med Genet A 2014;164A(12):2996-3002. PMID 25250762
- 27
- Garcha J, Jain A, Atwal H, Sevlam P, Atwal PS. Novel pathogenic variant in the Cys110 residue: a genotype-phenotype report of a patient with Norrie disease. J Pediatr Genet 2020;9(2):142-4. PMID 32341821
- 28
- Ghosh M, Sharma S, Shastri S, et al. Norrie disease: first mutation report and prenatal diagnosis in an Indian family. Indian J Pediatr 2012;79(11):1529-31. PMID 22674248
- 29
- Goodyear HM, Sonksen PM, McConachie H. Norrie’s disease: a perspective study of development. Arch Dis Child 1989;64:1587-92. PMID 2604418
- 30
- Guo L, Zhang H, Hou Y, Wei T, Liu J. Plasmalemma vesicle-associated protein: a crucial component of vascular homeostasis. Exp Ther Med 2016;12(3):1639-44. PMID 27602081
- 31
- Haider MZ, Devarajan LV, Al-Essa M, Kumar H. A C597-->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in premature Kuwaiti infants. J Biomed Sci 2002;9:365-70. PMID 12145535
- 32
- Haider MZ, Devarajan LV, Al-Essa M, et al. Retinopathy of prematurity: mutations in the Norrie disease gene and the risk of progression to advanced stages. Pediatr Int 2001;43:120-3. PMID 11285060
- 33
- Halpin C, Sims K. Twenty years of audiology in a patient with Norrie disease. Int J Pediatr Otorhinolaryngol 2008;72:1705-10. PMID 18817988
- 34
- Hatsukawa Y, Nakao T, Yamagishi T, Okamoto N, Isashiki Y. Novel nonsense mutation (Tyr44stop) of the Norrie disease gene in a Japanese family. Br J Ophthalmol 2002;86:1452-3. PMID 12446397
- 35
- Hendrickx M, Leyns L. Non-conventional Frizzled ligands and Wnt receptors. Dev Growth Differ 2008;50(4):229-43. PMID 18366384
- 36
- Hiraoka M, Berinstein DM, Trese MT, et al. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet 2001b;46:178-81. PMID 11322656
- 37
- Hiraoka M, Rossi R, Trese MT, et al. X-linked juvenile retinoschisis: mutations at the retinoschisis and Norrie disease gene loci. J Hum Genet 2001a;46:53-6. PMID 11281412
- 38
- Hiraoka M, Takahashi H, Orimo H, et al. Genetic screening of Wnt signaling factors in advanced retinopathy of prematurity. Mol Vis 2010;16:2572-7. PMID 21151595
- 39
- Holmstrom G, van Wijngaarden P, Coster DJ, Williams KA. Genetic susceptibility to retinopathy of prematurity: the evidence from clinical and experimental animal studies. Br J Ophthalmol 2007;91(12):1704-8. PMID 18024814
- 40
- Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis 2005;11:501-8. PMID 16052165
- 41
- Jacques D, Dubois T, Zdanowicz N, Gilain C, Garin P. Cochlear implants and psychiatric assessments: a Norrie disease case report. Psychiatr Danub 2017;29(Suppl 3):259-61. PMID 28953773
- 42
- Jakobiec FA, Zakka FR, D’Amato R, et al. Unilateral sporadic retinal dysplasia: results of histopathologic, immunohistochemical, chromosomal, genetic, and VDGF-A analyses. J AAPOS 2011;15:579-86. PMID 22153404
- 43
- Jia B, Huang L, Chen Y, et al. A novel contiguous deletion involving NDP, MAOB and EFHC2 gene in a patient with familial Norrie disease: bilateral blindness and leucocoria without other deficits. J Genet 2017;96(6):1015-20. PMID 29321361
- 44
- Kalamangalam GP, Ellis SJ. Migrainous brain stem disturbance in Norrie disease: case report. J Neurol Neurosurg Psychiatry 2001;70:815-6. PMID 11430297
- 45
- Khan AO, Aldahmesh MA, Meyer B. Correlation of ophthalmic examination with carrier status in females potentially harboring a severe Norrie disease gene mutation. Ophthalmology 2008;115(4):730-3. PMID 18387409
- 46
- Khan AO, Shamsi FA, Al-Saif A, Kambouris M. A novel missense Norrie disease mutation associated with a severe ocular phenotype. J Pediatr Ophthalmol Strabismus 2004;41(6):361-3. PMID 15609522
- 47
- Kim JH, Yu YS, Kim J, Park SS. Mutations of the Norrie gene in Korean ROP infants. Korean J Ophthalmol 2002;16:93-6. PMID 12546446
- 48
- Kondo H, Qin M, Kusaka S, et al. Novel mutations in Norrie disease gene in Japanese patients with Norrie disease and familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci 2007;48(3):1276-82. PMID 17325173
- 49
- Kubo F, Nakagawa S. Wnt signaling in retinal stem cells and regeneration. Dev Growth Differ 2008;50(4):245-51. PMID 18366385
- 50
- 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;43:2825-33. PMID 12202498
- 51
- Lev D, Weigl Y, Hasan M, et al. 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 A 2007;143(9):921-4. PMID 17334993
- 52
- Lin P, Shankar SP, Duncan J, Slavotinek A, Stone EM, Rutar T. Retinal vascular abnormalities and dragged maculae in a carrier with a new NDP mutation (c.268delC) that caused severe Norrie disease in the proband. J AAPOS 2010;14(1):93-6. PMID 20227630
- 53
- Liu D, Hu Z, Peng Y, et al. A novel nonsense mutation in the NDP gene in a Chinese family with Norrie disease. Mol Vis 2010;16:2653-8. PMID 21179243
- 54
- Luhmann UF, Meunier D, Shi W, et al. Fetal loss in homozygous mutant Norrie disease mice: a new role of Norrin in reproduction. Genesis 2005;42(4):253-62. PMID 16035034
- 55
- Luhmann UF, Neidhardt J, Kloeckener-Gruissem B, et al. Vascular changes in the cerebellum of Norrin /Ndph knockout mice correlate with high expression of Norrin and Frizzled-4. Eur J Neurosci 2008;27(10):2619-28. PMID 18547247
- 56
- McNeill B, Mazerolle C, Bassett EA, et al. Hedgehog regulates Norrie disease protein to drive neural progenitor self-renewal. Hum Mol Genet 2013;22(5):1005-16. PMID 23201751
- 57
- Meire FM, Lafaut BA, Speleman F, et al. Isolated Norrie disease in a female caused by a balanced translocation t(X,6). Ophthalmic Genet 1998;19:203-7. PMID 9895245
- 58
- Michaelides M, Luthert PJ, Moore AT, Cooling R, Firth H. Norrie disease and peripheral venous insufficiency. Br J Ophthalmol 2004;88(11):1475. PMID 15489496
- 59
- Mozo Cuadrado M, Tabuenca Del Barrio L, Zubicoa Enériz A, Antonia Ardanaz Aldave M. Ocular manifestations of Norrie disease. J Fr Ophtalmol 2020;43(5):439-41. PMID 32381368
- 60
- Musada GR, Jalali S, Hussain A, et al. Mutation spectrum of the Norrie disease pseudoglioma (NDP) gene in Indian patients with FEVR. Mol Vis 2016;22:491-502. PMID 27217716
- 61
- Nadol JB Jr, Eavey RD, Liberfarb RM, et al. Histopathology of the ears, eyes, and brain in Norrie's disease (oculoacousticocerebral degeneration). Am J Otolaryngol 1990;11:112-24. PMID 2343994
- 62
- 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;31(6):656-66. PMID 20340138
- 63
- Norrie G. Noble Blindhedsaarsager: en oversight. Hospitalstidende 1933;76:141-7.
- 64
- Ohlmann A, Scholz M, Goldwich A, et al. Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. J Neurosci 2005;25(7):1701-10. PMID 15716406
- 65
- Ohlmann AV, Adamek E, Ohlmann A, Lutjen-Drecoll E. Norrie gene product is necessary for regression of hyaloid vessels. Invest Ophthalmol Vis Sci 2004;45(7):2384-90. PMID 15223821
- 66
- Okumura A, Arai E, Kitamura Y, et al. Epilepsy phenotypes in siblings with Norrie disease. Brain Dev 2015;37(10):978-82. PMID 25944760
- 67
- Online Mendelian Inheritance in Man. OMIM. MIM Number 310600. Baltimore: Johns Hopkins University. Available at: Online Mendelian Inheritance in Man, OMIM. Accessed August 2001.
- 68
- Ott S, Patel RJ, Appukuttan B, et al. A novel mutation in the Norrie disease gene. J AAPOS 2000;4:125-6. PMID 10773814
- 69
- Parkes JD. Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome. J Sleep Res 1999;8(Suppl 1):14-22. PMID 10389102
- 70
- Parzefall T, Lucas T, Ritter M, et al. A novel missense NDP mutation [p.(Cys93Arg)] with a manifesting carrier in an Austrian family with Norrie Disease. Audiol Neurootol 2014;19(3):203-9. PMID 24801666
- 71
- Paulus YM, Alcorn DM, Gaynon M, Moshfeghi DM. Peripheral avascular retina in a term male neonate with microvillus inclusion disease and pancreatic insufficiency. Ophthalmic Surg Lasers Imaging Retina 2015;46(5):589-91. PMID 26057766
- 72
- Payabvash S, Anderson JS, Nascene DR. Bilateral persistent fetal vasculature due to a mutation in the Norrie disease protein gene. Neuroradiol J 2015;28(6):623-7. PMID 26459204
- 73
- Pelcastre EL, Villanueva-Mendoza C, Zenteno JC. Novel and recurrent NDP gene mutations in familial cases of Norrie disease and X-linked exudative vitreoretinopathy. Clin Experiment Ophthalmol 2010;38:367-74. PMID 20491809
- 74
- Rattner A, Wang Y, Zhou Y, Williams J, Nathans J. The role of the hypoxia response in shaping retinal vascular development in the absence of Norrin/Frizzled4 signaling. Invest Ophthalmol Vis Sci 2014;55(12):8614-25. PMID 25414188
- 75
- Ravia Y, Braier-Goldstein O, Bat-Miriam KM, et al. X-linked recessive primary retinal dysplasia is linked to the Norrie disease locus. Hum Mol Genet 1993;2:1295-7. PMID 8401512
- 76
- Rehm HL, Gutierrez-Espeleta GA, Garcia R, et al. Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency. Hum Mutat 1997;9(5):402-8. PMID 9143918
- 77
- Rehm HL, Zhang DS, Brown MC, et al. Vascular defects and sensorineural deafness in a mouse model of Norrie disease. J Neurosci 2002;22:4286-92. PMID 12040033
- 78
- Riveiro-Alvarez R, Trujillo-Tiebas MJ, Gimenez-Pardo A, et al. Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR. Mol Vis 2005;11:705-12. PMID 16163268
- 79
- Rivera-Vega MR, Chinas-Lopez S, et al. Molecular analysis of the NDP gene in two families with Norrie disease. Acta Ophthalmol Scand 2005;83(2):210-4. PMID 15799735
- 80
- Rodriguez-Revenga L, Madrigal I, Alkhalidi LS, et al. Contiguous deletion of the NDP, MAOA, MAOB, and EFHC2 genes in a patient with Norrie disease, severe psychomotor retardation and myoclonic epilepsy. Am J Med Genet A 2007;143(9):916-20. PMID 17431911
- 81
- Romaniello R, Arrigoni F, Citterio A, et al. Cerebroretinal microangiopathy with calcifications and cysts associated with CTC1 and NDP mutations. J Child Neurol 2012;28(12):1702-8. PMID 23220793
- 82
- Rosenberg T, Klie F, Garred P, Schwartz M. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis 2007;13:1962-9. PMID 17982420
- 83
- Royer G, Hanein S, Raclin V, et al. NDP gene mutations in 14 French families with Norrie disease. Hum Mutat 2003;22(6):499. PMID 14635119
- 84
- Saito M, Yamagata T, Matsumoto A, et al. MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus. Brain Dev 2013;36(1):64-9. PMID 23414621
- 85
- Schafer NF, Luhmann UF, Feil S, Berger W. Differential gene expression in Ndph-knockout mice in retinal development. Invest Ophthalmol Vis Sci 2009;50:906-16. PMID 18978344
- 86
- Shastry BS. Persistent hyperplastic primary vitreous: congenital malformation of the eye. Clin Experiment Ophthalmol 2009;37(9):884-90. PMID 20092598
- 87
- Shastry BS, Pendergast SD, Hartzer MK, et al. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol 1997;115:651-5. PMID 9152134
- 88
- Shastry BS, Trese MT. Overproduction and partial purification of the Norrie disease gene product, norrin, from a recombinant baculovirus. Biochem Biophys Res Commun 2003;312(1):229-34. PMID 14630047
- 89
- Shima C, Kusaka S, Kondo H, Hasebe H, Fujikado T, Tano Y. Lens-sparing vitrectomy effective for reattachment of newly developed falciform retinal detachment in a patient with Norrie disease. Arch Ophthalmol 2009;127:579-80. PMID 19365046
- 90
- Sims KB. Norrie disease. In: Geneclinics: Clinical Genetic Information Resource [database online]. Seattle: University of Washington. Available at Geneclinics Website. Accessed August 2001.
- 91
- Sims KB, Irvine AR, Good WV. Norrie disease in a family with a manifesting female carrier. Arch Ophthalmol 1997;115:517-9. PMID 9109762
- 92
- Sisk RA, Hufnagel RB, Bandi S, Polzin WJ, Ahmed ZM. Planned preterm delivery and treatment of retinal neovascularization in Norrie disease. Ophthalmology 2014;121(6):1312-3. PMID 24529712
- 93
- Sizmaz S, Yonekawa Y, T Trese M. Familial exudative vitreoretinopathy. Turk J Ophthalmol 2015;45(4):164-8. PMID 27800225
- 94
- Smith SE, Mullen TE, Graham D, Sims KB, Rehm HL. Norrie disease: extraocular clinical manifestations in 56 patients. Am J Med Genet A 2012;158A(8):1909-17. PMID 22786811
- 95
- Staropoli JF, Xin W, Sims KB. Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.3. J Med Genet 2010;47:786-90. PMID 20679667
- 96
- Suarez-Merino B, Bye J, McDowall J, et al. 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;17:523. PMID 11385715
- 97
- Talks SJ, Ebenezer N, Hykin P, et al. De novo mutations in the 5’ regulatory region of the Norrie disease gene in retinopathy of prematurity. J Med Genet 2001;38:E46. PMID 11748312
- 98
- Taylor PJ, Coates T, Newhouse ML. Episkopi blindness: hereditary blindness in a Greek Cypriot family. Brit J Ophthal 1959;43:340-4. PMID 13662558
- 99
- Todorich B, Thanos A, Yonekawa Y, Capone A Jr. Repair of total tractional retinal detachment in Norrie disease: report of technique and successful surgical outcome. Ophthalmic Surg Lasers Imaging Retina 2017;48(3):260-2. PMID 28297040
- 100
- Toomes C, Downey LM, Bottomley HM, et al. Identification of a fourth locus (EVR4) for familial exudative vitreoretinopathy (FEVR). Mol Vis 2004;10:37-42. PMID 14737064
- 101
- Van Nouhuys CE. Ultrastructural study of Norrie's disease. Am J Ophthalmol 1991;112(4):475-7. PMID 1928264
- 102
- Vossler DG, Wyler AR, Wilkus RJ, Gardner-Walker G, Vlcek BW. Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology 1996;46:1258-61. PMID 8628463
- 103
- Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol 2010a;128(4):456-60. PMID 20385941
- 104
- Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for bilateral combined anterior and posterior persistent fetal vasculature syndrome. Retina 2010b;30(4 Suppl):S2-8. PMID 20224462
- 105
- Walsh MK, Drenser KA, Capone A, et al. Norrie disease vs familial exudative vitreoretinopathy. Arch Ophthalmol 2011;129:819-20. PMID 21670366
- 106
- Warburg M. Norrie's disease: a new hereditary bilateral pseudotumour of the retina. Acta Ophthal (Copenhagen) 1961;39:757-72.
- 107
- Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol 2007;22(4):211-7. PMID 18097984
- 108
- Wu LH, Chen LH, Xie H, Xie YJ. Prenatal diagnosis of a case of Norrie disease with late development of bilateral ocular malformation. Fetal Pediatr Pathol 2017;36(3):240-5. PMID 28394646
- 109
- Wu WC, Drenser K, Trese M, Capone A, Dailey W. Retinal phenotype-genotype correlation of pediatric patients expressing mutations in the Norrie disease gene. Arch Ophthalmol 2007;125(2):225-30. PMID 17296899
- 110
- Xu Q, Wang Y, Dabdoub A, et al. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell 2004;116(6):883-95. PMID 15035989
- 111
- Yahalom C, Macarov M, Lazer-Derbeko G, et al. Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease. Ophthalmic Genet 2018;39(4):450-6. PMID 29781739
- 112
- Yamada K, Limprasert P, Ratanasukon M, et al. Two Thai families with Norrie disease (ND): association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier. Am J Med Genet 2001;100:52-5. PMID 11337749
- 113
- Yang H, Li S, Xiao X, Guo X, Zhang Q. Screening for NDP mutations in 44 unrelated patients with familial exudative vitreoretinopathy or Norrie disease. Curr Eye Res 2012;37(8):726-9. PMID 24661368
- 114
- Yonekawa Y, Wu WC, Kusaka S, et al. Immediate sequential bilateral pediatric vitreoretinal surgery: an international multicenter study. Ophthalmology 2016;123(8):1802-8. PMID 27221737
- 115
- Zhang B, Ma JX. Wnt pathway antagonists and angiogenesis. Protein Cell 2010;1(10):898-906. PMID 21204016
- 116
- Zhang XY, Jiang WY, Chen LM, Chen SQ. A novel Norrie disease pseudoglioma gene mutation, c.-12delAAT, responsible for Norrie disease in a Chinese family. Int J Ophthalmol 2013;18(6):739-43. PMID 24392318
- 117
- Zuercher J, Fritzsche M, Feil S, Mohn L, Berger W. Norrin stimulates cell proliferation in the superficial retinal vascular plexus and is pivotal for the recruitment of mural cells. Hum Mol Genet 2012;21:2619-30. PMID 22394677
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.
See Profile
Patient Profile
- Age range of presentation
-
- 0-01 month
- 01-23 months
- 02-05 years
- 06-12 years
- 13-18 years
- 19-44 years
- 45-64 years
- 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity typical
- heredity may be a factor
- X-linked recessive
- Population groups selectively affected
-
- none
- Occupation groups selectively affected
-
- none
ICD & OMIM codes
- ICD-9
-
- Norrie disease: 743.8
- ICD-10
-
- Other specified congenital malformations of eye: Q15.8
- OMIM
-
- Norrie disease: #310600
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Developmental Malformations
Achondroplasia
Apr. 16, 2023
-
General Child Neurology
Chiari malformation
Apr. 16, 2023
-
Developmental Malformations
Pituitary aplasia, dysplasia, and ectopic neurohypophysis
Apr. 15, 2023
-
Developmental Malformations
Collagen VI–related dystrophies: Ullrich congenital muscular dystrophy, Bethlem muscular dystrophy, and intermediate COL6-RD
Apr. 13, 2023
-
Developmental Malformations
X-linked hydrocephalus (L1 syndrome)
Apr. 11, 2023
-
Developmental Malformations
Rett syndrome
Apr. 04, 2023
-
Developmental Malformations
Dysplastic gangliocytoma of the cerebellum
Apr. 01, 2023