Norrie Disease

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Norrie Disease


Norrie disease is a hereditary genetic disorder that affects the retina, leading usually to blindness. In addition to the congenital ocular symptoms, some patients suffer from other systemic symptoms, including hearing loss, and learning or behavioral problems.

Patients with Norrie disease may develop retinal detachment, cataracts, leukocoria, iris atrophy and, and other developmental issues in the eye. An important number of patients will also have psychotic-like features or incoordination of movements.

Most patients are born with normal hearing; however, the onset of hearing loss is very common in the second decade of life. About 15% of patients are estimated to develop all the features of the disease.

The disease affects almost only male infants, owing to its X-linked recessive inheritance.

Disease Entity

Norrie disease (ND; OMIM 310600) is a rare X-linked disorder resulting from a mutation in the NDP gene that mainly affects the eye. It is characterized by retinopathy that leads to blindness in male infants at birth or soon after [1]. 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 [2][3], a group that includes: Persistent hyperplastic primary vitreous (PHPV), X-linked familial exudative vitreoretinopathy (X-linked FEVR), NDP-related retinopathy of prematurity (ROP), and Coats disease[4][5][6][7].

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 or adolescence and cause different degrees of visual impairment. Most of these also include diverse systemic features that can vary throughout and within families[8].

Other names for this disease include: ND, NDP, Anderson-Warburg syndrome, Norrie-Warburg syndrome, Whitnall-Norman syndrome, atrophia bulborum hereditaria, episkopi blindness, fetal iritis syndrome, congenital progressive oculo-acoustico-cerebral degeneration, oligophrenia microphthalmus, and pseudoglioma congenita.

Etiology

Norrie disease is a genetically inherited, X-linked 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 eye and ear. [9][10][11] Pathogenic variants that disrupt normal protein formation cause retinal dysgenesis that in turn results in the mentioned ocular phenotype.[12] 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, and many mutations are novel or at least rare as might be expected for a disorder that leads to a reduction in reproductive fitness. [2] [13]  While penetrance is complete (100%) in affected males, carrier females usually do not have any evidence of disease, save for rarely a partial hearing loss or mild ocular phenotype. This could occur, presumably secondary to non-random X-chromosome inactivation, or if both of the copies of the NDP gene bear mutations, which could be the case in consanguineous families or due to a spontaneous somatic mutation. [14]

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. [15] It is not associated with any specific racial or ethnic group, and it has actually been reported in all 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 original descriptions of Norrie disease were from Scandinavia (Denmark). [16] [17]

Risk Factors

Since it is a genetically inherited disorder there are no known risk factors or racial predisposition for this disease.

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. [12] Histology shows hemorrhagic necrosis of an undifferentiated glial mass.  The primary defect seems to lie in the neuroretina with absence of the ganglion cells and dysplasia of the remaining layers. After progression, many eyes become phthisical. [18]

Pathophysiology

The NDP gene provides instructions for a protein called norrin, which participates 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. [19] Norrin is one of many ligands that can bind to certain cell membrane receptors called frizzled receptors. Norrin binds with the receptor frizzled-4 (produced from the FZD4 gene), and initiates a process that regulates the activity of certain genes. [11] This pathway is believed to affect molecular processes that are crucial for normal development of the eye and other body systems. In particular, it seems to play critical roles in the specialization of cells in the retina and the establishment of a blood supply to the retina and the inner ear. [20] [21]

More than 75 mutations in the NDP gene have been identified in people with Norrie disease. [13] These mutations affect the ability of the norrin protein to bind with frizzled-4, interfering with the specialization of retinal cells. As a result, masses of immature retinal cells accumulate in the vitreous chamber. Disruption of norrin's role in the establishment of blood vessels supplying the eye also eventually causes some of the retinal tissues to break down. [22] All of this manifests into the typical ocular signs and symptoms described in the disease.

Norrin is also expressed in other bodily systems, and the effects of the disorder can be widespread, including intellectual disability, seizures, behavioral problems, and delayed development. [18] Specific abnormalities and their severity depend on the type and location of the NDP gene mutation. Mutations that delete portions of the NDP gene prevent production of norrin and result in severe problems affecting multiple systems in addition to the eyes.[8] Mutations that delete or change single amino acids usually result in less widespread effects.

Diagnosis

Norrie disease and other NDP related diseases are diagnosed with the combination of the characteristic clinical ocular findings and can be confirmed by molecular genetic testing. [3] This tests can identify pathogenic variants in approximately 95% of affected males. No biochemical or functional assays are available for diagnosis.

Molecular genetic testing is used for more than a confirmatory diagnosis. Currently it can also be 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 15% submicroscopic deletions that cannot be tested with sequence analysis. This method is also used for testing 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 member affected by the disease. [3] Prenatal testing for at-risk pregnancies is possible if the disease-causing mutation has been identified in the family. [23]

History

Norrie disease was first described as a defined hereditary syndrome in Acta Ophtalmologica on 1961.[16] In this report, Mette Warburg, a Danish ophthalmologist, reported a family showing seven cases of a hereditary degenerative disease throughout seven generations. The first member of the family to be thoroughly studied was a 12-month-old boy. In the aforementioned family, five of the seven cases developed deafness later in life. Also, in four of the seven, mental capacity was determined to be low. After Warburg researched literature under various medical categories, she discovered 48 similar cases which she believed were caused by this disease as well. She then suggested this disease be named after Danish ophthalmologist, Gordon Norrie (1855–1941), who was a highly recognized surgeon in the Danish Institute for the Blind for 35 years.

Norrie was actually the first investigator to describe these familial cases of congenital blindness in 1927, though he didn’t recognize them as a clinical syndrome.[17] Other physicians before Warburg, including Taylor (1959 in Episkopi, Greece), [24] Roberts (1937), [25] Whitnall, Norman (1940) [26] and Stephens (1947) [27] reported families with similar afflictions that were later assumed to be cases of Norrie disease. Nonetheless, Warburg was the one who further expanded the clinical description to include hearing loss and intellectual disability, noted the X-linked heritability of the disease and further define the characteristics of the disease.

Physical examination

On external examination, Norrie disease often presents at birth or soon after with leukocoria. Microphthalmia is another possible initial presentation. [8] On slit lamp biomicroscopy the irises, anterior chambers, cornea, intraocular pressure, and size of the globe may be normal at birth, though iris atrophy, cataracts, a shallow anterior chamber and synechiae can be noted as well. An important distinction of this disease is its predisposition for bilateral and symmetric manifestations. [15][18][28]

On fundoscopy, both 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. [29] Partial or complete retinal detachment evolves over the first few months. This mass consists of immature retinal cells and may be apparent a few days after birth or may not be noted until weeks or months later. This retinal changes are responsible for the noted leukocoria. It is important to remember Norrie disease in the possible differential diagnosis for any case of leukocoria (especially bilateral cases).

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. [30]

The main disorder is retinal degeneration which occurs in utero and results in blindness at birth or early infancy. [15] 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. This may be mistaken for a tumor, and is sometimes mentioned as ‘pseudoglioma’, which is a nonspecific term for any condition resembling retinoblastoma. ‘Pseudoglioma’ can have diverse causes, including inflammation, hemorrhage, trauma, neoplasia, or congenital malformation, and often shows unilateral involvement. [29] 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. This in turn can produce glaucoma and pain. [18] 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 ND, the corneas appear milky and opacified; the globes appear small and sunken in the orbital cavity. [3]

In addition, microphthalmia may be present at birth, the pupils may be dilated and the irises may be hypoplastic. The majority of patients are either blind from birth or eventually develop this during the course of the disease.[8] Cognitive/behavioral findings: Approximately 30%-50% of males with the ND phenotype have poorly characterized behavioral disturbances or developmental delay/intellectual disability and may show psychotic-like features. Abnormalities include autism or autism-like behavior, depression, and labile affect. [18] The most pervasive behavioral disturbance in men and boys with ND is autism or autism-like features (27%) including perseveration and sensory integration issues. The second most common behavioral issue is labile affect with up to 25% of patients exhibiting this finding. Intra- and interfamilial variability in the expression of the cognitive and behavioral difficulties is common. A severe neurologic phenotype including infantile spasms and chronic seizures has been reported in up to 9% of patients. [31] Dementia is rare but may occur in late adulthood.

Auditory findings: The majority of males with ND 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. [15] Audiologic data suggest the abnormality resides in the cochlea (specifically, the stria vascularis) and that retrocochlear and brain auditory system function is normal. [32][33] 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. Speech discrimination is relatively well preserved even when the threshold loss is severe . [34] 
Vascular findings: Peripheral vascular disease appears to be an associated clinical finding in a number of affected males. Patients have been reported with venous stasis ulcers, varicose veins, and erectile dysfunction (ED). [18][35] 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 ND patients experience ED at an early age (between ages 16 and 30).[15][33]

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 an ND patient includes congenital blindness, progressive hearing loss and cognitive-psychosocial disturbances. [3] 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 hyperplastic primary vitreous, hyaloid vessels, shallow anterior chamber, and vitreoretinal hemorrhages.
  • Microphthalmia and cataracts may be present.
  • 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 hyperplastic primary vitreous (PHPV), Coats disease, and advanced retinopathy of prematurity (ROP).[4][5][6][7] 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. [3]

One genetic testing strategy is molecular testing of NDP. Sequence analysis is performed first, [36] 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, the 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. 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. [3]

Laboratory test

No biochemical or functional assays are available.

Differential diagnosis

  1. Retinoblastoma
  2. Retinopathy of prematurity
  3. Persistent hyperplastic primary vitreous
  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 if the ocular presentation is predominantly that of unilateral pseudoglioma. [8] Because the usual presentation of ND is bilateral, diagnosis of RB is not always a consideration. Fundoscopic examination can distinguish between the two disorders. Other disorders related to NDP mutations such as retinopathy of prematurity in later stages, persistent hyperplastic primary vitreous, X-linked familial exudative vitreoretinopathy and coats disease can also be considered.[4][5][6][7] The retinal dysplasia that occurs in ND can be indistinguishable from the dysplasia found in trisomy 13 and Walker–Warburg syndrome (in the latter associated with lissencephaly).

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. [3]

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 systematically and comprehensively plan an affected child's treatment.

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 will not improve vision. Earlier in-utero treatment, as well as early vitrectomy have been reported in attempts to preserve vision, but so far no evidence is conclusive enough to warrant a systematic treatment approach.[37][38][39][40] Hearing aids may be of benefit for individuals with hearing loss and are usually successful into middle or late adulthood. When hearing is significantly impaired, a cochlear implant is also an option. Other treatment is symptomatic and supportive. [34]

Early intervention and appropriate specialized education is important in ensuring that children with Norrie disease reach their highest potential. Services that may be beneficial include special remedial or personalized education, other medical, social, and/or vocational services. Genetic counseling is important for genetic risk assessment in family members. [18]

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, 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. [18]

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 so that hearing loss can be detected early and managed appropriately -Observation for clinical evidence of venous stasis or other signs of vascular disease. -Follow up on developmental and behavioral abnormalities by special remedial professionals.


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

Surgery

The majority of males with the classic Norrie disease (ND) phenotype have complete retinal detachment at birth, therefore surgery may not offer much with regard to preservation of sight. Treatment for less than complete retinal detachment does include surgery, laser therapy and/or cryotherapy with the potential for improved outcomes if done at an early stage.[15] In the progressive stages, 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.

Hearing aids should be provided to correct hearing loss, and are usually successful well into middle or late adulthood. Cochlear implantation should be considered when hearing-assisted audiologic function is significantly impaired. [32][34]

Some reports have described successful laser photocoagulation at birth, helping preserve some degree of visual capacity. [37][38][39] Other reports mention early vitrectomy (done by age 12 months) help with documented maintenance of light perception in at least one eye.[40] 
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 has to be studied individually to see if surgery is a possibility, and to find the best treatment options.

Genetic Counseling

Genetic counseling should be offered to all affected families.

Norrie disease and other NDP-related retinopathies are inherited in an X-linked 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. [3][23]

Risk to Family Members [3]

Parents of a male proband:

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



Sibilings of a male proband (The risk to 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 sibilings who inherit the pathogenic variant will be affected; female sibilings 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 sibilings 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 [3]

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 [3]

  • 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. 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. [15]

Additional Resources

References

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