Norrie Disease -CEW

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====== Norrie Disease ======

====Main Features====

  * X-linked recessive disorder caused by mutations in the //NDP// gene (Xp11.3)
    * encodes **norrin**, a secreted Wnt-pathway ligand for frizzled-4 
    * Essential for retinal and inner-ear vascular development
  * Retinal vascular developmental defects lead to
    * Avascular peripheral retina
    * Retinal gliosis and vitreous
    * Retinal detachment 
      * Congenital bilateral blindness
  * **Progressive sensorineural hearing loss** occurs in ~30%, usually later onset (childhood into adulthood).
  * Neurodevelopmental
    * Developmental/motor delay (~30–50%), mild-to-moderate intellectual disability, behavioral problems/psychosis, autism features, and seizures. 
    * Larger deletions (complete norrin loss) → more severe multisystem disease.

====Eye Findings====

  * Retinal detachment, retinal gliosis, avascular peripheral retina
  * Retrolental mass ("pseudoglioma") — grayish-yellow mass of immature retinal cells resembling retinoblastoma
  * Leukocoria — hallmark sign; with retinal dysplasia and partial/complete retinal detachment.
  * Progressive anterior/globe changes — cataract, corneal opacification, iris atrophy, synechiae, secondary glaucoma/buphthalmos, and eventual phthisis bulbi, typically within the first decade.
  * Microphthalmia
  * Nystagmus
====Other Findings====

  * **Auditory:** progressive sensorineural hearing loss in ~30%, requiring surveillance and eventual hearing aids/cochlear implantation.*[1][2][5][6]
  * **Neurodevelopmental/psychiatric:** developmental delay, intellectual disability, psychosis/behavioral problems, autism features, seizures.*[1][2][4]
  * **Allelic conditions (NDP-related retinopathies):** familial exudative vitreoretinopathy (FEVR), [Coats disease](https://www.openevidence.com/rare-disease/coats-disease), persistent fetal vasculature (PHPV), and retinopathy of prematurity.

====Etiology====

  * **Gene/inheritance:** pathogenic variants in **//NDP//**, inherited **X-linked recessive**; affected males hemizygous, carrier females typically unaffected. >115 mutations reported (missense, splice, intragenic/large deletions), with genotype–phenotype correlation (deletions → severe).
  * **Mechanism:** loss of norrin disrupts Wnt/frizzled-4 signaling required for retinal and cochlear vascular development and retinal cell specification.
  * **Differential/phenocopies:** truncating //CTNNB1// mutations can cause a Norrie-like phenotype, with overlap with //KIF11//; ~30% of clinically diagnosed families have no identifiable //NDP// variant.
  * **Genetic testing:** Sanger sequencing for point mutations/small indels; **deletion/duplication analysis (MLPA/dosage)** for large deletions; **NGS/whole-exome sequencing** for ambiguous cases or to capture //CTNNB1///KIF11//. Once the familial variant is known, **carrier, prenatal (amniocentesis/CVS), and preimplantation** testing are available; third-trimester ultrasound may suggest the diagnosis.
  * **Treatment (supportive, multidisciplinary; no approved disease-modifying therapy):
    * **Ocular** — individualized pediatric vitreoretinal care; most infants have complete detachment at birth limiting surgery to preserving light perception/globe. In eyes **without complete detachment, prophylactic laser photocoagulation at/shortly after birth** has preserved useful vision. Vitrectomy (± lensectomy) in selected infants; manage secondary glaucoma; enucleation occasionally for a painful blind eye.
    * **Auditory** — audiologic monitoring, hearing aids, cochlear implantation.
    * **Neurodevelopmental** — developmental, behavioral, educational support; seizure and psychiatric management.
    * **Emerging** — systemic **AAV9-mediated //NDP// gene therapy** rescued retinal and cochlear pathology in a Norrie mouse model (preclinical).

====Resources====

  * [[https://medlineplus.gov/genetics/condition/norrie-disease/|MedlinePlus: Norrie disease]]
  * [[https://www.ncbi.nlm.nih.gov/books/NBK373729/|GeneReviews: NDP-Related Retinopathies (Scruggs, Reding, Schimmenti)]]
  * [[https://medlineplus.gov/genetics/gene/ndp/|MedlinePlus: NDP gene]]
  * [[https://www-clinicalkey-com.slhs.idm.oclc.org/#!/content/1-s2.0-S0161642010003763|Chow et al. Laser Photocoagulation at Birth Prevents Blindness in Norrie's Disease, Ophthalmology 2010]]

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syndrome