CASE OF THE MONTH: October 2022

Two siblings with bilateral retinal abnormalities

Summarized by Mrinali Gupta, MD (Retina Associates of Orange County)

History:

  • 2 year old female
  • Developmental delay and CNS abnormalities (inferior vermian agenesis, cerebellar dysplasia, posterior fossa cyst, enlarged fourth ventricle, and atrophic, superior cerebellar peduncles – Dandy Walker variant diagnosis)
  • Referred by pediatric ophthalmology for pigmentary retinal changes

Exam:

  • VISUAL ACUITY: Fix and follow OU
  • EOM: Esotropia; nystagmus
  • CRx: -16.0 D OU
  • IOP: soft OU
  • ANTERIOR SEGMENT: unrevealing
  • DILATED FUNDUS EXAMINATION: peripheral retinal avascularity OU

Exam under anesthesia


Marlow E, Chan RVP, Oltra E, Rusu I, Gupta MP. JAMA Ophthalmology 2018; 136: 96-97.


Brother

  • History of parental consanguinity (first cousins)
  • 4 year old brother had the same developmental and CNS abnormalities, Dandy Walker variant diagnosis
  • VISUAL ACUITY: Fix and follow
  • EOM: Esotropia; nystagmus
  • CRx: -15.5 D OU
  • IOP: soft OU
  • ANTERIOR SEGMENT: unrevealing
  • DILATED FUNDUS EXAM / EUA: similar to sister

Fluorescein angiogram – 3.5 years later (sister)



Marlow E, Chan RVP, Oltra E, Rusu I, Gupta MP. JAMA Ophthalmology 2018; 136: 96-97.


Fluorescein angiogram – 3.5 years later (brother)



Marlow E, Chan RVP, Oltra E, Rusu I, Gupta MP. JAMA Ophthalmology 2018; 136: 96-97.


Genetic testing

  • Whole exome gene sequencing
    • Both patients - compound heterozygote LAMA1 (laminin-1) mutations (c.664C>T p.Arg222* and c.2331C>G p.Tyr777*)
    • Diagnosis revised from Dandy Walker variant to PORETTI-BOLTSHAUSER SYNDROME
  • No FEVR-associated mutations were identified

Poretti-Boltshauser Syndrome

  • Mutations in the laminin-1 (LAMA1) gene, encoding laminin-1 protein
    • Heterotrimeric proteins, major component of extracellular matrix/basal lamina of basement membranes, influence cell differentiation, migration, adhesion
  • CNS findings
    • cerebellar dysplasia
    • cerebellar cyst
    • inferior vermian hypoplasia
    • enlarged fourth ventricle
    • other brainstem abnormalities
    • –developmental delay, especially motor/speech
  • Ocular phenotype
    • "retinal dystrophy"
    • No prior report of retinal vasculopathy

Laminin mutations and retinal biology

  • Basic science studies
    • Laminins mediate retinal angiogenesis including endothelial cell fate, migration, and adhesion
  • Zebrafish and mouse models of lama-1 knockout
    • Abnormal retinal angiogenesis (failure of regression of hyaloid vasculature, retinal avascularity, and retinal neovascularization)
  • Other ocular abnormalities and retinal abnormalities also noted

Clinical/molecular correlations to known retinal vasculopathies

  • The cases presented here exhibited some phenotypic overlap with FEVR
  • Tetraspanin 12 (TSPAN12), mutated in some FEVR cases, associates with a laminin-binding integrin to mediate retinal angiogenesis

Conclusions

  • Poretti-Boltshauser syndrome may manifest with retinal vasculopathy including retinal neovascularization (or sequelae) requiring intervention. Consider wide-field angiography in all
    • cases
  • There may be a role for laminin in the molecular pathophysiology of retinal vascular diseases

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Marlow E et al. JAMA Ophthalmology 2018; 136: 96-97.

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