ISCHEMIC STROKE / ETIOLOGY

Grange syndrome

Created 31/10/2022, last revision 06/12/2022

  • Grange syndrome  is a sporadic autosomal recessive (AR) condition characterized by severe early-onset vascular occlusive disease
  • additional features are present with variable penetrance (brachydactyly, syndactyly, fragile bones, and heart defects)
  • symptoms usually appear in childhood or young adulthood; variants characterized by later onset of vascular disease and a lack of developmental delay and bone fragility were reported  (Alamo, 2019)

Etiology

  • Grange syndrome results from mutations in the YY1AP1 gene
    • homozygous or compound heterozygous mutation in the YY1AP1 gene on chromosome 1q22
    • the parents of an individual with an autosomal recessive condition carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition
  • the protein produced by this gene is part of a group of proteins that play an important role in smooth muscle cell (SMC) regulation
  • mutations lead to the cell cycle arrest with reduced proliferation and differentiation of smooth muscle cells
    • it is unclear, however, how these changes lead to the narrowing and blockage of arteries
    • it is also unknown how YY1AP1 gene mutations are related to other features, such as bone abnormalities

Clinical presentation

  • vasculopathy
    • cerebrovascular disease
      • stroke/TIA
      • SAH
    • renovascular hypertension (uni-/bilateral renal artery stenosis)
    • coronary artery disease (CAD)
    • celiac artery stenosis (postprandial abdominal pain, etc.)
  • other symptoms (may be absent)
    • brachydactyly and/or syndactyly
    • fragile bones
    • heart defects, ECG abnormalities
    • migraine
    • learning disabilities, retardation
Grange syndrome - brachydactyly and syndactyly

Diagnostic evaluation

  • early-onset vasculopathy with brachy- and syndactyly and bone fragility are typical for this syndrome
  • oligosymptomatic forms presenting, for instance, as isolated intracranial stenoses are challenging

Vessel imaging (CTA, MRA, DSA)

  • stenoses of the internal carotid arteries and MCAs + collateral vessel formation  ⇒ moyamoya-like pattern

    • with the absence of inflammation on black blood sequences
  • stenosis of renal, celiac, or coronary arteries (US, CTA, DSA, MRA)
Grange syndrome with left MCA stenosis (moyamoya-like pattern)
Renal artery stenosis on MRA

Cardiac monitoring

  • check ECG regularly (prolonged QT interval was reported in Grange syndrome)
  • TTE (valvular abnormities, cardiomyopathy)

Genetic testing

  • collect DNA samples to identify pathogenic YY1AP1 variant

Management

  • no specific therapy
  • antiplatelet therapy if stroke or TIA symptoms occur
  • manage vascular risk factors in adults
  • consider angioplasty of carotid, renal or celiac stenoses
  • consider intracranial revascularization procedures in selected cases (as with moyamoya)
  • genetic counseling

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