Grange syndrome

David Goldemund M.D.
Updated on 14/01/2024, published on 31/10/2022

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


  • Grange syndrome results from mutations in the YY1AP1 gene
    • homozygous or compound heterozygous mutations in the YY1AP1 gene, which is located on chromosome 1q22, are associated with this condition
    • parents of an individual with an autosomal recessive condition carry one copy of the mutated gene but typically do not exhibit signs and symptoms of the syndrome
  • the YY1AP1 gene encodes a protein that plays an important role in regulating smooth muscle cell (SMC)
  • mutations lead to the cell cycle arrest with reduced proliferation and differentiation of SMC
    • the exact pathway linking these cellular changes to vascular narrowing remains unclear
    • 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 (hypertension due to 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 and ECG abnormalities
    • migraines
    • learning disabilities, retardation
Grange syndrome - brachydactyly and syndactyly

Diagnostic evaluation

  • early-onset vasculopathy with brachy- and syndactyly and bone fragility are characteristic features of this syndrome
  • oligosymptomatic forms, such as isolated intracranial stenoses, pose a diagnostic challenge

Vascular imaging (CTA, MRA, DSA)

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

    • signs of inflammation are absent on black blood sequences
  • stenosis of renal, celiac, or coronary arteries (can be assessed using US, CTA, DSA, MRA)
Grange syndrome with left MCA stenosis (moyamoya-like pattern)
Renal artery stenosis on MRA

Cardiac monitoring

  • regularly check ECG as prolonged QT interval has been reported in Grange syndrome
  • perform TTE to assess for valvular abnormalities and cardiomyopathy

Genetic testing

  • collect DNA samples to identify pathogenic YY1AP1 variant


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

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Grange syndrome