ISCHEMIC STROKE / ETIOLOGY

Grange syndrome

Created 31/10/2022, last revision 07/11/2023

Grange syndrome is a sporadic autosomal recessive (AR) condition characterized by severe early-onset vascular occlusive disease
- first reported in 1998 (Grange, 1998)
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 the later onset of vascular disease and a lack of developmental delay and bone fragility have bee 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 typically do not show signs and symptoms
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 the arteries
- it is also unknown how YY1AP1 gene mutations are related to other features, such as bone abnormalities

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
- migraines
- learning disabilities, retardation

early-onset vasculopathy with brachy- and syndactyly and bone fragility are typical for this syndrome
oligosymptomatic forms, such as isolated intracranial stenoses, are a diagnostic challenge

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 (US, CTA, DSA, MRA)

check ECG regularly (prolonged QT interval has been reported in Grange syndrome)
TTE (valvular abnormalities, cardiomyopathy)

no causal 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