The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome

Genes (Basel). 2021 Mar 4;12(3):364. doi: 10.3390/genes12030364.


Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.

Keywords: BPES I; BPES II; FOXL2; blepharophimosis; epicanthus inversus; premature ovarian failure; ptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Blepharophimosis / complications
  • Blepharophimosis / genetics*
  • Female
  • Forkhead Box Protein L2 / chemistry*
  • Forkhead Box Protein L2 / genetics*
  • Frameshift Mutation
  • Humans
  • Loss of Function Mutation
  • Male
  • Phenotype
  • Primary Ovarian Insufficiency / etiology*
  • Primary Ovarian Insufficiency / genetics
  • Protein Domains
  • Skin Abnormalities / complications
  • Skin Abnormalities / genetics*
  • Urogenital Abnormalities / complications
  • Urogenital Abnormalities / genetics*


  • FOXL2 protein, human
  • Forkhead Box Protein L2

Supplementary concepts

  • Blepharophimosis, Ptosis, and Epicanthus Inversus