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

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

Cécile Méjécase  1 , Chandni Nigam  2 , Mariya Moosajee  1   3   4   5 , John C Bladen  2
Affiliations
Review

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

Cécile Méjécase et al. Genes (Basel). .

Abstract

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.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Diagram showing forkhead box L2 (FOXL2), up- and downstream genomic position, protein structure, and hotspot located in the poly-alanine domain. (A) Chromosomal deletions were reported in at least 84 blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) patients, with the largest encompassing 3q22.3 to 3q24 (12 Mb) and the smallest encompassing FOXL2 or PIRST1 genes (UCSC: hg19:chr3:133,064,629-153,716,375). (B) FOXL2 is composed of one 2.9 kb exon (NM_02367.4). The stop codon is indicated with an asterisk (*). (C) FOXL2 is a 376 amino acid protein, composed of poly-glycine (amino acid position 35–43) depicted in light grey, a DNA binding protein or forkhead (amino acid 54–148) in dark, two poly-alanine (poly-Ala) region (amino acid 221–234 and 301–304) in grey, and a poly-proline region (amino acid 284–292) in light grey (Uniprot: P58012). The most common variants (more than five patients were reported) are represented herein, which affect the highly conserved poly-alanine domain (amino acid 221–234) with c.672_701dup p.(Ala224_Ala234dup) (n = 80), c.663_692dup p.(Ala221_Ala231dup) (n = 12), and c.664_693dup p.(Ala222_Ala231) (n = 5), or the poly-proline domain (amino acid 284–292) with c.843_859dup p.(Pro287Argfs*241) (n = 46), c.855_871del p.(Pro287Alafs*241) (n = 5), and c.855_871dup p.(His291Argfs*71) (n = 15). The nonsense variant c.655C>T p.(Gln219*) and the frameshift variant c.804dup p.(Gly269Argfs*265) were reported in 6 and 10 patients, respectively.
Figure 2
Figure 2
BPES patient with a heterozygous missense mutation in FOXL2 c.175T>G, p.(Tyr59Asp): (A) features seen at 4 months of age consisting of (B) four cardinal features: (a) blepharophimosis, (b) ptosis, (c) telecanthus, and (d) epicanthus inversus. (C) Bilateral correction of the ptosis at 12 months of age using a Supramid (artificial material) frontalis suspension technique and (D) eyelid position 6 months after the frontalis suspension operation.
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