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

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.

Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome: A Simple Remedy for Challenging Cases

“…Up to 75% of individuals with BPES have detectable FOXL2 mutation, which leads to haploinsufficiency. A majority of these mutations are intragenic and can be subdivided into indel frameshift, in-frame deletions, nonsense, missense, and duplications [ 3 ].…”

“…Both types of BPES are caused by mutations in the Forkhead Box L2 (FOXL2) gene, which encodes for a transcription factor that is expressed in the developmental stages of mesenchyme in eyelids and ovaries [ 3 ]. Because of this genetic involvement, molecular genetic testing for a pathogenic variant in FOXL2, along with clinical findings that include the four eyelid abnormalities, can be used to establish a diagnosis of BPES [ 4 ].…”

Case Report: Blepharophimosis and Ptosis as Leading Dysmorphic Features of Rare Congenital Malformation Syndrome With Developmental Delay – New Cases With TRAF7 Variants

“…Initially, the blepharophimosis-ptosis-epicanthus invertus syndrome (BPES) was suspected in the presented Case 1. BPES is a complex eyelid defect syndrome characterized by four main features: blepharophimosis, eyelid ptosis, epicanthus invertus and telecanthus (BPES II), as well as premature ovarian failure in BPES I (20). In both BPES and CAFDADD, a palpebral fissure defect is one of the characteristic clinical features.…”

Identification and functional analyses of a novel FOXL2 pathogenic variant causing blepharophimosis, ptosis, and epicanthus inversus syndrome

“…B lepharophimosis, ptosis, and epicanthus inversus syndrome (BPES; the Online Mendelian Inheritance in Men #110100), first reported by Ammon in 1841, is a rare congenital disease, whose prevalence is estimated as 1/50 000 according to statistics [1] . Depending on the clinical features, BPES is separated into two main phenotypes: the type I patients have premature ovarian insufficiency/failure (POI/POF) and eyelid malformations at the same time while the type II patients only have deformities in eyelids [2] .…”