Blepharophimosis-ptosis-epicanthus inversus syndrome (ORPHA:126)
A rare ophthalmic disorder characterized by blepharophimosis, ptosis, epicanthus inversus, and telecanthus, that can appear associated with (type 1) or without primary ovarian insufficiency (POI; type 2).
Epidemiology
The worldwide prevalence is unknown.
Clinical description
A congenital disorder characterized by a complex bilateral eyelid malformation including blepharophimosis, ptosis, epicanthus inversus and telecanthus. Other ophthalmic manifestations that are usually associated include lacrimal duct anomalies, amblyopia, strabismus, refractive errors and a lateral displacement of the inferior lacrimal puncta. Additional features include a broad nasal bridge, low-set ears, and a short philtrum. Affected females may develop POI, and are thus considered to have BPES type 1. Females without POI are classed as BPES type 2.
Etiology
The disorder is caused by an intragenic mutation (80%), gene deletion (10-12%), deletions of regulatory elements outside of the FOXL2 gene (3q23)(<5%), and translocations involving the FOXL2 region. FOXL2 encodes a forkhead transcription factor that contains a typical DNA-binding forkhead domain and a polyalanine tract of 14 residues strictly conserved in mammals. FOXL2 is expressed in peri-ocular tissues as well as in the fetal and adult ovaries.
Diagnostic methods
Diagnosis is based on presence at birth of the 4 major eyelids features with or without POI (amenorrhea for greater than 6 months, less than age 40 years and follicle stimulating hormone concentration greater than 40 IU/L). The clinical diagnosis is confirmed by the identification of a genetic defect in the FOXL2 gene or its regulatory region.
Differential diagnosis
The differential diagnoses includes those conditions in which ptosis or blepharophimosis are major features. However, this disorder can be relatively easily distinguished from most of these conditions as its facial appearance is very typical.
Antenatal diagnosis
Genetic prenatal testing may be possible where the pathogenic variant has been previously identified in an affected family member.
Genetic counseling
Whilst the disorder can occur sporadically (de novo), the pattern of inheritance is typically autosomal dominant and genetic counseling for affected families should be offered. Penetrance for the eyelid phenotype is complete and presence of POI varies between families. Germline mosaicism has been described as well as a recessive mutation (one family) involving a polyalanine expansion of intermediate length.
Management and treatment
The surgical management is traditionally performed in two stages and involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at ages 3 to 5 years, followed about a year later by ptosis correction. However, when ptosis is severe, surgical repair is recommended before age 3 years. Ophthalmologic follow-up is important for management of the oculoplastic surgery. All female patients should be assessed and followed up for POI. Management of POI is multidisciplinary ( requiring a geneticist, endocrinologist, gynaecologist) should include counseling of the patient and relatives. Egg donation may be considered as a reproductive option. In the case of a detectable ovarian reserve, therapeutic counseling can lead to fertility preservation.
Prognosis
Prognosis is good and patients have a normal lifespan.

                            Last update: 
                            March 2020


                            - Expert reviewer(s): 
                            Pr Elfride DE BAERE  - Dr Hannah VERDIN