Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome

Clinical characteristics: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by a complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and primary ovarian insufficiency; BPES type II includes only the four major features. Other ophthalmic manifestations that can be associated with BPES include dysplastic eyelids, lacrimal duct anomalies, strabismus, refractive errors, and amblyopia. Other craniofacial features may include a broad nasal bridge and low-set ears.

Diagnosis/testing: The diagnosis of BPES is established in a proband with suggestive findings and a heterozygous pathogenic variant in FOXL2 or its regulatory domain identified by molecular genetic testing.

Management: Treatment of manifestations: Management requires the input of a multidisciplinary team of specialists. Eyelid surgery traditionally involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at age three to five years, typically followed a year later by ptosis correction. Primary ovarian insufficiency is managed by hormone replacement therapy; fertility is addressed with reproductive technologies such as embryo donation, egg donation, and cryopreservation strategies.

Surveillance: Ophthalmic follow up depends on age, procedures performed in the past, and results of visual acuity testing. Endocrinologic and gynecologic follow up are advised for affected females. Psychological follow up is recommended.

Genetic counseling: BPES is almost always inherited in an autosomal dominant manner. More than half of individuals diagnosed with BPES have the disorder as the result of a pathogenic variant inherited from an affected parent. Each child of an individual with BPES has a 50% chance of inheriting the pathogenic variant. Once the BPES-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPES are possible.