Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES)

AD; FOXL2 (forkhead transcription factor) on 3q22. Two clinically distinct types based on whether ovarian function is affected:

• BPES type I: eyelid malformation plus premature ovarian insufficiency (POI) in affected females. FOXL2 loss-of-function mutations.
• BPES type II: eyelid malformation only; normal female fertility. Different FOXL2 mutations (mostly missense in the forkhead domain).

The same gene can cause both; outcome depends on the specific variant.

The four cardinal eyelid findings (the syndrome name spells them):

• Blepharophimosis: narrowed horizontal palpebral fissure
• Ptosis: bilateral, severe, often requiring frontalis sling
• Epicanthus inversus: skin fold from lower lid up toward nasal bridge (reversed direction vs. typical epicanthus)
• Telecanthus: increased distance between inner canthi

Plus, in type I females:

• Premature ovarian insufficiency: secondary amenorrhea, low estrogen, elevated FSH, infertility before age 40

• Clinical recognition of the four eyelid findings
• FOXL2 sequencing; large deletions detected by CMA or MLPA
• Distinction between type I and type II often awaits adolescent ovarian function

• Ophthalmology / oculoplastics: surgical correction of ptosis and telecanthus typically in early childhood to prevent amblyopia (frontalis sling for severe ptosis); staged repair through adolescence
• Females (any age, any type): monitor pubertal development and menstrual function; if POI emerges, hormone replacement and fertility counseling (IVF with donor eggs)
• Genetic counseling: AD with 50% recurrence; type I → POI → fertility implications

• Isolated congenital ptosis: no telecanthus, no blepharophimosis
• Waardenburg syndrome: telecanthus (W index) + pigmentary anomalies + sensorineural deafness
• Saethre-Chotzen syndrome: ptosis with craniosynostosis; different facies