"Blepharophimosis-plus" syndromes: Frequency of systemic genetic disorders that also include blepharophimosis

To determine the frequency of isolated blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) versus systemic genetic disorders in patients presenting with blepharophimosis.

Retrospective clinical records review. The records of all patients with blepharophimosis seen in the Division of Ophthalmology at the Children's Hospital of Philadelphia during a 12-year-period (2009-2020) were reviewed for medical history, clinical examination findings and results of genetic analyses.

The 135 patients identified with blepharophimosis included 72 females (53%) and 63 males (47%) whose mean ± standard deviation age at first visit was 3.5 ± 6.4 years (range 0-39.8 years). Sixty-seven of the patients (50%) had undergone genetic testing for FOXL2 gene mutation. Fifty-four (81%) harboured FOXL2 gene mutations and 13 (19%) did not. Altogether, 126 patients (93%) had a final diagnosis of isolated BPES. The remaining nine (7%) had syndromic diagnoses ("blepharophimosis-plus"), including Dubowitz syndrome (n = 2), Ohdo syndrome (n = 1), 22q11.2 duplication (n = 1) and 3q22 deletion (n = 2). Three patients with multiple congenital anomalies remain undiagnosed.

Blepharophimosis is an eyelid feature occurring most commonly in isolation due to FOXL2 gene mutation, but can also be a harbinger of multisystem disease not exclusive to isolated BPES, as observed in 7% of cases in this series. The ophthalmologist is often the first to recognise these unique features, and must consider and rule out non-BPES syndromes before establishing a diagnosed classic BPES. A comprehensive genetic evaluation is, therefore, indicated in all cases.