Approximately 75% of cases of blepharophimosis have a positive family history, and inheritance is usually autosomal dominant, mostly through the father.⁹ The remaining cases are sporadic, where the proband acquires the syndrome through a de novo mutation in the afflicted child or one of its parents. These figures, however, are not universal. In a recent study in the Indian population, only 23% of the affected patients showed a positive family history and 24% of patients showed chromosomal anomalies on cytogenetic analysis.¹⁰

The gene responsible for the clinical manifestations of the syndrome, the FOXL2 gene (forkhead transcription factor gene 2), is strongly expressed in the developing as well as the adult eyelids, in the pituitary gland, and the ovaries, but not in the testes, which explains the female, not male, infertility. It is located on the long arm of chromosome 3 (3q22-26).¹⁰,¹¹,¹² Approximately 5% of the mutations occur outside the designated region of FOXL2, which may explain the occasional finding of atypical associated conditions like mental retardation.¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶ In general, a sibling of a patient with BPES has minimal risk of developing the disease if the eyelids of both parents are normal¹³; however, it should be noted that because germline mosaicism has been documented with BPES, the exact risk of having another child with blepharophimosis should depend upon the results of genetic testing of both parents.¹³ If a parent has a FOXL2 mutation, the risk of transmission is 50%, but if the parents are free, the risk of developing another de novo mutation in a sibling is exceedingly low.¹⁴

The existence of two types of blepharophimosis based on female infertility was proposed in 1983.¹⁵ In type I, the syndrome is transmitted only by males with 100% penetrance, as affected females are infertile. In type II, females are fertile, and the genetic defect is transmitted by both affected males and females with a 96.5% penetrance.¹⁵ The distinction between types I and II is mainly based on genetic testing. So far, 271 different mutations or allelic variables have been reported to cause blepharophimosis syndrome.¹⁶ In general, type 1 mutations usually result from deletions in the FOXL2 gene and cause complete loss of gene function, whereas type 2 mutations usually result from an extended or an elongated FOXL2 gene causing a partial loss of gene function.¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶ Recently, however, the concept of two distinct types of blepharophimosis has been challenged. Even when sharing the same mutation, intrafamilial phenotypic variability, as well as the genotypic overlap between types I and II, have been demonstrated,¹⁷,¹⁸,¹⁹ calling into question the strict classification of blepharophimosis syndrome into types 1 and 2.

Blepharophimosis syndrome is not uncommon, with a reported incidence of 1/50,000 live births.²⁰ Because of the peculiar features that are instantly obvious at birth, patients typically present very early in life. Blepharophimosis, or narrowing of the horizontal palpebral fissure, is profound.²¹ In the adult blepharophimosis patient, palpebral fissure length
is reduced and ranges from 20 to 22 mm (normal range 25-30 mm).⁸,¹⁰,²¹

Most patients with blepharophimosis have severe, bilateral, and usually symmetric upper eyelid ptosis with very poor to absent levator muscle function. Ptosis is usually so severe that most of these children assume the typical chin-up head position with pronounced high arched eyebrows from frontalis contraction (Figure 28.2). In the past, this led some researchers to erroneously postulate a bony abnormality of the supraorbital rim.⁹,²⁰ Factors underlying this severe ptosis in blepharophimosis syndrome remain unexplained.²² Until recently, this was simply attributed to severe dysplasia or even absence of the levator muscle,⁸,²¹ but this concept was recently challenged by demonstrating that, contrary to simple congenital ptosis, there was a significant improvement in levator function after supramaximal levator resections.²² In a subsequent paper, the authors offered new insights into the pathophysiologic mechanisms leading to severe ptosis.²³ On preoperative MRI scans the levator aponeurosis was unusually thinned and elongated (25 mm). This finding was also supported intraoperatively, and histopathology showed a disorganized, exceedingly long aponeurosis with a healthy-looking well-defined muscle belly posteriorly. However, this normal muscle portion was situated too deep in the orbit and was poorly connected to the tarsal plate through the abnormal aponeurosis.²³

Epicanthus inversus is defined as an epicanthal fold emerging from the lower eyelid and curving upward obliterating the regular concavity in the medial canthal area. It is usually more pronounced at a very young age but tends to improve with age.⁸,²⁴ Telecanthus or lateral displacement of the medial canthus is observed in the vast majority of patients with subsequent lateral displacement of the inferior punctum.¹,²⁴,²⁵,²⁶ This is classically attributed to an abnormally long inferior crus of the medial canthal
tendon (MCT).¹ Recently, however, it was hypothesized that a loose attachment of the MCT to the lower eyelid or an abnormal bifurcation of the medial canthal tendon is the underlying anatomical cause for the peculiar deformities of BPES that are classically observed in the medial canthal region.²⁴ The authors noticed that, in patients with BPES, the normal temporal fork-like splitting of the medial canthal tendon is not observed. Instead, the lower crus seemed to be markedly less formed and the medial canthal tendon, which was unusually thin, appeared to be mainly connected to the upper eyelid without the classic Y-shaped bifurcation.²⁴ Of note is that because of the associated phimosis of the palpebral fissure, hypertelorism is not observed in patients with BPES.⁸