Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome (BPES) is a rare, congenital developmental disorder that primarily affects the eyelids and the surrounding area. The condition is present from birth, causing a distinct facial appearance. This article clarifies that BPES is caused by a precise genetic mutation. It is important to note that BPES is not generally the result of consanguinity, which is a common but mistaken assumption for many rare disorders.
Physical Features of Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome (BPES)
The name of the syndrome directly describes the three malformations consistently seen in affected individuals. Blepharophimosis refers to the shortening of the horizontal opening of the eye, making the eyes appear small and narrow. Ptosis is the medical term for droopy upper eyelids, which can be severe enough to cover the pupil and impair vision.
The third feature, Epicanthus Inversus, describes an upward-curving skin fold that runs from the lower eyelid toward the inner corner of the eye. These three features are often accompanied by an increased distance between the inner corners of the eyes (telecanthus). These physical traits result from a failure in the normal embryonic development of the eyelids and related structures.
The severity of the eyelid malformation can vary significantly among affected individuals, even within the same family. BPES is classified into two types. Type I involves premature ovarian insufficiency in females, in addition to the ocular signs.
Genetic Origin: The Role of the FOXL2 Gene
The underlying cause of BPES is almost always traced back to a specific alteration in a single gene. The gene responsible for the vast majority of BPES cases is the FOXL2 gene, located on chromosome 3. FOXL2 contains the instructions for making a protein that functions as a transcription factor.
This transcription factor is a master switch that controls the activity of many other genes by binding to specific DNA sequences. The protein produced by FOXL2 is crucial for the proper development of the eyelids and the ovaries. When a mutation occurs, the resulting protein is either non-functional or works improperly.
Mutations in FOXL2 can take many forms, including small deletions, duplications, or changes in a single DNA building block. A common type involves an expansion of a section of the gene that codes for a chain of the amino acid alanine. The resulting dysfunctional protein disrupts normal developmental signals in the face and, in Type I BPES, in the ovaries.
Understanding Inheritance Patterns and the Link to Consanguinity
BPES is overwhelmingly characterized by an Autosomal Dominant inheritance pattern. This means an individual only needs to inherit one copy of the altered FOXL2 gene from one parent to develop the syndrome. The presence of a single non-working copy of the gene is sufficient to cause the physical changes seen in BPES.
This inheritance pattern means an affected parent has a 50% chance of passing the condition on to each child. However, the genetic change is often a de novo mutation, meaning it appeared spontaneously in the affected individual and was not inherited. Approximately half of all BPES cases result from these new mutations rather than direct inheritance.
Diseases commonly associated with consanguinity, or “inbreeding,” are typically Autosomal Recessive conditions. Recessive disorders require inheriting two copies of a mutated gene, one from each parent. Because BPES is a dominant condition, the link to consanguinity is generally not applicable.
The condition’s primary genetic mechanism is autosomal dominant inheritance or a new genetic mutation. While extremely rare instances of BPES caused by two copies of a specific FOXL2 change have been reported in consanguineous families, this is not the typical pattern.