Blepharophimosis Syndrome

What is Blepharophimosis Syndrome?

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), also known as blepharophimosis syndrome, is a rare genetic condition you’re born with. It has four main features: blepharophimosis, where the eye opening is small; ptosis, which is a droopy eyelid; epicanthus inversus, where the skin fold of the upper eyelid covers the inner corner of the eye; and telecanthus, where the inner corners of the eyes are further apart than usual. This condition was first described by Dr. Komoto in 1921.

If these features aren’t corrected with surgery, there’s a high risk of developing a vision problem known as amblyopia, often referred to as “lazy eye”. There are two types of BPES. Type I involves the facial features mentioned above and is also linked with premature ovarian failure (POF) which is the loss of normal function of your ovaries before age 40. Type II involves just the facial features and doesn’t include the complications with the ovaries.

What Causes Blepharophimosis Syndrome?

The genetic reason behind BPES (Blepharophimosis, ptosis, and epicanthus inversus syndrome) was uncovered in 2001 after researchers sequenced the genes of 7 families affected by BPES. They found harmful changes or mutations in a gene known as FOXL2, located on chromosome 3q23, to be responsible for BPES. The FOXL2 gene makes a protein referred to as a forkhead transcription factor. This protein is made up of 376 amino acids, including a chain of 14 alanine amino acids. To date, over 100 unique FOXL2 mutations have been identified in families with BPES.

While scientists are not entirely sure what the FOXL2 protein does, they have found that it is active in certain parts of the body. For example, it has been found in the connective tissue of developing eyelids in fetuses and in particular cells present in the ovaries of fetuses and adults.

BPES has two types which looks similar on the outside, but can be accurately identified through genetic testing. If the FOXL2 protein is cut short before the chain of alanine amino acids, it results in BPES type I. On the other hand, if the chain of alanine amino acids in the protein is lengthened, it leads to BPES type II.

Risk Factors and Frequency for Blepharophimosis Syndrome

BPES, also known as Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome, is a condition that affects about 1 in every 50,000 newborn babies. A large portion, up to 75%, of those affected have a mutation in the FOXL2 gene. This condition appears more commonly in females, with women making up around 64% of cases.

There are two types of this condition. Type I, which always shows symptoms (100% penetrance), is usually passed down through males, as females with this type often have reduced fertility. Type II, which shows symptoms 96.5% of the time (96.5% penetrance), can be passed down by both males and females.

• 20 to 27% of people with BPES develop strabismus, a condition that causes the eyes to not line up in the same direction.
• Between 39 and 56% of people with BPES develop amblyopia due to ptosis or strabismus. Amblyopia, commonly known as lazy eye, is when one eye doesn’t develop good vision.
• A very high percentage of BPES sufferers, as much as 94%, have refractive error, with hyperopia (farsightedness) being the most common type.

Signs and Symptoms of Blepharophimosis Syndrome

BPES, or Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome, is a condition that is typically diagnosed based on physical symptoms. Key features of BPES would include:

• Blepharophimosis: This represents an eye condition where the opening between the upper and lower eyelids is unusually short, normally it’s about 25-30 mm, but in BPES, it’s about 20 to 22 mm.
• Ptosis: The eyelids sag or droop due to muscle dysplasia, affecting both eyes.
• Epicanthus inverus: An inward and upward skin fold that starts from the inside corner of the lower eyelid and extends towards the upper eyelid. This happens on both eyes and gives a distinctive look.
• Telecanthus: In BPES, the connective tissue around the eye (the medial canthal tendons) are stretched, causing the corners of the eyes to be farther apart. However, the distances between the pupils remain normal.

Using these symptoms as a basis, there are two types of BPES:

• Type I BPES includes the four classic symptoms mentioned above, accompanied by premature ovarian failure.
• Type II BPES also presents the four classic symptoms but without premature ovarian failure.

Individuals with BPES may also have coexisting abnormalities or deformities such as misshapen eyelids, tearduct problems, vision conditions like strabismus or microphthalmos, and physical facial characteristics like a flat nasal bridge, and ears that are tipped forward. To make up for their drooping eyelids, individuals may frequently raise their chins and constantly contract the forehead muscles, which can give their eyebrows an arched and prominent appearance, making the individual seem constantly surprised.

Testing for Blepharophimosis Syndrome

People showing the typical signs of BPES can undergo special genetic tests that look for changes or mutations in a specific gene named FOXL2, located on chromosome three. If there aren’t any abnormal variations detected in the FOXL2 gene, more thorough genetic testing can happen. This thorough testing aims to find changes in the size of the FOXL2 region – where parts of the gene may be duplicated (exists more than once) or deleted (missing altogether). In some cases, additional genetic testing is done to check for unusual rearrangements or other disruptions within the FOXL2 region.

In some women with BPES Type I, an issue with how their ovaries function can develop. This can show up as a delay in puberty, missing periods, or having irregular periods that are spaced far apart. Certain laboratory tests can help in diagnosing this condition. Levels of specific hormones related to reproductive functions, such as follicle-stimulating hormone and luteinizing hormone, will be higher than normal. On the other hand, the levels of hormones related to the menstrual cycle, like estrogen and progesterone, will be lower than usual. A type of ultrasound scan called a transvaginal ultrasound can count the number of potential egg-producing follicles in the ovaries. This information can determine the health of the ovaries and can guide conversations about reduced fertility potential.

Treatment Options for Blepharophimosis Syndrome

The goal of treatment for Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome (BPES) is to correct eyelid abnormalities for better vision and improved appearance, relieve neck strain due to an upward-tilted head position, and to manage premature menopause and infertility in women with BPES type I. An eye specialist, or pediatric ophthalmologist, will assess for lazy eye (amblyopia), misalignment of the eyes (strabismus), and the need for glasses (refractive error). A plastic surgeon specializing in eye conditions, or an oculoplastic surgeon, will be able to assess the level of droopy eyelids (ptosis), narrowing of the eye opening (blepharophimosis), and an abnormal fold near the inner corner of the eye (epicanthus inversus).

Historically, eye conditions in BPES were often addressed in two surgeries when the child is 3 to 5 years old. The first surgery focused on correcting both the narrowing and abnormal fold near the inner corner of the eye. This was followed by a second surgery 6 to 12 months later to address the droopy eyelid. This two-stage process avoids the tension that would result if both surgeries were performed at the same time. Some surgeons support this sequence because fixing the inner corner of the eye first might worsen the drooping eyelid. On the other hand, some suggest repairing the drooping eyelids first because it can help prevent lazy eye. Recent reports suggest a single operation might be enough and produce successful results for some individuals. More research is needed to compare the results of one versus two surgeries for BPES.

The surgical plan depends on the specific eye conditions:
If the vision field is clear, surgical repair can be delayed until the child is 3 to 5 years old.
If the vision field is blocked but the vertical eye opening is more than 2 mm, either single or two-stage surgery can produce good results.
If the vision field is blocked and the vertical eye opening is less than 2 mm, two surgeries should be done as soon as possible, starting with drooping eyelid repair to avoid lazy eye, followed by inner corner of the eye surgery.

Females with BPES type I, which is typically inherited from their father, should consult with a genetics specialist. This can help them understand the nature of the genetic condition, how it is inherited, and possible fertility issues. Since these women are at risk of premature menopause, they should also see a hormone specialist (endocrinologist) or women’s health specialist (gynecologist) to monitor their ovarian health. While there is no definitive research on hormone replacement therapy for BPES type I, it may be advisable to help maintain bone health. Options available for those who wish to have children include adoption, foster parenthood, embryo donation, egg donation, and freezing of eggs or embryos for future use.

What else can Blepharophimosis Syndrome be?

Most of the time, patients have a family history of their condition. However, it’s also possible for a new mutation to occur that wasn’t present in the family history. If a person has symptoms affecting the eyelid, like drooping (ptosis) and narrowing (blepharophimosis), but no clear family history, then doctors might think about other potential conditions. These could include:

• NR2F2-associated 46, XX sex reversal 5
• Say-Barber-Biesecker variant of Ohdo syndrome
• Congenital ptosis (birth defect causing drooping eyelids)
• Ptosis with external ophthalmoplegia (eye muscle weakness)
• Noonan syndrome
• Marden-Walker syndrome
• Schwartz Jampel syndrome
• Waardenburg syndrome
• William syndrome
• Trisomy 18 (an extra chromosome 18 causing various health problems)
• Cerebro-oculo-facial-digital syndrome
• Dubowitz syndrome
• Smith-Lemli-Opitz syndrome

What to expect with Blepharophimosis Syndrome

Treating patients calls for a team approach and good coordination between different medical specialists. If treatment, which can include medication and surgery, is started early in a person’s life, the outlook is excellent. The severity of the disorder can determine if more than one surgery is needed, but the results are usually very successful. It’s important to note that people with BPES can expect to live a normal lifespan.

Possible Complications When Diagnosed with Blepharophimosis Syndrome

After eyelid surgery, complications may arise. Earlier, commonly used techniques like the Mustarde technique and z-epicanthoplasty often led to significant scarring. However, new methods, such as the Y to V technique and medial epicanthoplasty with skin reshaping, have been developed to improve cosmetic outcomes.

Different types of materials are used in frontalis sling suspension, a surgical procedure to treat drooping eyelids. Synthetic materials used include braided polyester stitches, polypropylene stitches, expanded polytetrafluorethylene, and silastic bands. However, these non-biological materials can sometimes cause unwanted reactions in the body, leading to the formation of granulomatous (inflamed tissue), infection, or extrusion (the material being pushed out from where it was placed).

Homografts, which are grafts from the same species, like autogenous fascia lata (a tissue graft from the patient’s thigh), could lead to longer recovery time and an additional potential source of infection. Overcorrection while treating drooping eyelids could result in lagophthalmos (the inability to close the eyes completely), which can, in turn, cause complications of the cornea.

Some complications include:

• Significant scarring
• Formation of inflamed tissue
• Infection in case of homografts
• Extrusion of the non-biological material
• Lagophthalmos and related corneal complications in case of overcorrection

Preventing Blepharophimosis Syndrome

It’s important for families to recognize that lifelong regular eye check-ups are needed, even into adulthood. Many individuals may need eye surgery early in life to prevent a condition known as amblyopia, which results in decreased vision not correctable by glasses or contact lenses. In some cases, a second surgery might be needed later in life to improve the appearance of the eyes, if the person desires.

There are various procedures available to repair ptosis, a drooping or falling of the upper or lower eyelid. The choice of treatment should be tailored to the person’s requirements. Families and patients should be aware of the option to wait and monitor the condition without immediate intervention. This ‘do nothing’ approach should be considered and discussed before deciding to proceed with any surgical operation.

For teen girls, this can be a challenging period and they may need guidance from a team of diverse healthcare providers. Genetic testing, which can identify specific inherited disorders, involves various methods. Additionally, girls should have conversations about potential infertility and family planning with a genetic counselor, who can help navigate these complex issues.