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Blepharophimosis-ptosis-epicanthus inversus (BPES)
BPES presents with reduced eyelid opening (blepharophimosis), drooping eyelids (ptosis), and an unusual fold of skin in the inner corner of the eye (epicanthus inversus). Some women with BPES also experience difficulties with fertility.
Overview
Blepharophimosis-ptosis-epicanthus inversus syndrome, commonly known as BPES, is a rare genetic condition primarily affecting the development of the eyelids. The main features are blepharophimosis, which means the eyelids are abnormally narrow horizontally; ptosis, where one or both upper eyelids droop; and epicanthus inversus, an upward-curving skin fold in the inner corner of the eye [PMID:36528761]. These features can make the eyes appear small.
BPES is categorised into two types. Type I includes both the distinctive eyelid features and primary ovarian insufficiency, which affects female fertility. Type II includes only the eyelid features [PMID:16121289]. The condition can have a variable impact on individuals, with some experiencing more pronounced features than others.
Symptoms & clinical features
The most prominent symptoms of BPES are related to the eyes. Blepharophimosis refers to a reduced horizontal opening of the eyelids. Ptosis, or drooping of the upper eyelids, can range from mild to severe, sometimes affecting vision if it covers the pupil. Epicanthus inversus is a characteristic upward-curving skin fold at the inner corner of the eye, which contributes to the distinctive appearance.
In some cases, the ptosis can be significant enough to interfere with a child's vision development, potentially leading to amblyopia (sometimes called 'lazy eye'). Individuals with severe ptosis might develop a compensatory head tilt or raise their eyebrows to improve their sight [PMID:38153099]. Beyond the eye features, women with BPES Type I experience primary ovarian insufficiency, meaning their ovaries do not function correctly. This can lead to irregular or absent menstrual periods and difficulties conceiving naturally.
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Affected organs
The primary organs affected by BPES are the eyes and, in females with BPES Type I, the ovaries. The eyelid structures, including the upper and lower eyelids and the surrounding skin folds, are consistently involved. The muscles that control eyelid movement may also be impacted, contributing to ptosis.
In women with BPES Type I, the ovaries are affected, leading to primary ovarian insufficiency. This means the ovaries may not produce eggs or sufficient reproductive hormones, which impacts fertility.
Risks & severity
The severity of BPES can vary greatly between individuals, even within the same family. Some people may have mild eyelid anomalies that do not significantly affect vision, while others may experience severe ptosis requiring surgical intervention to prevent vision impairment, especially during childhood. Early identification and management of severe ptosis are important to support normal visual development.
For females with BPES Type I, the main long-term risk relates to fertility. Primary ovarian insufficiency can lead to infertility, making conception without assisted reproductive technologies challenging or impossible. The exact prevalence of BPES is not well established, but it is considered a rare condition.
Genetic causes
BPES is caused by pathogenic variants in the FOXL2 gene. This gene provides instructions for making a protein called Forkhead box protein L2. The FOXL2 protein is a transcription factor, meaning it plays a crucial role in regulating the activity of other genes.
Specifically, the FOXL2 protein is essential for the normal development of the eyelids and for ovarian function. Pathogenic changes in the FOXL2 gene can disrupt the protein's ability to regulate these developmental processes, leading to the characteristic features of BPES [PMID:16121289]. These genetic changes interfere with the precise control needed for embryonic development of facial structures and reproductive organs.
- FOXL2 forkhead box L2
Inheritance pattern
BPES is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered FOXL2 gene from either parent to develop the condition. If a parent has BPES, there is a 50% chance with each pregnancy that their child will also inherit the condition.
In some instances, BPES can occur as a new (de novo) genetic change in an individual, meaning neither parent has the condition. In such cases, the genetic change first appears in the affected individual. Once a person has BPES, whether inherited or de novo, they have a 50% chance of passing it on to their children.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of BPES typically begins with a clinical evaluation based on the characteristic facial features, particularly the eyelid anomalies. A referral to a clinical geneticist or ophthalmic specialist may be recommended for further assessment.
Confirmation of BPES is usually achieved through genetic testing, which looks for pathogenic variants in the FOXL2 gene [PMID:36528761]. This testing is available through the NHS Genomic Medicine Service, often initiated after referral from a specialist. The relevant R-code for genomic testing for an inherited eye disorder or specific syndromic ophthalmopathy would guide the testing pathway.
Management & lifestyle
Management for individuals with BPES focuses on addressing the specific features of the condition. For eyelid anomalies, surgical correction may be considered, especially if ptosis significantly obstructs vision or affects visual development in childhood. Ophthalmologists and oculoplastic surgeons often manage these aspects.
For women with BPES Type I, gynaecological and fertility specialists provide care for primary ovarian insufficiency, including discussions about hormone replacement therapy and options for family planning. Genetic counselling is an important part of the care pathway for individuals and families affected by BPES, offering information about the condition, inheritance patterns, and reproductive options. Ongoing surveillance for potential complications and regular follow-up with relevant specialists are generally recommended.
UK care pathway
In the UK, individuals suspected of having BPES can be referred by their GP or another specialist to a clinical genetics service. This service can provide a confirmed diagnosis through genetic testing via the NHS Genomic Medicine Service, often guided by specific R-codes for inherited ophthalmological or endocrine conditions. Genetic counsellors within these services offer support and information about the condition, its inheritance, and implications for family members.
Once a diagnosis is confirmed, care pathways typically involve multidisciplinary teams, including ophthalmologists, oculoplastic surgeons, and gynaecologists for women with Type I BPES.
Frequently asked questions
What is the difference between BPES Type I and Type II?
BPES Type I includes both the characteristic eyelid abnormalities (blepharophimosis, ptosis, epicanthus inversus) and primary ovarian insufficiency in females. BPES Type II includes only the eyelid abnormalities, without affecting ovarian function.
Can BPES affect vision?
Yes, especially if the drooping of the upper eyelids (ptosis) is severe, it can block the pupil and interfere with vision. This can lead to conditions like amblyopia (lazy eye) in children if not managed appropriately.
Is BPES always inherited from a parent?
BPES is an autosomal dominant condition, meaning it can be inherited from an affected parent. However, in some cases, it can also arise as a new genetic change (de novo) in an individual, with no family history of the condition.
Can men with BPES pass it on to their children?
Yes, men with BPES have a 50% chance of passing the condition on to each of their children, regardless of the child's sex. Even though primary ovarian insufficiency only affects women, the genetic change can be inherited by sons and daughters.
What kind of doctors manage BPES?
A team of specialists often manages BPES. This typically includes ophthalmologists (eye doctors) and oculoplastic surgeons for eyelid issues, gynaecologists and fertility specialists for women with primary ovarian insufficiency, and clinical geneticists for overall coordination and genetic counselling.