Blepharophimosis Ptosis Epicanthus Inversus: Symptoms, Types, Causes and Treatment

Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) is a rare, complex congenital disorder of the eyelids that affects both appearance and, in some cases, reproductive health. This comprehensive guide explores the syndrome’s distinctive symptoms, its subtypes, underlying genetic causes, and the modern approaches to treatment. Whether you are a patient, family member, or healthcare professional, understanding BPES can empower informed decisions and compassionate care.

Symptoms of Blepharophimosis Ptosis Epicanthus Inversus

BPES presents a unique constellation of eyelid and facial abnormalities, which are often evident at birth. Recognizing these features is the first step to diagnosis and appropriate management.

Symptom	Description	Frequency/Severity	Source(s)
Blepharophimosis	Narrowed horizontal eye opening	Almost always present, severe	2 5 15
Ptosis	Drooping of the upper eyelids	Bilateral, severe, symmetric	2 5 15
Epicanthus Inversus	Upward-folding skin from lower eyelid	Characteristic, bilateral	2 3 5 15
Telecanthus	Increased distance between inner eyelid corners	Common, normal interpupillary distance	2 15
Amblyopia	"Lazy eye" due to vision obstruction	High incidence	12 15
Strabismus	Misalignment of the eyes	Frequently associated	12 15
Refractive Errors	Vision issues like astigmatism or myopia	Common in BPES	12 15
Minor Features	Broad nasal bridge, low-set ears, short philtrum	Sometimes observed	15

Table 1: Key Symptoms

Major Eyelid Abnormalities

BPES is defined by four hallmark features:

• Blepharophimosis: The horizontal eyelid opening is notably shortened, usually measuring 20–22 mm versus the normal 25–30 mm in adults. This narrowing gives the eyes a "squinted" appearance. It is profound and always present in BPES 2 5.
• Ptosis: Severe, bilateral drooping of the upper eyelids is caused by poor levator muscle function. To compensate, individuals may tilt their head back or raise their eyebrows to maintain their visual field 2 15.
• Epicanthus Inversus: Unlike the more common epicanthal fold (which extends downward from the upper lid), epicanthus inversus is a vertical fold starting from the lower eyelid and running upward, often near the inner corner of the eye 2 3 5 15.
• Telecanthus: This refers to the increased distance between the inner corners of the eyes (medial canthi) while the distance between the pupils remains normal, contributing to a broad nasal bridge appearance 2 15.

Associated Ocular Features

BPES can also lead to secondary ocular issues:

• Amblyopia: Nearly half of BPES patients develop amblyopia, often due to visual obstruction from ptosis, refractive errors, or strabismus 12. Both unilateral and bilateral forms are seen, with bilateral amblyopia being especially prevalent.
• Strabismus: Eye misalignment is common and further increases the risk of amblyopia 12.
• Refractive Errors: These include astigmatism, myopia, or hyperopia, found in about 70% of cases 12.
• Lacrimal Duct Anomalies: Some BPES patients have issues with tear drainage 15.

Minor and Extraocular Features

While less common, BPES can be accompanied by:

• Broad nasal bridge
• Low-set ears
• Short philtrum (upper lip area)
• Normal intelligence, except in rare cases with larger chromosomal rearrangements 3 15.

Types of Blepharophimosis Ptosis Epicanthus Inversus

Not all BPES cases are the same. The condition is classified into two major types, which differ in their impact on reproductive health and inheritance patterns.

Type	Key Features	Inheritance/Distinctive Trait	Source(s)
Type I	Eyelid abnormalities + premature ovarian failure	Autosomal dominant, female infertility	1 4 5 6 7 8 9 10 11 15
Type II	Eyelid abnormalities only	Autosomal dominant, normal fertility	1 5 6 7 8 15
Sporadic	Similar features, variable severity	No family history, may have cognitive impact	3 5 15

Table 2: BPES Types

BPES Type I

This form combines the classic eyelid features with premature ovarian insufficiency (POI) or failure in affected females. Women with Type I BPES often experience primary amenorrhea (failure to begin menstruation) or early loss of ovarian function, leading to infertility. This is a crucial distinction for family planning and genetic counseling 1 4 5 6 7 8 9 10 11 15.

BPES Type II

Type II involves only the eyelid malformations—blepharophimosis, ptosis, epicanthus inversus, and telecanthus—without affecting ovarian function. Both males and females have normal fertility. Incomplete penetrance and variation in severity can be seen, but overall, reproductive health is not impacted 1 5 6 7 8 15.

Sporadic and Other Presentations

Although BPES is typically autosomal dominant, sporadic cases do occur. These may arise from new mutations and can show greater variability in severity. Rarely, associated features such as mild cognitive impairment have been reported, especially in cases involving chromosomal rearrangements larger than the FOXL2 gene region 3 5 15.

Causes of Blepharophimosis Ptosis Epicanthus Inversus

BPES is primarily a genetic disorder. Understanding its molecular origins not only clarifies inheritance but also guides modern diagnostic and management strategies.

Cause	Mechanism	Notes/Details	Source(s)
FOXL2 Mutation	Defective forkhead transcription factor	Autosomal dominant, chromosome 3q23	6 7 8 9 10 11 15
Chromosomal Rearrangement	Deletion/translocation affecting FOXL2 and nearby genes	May cause more severe or additional symptoms	5 15
Inheritance	Usually autosomal dominant	50% chance for offspring if parent affected	1 4 5 6 7 8 15
Genotype-Phenotype Correlation	Type of FOXL2 mutation determines BPES type	Truncating → Type I; duplicating/extension → Type II	7 8 11

Table 3: Genetic Causes of BPES

The Role of FOXL2

The FOXL2 gene, located on chromosome 3q23, encodes a forkhead transcription factor crucial for eyelid and ovarian development. Mutations in FOXL2 are responsible for both BPES types 6 7 8 9 10 11 15.

• Type I BPES: Usually caused by mutations that result in a truncated (shortened) FOXL2 protein, which lacks all or part of its forkhead domain. This impairs both eyelid and ovarian development, leading to the classic combination of symptoms 7 8 11.
• Type II BPES: Typically results from mutations that create an extended or altered FOXL2 protein, but with a preserved forkhead domain, affecting mostly the eyelids 7 8 11.

Chromosomal Rearrangements and Rare Mechanisms

Occasionally, larger chromosomal deletions or translocations that affect FOXL2 and adjacent genes can cause BPES. These cases may present with additional symptoms such as cognitive impairment 5 15.

Patterns of Inheritance

BPES is most frequently inherited in an autosomal dominant fashion, meaning each child of an affected parent has a 50% chance of inheriting the syndrome. There are rare reports of autosomal recessive inheritance in consanguineous families 1 4 5 6 7 8 15.

FOXL2 and Ovarian Function

FOXL2 plays a critical role in ovarian development in vertebrates. Mutations disrupt ovarian follicle maturation, leading to premature ovarian insufficiency in Type I BPES 9 11.

Genotype-Phenotype Correlation

Recent research highlights a clear correlation between the type of FOXL2 mutation and the clinical presentation:

• Truncating mutations (producing a shortened, nonfunctional protein): BPES Type I with ovarian failure 7 8 11.
• Duplication or extension mutations (producing a longer or differently shaped protein): BPES Type II without ovarian involvement 7 8 11.

Treatment of Blepharophimosis Ptosis Epicanthus Inversus

Managing BPES requires a multidisciplinary approach, involving ophthalmologists, geneticists, and, for Type I, endocrinologists and gynecologists. The primary goals are to preserve vision, improve appearance, and address reproductive concerns.

Treatment	Purpose/Target	Key Details/Outcomes	Source(s)
Eyelid Surgery	Correct eyelid malformations	Multi-stage or single-stage options	13 14 15 16
Medial Canthoplasty	Correct telecanthus/epicanthus	Often performed at ages 3–5	13 14 15
Ptosis Correction	Restore visual axis	May be staged after canthoplasty	13 15 16
One-Stage Approach	Combined eyelid correction	Improved efficiency, good outcomes	13 14
Vision Therapy	Prevent/treat amblyopia	Glasses, occlusion, strabismus surgery as needed	12 15
Hormone Therapy	Manage ovarian insufficiency	For affected females (Type I)	15
Reproductive Tech	Address infertility	Egg/embryo donation, ART	15
Genetic Counseling	Family planning, risk assessment	Essential for all families	1 4 5 15

Table 4: Treatment Overview

Surgical Management

Eyelid surgery is central to BPES management and aims to improve both function and appearance.

• Traditional Multi-Stage Approach: Medial canthoplasty (correction of telecanthus and epicanthus inversus) is typically performed at ages 3–5, followed by ptosis repair about a year later 15 16.
• One-Stage Procedures: Recent advances allow for all corrections to be performed in a single operation, often using a combination of medial and lateral canthoplasty with frontalis muscle transfer. This approach is safe, efficient, and offers good functional and cosmetic results 13 14.
• Medial Epicanthoplasty: Techniques such as the skin redraping method can effectively reduce telecanthus and epicanthus inversus with minimal scarring 14.

Vision Preservation

Children with BPES are at high risk for amblyopia and refractive errors:

• Early ophthalmic evaluation is critical.
• Glasses, occlusion therapy (patching), and strabismus surgery may be necessary to ensure proper visual development 12 15.
• Regular follow-up is required to monitor visual acuity and ocular alignment.

Management of Ovarian Insufficiency and Infertility

For females with BPES Type I, premature ovarian failure is managed by:

• Hormone replacement therapy to address estrogen deficiency and maintain secondary sexual characteristics 15.
• Reproductive technologies, such as egg or embryo donation, provide fertility options 15.

Genetic Counseling

Essential for all families, genetic counseling addresses:

• Inheritance risks
• Family planning
• Prenatal testing (if the family-specific mutation is known) 1 4 5 15

Long-Term Monitoring

• Ophthalmic surveillance should be tailored to the patient's age, surgical history, and visual needs.
• Endocrinologic and gynecologic follow-up is crucial for affected females to monitor ovarian function and overall health 15.

Conclusion

Blepharophimosis Ptosis Epicanthus Inversus Syndrome is a rare but well-characterized genetic condition. Early recognition and multidisciplinary management can significantly improve both functional and cosmetic outcomes, as well as reproductive health and quality of life.

Key points:

• BPES is defined by a combination of four major eyelid features, often present at birth.
• The syndrome is classified into two types: Type I (with premature ovarian failure) and Type II (eyelid features only).
• FOXL2 gene mutations on chromosome 3q23 are the primary cause.
• Treatment involves staged or single-operation eyelid surgery, vision therapy, and, for Type I, hormonal and reproductive management.
• Genetic counseling is vital for affected families.

With advances in genetics and surgical techniques, individuals with BPES can achieve excellent functional and psychosocial outcomes when cared for by a knowledgeable, coordinated team.