Blepharophimosis, Ptosis, And Epicanthus Inversus
Summary
Clinical characteristics.
Blephariphimosis, ptosis, and epicanthus inversus syndrome (BPES) is a complex eyelid malformation invariably characterized by four major features: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and premature ovarian insufficiency (POI); BPES type II includes only the four major features. Other ophthalmic manifestations that can be associated with BPES include lacrimal duct anomalies, amblyopia, strabismus, and refractive errors. Minor features include a broad nasal bridge, low-set ears, and a short philtrum. Individuals with BPES and an intragenic FOXL2 pathogenic variant are expected to have normal intelligence, in contrast to affected individuals with cytogenetic rearrangements that involve FOXL2 and additional genes.
Diagnosis/testing.
The diagnosis of BPES is primarily based on clinical findings. Occasionally individuals with BPES have cytogenetic rearrangements, such as interstitial deletions and translocations involving 3q23. FOXL2 is the only gene currently known to be associated with BPES.
Management.
Treatment of manifestations: Timing of eyelid surgery involves balancing the benefits of early surgery to prevent deprivation amblyopia versus late surgery to allow for more reliable ptosis measurements. Surgery traditionally involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at age three to five years, typically followed a year later by ptosis correction; recently, a one-stage surgical procedure has been described. Premature ovarian failure is treated with hormone replacement therapy; fertility is addressed with reproductive technologies such as embryo donation and egg donation.
Surveillance: Ophthalmic follow up depends on age, procedures performed in the past, and results of visual acuity testing. Endocrinologic and gynecologic follow up are advised for affected females.
Genetic counseling.
BPES is usually inherited in an autosomal dominant manner; autosomal recessive inheritance has been reported in one consanguineous family. For autosomal dominant inheritance: Each child of an individual with BPES has a 50% chance of inheriting the FOXL2 pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family has been identified; however, requests for prenatal testing for conditions such as BPES are not common.
Diagnosis
Clinical Diagnosis
The diagnosis of blepharophimosis syndrome (BPES) is based primarily on the following four clinical findings, which are present at birth [Oley & Baraitser 1995]:
- Blepharophimosis. Narrowing of the horizontal aperture of the eyelids. In normal adults, the horizontal palpebral fissure measures 25-30 mm; in individuals with BPES, it generally measures 20-22 mm.
- Ptosis. Drooping of the upper eyelid causing a narrowing of the vertical palpebral fissure. In individuals with BPES, ptosis is secondary to dysplasia of the musculus levator palpebrae superioris. To compensate for the ptosis, affected individuals:
- Use the musculus frontalis, wrinkling the forehead to draw the eyebrows upward, which results in a characteristic facial appearance
- Tilt their head backward into a chin-up position
- Epicanthus inversus. A skin fold arising from the lower eyelid and running inwards and upwards.
- Telecanthus. Lateral displacement of the inner canthi with normal interpupillary distance.
Note: A study of ten individuals with molecularly confirmed BPES showed that all had lateral displacement of the inferior punctum (i.e., in the lower eyelid) resulting from a temporal displacement of the entire lower eyelid. This proved to be an important anatomical hallmark in the diagnosis of BPES [Decock et al 2011a].
Two types of blepharophimosis syndrome have been described [Zlotogora et al 1983]:
- BPES type I includes the four major features and female infertility caused by premature ovarian insufficiency (POI).
- BPES type II includes only the four major features.
Testing
Females with premature ovarian insufficiency (POI) have:
- Endocrinologic findings of hypergonadotropic hypogonadism:
- Elevated serum concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
- Decreased serum concentrations of estradiol and progesterone
- A small hypoplastic uterus and streak ovaries on pelvic ultrasound examination
Cytogenetic testing. Cytogenetic rearrangements involving 3q23 (i.e., unbalanced translocations and interstitial deletions) causing BPES have been reported [Fukushima et al 1991, Jewett et al 1993, Boccone et al 1994, Lawson et al 1995, De Baere et al 1999, Praphanphoj et al 2000, de Ru et al 2005, Alao et al 2012, González-González et al 2012 and references therein, Schlade-Bartusiak et al 2012]. Such cytogenetic rearrangements are estimated to occur in a very small fraction of individuals with BPES [Beysen et al 2009].
Molecular Genetic Testing
Gene. FOXL2 is the only gene currently known to be associated with BPES (Table 1).
Table 1.
Summary of Molecular Genetic Testing Used in Blepharophimosis, Ptosis, and Epicanthus Inversus
| Gene 1 | Test Method | Proportion of Probands with a Pathogenic Variant Detectable by This Method 2 |
|---|---|---|
| FOXL2 | Sequence analysis 3 | 72% 4 |
| Deletion/duplication analysis 5 | 10%-15% 6, 7 | |
| Regulatory regions extragenic to FOXL2 | Deletion/duplication analysis of regions upstream of FOXL2 5 | 5% 8, 9 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.
- 2.
The detection rate using sequence analysis and MLPA is around 82% in familial as well as in simplex cases (i.e., a single occurrence in a family) [De Baere et al 2003, Beysen et al 2005, Beysen et al 2009].
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
De Baere et al [2003], Beysen et al [2008a], Beysen et al [2009]
- 5.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
- 6.
Multiplex ligation-dependent probe amplification (MPLA) detected partial- or whole-gene deletions in approximately 10% of individuals with typical BPES [Beysen et al 2005, Beysen et al 2009].
- 7.
Cytogenetic rearrangements involving 3q23 (i.e., unbalanced translocations and interstitial deletions) that cause BPES are often accompanied by additional findings, such as microcephaly, intellectual disability, and growth delay [Fukushima et al 1991, Jewett et al 1993, Boccone et al 1994, Lawson et al 1995, De Baere et al 1999, Praphanphoj et al 2000, de Ru et al 2005 and references therein, Alao et al 2012, González-González et al 2012, Schlade-Bartusiak et al 2012]. Note: Balanced translocations involving 3q23 lead to classic BPES type I or II without additional findings.
- 8.
MLPA and other methods for deletion/duplication analysis (see footnote 6) may detect partial-, whole-, or contiguous-gene deletions or upstream regulatory deletions, depending on the experimental design [Beysen et al 2009, D'haene et al 2009].
- 9.
Beysen et al [2005], Beysen et al [2009], D'haene et al [2009], Verdin et al [2013]
Testing Strategy
To confirm the diagnosis in a proband
- Molecular genetic testing of FOXL2, including sequence analysis and deletion/duplication analysis
- If no FOXL2 pathogenic variant or genomic rearrangement of FOXL2 and neighboring region(s) can be identified on molecular genetic testing, chromosome analysis may be considered depending on the family history and the individual’s phenotype (e.g., chromosomal microarray to screen for copy number variants in targeted regulatory regions 5' to FOXL2 and karyotyping to screen for chromosomal structural rearrangements such as balanced translocations or inversions).
- In persons with BPES-like phenotypes without a FOXL2 pathogenic variant or genomic rearrangement of FOXL2 and neighboring region(s), whole-genome chromosomal microarray to screen for copy number variants [Gijsbers et al 2008] is recommended to identify the underlying genetic cause of the phenotype (see Genetically Related Disorders).
Clinical Characteristics
Clinical Description
Blepharophimosis syndromes (BPES) type I and type II are a complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I also includes female infertility caused by premature ovarian insufficiency (POI).
Other features frequently observed in both BPES type I and type II are a broad nasal bridge, low-set ears, and a short philtrum.
Associated ophthalmic manifestations include dysplastic eyelids (lack of eyelid folds and thin skin); S-shaped border of the upper eyelid and abnormal downward concavity of the lower eyelid with lateral ectropion; and nasolacrimal drainage problems caused by lateral displacement, duplication, or stenosis of the lacrimal puncta.
A retrospective study in 204 individuals with BPES showed manifest strabismus in 20%, a significant refractive error in 34%, and bilateral or unilateral amblyopia in 21% and 20%, respectively [Dawson et al 2003]. The incidences of strabismus, refractive errors (anisometropic hypermetropia and myopia), and amblyopia are higher in individuals with BPES than in the general population [Beckingsale et al 2003, Dawson et al 2003, Choi et al 2006].
Secondary sexual characteristics are usually normal in both BPES type I and type II.
In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea.
Individuals with BPES who have an intragenic FOXL2 pathogenic variant (in contrast to individuals with a contiguous gene deletion that includes FOXL2) are expected to have normal intelligence.
Genotype-Phenotype Correlations
Pathogenic variants predicted to result in proteins truncated before the polyalanine tract preferentially lead to POI (BPES type I). Note: The need for careful interpretation of genotype-phenotype correlations is illustrated by the co-occurrence of BPES type I and isolated POI in a three-generation family.
Polyalanine expansions preferentially lead to BPES type II. The first case with a positive correlation between the size of the polyalanine expansion, its dosage, and the penetrance of the BPES phenotype was reported by Nallathambi et al [2007].
Click here (pdf) for additional findings observed with some FOXL2 pathogenic variants.
Penetrance
To date, almost all individuals heterozygous for a FOXL2 pathogenic variant have the BPES phenotype; thus, penetrance is nearly complete for the eyelid phenotype.
The exception is a consanguineous Indian family in which heterozygotes for a short polyalanine expansion of 19 alanines are unaffected, but homozygotes have typical BPES (with documented POI in one female) [Nallathambi et al 2007] (see Molecular Genetics).
Prevalence
The prevalence of BPES is unknown.
No differences in prevalence based on sex, race, or ethnicity have been reported.
Differential Diagnosis
The differential diagnosis of BPES includes those conditions in which ptosis or blepharophimosis is a major feature (Table 2) [Oley & Baraitser 1995]; however, in clinical practice, blepharophimosis syndrome can be relatively easily distinguished from most of these conditions.
Table 2.
Overview of Conditions in which Ptosis and/or Blepharophimosis is a Prominent Feature
| Syndrome | MOI | Characteristics | OMIM |
|---|---|---|---|
| Hereditary congenital ptosis 1 (PTOS1) | AD | Ptosis | 178300 |
| Hereditary congenital ptosis 2 (PTOS2) | XL | Ptosis | 300245 |
| Ohdo blepharophimosis syndrome | AD 1 |
| 249620 |
| 3MC syndrome 1 (Michels syndrome) |
| 257920 | |
| Ptosis with external ophthalmoplegia | AR | Ptosis, ophthalmoplegia, miosis, decreased accommodation, strabismus, amblyopia | 258400 |
| Noonan syndrome | AD |
| 163950 |
| Marden-Walker syndrome | AR |
| 248700 |
| Schwartz-Jampel syndrome |
| 255800 | |
| Dubowitz syndrome |
| 223370 | |
| Smith-Lemli-Opitz syndrome |
| 270400 | |
| KANSL1-related intellectual disability syndrome (17q21.31 microdeletion syndrome) 2 | AD |
| 610443 |
Oley & Baraitser [1995], OMIM
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GI = gastrointestinal; GU = genitourinary; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Presumed mode of inheritance
- 2.
Gijsbers et al [2008]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with blepharophimosis syndrome (BPES), the following evaluations are recommended:
- Examination by a (pediatric) ophthalmologist for visual acuity, refractive error, extraocular movement, strabismus, size of palpebral apertures, and eyelid elevation. Those with amblyopia or strabismus should be referred to a pediatric ophthalmologist for management [Beckingsale et al 2003].
- Genetic evaluation and genetic counseling by a clinical geneticist to discuss recurrence risk and assess risk for premature ovarian insufficiency (POI). In girls with BPES, the family history can indicate the type of BPES in affected females (with type I inferred by the association with subfertility or infertility). In uninformative families or simplex cases (i.e., single occurrence in a family), molecular genetic testing may be helpful in some cases in assessing the risk for POI.
- Referral of females with BPES to a pediatric or adult endocrinologist during late puberty or early adulthood to assess onset and course of POI
Treatment of Manifestations
Management requires the input of specialists including a clinical geneticist, pediatric ophthalmologist, oculoplastic surgeon, (pediatric or adult) endocrinologist, reproductive endocrinologist, and gynecologist.
Eyelid surgery. Timing of eyelid surgery is controversial; it involves weighing the balance of early surgery to prevent deprivation amblyopia and late surgery to allow for more reliable ptosis measurements, the latter of which provides a better surgical outcome. Furthermore, ptosis surgery is hampered by the dysplastic structure of the eyelids [Beckingsale et al 2003].
The surgical management is traditionally performed in two stages and involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at ages three to five years, followed about a year later by ptosis correction, which usually requires a brow suspension procedure.
Many surgical techniques have been described for medial canthoplasty and none of the existing methods is free from criticism. If the epicanthal folds are small, a Y-V canthoplasty is traditionally used; if the epicanthal folds are severe, a double Z-plasty is used. An alternate technique for medial canthoplasty has been described recently using the skin redraping method, which has a simple flap design, less scarring, and the effective repair of epicanthus inversus and telecanthus [Sa et al 2012].
To correct telecanthus, the medial canthal tendon is usually shortened or fused with a transnasal wire.
Ptosis correction is particularly important as it can address the disfigurement as well as functional concerns. Frontal muscle flap suspension is mostly used for severe ptosis in adults; however, it remains controversial. A major concern is that the frontal muscle development may be restrained by surgery. Decock et al [2011b] reported that super-maximal resection and frontalis suspension is the preferred method as it leads to a good cosmetic outcome as well as to an improved muscle function.
Alternatively, a one-stage procedure in which medial canthoplasty and ptosis correction are performed simultaneously has been described [Wu et al 2008]. Two recent retrospective, interventional studies including 21 patients demonstrated that one-stage correction using a standard combination of surgical techniques is safe and efficient [Sebastiá et al 2011, Liu et al 2014].
Recent insights into the causes of the abnormal lower eyelid positioning allow a more targeted surgical reconstruction that produces a more natural appearance [Decock et al 2011a]. Ten individuals with molecularly proven BPES were noted to have a laterally displaced inferior punctum (i.e., in the lower eyelid) due to temporal displacement of the entire lower eyelid. Addition of a simple surgical step corrected the position of the lower eyelid and its abnormal downward concavity (the temporal ectropion), and the lateral displacement of the inferior punctum. This approach eliminates the epicanthus inversus fold without the need for double Z-plasty [Decock et al 2011b].
Ovarian insufficiency. Management of premature ovarian insufficiency (POI) needs to address the two following major medical issues that are applicable to primary ovarian insufficiency in general and not specific for BPES (no data specific to BPES are available):
- Hormone replacement therapy (HRT). The American Society for Reproductive Medicine and the International Menopause Society recommend estrogen replacement therapy for women with primary ovarian insufficiency (amenorrhea and a menopausal serum FSH concentration). Although no data from randomized trials guide the use of hormonal therapy in women with BPES and POI, a reasonable regimen would be 100 μg of transdermal estradiol and 10 mg of oral medroxyprogesterone acetate daily for the first 12 days of each month. Women should keep a menstrual calendar and have a pregnancy test promptly in the case of late menses [Nelson 2009].A pelvic ultrasound examination and measurement of bone mineral density are indicated at the time of diagnosis of ovarian insufficiency. Women with primary ovarian insufficiency should be encouraged to maintain a lifestyle that optimizes bone and cardiovascular health, including engaging in regular weight-bearing exercise, maintaining an adequate intake of calcium (1200 mg daily) and vitamin D (at least 800 IU daily), eating a healthy diet to avoid obesity, and undergoing screening for cardiovascular risk factors, with treatment of any identified risk factors.
- Infertility. No therapies have been shown to restore ovarian function and fertility. Some couples are averse to adoption and to reproductive technologies and are content not to become parents.For couples who decide to pursue parenthood actively, the options are adoption, foster parenthood, embryo donation, and egg donation. The rates of pregnancy with egg donation appear to be similar among older and younger women. Women with primary ovarian insufficiency who become pregnant as a result of oocyte donation may have an increased risk of delivering infants who are small for gestational age and of having pregnancy-induced hypertension and postpartum hemorrhage, but these findings are controversial [Nelson 2009].The issue of POI is emotionally charged and should be discussed with the patient with this in mind.
Surveillance
The frequency of ophthalmic follow-up should be individualized depending on age, procedures performed in the past, and results of visual acuity testing.
Endocrinologic and gynecologic follow up are advised in females in whom the BPES type is unknown or in whom BPES type I is suspected based on a positive family history or FOXL2 pathogenic variant. Frequency of endocrinologic follow-up to monitor ovarian status is individualized and can involve pelvic ultrasound examination, measurement of serum FSH concentrations, and assessment of menstrual pattern (ages of menarche and onset of oligomenorrhea and secondary amenorrhea).
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Ovarian transplantation has been performed in rare instances in which the affected woman has an identical twin sister with normal ovarian function [Nelson 2009].
Note: (1) Cryopreservation has not yet been reported in BPES. (2) Children who are at risk for POI are most likely to benefit from cryopreservation as their ovaries contain more primordial follicles than those of adult women; it is expected that by the time these children are mature and need their ovarian tissue, the modalities for its optimal use would become available. (3) At the time that they might wish to consider an IVF procedure, adult women with BPES usually do not have sufficient appropriate primordial follicles for embryo cryopreservation.
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