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Blepharophimosis, Ptosis, and Epicanthus Inversus

Synonyms: BPES, Blepharophimosis Syndrome

, MSc, PhD and , MD, PhD.

Author Information
, MSc, PhD
Center for Medical Genetics
Ghent University Hospital
Ghent, Belgium
, MD, PhD
Center for Medical Genetics
Ghent University Hospital
Ghent, Belgium

Initial Posting: ; Last Update: February 5, 2015.

Summary

Disease 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 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method 2
FOXL2Sequence analysis 372% 4
Deletion/duplication analysis 510%-15% 6, 7
Regulatory regions extragenic to FOXL2Deletion/duplication analysis of regions upstream of FOXL2 55% 8, 9
1.

See Table A. Genes and Databases for chromosome locus and protein name. 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 unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic 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 exonic 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

Clinical Description

Natural History

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

SyndromeMOICharacteristicsOMIM
Hereditary congenital ptosis 1 (PTOS1)AD
  • Ptosis
178300
Hereditary congenital ptosis 2 (PTOS2)XL
  • Ptosis
300245
Ohdo blepharophimosis syndrome AD 1
  • Blepharophimosis
  • Blepharoptosis
  • Intellectual disability
  • Congenital heart defects
  • Hypoplastic teeth
249620
3MC syndrome 1 (Michels syndrome)
  • Blepharophimosis
  • Blepharoptosis
  • Epicanthus inversus
  • Ophthalmic anterior segment defects (cornea)
  • Cleft lip/palate
  • Minor skeletal abnormalities
257920
Ptosis with external ophthalmoplegiaAR
  • Ptosis
  • Ophthalmoplegia
  • Miosis
  • Decreased accommodation
  • Strabismus
  • Amblyopia
258400
Noonan syndrome AD
  • Ptosis
  • Short stature
  • Heart defects
  • Blood clotting deficiencies
163950
Marden-Walker syndromeAR
  • Ptosis
  • Blepharophimosis
  • Growth retardation
  • Neurologic defects (intellectual disability, absent primitive reflexes)
248700
Schwartz-Jampel syndrome
  • Intermittent ptosis
  • Blepharophimosis
  • Telecanthus
  • Cataract
  • Short stature
  • Cartilage and skeletal anomalies
  • Muscle hypertrophy
255800
Dubowitz syndrome
  • Ptosis
  • Blepharophimosis
  • Lateral telecanthus
  • Short stature
  • Intellectual disability
  • Immunologic deficiencies
223370
Smith-Lemli-Opitz syndrome
  • Ptosis
  • Epicanthus
  • Cataract
  • Growth retardation, intellectual disability
  • Severe genitourinary, cardiac, gastrointestinal anomalies
270400
KANSL1-related intellectual disability syndrome (17q21.31 microdeletion syndrome2AD
  • Developmental delay with mild-to-moderate intellectual disability
  • Characteristic facies: long face, high forehead, ptosis, blepharophimosis, large low-set ears, bulbous nasal tip, pear-shaped nose
  • Nasal speech
  • Cardiac septal defects, seizures, cryptorchidism
  • Friendly disposition
610443

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to SimulConsult®, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

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.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is almost always inherited in an autosomal dominant manner. Autosomal recessive inheritance has been reported in a single consanguineous family [Nallathambi et al 2007].

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Some individuals diagnosed with autosomal dominant BPES have an affected parent.
  • A proband with AD BPES may have the disorder as the result of de novo mutation.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include molecular genetic testing of FOXL2 if the pathogenic variant has been identified in the proband and clinical examination for subtle features of BPES.

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected [unpublished data].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and do not have a FOXL2 pathogenic variant, the risk to the sibs of a proband appears to be low.
  • If a FOXL2 pathogenic variant cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. The risk to the sibs of the proband depends on the probability of germline mosaicism in a parent of the proband and the spontaneous mutation rate of FOXL2.
  • Germline mosaicism has been observed in AD BPES and demonstrated at the molecular level [Beysen et al 2005]; its incidence is unknown.

Offspring of a proband. Each child of an individual with AD BPES has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that mutation occurred de novo in the proband. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal diagnosis is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. In addition, families in which (1) women with BPES have had premature ovarian failure or (2) women with BPES have an unknown risk for premature ovarian insufficiency (POI) should be informed regarding this risk so that they may consider early childbearing.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the FOXL2 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for conditions such as BPES are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • National Foundation for Facial Recontruction (NFFR)
    317 East 34th Street
    Room 901
    New York NY 10016
    Phone: 212-263-6656
    Fax: 212-263-7534
    Email: info@nffr.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Blepharophimosis, Ptosis, and Epicanthus Inversus: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FOXL23q22​.3Forkhead box protein L2FOXL2 homepage - FOXL2 @ LOVDFOXL2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Blepharophimosis, Ptosis, and Epicanthus Inversus (View All in OMIM)

110100BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS; BPES
605597FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2

Gene structure. FOXL2 is a small single-exon gene of 2.7 kb. The entire open reading frame is highly conserved in several vertebrate species [Cocquet et al 2002, Cocquet et al 2003, Udar et al 2003]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. The normal alleles have 14 copies of the Ala repeat, p.Ala221[14]. See Table 3.

Table 3.

Selected FOXL2 Benign Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
See footnote 1p.Ala221[14] 2NM_023067​.3
NP_075555​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

The polyalanine expansion is an imperfect trinucleotide repeat that may consist of each of the four codons for alanine (GCA, GCC, GCG, GCT). Nucleotide changes resulting in varying numbers of Ala repeats are described as deletion and duplication mutations (for details see LOVD database).

2.

Indicates that a stretch of alanines (Ala) is present, starting at amino acid position 221. Benign allelic variants are designated as p.Ala221[14] because they have exactly 14 Ala repeat units.

Pathogenic allelic variants. See Table 4. More than 125 FOXL2 pathogenic variants have been described in individuals with BPES type I and type II, demonstrating that both phenotypic features (eyelid defect and POI) are caused by the pleiotropic effect of mutation of a single gene, rather than by a contiguous gene syndrome. To date, a total of 106 unique intragenic FOXL2 pathogenic variants (i.e., different mutations that are unique to the world-wide collection of allelic variants) have been identified in 206 unrelated, ethnically diverse families with BPES [Beysen et al 2009 and references therein]. Detailed information on most FOXL2 pathogenic variants and affected individuals or families with BPES is available in the FOXL2 Mutation Database (see Table A). Each family has a unique FOXL2 database identifier (FOXL2db-Id), indicated with a number and the prefix “FOXL2.”

The occurrence of two mutational hotspots previously described by the author [De Baere et al 2001, De Baere et al 2003] was corroborated by subsequent findings. Pathogenic variants leading to an expansion of the poly-Ala tract account for 31% (63/206) and the 17-bp duplication c.843_859dup accounts for 13% (26/206) of all intragenic FOXL2 pathogenic variants. Another, less frequent 17-bp duplication c.855_871dup, along with c.841_857dup, c.843_865dup, c.854delC, and c.855_871del17, are all clustered, perhaps because of the hypermutability of this region. Other less frequent pathogenic variants are c.655C>T and c.804dupC [De Baere et al 2003, Beysen et al 2009].

Larger genomic rearrangements, including deletions involving FOXL2, accounted for 10% of the molecular defects found in families with typical BPES [Beysen et al 2005]. The extent of the deletions ranges from a partial- and total-gene deletion to microdeletions encompassing FOXL2 and neighboring genes including the Seckel syndrome-associated gene, ATR, located 5’ to FOXL2 [Beysen et al 2005, D'Haene et al 2010]. Cytogenetically detectable deletions include a 7.7-Mb deletion encompassing FOXL2 and ATR in an individual with BPES with microcephaly and developmental delay [de Ru et al 2005], a deletion of unknown extent in a simplex case involving an individual with BPES and normal psychomotor development [Or et al 2006], and others reviewed in de Ru et al [2005] and references therein.

Rearrangements outside the FOXL2 transcription unit are estimated to account for 5% of all molecular defects found in BPES [Beysen et al 2005] and implicate an effect of long-range cis-regulatory elements in regulating FOXL2 expression.

In a four-generation Chinese family with BPES type II showing linkage to the FOXL2 locus, an insertion mutation in the 3' UTR of FOXL2 segregated with the phenotype. This variant was shown to be located in an AU-rich repeat; however, the functional significance of this 3' UTR insertion on FOXL2 transcript stability and translation remains to be proven [Qian et al 2004].

In addition, one 5’ UTR and two 3’ UTR variants were identified in Chinese families with BPES [Li et al 2009]; however, the functional significance of these UTR variants on FOXL2 transcript stability and translation are not yet demonstrated.

Table 4.

Selected FOXL2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.560G>Ap.Gly187AspNM_023067​.3
NP_075555​.1
c.650C>Tp.Ser217Phe
c.655C>Tp.Gln219Ter
See footnote 1p.Ala221(15_24) 2
c.804dupC p.Gly269ArgfsTer265
c.841_857dup p.Pro287ArgfsTer75
c.843_859dup p.Pro287ArgfsTer75
c.843_865dup p.His289ArgfsTer75
c.854delC p.Pro285ArgfsTer71
c.855_871dup p.His291ArgfsTer71
c.855_871del17 p.Pro287AlafsTer241

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Note: The polyalanine expansion does not result from a simple trinucleotide repeat, but often consists of each of the four codons for alanine (GCA, GCC, GCG, GCT). Nucleotide changes resulting in varying numbers of Ala repeats are described as deletion and duplication mutations (for details see LOVD database).

2.

Indicates that a stretch of alanines (Ala) is present, starting at amino acid position 221, which is found with a variable length from 14 to 24; the underscore is used to indicate the range (from residue to residue). Normal alleles are designated as p.Ala221[14] because they have exactly 14 Ala repeat units (Table 3); Pathogenic alleles, designated as p.Ala221(15_24), can have 15 to 24 Ala repeat units (for details see LOVD database).

Normal gene product. The FOXL2 protein of 376 amino acids belongs to the large family of winged-helix/forkhead transcription factors. Forkhead proteins are present in all eukaryotes and have important functions in the establishment of the body axis and the development of tissues from all three layers in animals. Apart from the following two domains no similarities to other known proteins or domains have been identified [Crisponi et al 2001].

  • FOXL2 also contains a characteristic DNA-binding domain of 110 amino acids that was originally identified in Drosophila melanogaster fork head mutant; the domain was nearly perfectly conserved between fork head and the mammalian HNF-3 transcription factors.
  • FOXL2 contains a polyalanine tract of 14 residues, the role of which has not yet been elucidated. Expansions from 14 to 24 alanine residues in this region represent about 30% of all intragenic FOXL2 pathogenic variants and lead mainly to BPES type II [De Baere et al 2003].

Click here (pdf) for detailed information on forkhead transcription factor, evolution, expression, subcellular localization, protein interactions.

Abnormal gene product. In general, haploinsufficiency of FOXL2 appears to be the cause of BPES as 82% of pathogenic variants are either intragenic mutations or partial/total deletions of FOXL2 or microdeletions and submicroscopic deletions encompassing FOXL2 and neighboring genes [De Baere et al 2001, De Baere et al 2003, Beysen et al 2005, Beysen et al 2009, D'Haene et al 2010].

In recent years, some insights into the phenotypic effects of FOXL2 pathogenic variants were gained by in vitro studies of several types of natural and artificial FOXL2 mutations. It was shown that the most recurrent polyalanine expansion led to intranuclear aggregation and mislocalization of the protein as a result of extensive cytoplasmic aggregation, whereas the normal FOXL2 protein exclusively localizes in the nucleus in a diffuse manner [Caburet et al 2004]. Moreover, a dominant negative effect was demonstrated. Although polyalanine expansions cause an eyelid phenotype indistinguishable from that caused by other intragenic mutations, a mild ovarian phenotype is observed only in a fraction of heterozygotes. This may be attributed to a difference in functional thresholds or in tissue-specific aggregation of the mutant protein in eyelid mesenchyme and follicular cells, due to tissue-specific co-aggregation partners [Caburet et al 2004]. In turn, the small polyalanine expansion (19 alanines) only leads to cytoplasmic staining in a minority of transfected cells and to no detectable aggregation [Nallathambi et al 2007]. Subsequently it was shown that polyalanine expansions lead to protein mislocalization, aggregation and altered intranuclear mobility in a length-dependent manner. Luciferase assays and real time RT-PCR of several target genes showed that various polyalanine expansions induce differential downregulation depending on the target promoters analyzed [Moumné et al 2008].

Moreover, it was shown that the steroidogenic acute regulatory gene STAR (StAR), whose protein is a marker of granulosa cell differentiation, is a direct target gene of FOXL2, acting as a repressor of StAR [Pisarska et al 2004]. Two disease-associated truncating mutations of FOXL2 (truncation of 93 and 218 amino acids) did not result in complete loss of repressor activity. In addition, these FOXL2 truncated proteins were shown to exhibit a dominant negative effect. It was concluded that the entire alanine/proline-rich carboxyl terminus is important for the repressor activity of FOXL2 and that truncating mutations may preferentially lead to BPES and ovarian dysfunction by accelerated differentiation of granulosa cells and secondary depletion of the primordial follicle pool [Pisarska et al 2004]. The identification of a considerable number of ovarian FOXL2 targets [Batista et al 2007] may be essential to reveal more insight into phenotypic effects of FOXL2 pathogenic variants in the (adult) ovary.

Several artificial (i.e., not naturally occurring or reported pathogenic variants in affected individuals but constructed in vitro) nonsense mutations have been shown to lead to the production of N-terminal truncated proteins by reinitiation of translation downstream of the premature stop codon. They display strong nuclear aggregation, and partial mislocalization to the cytoplasm. In addition, it was shown that these truncated proteins retain a fraction of the wild-type protein, suggesting a dominant negative effect. Luciferase assays with natural nonsense mutations demonstrated the importance of the entire alanine/proline-rich carboxyl terminus of FOXL2 for transcriptional repression of the STAR (StAR) promoter. It was also demonstrated that these pathogenic variants produce a protein with a weak dominant negative effect [Moumné et al 2005].

The present authors subsequently studied the molecular consequences of 17 naturally occurring FOXL2 missense mutations. Most mapped to the conserved DNA-binding forkhead domain. The subcellular localization and aggregation pattern of the mutant FOXL2 proteins was variable and ranged from a diffuse nuclear distribution (resembling wild-type) to extensive nuclear aggregation often in combination with cytoplasmic mislocalization and aggregation. The authors also studied the transactivation capacity of the mutant proteins in FOXL2-expressing cells. Several led to a loss of function, while others are suspected to induce a dominant negative effect. Interestingly, one variant located outside the forkhead domain (p.Ser217Phe) appeared to be a hypermorphic allele, i.e. causing an increase in normal gene function, leading to a mild BPES phenotype [Beysen et al 2008b].

Click here (pdf) for detailed information on polled intersex syndrome (PIS) in goat and mouse models, structure, evolution, and expression.

References

Literature Cited

  1. Alao MJ, Lalèyè A, Lalya F, Hans Ch, Abramovicz M, Morice-Picard F, Arveiler B, Lacombe D, Rooryck C. Blepharophimosis, ptosis, epicanthus inversus syndrome with translocation and deletion at chromosome 3q23 in a black African female. Eur J Med Genet. 2012;55:630–4. [PubMed: 22906557]
  2. Batista F, Vaiman D, Dausset J, Fellous M, Veitia RA. Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. Proc Natl Acad Sci U S A. 2007;104:3330–5. [PMC free article: PMC1805535] [PubMed: 17360647]
  3. Beckingsale PS, Sullivan TJ, Wong VA, Oley C. Blepharophimosis: a recommendation for early surgery in patients with severe ptosis. Clin Experiment Ophthalmol. 2003;31:138–42. [PubMed: 12648048]
  4. Beysen D, De Jaegere S, Mowat D, Laframboise R, Gillessen-Kaesbach G, Fellous M, Veitia RA, Boucard P, Touraine P, Leroy BP, De Cock C, Delbeke P, Leppig K, Ensenauer R, Ebinger F, Barel D, Plomp A, Kimonis V, Hendriks Y, Clayton-Smith J, Grix AW, Van Regemorter N, Hennekam R, Meire F, Oyen N, Wilson LC, De Paepe A, De Baere E. Mutation in Brief: Identification of 34 novel and 56 known FOXL2 mutations in patients with blepharophimosis syndrome. Hum Mutat. 2008a;29:E205–19. [PubMed: 18642388]
  5. Beysen D, De Paepe A, De Baere E. Mutation update: FOXL2 mutations and genomic rearrangements in BPES. Hum Mutat. 2009;30:158–69. [PubMed: 18726931]
  6. Beysen D, Moumné L, Veitia R, Peters H, Leroy BP, De Paepe A, De Baere E. Missense mutations in the forkhead domain of the transcription factor FOXL2 lead to nuclear and cytoplasmic protein aggregation. Hum Mol Genet. 2008b;17:2030–8. [PubMed: 18372316]
  7. Beysen D, Raes J, Leroy BP, Lucassen A, Yates JR, Clayton-Smith J, Ilyina H, Brooks SS, Christin-Maitre S, Fellous M, Fryns JP, Kim JR, Lapunzina P, Lemyre E, Meire F, Messiaen LM, Oley C, Splitt M, Thomson J, Van de Peer Y, Veitia RA, De Paepe A, De Baere E. Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome. Am J Hum Genet. 2005;77:205–18. [PMC free article: PMC1224524] [PubMed: 15962237]
  8. Boccone L, Meloni A, Falchi AM, Usai V, Cao A. Blepharophimosis, ptosis, epicanthus inversus syndrome, a new case associated with de novo balanced autosomal translocation. Am J Med Genet. 1994;51:258–9. [46,XY,t(3;7)(q23;q32)] [PubMed: 8074155]
  9. Bodega B, Porta C, Crosignani PG, Ginelli E, Marozzi A. Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. Mol Hum Reprod. 2004;10:555–7. [PubMed: 15181179]
  10. Caburet S, Demarez A, Moumne L, Fellous M, De Baere E, Veitia RA. A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation. J Med Genet. 2004;41:932–6. [PMC free article: PMC1735658] [PubMed: 15591279]
  11. Choi KH, Kyung S, Oh SY. The factors influencing visual development in blepharophimosis-ptosis-epicanthus inversus syndrome. J Pediatr Ophthalmol Strabismus. 2006;43:285–8. [PubMed: 17022162]
  12. Cocquet J, De Baere E, Gareil M, Pannetier M, Xia X, Fellous M, Veitia RA. Structure, evolution and expression of the FOXL2 transcription unit. Cytogenet Genome Res. 2003;101:206–11. [PubMed: 14684984]
  13. Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA. Evolution and expression of FOXL2. J Med Genet. 2002;39:916–21. [PMC free article: PMC1757225] [PubMed: 12471206]
  14. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27:159–66. [PubMed: 11175783]
  15. Crisponi L, Uda M, Deiana M, Loi A, Nagaraja R, Chiappe F, Schlessinger D, Cao A, Pilia G. FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences. Genomics. 2004;83:757–64. [PubMed: 15081106]
  16. Dawson EL, Hardy TG, Collin JR, Lee JP. The incidence of strabismus and refractive error in patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES). Strabismus. 2003;11:173–7. [PubMed: 14710475]
  17. De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet. 2003;72:478–87. [PMC free article: PMC379240] [PubMed: 12529855]
  18. De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, Gillerot Y, Mortier G, Meire F, Van Maldergem L, Courtens W, Hjalgrim H, Huang S, Liebaers I, Van Regemorter N, Touraine P, Praphanphoj V, Verloes A, Udar N, Yellore V, Chalukya M, Yelchits S, De Paepe A, Kuttenn F, Fellous M, Veitia R, Messiaen L. Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. Hum Mol Genet. 2001;10:1591–600. [PubMed: 11468277]
  19. De Baere E, Fukushima Y, Small K, Udar N, Van Camp G, Verhoeven K, Palotie A, De Paepe A, Messiaen L. Identification of BPESC1, a novel gene disrupted by a balanced chromosomal translocation, t(3;4)(q23;p15.2), in a patient with BPES. Genomics. 2000;68:296–304. [PubMed: 10995571]
  20. De Baere E, Lemercier B, Christin-Maitre S, Durval D, Messiaen L, Fellous M, Veitia R. FOXL2 mutation screening in a large panel of POF patients and XX males. J Med Genet. 2002;39:e43. [PMC free article: PMC1735205] [PubMed: 12161610]
  21. De Baere E, Van Roy N, Speleman F, Fukushima Y, De Paepe A, Messiaen L. Closing in on the BPES gene on 3q23: mapping of a de Novo reciprocal translocation t(3;4)(q23;p15.2) breakpoint within a 45-kb cosmid and mapping of three candidate genes, RBP1, RBP2, and beta'-COP, distal to the breakpoint. Genomics. 1999;57:70–8. [PubMed: 10191085]
  22. de Ru MH, Gille JJ, Nieuwint AW, Bijlsma JB, van der Blij JF, van Hagen JM. Interstitial deletion in 3q in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and microcephaly, mild mental retardation an growth delay: clinical report and review of the literature. Am J Med Genet A. 2005;137:81–7. [PubMed: 16015581]
  23. Decock CE, Claerhout I, Leroy BP, Kesteleyn P, Shah AD, De Baere E. Correction of the lower eyelid malpositioning in the blepharophimosis-ptosis-epicanthus inversus syndrome. Ophthal Plast Reconstr Surg. 2011a;27:368–70. [PubMed: 21562436]
  24. Decock CE, Shah AD, Delaey C, Forsyth R, Bauters W, Kestelyn P, De Baere E, Claerhout I. Increased levator muscle function by supramaximal resection in patients with blepharophimosis-ptosis-epicanthus inversus syndrome. Arch Ophthalmol. 2011b;129:1018–22. [PubMed: 21825186]
  25. D'Haene B, Attanasio C, Beysen D, Dostie J, Lemire E, Bouchard P, Field M, Jones K, Lorenz B, Menten B, Buysse K, Pattyn F, Friedli M, Ucla C, Rossier C, Wyss C, Speleman F, De Paepe A, Dekker J, Antonarakis SE, De Baere E. Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. PLoS Genet. 2009;5:e1000522. [PMC free article: PMC2689649] [PubMed: 19543368]
  26. D'Haene B, Nevado J, Pugeat M, Pierquin G, Lowry RB, Reardon W, Delicado A, García-Miñaur S, Palomares M, Courtens W, Stefanova M, Wallace S, Watkins W, Shelling AN, Wieczorek D, Veitia RA, De Paepe A, Lapunzina P, De Baere E. FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions. Hum Mutat. 2010;31:e1332–47. [PubMed: 20232352]
  27. Fukushima Y, Wakui K, Nishida T, Ueoka Y. Blepharophimosis sequence and de novo balanced autosomal translocation [46,XY,t(3;4)(q23;p15.2)]: possible assignment of the trait to 3q23. Am J Med Genet. 1991;40:485–7. [PubMed: 1746616]
  28. Gersak K, Harris SE, Smale WJ, Shelling AN. A novel 30 bp deletion in the FOXL2 gene in a phenotypically normal woman with primary amenorrhoea: case report. Hum Reprod. 2004;19:2767–70. [PubMed: 15459170]
  29. Gijsbers ACJ, D’Haene B, Hilhorst-Hofstee Y, Mannens M, Albrecht B, Bartholdi D, Seidel J, Witt DR, Fong C, Maisenbacher MK, Loeys B, Sangha K, Hennekam R, Bakker E, Breuning MH, De Baere E, Ruivenkamp CAL. Identification of novel candidate loci associated with blepharophimosis phenotypes. Hum Genet. 2008;124:489–98. [PubMed: 18953567]
  30. González-González C, García-Hoyos M, Hernaez Calzón R, Arroyo Díaz C, González Fanego C, Lorda Sánchez I, Sánchez-Escribano F. Microdeletion found by array-CGH in girl with blepharophimosis syndrome and apparently balanced translocation t(3;15)(q23;q25). Ophthalmic Genet. 2012;33:107–10. [PubMed: 22171663]
  31. Harris SE, Chand AL, Winship IM, Gersak K, Aittomaki K, Shelling AN. Identification of novel mutations in FOXL2 associated with premature ovarian failure. Mol Hum Reprod. 2002;8:729–33. [PubMed: 12149404]
  32. Jewett T, Rao PN, Weaver RG, Stewart W, Thomas IT, Pettenati MJ. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) associated with interstitial deletion of band 3q22: review and gene assignment to the interface of band 3q22.3 and 3q23. Am J Med Genet. 1993;47:1147–50. [PubMed: 8291545]
  33. Laissue P, Lakhal B, Benayoun BA, Dipietromaria A, Braham R, Elghezal H, Philibert P, Saâd A, Sultan C, Fellous M, Veitia R. Functional evidence implicating FOXL2 in non syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J Med Genet. 2009;46:455–7. [PubMed: 19429596]
  34. Lawson CT, Toomes C, Fryer A, Carette MJ, Taylor GM, Fukushima Y, Dixon MJ. Definition of the blepharophimosis, ptosis, epicanthus inversus syndrome critical region at chromosome 3q23 based on the analysis of chromosomal anomalies. Hum Mol Genet. 1995;4:963–7. [PubMed: 7633459]
  35. Li D, Zeng W, Tao J, Li S, Liang C, Chen X, Mu W, Wang X, Qin Y, Jie Y, Wei W. Mutations of the transcription factor FOXL2 gene in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. Genet Test Mol Biomarkers. 2009;13:257–68. [PubMed: 19371227]
  36. Liu H, Shao Y, Zhao Z, Zhang D. One-stage correction of blepharophimosis-ptosis-epicanthus inversus syndrome using a frontalis muscle transfer technique. J Plast Surg Hand Surg. 2014;48:74–9. [PubMed: 23968369]
  37. Moumné L, Dipietromaria A, Batista F, Kocer A, Fellous M, Pailhoux E, Veitia RA. Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. Hum Mol Genet. 2008;17:1010–9. [PubMed: 18158309]
  38. Moumné L, Fellous M, Veitia RA. Deletions in the polyAlanine-containing transcription factor FOXL2 lead to intranuclear aggregation. Hum Mol Genet. 2005;14:3557–64. [PubMed: 16219626]
  39. Nallathambi J, Moumné L, De Baere E, Beysen D, Usha K, Sundaresan P, Veitia R. A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction. Hum Genet. 2007;121:107–12. [PubMed: 17089161]
  40. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360:606–14. [PMC free article: PMC2762081] [PubMed: 19196677]
  41. Oley C, Baraitser M. Textbook of Congenital Malformation Syndromes. 1995.
  42. Or SF, Tong MF, Lo FM, Lam TS. Three novel FOXL2 gene mutations in Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome. Chin Med J (Engl) 2006;119:49–52. [PubMed: 16454982]
  43. Pisarska MD, Bae J, Klein C, Hsueh AJ. Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinology. 2004;145:3424–33. [PubMed: 15059956]
  44. Praphanphoj V, Goodman BK, Thomas GH, Niel KM, Toomes C, Dixon MJ, Geraghty MT. Molecular cytogenetic evaluation in a patient with a translocation (3;21) associated with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES). Genomics. 2000;65:67–9. [PubMed: 10777667]
  45. Prueitt RL, Zinn AR. A fork in the road to fertility. Nat Genet. 2001;27:132–4. [PubMed: 11175772]
  46. Qian X, Shu A, Qin W, Xing Q, Gao J, Yang J, Feng G, He L. A novel insertion mutation in the FOXL2 gene is detected in a big Chinese family with blepharophimosis-ptosis-epicanthus inversus. Mutat Res. 2004;554:19–22. [PubMed: 15450400]
  47. Sa HS, Lee JH, Woo KI, Kim YD. A new method of medial epicanthoplasty for patients with blepharophimosis-ptosis-epicanthus inversus syndrome. Ophthalmology. 2012;119:2402–7. [PubMed: 22835816]
  48. Schlade-Bartusiak K, Brown L, Lomax B, Bruyère H, Gillan T, Hamilton S, McGillivray B, Eydoux P. BPES with atypical premature ovarian insufficiency, and evidence of mitotic recombination, in a woman with trisomy X and a translocation t(3;11)(q22.3;q14.1). Am J Med Genet A. 2012;158A:2322–7. [PubMed: 22887799]
  49. Sebastiá R, Herzog Neto G, Fallico E, Lessa S, Solari HP, Ventura MP. A one-stage correction of the blepharophimosis syndrome using a standard combination of surgical techniques. Aesthetic Plast Surg. 2011;35:820–7. [PubMed: 21455822]
  50. Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K. Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients. Hum Mutat. 2003;22:222–8. [PubMed: 12938087]
  51. Verdin H, D'Haene B, Beysen D, Novikova Y, Menten B, Sante T, Lapunzina P, Nevado J, Carvalho C, Lupski JR, De Baere E. Microhomology-mediated replication-based mechanisms underly non-recurrent pathogenic microdeletions of the FOXL2 gene or its regulatory domain. PLoS Genet. 2013;9:e1003358. [PMC free article: PMC3597517] [PubMed: 23516377]
  52. Wu SY, Ma L, Tsai YJ, Kuo JZ. One-stage correction for blepharophimosis syndrome. Eye (Lond) 2008;22:380–8. [PubMed: 17115018]
  53. Zlotogora J, Sagi M, Cohen T. The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am J Hum Genet. 1983;35:1020–7. [PMC free article: PMC1685801] [PubMed: 6613996]

Suggested Reading

  1. Beysen D, Vandesompele J, Messiaen L, De Paepe A, De Baere E. The human FOXL2 mutation database. Hum Mutat. 2004;24:189–93. [PubMed: 15300845]

Chapter Notes

Revision History

  • 5 February 2015 (me) Comprehensive update posted live
  • 12 November 2009 (me) Comprehensive update posted live
  • 15 February 2006 (cd) Revision: prenatal diagnosis available
  • 12 July 2005 (me) Comprehensive update posted to live Web site
  • 8 July 2004 (me) Review posted to live Web site
  • 1 March 2004 (edb) Original submission
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