Clinical characteristics.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by a complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and primary ovarian insufficiency; BPES type II includes only the four major features. Other ophthalmic manifestations that can be associated with BPES include dysplastic eyelids, lacrimal duct anomalies, strabismus, refractive errors, and amblyopia. Other craniofacial features may include a broad nasal bridge and low-set ears.

Diagnosis/testing.

The diagnosis of BPES is established in a proband with suggestive findings and a heterozygous pathogenic variant in FOXL2 or its regulatory domain identified by molecular genetic testing.

Management.

Treatment of manifestations: Management requires the input of a multidisciplinary team of specialists. Eyelid 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. Primary ovarian insufficiency is managed by hormone replacement therapy; fertility is addressed with reproductive technologies such as embryo donation, egg donation, and cryopreservation strategies.

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. Psychological follow up is recommended.

Genetic counseling.

BPES is almost always inherited in an autosomal dominant manner. More than half of individuals diagnosed with BPES have the disorder as the result of a pathogenic variant inherited from an affected parent. Each child of an individual with BPES has a 50% chance of inheriting the pathogenic variant. Once the BPES-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPES are possible.

Suggestive Findings

BPES should be suspected in individuals with the following clinical findings and family history.

Major clinical findings, all present at birth:

• Blepharophimosis. Narrowing of the horizontal aperture of the eyelids
• Ptosis. Drooping of the upper eyelid causing a narrowing of the vertical palpebral fissure
• Epicanthus inversus. A skin fold arising from the lower eyelid and running inward and upward
• Telecanthus. Lateral displacement of the inner canthi and the inferior punctum with normal interpupillary distance

Additionally, primary ovarian insufficiency is present in individuals with BEPS type 1.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of BPES is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in FOXL2 or its regulatory domain identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous variant of FOXL2 (or its regulatory domain) of uncertain significance does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing) and comprehensive genomic testing (exome sequencing, genome sequencing, chromosomal microarray analysis) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the clinical diagnosis of BPES has not been considered or is less certain are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus.

Two types of BPES have been described [Zlotogora et al 1983]:

• BPES type I includes the four major features and female infertility caused by primary ovarian insufficiency.
• BPES type II includes only the four major features.

Complex eyelid malformation

• 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 inward and upward
• Telecanthus. Lateral displacement of the inner canthi with normal interpupillary distance

Associated ophthalmic manifestations

• 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
• Nasolacrimal drainage problems caused by lateral displacement, duplication, or stenosis of the lacrimal puncta
  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 anatomic hallmark in the diagnosis of BPES [Decock et al 2011].
• Strabismus, refractive errors (anisometropic hypermetropia and myopia), and amblyopia are more common in individuals with BPES than in the general population [Beckingsale et al 2003, Dawson et al 2003, Choi et al 2006]. 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].

Other craniofacial features frequently observed in BPES are a broad nasal bridge and low-set ears.

Primary ovarian insufficiency (POI)

• Secondary sexual characteristics are usually normal in both BPES type I and BPES type II.
• In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea.
  • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound.
  • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [Huhtaniemi et al 2018].
  • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [Huhtaniemi et al 2018]; and decreased serum concentrations of estradiol and progesterone.

Cognitive development is expected to be normal in individuals with BPES unless the disorder occurs as part of a contiguous gene deletion with associated developmental delay / intellectual disability (see Genetically Related Disorders).

Pituitary hormone deficiency. A recent study showed that some individuals with BPES have hypopituitarism with no molecular explanation other than a FOXL2 pathogenic variant, suggesting a role for FOXL2 in human pituitary development [Castets et al 2020].

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 [Beysen et al 2008] and the occurrence of both BPES type I and BPES type II within a single family [Yang et al 2017].

Polyalanine expansions preferentially lead to BPES type II.

Penetrance

All individuals heterozygous for a FOXL2 pathogenic variant have a BPES phenotype; thus, penetrance is 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 1 female) [Nallathambi et al 2007].

Prevalence

The prevalence of BPES is estimated at 1:50,000 births in the general population.

No differences in prevalence based on sex, race, or ethnicity have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BPES, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management requires the input of a multidisciplinary team with specialists including a clinical geneticist, genetic counselor, pediatric ophthalmologist, oculoplastic surgeon, (pediatric or adult) endocrinologist, reproductive endocrinologist, and gynecologist.

Surveillance

Evaluation of Relatives at Risk

It is appropriate to clarify the status of older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from ophthalmic surveillance and, in female relatives, endocrinologic surveillance to monitor ovarian status (see Surveillance). Evaluations can include:

• Molecular genetic testing if a FOXL2 pathogenic variant has been identified in an affected family member;
• Clinical examination for features of BPES if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is almost always inherited in an autosomal dominant manner.

BPES associated with biallelic FOXL2 pathogenic variants has been reported in one family to date: a consanguineous Indian family in which individuals heterozygous for a short polyalanine expansion are unaffected while individuals homozygous for this expansion have typical BPES [Nallathambi et al 2007].

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• More than half of individuals diagnosed with BPES have an affected parent.
  A recent study showed more female than male probands and a highly significant bias in the parental origin of inherited pathogenic variants, with 20/21 pathogenic variants found to be paternal in origin (95%). The latter may be due to the association of BPES and primary ovarian insufficiency (POI) [Bunyan & Thomas 2019].
• Some probands with BPES have the disorder as the result of a de novo pathogenic variant.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the proband has BPES as the result of a cytogenetic rearrangement involving 3q23, recommendations for the evaluation of asymptomatic parents include genomic testing to determine if a balanced chromosome rearrangement involving the 3q23 region is present.
• If the pathogenic variant identified in the proband is not found in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    Parental mosaicism has been observed in BPES [Beysen et al 2005, Beysen et al 2009, Bunyan & Thomas 2019]. In a recent study, presumed parental mosaicism was reported in two of 28 families in whom the pathogenic variant was originally thought to have occurred de novo in the proband [Bunyan & Thomas 2019].
• The family history of some individuals diagnosed with BPES may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of the BPES eyelid phenotype in heterozygous family members is 100%.
• If the proband has a known BPES-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Beysen et al 2005, Beysen et al 2009, Bunyan & Thomas 2019].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism.
• If a parent has a balanced structural chromosome rearrangement involving the 3q23 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.

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

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the BPES-causing pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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.
• Women with BPES should be informed regarding the risk of POI and recommendations for endocrinologic surveillance to monitor ovarian status (see Surveillance).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the BPES-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPES are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

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.

Mechanism of disease causation. Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) occurs via a loss-of-function mechanism (haploinsufficiency).

FOXL2-specific laboratory technical considerations

• FOXL2 is a small single-exon gene of 2.7 kb.
• 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.
• 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].

Author Notes

Dr Elfride De Baere's research is focused on the molecular pathogenesis of genetically heterogeneous mendelian disorders (such as rare eye diseases) and on noncoding variation of rare eye diseases and transcription factor-associated developmental diseases. Achievements in the field of rare eye disease genomics include identification of novel disease genes for inherited retinal diseases and characterization of new disease mechanisms. For the functional characterization of disease genes, Dr De Baere makes use of integrated omics and cellular and animal models, such as Xenopus tropicalis. She has published 34 papers on FOXL2 and/or BPES: pubmed.ncbi.nlm.nih.gov.

Author websites: www.debaerelab.com and orcid.org

Revision History

• 10 March 2022 (ha) Comprehensive update posted live
• 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 live
• 8 July 2004 (me) Review posted live
• 1 March 2004 (edb) Original submission

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