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Blepharophimosis, Ptosis, and Epicanthus Inversus

Synonyms: BPES, Blepharophimosis Syndrome
, MD, PhD
Center for Medical Genetics
Ghent University Hospital
Ghent, Belgium

Initial Posting: ; Last Update: November 12, 2009.

Summary

Disease characteristics. Blepharophimosis 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 failure (POF); BPES type II includes only the four major features. Other ophthalmic manifestations 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 disease-causing mutation are expected to have normal intelligence.

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 involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at age three to five years, usually followed a year later by ptosis correction; however, when ptosis is severe, surgical repair is recommended before age three years. 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 in whom the BPES type is unknown or in whom BPES type I is suspected.

Genetic counseling. BPES is usually inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations is estimated to be more than 50%. Each child of an individual with BPES has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation 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 FOXL2 mutation-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 [De Cock et al 2011].

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 failure (POF).
  • BPES type II includes only the four major features.

Testing

Females with premature ovarian failure (POF) have:

  • Endocrinologic findings of hypergonadotrophic 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, Praphanphoj et al 2000, de Ru et al 2005 and references therein]. Such cytogenetic rearrangements are estimated to occur in 2% of individuals with BPES [Beysen et al 2009].

Molecular Genetic Testing

Gene. FOXL2 is the only gene currently known to be associated with blepharophimosis syndrome.

Clinical testing

  • Sequence analysis of the single coding exon of FOXL2. All intragenic FOXL2 mutations identified to date are confined to this exon [De Baere et al 2003, Beysen et al 2008a, Beysen et al 2009]. They are estimated to occur in 72% of individuals with a clinical diagnosis of BPES [Beysen et al 2008a].
  • Deletion/duplication analysis. Deletions involving FOXL2 vary greatly in size from a partial deletion (5’ or 3’ end of gene) to a whole-gene deletion to a contiguous gene deletion that encompasses FOXL2 and adjacent gene(s) (see Table A). The size of deletions that are detectable may vary by test method, probe, and clinical laboratory. Depending on probe design, fluorescence in situ hybridization (FISH) may not detect partial or subtle FOXL2 deletions. Multiplex ligation-dependent probe amplification (MPLA) detected partial- or total-gene deletions in approximately 10% of individuals with typical BPES. Such deletions represent approximately 12% of all molecular defects found in individuals with BPES [Beysen et al 2005, Beysen et al 2009]. Quantitative PCR and array genomic hybridization (aGH) may detect partial-, whole-, or contiguous-gene deletions depending on the resolution of the platform used [D’Haene et al 2009, Beysen et al 2009].

    Regulatory deletions outside the FOXL2 gene represent about 5% of genetic defect of BPES [Beysen et al 2005, D’Haene et al 2009]. Such deletions may not always be detected, as extent of deletions detected may vary among diagnostic laboratories.
  • Combined sequence analysis and MLPA testing. The detection rate of the combined approach consisting of sequence and MLPA analysis 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].

Research testing can be complementary to clinical testing.

Table 1. Summary of Molecular Genetic Testing Used in Blepharophimosis, Ptosis, and Epicanthus Inversus

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
FOXL2Sequence analysis 4Sequence variants in the coding region 572%
FISH 6 and/or deletion/duplication analysis 7Partial- or whole-gene or contiguous-gene deletions 810%-15% 8

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, partial-, whole-, or multigene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. All intragenic mutations identified to date are in the single exon 1 (containing the entire coding region).

6. Depending on probe design, FISH testing may not be appropriate to identify partial or subtle FOXL2 gene deletions.

7. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and array GH may be used.

8. Extent of deletion detectable may vary by test method, probes, and clinical laboratory.

Testing Strategy

To confirm the diagnosis in a proband

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Blepharophimosis syndromes type I and II are a complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Other features frequently observed in BPES 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 BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea.

Individuals with BPES who have an intragenic disease-causing mutation are expected to have normal intelligence.

Genotype-Phenotype Correlations

Intragenic Mutations

For some FOXL2 mutations, inter- and intrafamilial variable expressivity of the ovarian phenotype (female infertility, premature ovarian failure) is observed [De Baere et al 2003].

Mutations predicted to result in proteins truncated before the polyalanine tract preferentially lead to POF (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 POF in a three-generation family in which all individuals with BPES had the nonsense mutation c.244C>T (p.Gln82Ter) and the females with isolated POF did not. Although this mutation belongs to a group of mutations that is preferentially associated with BPES type I [De Baere et al 2003], it is unclear whether the POF in the women in this family results from the FOXL2 mutation or from another genetic or non-genetic cause [Beysen et al 2008b, Beysen et al 2009].

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 recently. In a consanguineous Indian family, individuals heterozygous for a short polyalanine expansion of 19 alanines (c.684_698dup15; p.Ala230_Ala234dup) were unaffected, but individuals who were homozygous had typical BPES (with documented POF in one female) [Nallathambi et al 2007]. This was the first report on a homozygous FOXL2 mutation providing evidence of a recessive form of BPES associated with ovarian dysfunction. Note: The polyalanine expansion does not result from a simple trinucleotide repeat (see Table 3, footnote 2).

The following cases emphasize the importance of clinical long-term follow-up of ovarian function in women with a poly-Ala expansion when gathering data on POF.

  • Variable degrees of ovarian dysfunction were observed in seven women with BPES who were heterozygous for a FOXL2 allele with a poly-Ala expansion. However, when hormonal status could be assessed, hypergonadotrophic hypogonadism was not observed, suggesting that these polyalanine expansion mutations may result in late-onset ovarian failure [Beysen et al 2009].
  • A 16-year old young woman thought to have BPES type I with the poly-Ala expansion c.667_702dup (p.Ala221_Ala234dup) had an extremely large corpus luteum cyst that caused transient ovarian dysfunction [Raile et al 2005]. Although it was postulated that this transient ovarian insufficiency might be caused by malfunction of the FOXL2 protein, the ovarian dysfunction seen in BPES type I is progressive, not transient. However, the role of the compressing cyst or cystectomy in the cause of ovarian dysfunction in this patient is unclear.

Mutations that predict a truncated or extended protein containing an intact forkhead and polyalanine tract are not known to have a genotype-phenotype correlation.

Missense mutations in the forkhead domain, in general, do not correlate with ovarian phenotype. However, recent studies might offer some predictive value regarding ovarian phenotype. Missense mutations in the forkhead domain that lead to mislocalization and aggregation and, thus, severely impair transactivation, tend to have a more severe ovarian phenotype than missense mutations that do not significantly affect protein localization and function [Beysen et al 2008b].

Missense mutations outside the forkhead domain. Two mutations downstream of the forkhead domain (p.Ser217Phe and p.Ser217Cys) had a mild BPES phenotype [Beysen et al 2008b].

Additional findings observed with some intragenic mutations. Although intragenic FOXL2 mutations usually lead to BPES type I or II without any associated findings, the following case reports describe individuals who have additional atypical features that could result from pleiotropic effects of these mutations.

  • A ventricular septal defect (VSD) was found in an individual with a poly-Ala expansion (c.672_701dup; p.Ala225_Ala234dup) and one with a missense mutation in the forkhead domain (c.205G>A; p.Glu69Lys).
  • Developmental delay was reported in: two affected males of a four-generation family with BPES type I (c.273C>G; p.Tyr91Ter); a four-year-old simplex case (i.e., a single occurrence in a family) (c.663_692dup; p.Ala225_Ala234dup); and an 11-year old girl who was a simplex case (c.1056delG; p.Glu352AspfsTer4).
  • The combination of a complex heart defect and severe developmental delay was described in a one-year-old simplex case with the mutation c.665C>T (p.Gln219Ter).
  • An association between BPES and Duane syndrome was found in a one-year-old with an expansion of the poly-Ala tract (c.672_701dup; p.Ala225_Ala234dup) [Vincent et al 2005]. The same mutation was found in a 12-year old male who had had Burkitt lymphoma.
  • In another family with the c.663_692dup (p.Ala221_Ala231dup) mutation, a seven-year old male had BPES and a cleft palate (Pierre Robin sequence) and his mother had typical BPES. An individual with the missense mutation c.305T>C (p.Ile102Thr) had a cleft lip.
  • Growth hormone deficiency, which has previously been described in two individuals with BPES without any other associated findings [Varghese et al 2002, Wales 1998], was found in one individual with the 17-bp duplication c.672_701dup (p.Ala225_Ala234dup) [Crisponi et al 2002] and two sisters with the missense mutation c.650C>T (p.Ser217Phe). In one individual with BPES with the mutation c.500_501delTCinsAA [Crisponi et al 2001], growth retardation was observed but growth hormone was not assayed.

    Growth hormone deficiency may be attributed to FOXL2 expression in Rathke’s pouch [Treier et al 1998]. FOXL2 is essential for pituitary development and function and FOXL2 expression precedes expression of genes involved in gonadotrope-specific development [Ellsworth et al 2006]. However, most individuals with BPES do not have recognizable pituitary abnormalities, suggesting that the pituitary is less sensitive to FOXL2 dosage than the developing eyelids and ovary.

It is rather unlikely that the other associated features mentioned (e.g., growth hormone deficiency, Duane syndrome) result from a wider pleiotropic effect of FOXL2 in development.

Genomic Rearrangements

Deletions encompassing FOXL2. No reliable genotype-phenotype correlations with respect to POF could be established [Beysen et al 2005]. Although it was postulated that intellectual disability in individuals with a microdeletion of the FOXL2 region could be attributed to haploinsufficiency of ATR [de Ru et al 2005], a consistent correlation could not be found [Beysen et al 2005].

Deletions outside FOXL2. The BPES type could only be assessed in two of nine families, which appeared to have BPES type II [Beysen et al 2005, D’Haene et al 2009]. Developmental delay was not observed.

Penetrance

To date, almost all individuals heterozygous for a FOXL2 mutation 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 (c.684_698dup15; p.Ala230_Ala234dup) are unaffected, but homozygotes have typical BPES (with documented POF in one female) [Nallathambi et al 2007] (see Polyalanine expansions).

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 are major features (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 are Prominent Features

SyndromeInheritance 1 CharacteristicsOMIM
Hereditary congenital ptosis 1 (PTOS1)ADPtosis 178300
Hereditary congenital ptosis 2 (PTOS2)XLPtosis 300245
Ohdo blepharophimosis syndromeAD 2 Blepharophimosis
Blepharoptosis
Intellectual disability
Congenital heart defects
Hypoplastic teeth
249620
Michels syndromeBlepharophimosis
Blepharoptosis
Epicanthus inversus
Ophthalmic anterior segment defects (cornea)
Cleft lip/palate
Minor skeletal abnormalities
257920
Ptosis with external ophthalmoplegiaARPtosis
Ophthalmoplegia
Miosis
Decreased accommodation
Strabismus
Amblyopia
258400
Noonan syndrome ADPtosis
Short stature
Heart defects
Blood clotting deficiencies
163950
Marden-Walker syndromeARPtosis
Blepharophimosis
Growth retardation
Neurologic defects (intellectual disability, absent primitive reflexes)
248700
Schwartz-Jampel syndromeIntermittent ptosis
Blepharophimosis
Telecanthus
Cataract
Short stature
Cartilage and skeletal anomalies
Muscle hypertrophy
255800
Dubowitz syndromePtosis
Blepharophimosis
Lateral telecanthus
Short stature
Intellectual disability
Immunologic deficiencies
223370
Smith-Lemli-Opitz syndrome Ptosis
Epicanthus
Cataract
Growth and intellectual disability
Severe genitourinary, cardiac, and gastrointestinal anomalies
270400
17q21.31 microdeletion syndrome 3Developmental 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, and cryptorchidism
Friendly disposition
610443

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, 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 in an individual diagnosed with blepharophimosis syndrome, 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 POF. In girls with BPES, the family history can indicate the type of BPES in affected females (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 POF.
  • Referral of females with BPES to a (pediatric or adult) endocrinologist during late puberty or early adulthood to assess onset and course of POF

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.

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 traditionally 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. 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. To correct telecanthus, the medial canthal tendon is usually shortened or fused with a transnasal wire.

Recent insights into the causes of the abnormal lower eyelid positioning allow a more targeted surgical reconstruction that produces in a more natural appearance [De Cock et al 2011]. 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 [De Cock et al 2011].

Management of POF needs to address the two major following medical issues that are applicable to primary ovarian insufficiency in general and not specific for BPES, as 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 POF, 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 or to accept the unlikely but real chance that the infertility will resolve spontaneously (see Natural History).

    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 POF 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 mutation type. 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 cases 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 POF 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 is usually inherited in an autosomal dominant manner. Autosomal recessive inheritance has been reported in one consanguineous family.

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 a de novo gene mutation. The proportion of cases caused by de novo mutations is estimated at more than 50% [unpublished data].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of FOXL2 if a mutation has been identified in the proband and clinical examination for subtle features of BPES.

Note: Variable expressivity of BPES features has only been reported in mosaic cases [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 mutation, the risk to the sibs of a proband appears to be low.
  • If a disease-causing FOXL2 mutation 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 mutation.

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.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • To date, autosomal recessive BPES has been described in only one consanguineous Indian family in which a short poly-Ala expansion of 19 alanines (c.684_698dup15; p.Ala230_Ala234dup) was segregating. In this family, heterozygous individuals are unaffected and homozygous individuals have the typical BPES phenotype, with proven POF in one female [Nallathambi et al 2007].
  • The parents of an individual with autosomal recessive BPES are obligate heterozygotes of the short poly-Ala expansion.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an individual with autosomal recessive BPES has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with autosomal recessive BPES has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for the short poly-Ala expansion in FOXL2.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the poly-Ala expansion in FOXL2 been identified in the family.

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 disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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 POF 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 disease-causing mutation(s) have 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]. The benign alleles have 14 copies of the Ala repeat, p.Ala221[14]. See Table 3. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Table 3. Selected FOXL2 Benign Allelic 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 author. 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 mutations have been described in individuals with BPES types I and II, demonstrating that both phenotypic features (eyelid defect and POF) are caused by the pleiotropic effect of a single gene, rather than by a contiguous gene syndrome. To date, a total of 106 unique intragenic FOXL2 mutations (i.e., different mutations that are unique to the world-wide collection of gene variants) have been identified in 206 unrelated families with BPES of different ethnic origins [Beysen et al 2009 and references therein]. Detailed information on most FOXL2 mutations 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 our recent findings. Mutations 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 mutations. 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 mutations 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. 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 BPES case with 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. The occurrence of three translocation breakpoints located upstream of FOXL2 [De Baere et al 2000, Praphanphoj et al 2000, Crisponi et al 2004] illustrated that a position effect may also be implicated in the causation of BPES. Beysen et al [2005] reported on five FOXL2-extragenic deletions in individuals with typical features of BPES.

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 still needs to be proven [Qian et al 2004].

Table 4. Selected FOXL2 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.205G>Ap.Glu69LysNM_023067​.3
NP_075555​.1
c.244C>T p.Gln82Ter
c.273C>Gp.Tyr91Ter
c.500_501delTCinsAA
(c.500T>A; c.501C>A)
p.Phe167Ter
c.560G>Ap.Gly187Asp
c.650C>Tp.Ser217Phe
c.650C>Gp.Ser217Cys
c.655C>Tp.Gln219Ter
See footnote 2p.Ala221(15_24) 3
c.655C>T p.Gln219Ter
c.663_692dupp.Ala225_Ala234dup
c.667_702dupp.Ala221_Ala234dup
c.684_698dup15p.Ala230_Ala234dup
c.672_701dupp.Ala225_Ala234dup
c.804dupC p.Gly269ArgfsTer265
c.841_857dup p.Pro287ArgfsTer75
c.843_859dupp.Pro287ArgfsTer75
c.843_865dup p.His289ArgfsTer75
c.854delC p.Pro285ArgfsTer71
c.855_871dup p.His291ArgfsTer71
c.855_871del17 p.Pro287AlafsTer241
c.305T>Cp.Ile102Thr
c.1056delGp.Glu352AspfsTer4
Partial- and whole-gene deletions
7.7-Mb deletion (encompasses FOXL2 and ATR)

Note on variant classification: Variants listed in the table have been provided by the author. 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. Variant designation that does not conform to current naming conventions

2. 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).

3. 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). Benign 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 mutations 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 mutations 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]. In recent years, some insights into the phenotypic effects of FOXL2 mutations 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 a 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]. More recently, 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), 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 mutations in the (adult) ovary.

Several artificial (i.e. not naturally occurring or reported mutations in affected individuals but constructed in vitro) nonsense mutations have been shown to lead to the production of N-terminal truncated proteins by re-initiation 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 gene promoter. Furthermore, it was also demonstrated that these mutations produce a protein with a weak dominant negative effect [Moumné et al 2005].

Recently, we studied the molecular consequences of 17 naturally occurring FOXL2 missense mutations. Most of them map 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 like the wild-type to extensive nuclear aggregation often in combination with cytoplasmic mislocalization and aggregation. We also studied the transactivation capacity of the mutants in FOXL2-expressing cells. Several mutants led to a loss of function, while others are suspected to induce a dominant negative effect. Interestingly, one mutant located outside the forkhead domain (p.Ser217Phe) appeared to be hypermorphic and had no effect on intracellular protein distribution.

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

References

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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

  • 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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