BPES BPES, TYPE I, INCLUDED
BPES WITH OVARIAN FAILURE, INCLUDED
BPES WITH DUANE RETRACTION SYNDROME, INCLUDED
BPES, TYPE II, INCLUDED
BPES WITHOUT OVARIAN FAILURE, INCLUDED
BPES, TYPE I, AUTOSOMAL RECESSIVE, INCLUDED
Blepharophimosis types 1 and 2
Vignes (1889) probably first described this entity, a dysplasia of the eyelids. In addition to small palpebral fissures, features include epicanthus inversus (fold curving in the mediolateral direction, inferior to the inner canthus), low nasal bridge, and ptosis ... Vignes (1889) probably first described this entity, a dysplasia of the eyelids. In addition to small palpebral fissures, features include epicanthus inversus (fold curving in the mediolateral direction, inferior to the inner canthus), low nasal bridge, and ptosis of the eyelids (Sacrez et al., 1963; Johnson, 1964; Smith, 1970). The condition should be considered distinct from congenital ptosis (178300). Owens et al. (1960) updated the pedigree of a family that was first reported by Dimitry (1921), which had affected members in 6 generations. The patients had the classic syndrome triad of blepharophimosis, ptosis, and epicanthus inversus. Raviotta (1971), a physician who is an affected member of the pedigree studied by Owens et al. (1960), provided a first-hand description. Smith (1970) described affected mother and daughter. Moraine et al. (1976) suggested that female infertility is a pleiotropic effect of the gene. Townes and Muechler (1979) reported a family in which all affected females had primary ovarian failure. They had a normal female karyotype and normal breast development; pubic and axillary hair was scant, but in a normal female distribution. Laparoscopy showed a small uterus and small atrophic ovaries. Zlotogora et al. (1983) suggested that there are 2 forms of BPES: type I with infertility of affected females and type II with transmission by both males and females. The infertility is inherited as an autosomal dominant sex-limited trait. Jones and Collin (1984) reviewed 37 known cases; of the 6 females of child-bearing age, 1 had primary amenorrhea with raised gonadotropins and low estrogen and progesterone. Oley and Baraitser (1988) provided an illustrated review of BPES. Fraser et al. (1988) and Smith et al. (1989) described 4 women from 3 families with blepharophimosis, epicanthus inversus, and ptosis who had premature ovarian failure. Two were sisters; they had another affected sister who was not investigated. Two of the 3 families had multiple affected members. Smith et al. (1989) suggested that these cases, type I in the classification of Zlotogora et al. (1983), represented a 'contiguous gene syndrome' (Schmickel, 1986) with a combination of blepharophimosis and familial precocious ovarian failure. Temple and Baraitser (1989) reported a family in which an uncle and nephew were clearly affected. The carrier mother had no abnormality as an adult, but photographs of her as a child showed unilateral minimal ptosis without epicanthus inversus. Finley et al. (1990) studied 14 sporadic cases of this syndrome (which they abbreviated BPEI) and found an apparent maternal age effect, but no paternal age effect. Panidis et al. (1994) described blepharophimosis in 2 sisters, a brother, and their father. The elder sister presented initially with 'resistant ovary syndrome' and thereafter true premature menopause, while the younger sister presented with resistant ovary syndrome. Cunniff et al. (1998) reported 22 individuals referred for genetic evaluation because of blepharophimosis. The blepharophimosis syndrome was present in 14 of the 22, and was familial in 5, sporadic in 9. The other 8 children had a malformation syndrome other than the blepharophimosis syndrome. All 8 were mentally retarded or developmentally delayed. Two of the 8 had recognized disorders, branchiootorenal syndrome (113650) in one and a ring chromosome 4 in the other; the remaining 6 had unrecognized malformation syndromes, each distinctive from the others.
By positional cloning, Crisponi et al. (2001) identified the FOXL2 gene and identified mutations resulting in truncated proteins in affected individuals with both types I and II BPES (605597.0001 and 605597.0002). Consistent with an involvement in those tissues, ... By positional cloning, Crisponi et al. (2001) identified the FOXL2 gene and identified mutations resulting in truncated proteins in affected individuals with both types I and II BPES (605597.0001 and 605597.0002). Consistent with an involvement in those tissues, FOXL2 was found to be selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appeared predominantly in the ovary. In 2 sporadic patients and 2 families with BPES, Beysen et al. (2005) identified 4 overlapping extragenic microdeletions 230 kb upstream of the FOXL2 gene. The shortest region of deletion overlap contains several conserved nongenic sequences harboring putative transcription factor-binding sites and representing potential long-range cis-regulatory elements. Affected females in the 2 families had BPES type II; BPES type could not be assessed in the sporadic patients. In another family with BPES, Beysen et al. (2005) identified an approximately 188-kb microdeletion downstream of the FOXL2 gene. The father of the 2 affected half-sisters was unaffected, suggestive of germinal mosaicism; quantitative analysis using 3 SNPs located in the deletion showed that about 10% of paternal germ cells and 5% of somatic peripheral blood lymphocytes carried the mutation. Vincent et al. (2005) reported an 18-month-old girl with sporadic BPES and bilateral type 1 Duane syndrome (see 126800), in whom they identified a heterozygous duplication of 10 alanine residues in the FOXL2 gene (605597.0002). In 3 affected males and 1 affected female of a consanguineous Indian family with BPES type I, Nallathambi et al. (2007) identified a homozygous duplication in the FOXL2 gene (605597.0019), resulting in a polyalanine expansion from 14 to 19 residues (Ala19). Several unaffected relatives were heterozygous for the mutation, indicating autosomal recessive inheritance in this family. The affected 30-year-old woman had amenorrhea and impaired fertility, consistent with ovarian dysfunction. Nallathambi et al. (2007) noted that ala19 is the shortest polyalanine expansion (+5) described in the FOXL2 gene and may confer residual enzyme activity. In an Indian cohort comprising 6 familial and 2 sporadic cases of BPES type I or type II, Kaur et al. (2011) identified 6 heterozygous mutations in the FOXL2 gene, 3 of which were novel (see, e.g., 605597.0020). In 1 family, an affected female also had polycystic ovarian disease. Kaur et al. (2011) noted that mutations in the region downstream of the forkhead domain were predominantly responsible for BPES among Indian patients.
The diagnosis of blepharophimosis syndrome (BPES) is based primarily on the following four clinical findings, which are present at birth [Oley & Baraitser 1995]:...
DiagnosisClinical DiagnosisThe 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, unpublished]. 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. TestingFemales 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 examinationCytogenetic 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 TestingGene. FOXL2 is the only gene currently known to be associated with blepharophimosis syndrome. Clinical testingSequence 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 InversusView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFOXL2Sequence analysisSequence variants in the coding region 272%ClinicalFISH 3 and/or deletion/duplication analysis 4Partial- or whole-gene or contiguous-gene deletions 510%-15% 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. All intragenic mutations identified to date are in the single exon 1 (containing the entire coding region).3. Depending on probe design, FISH testing may not be appropriate to identify partial or subtle FOXL2 gene deletions.4. 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.5. Extent of deletion detectable may vary by test method, probes, and clinical laboratory.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm the diagnosis in a probandMolecular genetic testing of FOXL2, including sequence analysis and deletion testing If no FOXL2 mutation or genomic rearrangement of FOXL2 and neighboring region can be identified on molecular genetic testing, chromosome analysis to screen for rearrangements elsewhere in the genome may be considered depending on the family history and the individual's phenotype. In persons with BPES-like phenotypes without FOXL2 mutation or genomic rearrangement of FOXL2 and neighboring region, whole-genome copy number screening (using an array GH platform is recommended to identify the underlying genetic causes of these phenotypes [Gijsbers et al 2008] (see Genetically Related Disorders). Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersCytogenetic rearrangements of 3q23. BPES caused by cytogenetic rearrangements involving 3q23 (i.e., unbalanced translocations and interstitial deletions) 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, Praphanphoj et al 2000, de Ru et al 2005 and references therein]. Note: Balanced translocations involving 3q23 lead to classic BPES without additional findings.Nonsyndromic premature ovarian failure (POF). Considering that POF is part of the phenotypic spectrum of FOXL2 mutations, FOXL2 was assumed to be a possible candidate gene for nonsyndromic POF [Crisponi et al 2001, Prueitt & Zinn 2001]. Recently, the first functional study supporting a role of FOXL2 mutations in nonsyndromic POF was reported [Laissue et al 2009]. A novel FOXL2 missense mutation p.Gly187Asp was found in a woman with POF in the absence of BPES. The subcellular localization of the mutant protein was normal but the transactivation capacity of the mutant protein on two ovary-specific reporter promoters proved to be lower than that of normal FOXL2 protein. In addition, the mutant protein was found to strongly activate an in vitro reporter construct driven by the Osr2 promoter, a gene assumed to be a craniofacial target of FOXL2. Other studies found rare or no FOXL2 sequence variants in phenotypically normal women with POF [De Baere et al 2001, De Baere et al 2002 , Bodega et al 2004, Harris et al 2002, Gersak et al 2004, Laissue et al 2009].
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. ...
Natural HistoryBlepharophimosis 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.
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]. ...
Genotype-Phenotype CorrelationsIntragenic MutationsFor 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.Gln82X) 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.Tyr91X); 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.Glu352Aspfs*4). 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.Gln219X). 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 RearrangementsDeletions 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.
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. ...
Differential DiagnosisThe 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 FeaturesView in own windowSyndromeInheritance 1 CharacteristicsOMIMHereditary 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 disposition610443Oley & Baraitser [1995], OMIM1. AD=autosomal dominant; AR=autosomal recessive, XL=X-linked2. Presumed mode of inheritance3. Gijsbers et al [2008]Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with blepharophimosis syndrome, the following evaluations are recommended:...
ManagementEvaluations 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 ManifestationsManagement 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, unpublished]. 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, unpublished]. 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. SurveillanceThe 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 RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Therapies Under InvestigationOvarian 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFOXL23q22.3Forkhead box protein L2FOXL2 at Center for Medical Genetics, Ghent, Belgium FOXL2 homepage - Mendelian genesFOXL2Data 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) View in own window 110100BLEPHAROPHIMOSIS, PTOSIS, AND EPICANTHUS INVERSUS; BPES 605597FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2Normal allelic variants. 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 normal alleles have 14 copies of the Ala repeat, p.Ala221[14]. See Table 3.Table 3. Selected FOXL2 Normal Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid ChangeReference SequencesSee footnote 1p.Ala221[14] 2NM_023067.3 NP_075555.1 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. Normal allelic variants are designated as p.Ala221[14] because they have exactly 14 Ala repeat units.Pathologic 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 Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.205G>Ap.Glu69LysNM_023067.3 NP_075555.1c.244C>T p.Gln82Xc.273C>Gp.Tyr91Xc.500_501delTCinsAA (c.500T>A; c.501C>A) p.Phe167Xc.560G>Ap.Gly187Aspc.650C>Tp.Ser217Phec.650C>Gp.Ser217Cysc.655C>Tp.Gln219X See footnote 2p.Ala221(15_24) 3c.655C>T p.Gln219Xc.663_692dupp.Ala225_Ala234dupc.667_702dupp.Ala221_Ala234dupc.684_698dup15p.Ala230_Ala234dupc.672_701dupp.Ala225_Ala234dupc.804dupC p.Gly269Argfs*265c.841_857dup p.Pro287Argfs*75c.843_859dupp.Pro287Argfs*75c.843_865dup p.His289Argfs*75c.854delC p.Pro285Argfs*71c.855_871dup p.His291Argfs*71c.855_871del17 p.Pro287Alafs*241c.305T>Cp.Ile102Thrc.1056delGp.Glu352Aspfs*4Partial- and whole-gene deletions7.7 Mb deletion (encompasses FOXL2 and ATR)See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. 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). Normal alleles are designated as p.Ala221[14] because they have exactly 14 Ala repeat units (Table 3); pathologic 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.