Guest guest Posted July 24, 2004 Report Share Posted July 24, 2004 I wrote to Dr De Baere asking about the prevalence of BPES. Here is her reply. (my email and her response) Also - she has kind attached a very useful document. (also forwarded here, as an attachment). I would recommend that people consider printing this off and sending a copy of it to the medical staff that intend to meet with in advance of the meeting. This way whatever questions you have, you can refer to this article as a baseline for the discussion. And whoever you are meeting with will have had plenty of time to read the article. Shireen -----Original Message-----From: Elfride De Baere [mailto:Elfride.DeBaere@...]Sent: 23 July 2004 18:36andy.bowles@...Subject: Re: question about BPES statistics Dear Mrs. Mohandes, thank you for your interest. Your question is not simple as you say ! There are no sound figures on the prevalence or incidence of BPES so far. The condition is catalogued as a "rare disorder" (although probably underdiagnosed). The prevalence of 1 in 200.000 may be realistic. BPES is occurring in all ethnic groups: European, North-American, Australian, New-Zealand, oriental, Hispanic (South-America), Africa (in our patient population we have only 2 BPES patients of African origin). There is no gender preference. I attached a review on BPES for your information. I hope this may help. Please let me know if you have more questions. Yours sincerely, Elfride De Baere -----------------------------------------------------------------Elfride De Baere, MD, PhDCenter for Medical GeneticsGhent University HospitalDe Pintelaan 185B-9000 GhentBelgiumPhone: 0032 9 240 5186 (direct) 0032 9 240 3972 (lab) 0032 9 240 3603 (secretary)Fax: 0032 9 240 4970Email: Elfride.DeBaere@... question about BPES statistics > Dear Dr De Baere> > I have BPES and I wondered if I could ask you a simple question. But it> might be not so simple to answer.> > I am trying to find out, very approximately, how many people have BPES.> Based on my research (as a lay person) I think that for people in Australia,> North America and Europe, it is about 1 in 200,000.> > If I should be directing my question to another person, I would be very> grateful if you could tell me who.> > Meanwhile, I hope I have not wasted your time, and if I can do anything to> help you, please let me know.> > Kind regards> > Shireen Mohandes> London, England> > Funded by the NIH • Developed at the University of Washington, Seattle Blepharophimosis, Ptosis, and Epicanthus Inversus [bPES, Blepharophimosis Syndrome. Includes: Blepharophimosis, Ptosis, and Epicanthus Inversus Type I (BPES I); Blepharophimosis, Ptosis, and Epicanthus Inversus Type II (BPES II)] Author: Elfride De Baere, MD, PhD About the Author Posted: 8 July 2004 Summary Disease characteristics. Classic blepharophimosis syndrome (BPES) is a complex eyelid malformation invariably characterized by four major features: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Two types of blepharophimosis syndrome have been described: 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. 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. Mutations are identified in ~70% of affected individuals by using a combination of sequence analysis of the coding region (single exon) and fluorescence in situ hybridization (FISH). This testing is clinically available. Genetic counseling. BPES is inherited in an autosomal dominant manner. Many individuals diagnosed with BPES have an affected parent. A proband with BPES may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with BPES has a 50% chance of inheriting the mutation. Prenatal testing may be available through laboratories offering custom prenatal testing; 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 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 typical facial appearance Tilt their head backward into a chin-up position Epicanthus inversus: A skinfold arising from the lower eyelid and running inwards and upwards. Telecanthus: Lateral displacement of the inner canthi with normal interpupillary distance. Two types of blepharophimosis syndrome have been described: 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 [Zlotogora et al 1983]. Testing Females with premature ovarian failure have endocrinological findings of hypergonadotrophic hypogonadism: elevated serum concentration of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and decreased serum concentration of estradiol and progesterone. Ultrasonography reveals a small hypoplastic uterus and streak ovaries. Typical anatomic pathological findings of the ovary are "resistant-ovary syndrome" (presence of primordial follicles, but no follicular development) progressing into a "true premature menopause" (presence of scars in place of primordial follicles) [Fraser et al 1988]. Molecular Genetic Testing GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by at least one US CLIA-certified laboratory or a clinical laboratory outside the US. GeneTests does not independently verify information provided by laboratories and does not warrant any aspect of a laboratory's work; listing in GeneTests does not imply that laboratories are in compliance with accreditation, licensure, or patent laws. Clinicians must communicate directly with the laboratories to verify information. —ED. Gene. FOXL2 is the only gene currently known to be associated with blepharophimosis syndrome. Molecular genetic testing: Clinical uses Confirmatory diagnostic testing Prenatal diagnosis Molecular genetic testing: Clinical methods 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, in press]. Deletion detection using fluorescence in situ hybridization (FISH). FISH with FOXL2-containing BAC RP11-548O1 may be used to detect microdeletions of the FOXL2 region in individuals in whom sequence analysis does not reveal a mutation. Exact frequencies of FOXL2 microdeletions resulting in BPES are not known. The detection rate of the combined approach consisting of sequence and FISH analysis is around 70% in familial as well as in simplex cases [De Baere et al 2003]. This percentage may be explained by a misdiagnosis in some cases, by a total gene deletion, or by a defect residing outside the transcription unit (position effect) that may be missed through the current screening method. Table 1. Molecular Genetic Testing Used in Blepharophimosis, Ptosis, and Epicanthus Inversus Test Method Mutations Detected Mutation Detection Rate Test Availability Sequence analysis Mutations in open reading frame of FOXL2 1 70% Clinical FISH Microdeletions of 3q23 (including FOXL2) 1. All intragenic mutations identified to date are in the single exon 1 (containing the entire coding region). Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here. Testing Strategy for a Proband Depending on the family history and the individual's phenotype, chromosome analysis may be considered if no FOXL2 mutation or microdeletion of the FOXL2 region can be identified. Cytogenetic testing should particularly be pursued in individuals with BPES having developmental delay and associated features (see Genetically Related Disorders). Genetically Related Disorders Deletion of 3q23 Individuals with BPES caused by cytogenetic rearrangements involving 3q23 (i.e., translocations and interstitial deletions) have been reported [Fukushima et al 1991 , Jewett et al 1993 , Boccone et al 1994 , Lawson et al 1995 , Praphanphoj et al 2000 , Engelen et al 2002]. (Micro)deletion of region 3q23 may be associated with psychomotor retardation, microcephaly, cardiac defects, syndactyly, and joint contractures [De Baere et al 2003]. Nonsyndromic premature ovarian failure (POF). FOXL2 mutations have been suggested as playing a role in nonsyndromic POF [Crisponi et al 2001 , Prueitt & Zinn 2001]. Several FOXL2 polymorphisms [Crisponi et al 2002 , De Baere et al 2002 , et al 2002 , Bodega et al 2004] and variations with presumably pathogenic effect in individuals affected with isolated POF have been reported [ et al 2002]. Clinical Description 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. 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. The incidences of amblyopia, strabismus, and refractive errors (hypermetropia, astigmatism) are higher in individuals with BPES than in the general population [beckingsale et al 2003]. Nystagmus and microphthalmos can occur. Individuals with BPES having an intragenic disease-causing mutation are expected to have normal intelligence. Minor features observed in BPES are a broad nasal bridge, low set ears, and a short philtrum. In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea. Secondary sexual characteristics are usually normal. Genotype-Phenotype Correlations Initial studies suggested FOXL2 haploinsufficiency as the cause of BPES and demonstrated a preliminary genotype-phenotype correlation [Crisponi et al 2001 , De Baere et al 2001]. For some FOXL2 mutations, intra- and interfamilial variable expressivity of the development of POF has been observed [De Baere et al 2003]. A revised genotype-phenotype correlation has been proposed: predicted proteins with a truncation before the polyalanine tract may lead to the development of POF (BPES type I). For mutations leading to a truncated or extended protein containing an intact forkhead and polyalanine tract, no correlations can be made. Polyalanine expansions may lead to BPES type II. For missense mutations (mainly in the highly conserved forkhead domain), no correlations can yet be made. The two microdeletions described to date lead to BPES associated with mental retardation [De Baere et al 2003]. Penetrance To date, all individuals found to have a FOXL2 mutation have the BPES phenotype. For some FOXL2 mutations, inter- and intrafamilial variable expressivity of female infertility (premature ovarian failure) is observed. [De Baere et al 2003]. Prevalence No exact figures are known about the prevalence of BPES. No apparent enrichment in any ethnic or racial group nor gender has been reported. Differential Diagnosis For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED. The differential diagnosis of BPES includes those conditions in which ptosis or blepharophimosis is a major feature (Table 2) [Oley & Baraitser 1995]; however, in clinical practice, blepharophimosis syndrome can be relatively easily distinguished from most of these conditions. Table 2. Overview of Conditions in which Ptosis and/or Blepharophimosis are a Major Feature Syndrome Inheritance 1 Characteristics OMIM Hereditary congenital ptosis 1 (PTOS1) AD Ptosis 178300 Hereditary congenital ptosis 2 (PTOS2) XL Ptosis 300245 Ohdo blepharophimosis syndrome AD 2 Blepharophimosis Blepharoptosis Mental retardation Congenital heart defects Hypoplastic teeth 249620 Michels syndrome Blepharophimosis Blepharoptosis Epicanthus inversus Ophthalmic anterior segment defects (cornea) Cleft lip/palate Minor skeletal abnormalities 257920 Ptosis with external ophthalmoplegia AR Ptosis Ophthalmoplegia Miosis Decreased accommodation Strabismus Amblyopia 258400 Noonan syndrome AD Ptosis Short stature Heart defects Blood clotting deficiencies 163950 Marden- syndrome AR Ptosis Blepharophimosis Growth retardation Neurological defects (mental retardation, absent primitive reflexes) 248700 Schwartz-Jampel syndrome Intermittent ptosis Blepharophimosis Telecanthus Cataract Short stature Cartilage and skeletal anomalies Muscle hypertrophy 255800 Dubowitz syndrome Ptosis Blepharophimosis Lateral telecanthus Short stature Mental retardation Immunological deficiencies 223370 -Lemli-Opitz syndrome Ptosis Epicanthus Cataract Growth and mental retardation Severe genitourinary Cardiac and gastrointestinal anomalies 270400 Oley & Baraitser 1995 , OMIM 1. AD=autosomal dominant; AR=autosomal recessive, XL=X-linked 2. Presumed mode of inheritance Management Management requires the input of several specialists including a geneticist, (pediatric) ophthalmologist, oculoplastic surgeon, pediatrician, reproductive endocrinologist, and gynecologist. Evaluations at Initial Diagnosis Individuals should be thoroughly examined by a (pediatric) opthalmologist for visual acuity measurement, refraction, measurement of ocular movements and strabismus, and measurement of palpebral apertures and eyelid elevation. Individuals with evidence of amblyopia or strabismus should be referred to a pediatric ophthalmologist for appropriate management [beckingsale et al 2003]. Individuals with BPES should be referred to a clinical geneticist for an appropriate genetic workup and counseling. In girls affected with BPES, the family history can already give an indication of the type of BPES (association with subfertility or infertility in affected females). In uninformative families or simplex cases (i.e., no other family members are affected), molecular genetic testing may be helpful for assessing for premature ovarian failure risk in some cases. Treatment of Manifestations 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. 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 three to five years of age, followed about a year later by ptosis correction, which usually requires a brow suspension procedure. Autogeneous fascia lata gives excellent results, but is not reliable before 3.5 - 4 years of age because of a lack of available autogeneous fascia lata. In children below this age, silastic slings give good results and are easily adjusted if necessary. For individuals with severe ptosis, surgical ptosis repair is recommended before the age of three years, followed by medial canthoplasty if necessary. For individuals with moderate ptosis, correction of ptosis may be deferred until the age of five years when surgery is often recommended for cosmetic reasons before starting school. Ovum donation is the only possible therapy for the female infertility resulting from premature ovarian failure because there is a lack of normally differentiated follicles [Hovav et al 1995]. Surveillance The frequency of ophthalmic follow-up is variable depending on the individual's age, procedures performed, and results of visual testing. Endocrinologic and gynecologic follow-up are advised in affected females in whom the BPES type is unknown or in whom BPES type I is suspected based on a positive family history or suggestive FOXL2 mutation. Monitoring of the ovarian status can be done by ultrasonography of ovaries and uterus, hormonal measurements (FSH, LH, estrogen, progesterone), and following the natural history of menses (age of menarche and ages of onset of oligomenorrhea and secondary amenorrhea). 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 or cultural 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 inherited in an autosomal dominant manner. Risk to Family Members Parents of a proband Many individuals diagnosed with BPES have an affected parent. A proband with 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 the FOXL2 gene if a mutation has been identified in the proband and clinical examination for subtle features of BPES (although non-penetrance or incomplete penetrance has not been reported to date). Sibs of a proband The risk to the sibs of the proband depends upon 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 BPES [unpublished data], although its incidence is currently unknown. Offspring of a proband. Each child of an individual with BPES has a 50% chance of inheriting the mutation. Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk. Related Genetic Counseling Issues Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the 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 germline mosaicism, alternate paternity, or undisclosed adoption could also be considered. Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service. Prenatal Testing No laboratories offering molecular genetic testing for prenatal diagnosis for BPES are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see .. 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, careful discussion of these issues is appropriate. Molecular Genetics Information in the Molecular Genetics tables may differ from that in the text; tables may contain more recent information. —ED. Molecular Genetics of Blepharophimosis, Ptosis, and Epicanthus Inversus Gene SymbolChromosomal LocusProtein Name FOXL23q23Forkhead box protein L2 Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot. OMIM Entries for Blepharophimosis, Ptosis, and Epicanthus Inversus 110100 BLEPHAROPHIMOSIS, EPICANTHUS INVERSUS, AND PTOSIS; BPES 605597 FORKHEAD TRANSCRIPTION FACTOR FOXL2; FOXL2 Genomic Databases for Blepharophimosis, Ptosis, and Epicanthus Inversus Gene SymbolLocus SpecificEntrez GeneHGMDGeneCardsGDBGenAtlas FOXL2 FOXL2 605597 129025 FOXL2 129025 FOXL2 For a description of the genomic databases listed, click here. Molecular Genetic Pathogenesis Normal allelic variants: The FOXL2 gene is a small single exon gene of 2.7 kb. A comparative sequence analysis of FOXL2 sequences has been performed in a number of vertebrate species. It has been shown that the entire open reading frame is highly conserved in several species [Cocquet et al 2002 , Cocquet et al 2003 , Udar et al 2003]. Pathologic allelic variants: Over 125 FOXL2 mutations and variations have been described in individuals with BPES types I and II and in women with isolated POF. Initial studies suggested an involvement of FOXL2 haploinsufficiency in the causation of BPES and demonstrated a preliminary genotype-phenotype correlation [Crisponi et al 2001 , De Baere et al 2001]. Two mutational "hot spots" have been demonstrated: 30% of FOXL2 mutations lead to polyalanine expansions, and 13% are the 17-bp duplication 1080-1096dup17. A locus-specific Human FOXL2 Mutation Database (medgen.ugent.be/foxl2) has been created. It contains general information about the FOXL2 gene, as well as details about 135 intragenic mutations and variants of FOXL2, obtained from published papers, abstracts of meetings and from unpublished data. Not included in the current version of the database are variants residing outside the coding region of FOXL2 and molecular cytogenetic rearrangements of the FOXL2 locus [beysen et al, in press]. Mutations are named following the most recent HGVS guidelines, in three different ways: common, systematic, and trivial. What has been classified as "common" names are the mutations numbered using the reference sequence AF301906 (initiated by Crisponi et al 2001). The common names are preceded by a "g." following the HGVS recommendations. The "systematic" names have been numbered using the cDNA reference numbering with +1 as A of the initation codon ATG. The "trivial" names reflect the mutations on the protein level and the notation has been adapted following the most recent guidelines. Normal gene product: The FOXL2 protein of 376 amino acids belongs to the large family of forkhead transcription factors and contains a 100-amino acid DNA-binding forkhead domain. FOXL2 also 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]. The expression of the FOXL2 transcript and protein has been studied in mammals; in human, mouse, and goat, it has only been demonstrated in developing eyelids and in fetal and adult ovaries [Crisponi et al 2001 , Cocquet et al 2002 , Cocquet et al 2003 , Pisarska et al 2004]. Its protein localization has been shown to be nuclear, which is in line with its putative function as a transcription factor [Cocquet et al 2002]. Mouse Foxl2 transcript (previously named P-Frk for pituitary forkhead factor) was also found to be expressed in Rathke's pouch of the developing pituitary gland [Treier et al 1998]. In non-mammalian vertebrates, FoxL2 mRNA has been shown to be expressed at an early stage in the developing female gonad and to have a sex-dimorphic expression [Loffler et al 2003]. The conservation of FOXL2 sequence and pattern of expression throughout evolution leads to the conclusion that it is, to date, the earliest known sex-dimorphic marker of ovarian determination/differentiation in vertebrates and might be a key factor in the early development and maintenance of the vertebrate female gonad [Cocquet et al 2002 , Cocquet et al 2003]. FoxL2 is the first human autosomal gene shown to be implicated in ovarian maintenance. In addition, its pituitary expression has suggested an involvement in pituitary organogenesis [Treier et al 1998]. At the level of protein interactions, FoxL2 has been shown to be capable of interacting at GRAS, or GnRH receptor activating sequence, which is a regulatory element of the murine GnRH receptor gene promoter mediating activin responsiveness. FoxL2 activation at GRAS is lost with mutation of either the 5' Smad binding site or a putative forkhead binding site located at the 3' end of the element. It has been suggested that GRAS is a composite regulatory element whose functional activity is dependent on the organization of a multi-protein complex consisting of Smads, AP-1 and a member of the forkhead family of DNA binding proteins [Ellsworth et al 2003]. Abnormal gene product: In vivo studies: In goats, the polled intersex syndrome (PIS), associating polledness and intersexuality, has been proposed as an animal model for BPES; the disease locus was shown to be located at goat chromosome 1q43, a region syntenic to human chromosome band 3q23 [Vaiman et al 1999]. Pailhoux et al (2001) have shown that PIS has been caused by an 11.7 kb deletion, located at a distance of 200 kb upstream of FOXL2. It was demonstrated that the deletion affects FOXL2 expression, suggesting a long-range position effect on FOXL2 transcription. This model represents a putative disease-causing mechanism for BPES in humans. A recent study presenting homozygous Foxl2lacZ mutant mice has shed light on the function of FOXL2 during folliculogenesis in vivo. In Foxl2lacZ, granulosa cells from homozygous mutant ovaries do not complete the squamous-to-cuboidal transition, leading to the absence of secondary follicles and oocyte atresia. Activin-bA and anti-Mullerian inhibiting hormone expression is absent or strongly diminished in Foxl2lacZ homozygous mutant ovaries. Two weeks after birth, most, if not all, oocytes expressed Gdf9 in Foxl2lacZ homozygous mutant ovaries, indicating that nearly all primordial follicles have already initiated folliculogenesis at this stage. This activation, in the absence of functional granulosa cells, leads to oocyte atresia and progressive follicular depletion. In addition to providing a molecular mechanism for premature ovarian failure in BPES, this study showed that granulosa cell function is not only crucial for oocyte growth but also for ovary maintenance in vivo [schmidt et al 2004]. A second report confirmed that mice lacking Foxl2 recapitulate features of human BPES and that granulosa cell development fails in Foxl2-null animals from the time of primordial follicle formation [uda et al 2004]. In vitro studies: Promoter reporter studies revealed that FOXL2 is a transcriptional repressor of the StAR gene, a marker of granulosa cell differentiation. DNA-binding studies revealed that FOXL2 directly interacts with the first 95 bp upstream of the start site of the StAR promoter. FOXL2 mutants that lack the entire alanine/proline-rich carboyl-terminus and that have been found in individuals with BPES with POF show loss of repressor activity. In addition, they exhibit a dominant-negative effect by blocking the repressor activity of wild-type FOXL2. It has been concluded that FOXL2 mutations resulting in BPES type I may be associated with accelerated differentiation of granulosa cells and secondary depletion of the primordial follicle pool [Pisarska et al 2004]. Resources GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED. AboutFace International 123 Street, Suite 1003 Toronto, Ontario M5G 1E2 Canada Phone: 800-665-FACE (800-665-3223) Email: info@... www.aboutfaceinternational.org Children's Craniofacial Association 13140 Coit Road, Suite 307 Dallas, TX 75240 Phone: 800-535-3643; 214-570-9099 Email: contactCCA@... www.ccakids.com FACES: The National Craniofacial Association PO Box 11082 Chattanooga, TN 37401 Phone: 800-332-2373; 423-266-1632 Email: faces@... www.faces-cranio.org Forward Face, Inc 317 East 34th Street, Room 901a New York, NY 10016 Phone: 800-393-3223; 212-684-5860 Fax: 212-684-5864 Email: linda@... www.ForwardFace.org Society for the Rehabilitation of the Facially Disfigured 550 First Avenue New York, NY 10016 Phone: 212-340-5400 Resources Printable Copy References Published Statements and Policies Regarding Genetic Testing No specific guidelines regarding genetic testing for this disorder have been developed. 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Am J Hum Genet 35:1020-7 [Medline] Author Information Elfride De Baere, MD, PhD Center for Medical Genetics Ghent University Hospital Ghent, Belgium Revision History 8 July 2004 (me) Review posted to live Web site 7 July 2004 (ca) BP copy edits 2 July 2004 (mr) Conversion to xml from wiki 2 March 2004 (me) Initial conversion 1 March 2004 (edb, db, lm) Original submission ContactGeneTests Copyright© 1993-2004, University of Washington, Seattle Terms of Use Funding Support National Library of Medicine, NIH National Human Genome Research Institute, NIH Sponsoring Institution University of Washington Seattle, Washington Quote Link to comment Share on other sites More sharing options...
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