Characterization of endocrine features and genotype–phenotypes correlations in blepharophimosis–ptosis–epicanthus inversus syndrome type 1
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Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype–phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT).
Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype–phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated.
All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype–phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche.
This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.
KeywordsBlepharophimosis–ptosis–epicanthus inversus syndrome FOXL2 Ovarian dysfunction Genotype–phenotype correlation Genetic counseling
Conflict of interest
The authors have no conflict of interest in relation to this work.
All the procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
- 2.Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, Bisceglia L, Zelante L, Nagaraja R, Porcu S, Ristaldi MS, Marzella R, Rocchi M, Nicolino M, Lienhardt-Roussie A, Nivelon A, Verloes A, Schlessinger D, Gasparini P, Bonneau D, Cao A, Pilia G (2001) The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 27:159–166PubMedCrossRefGoogle Scholar
- 6.De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, De Sutter P, Devriendt K, Dixon M, Fellous M, Fryns JP, Garza A, Jonsrud C, Koivisto PA, Krause A, Leroy BP, Meire F, Plomp A, Van Maldergem L, De Paepe A, Veitia R, Messiaen L (2003) FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet 72:478–487PubMedPubMedCentralCrossRefGoogle Scholar
- 10.Raile K, Stobbe H, Tröbs RB, Kiess W, Pfäffle R (2005) A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome. Eur J Endocrinol 153:353–358PubMedCrossRefGoogle Scholar
- 15.Todeschini AL, Dipietromaria A, L’Hôte D, Boucham FZ, Georges AB, Pandaranayaka PJE, Krishnaswamy S, Rivals I, Bazin C, Veitia RA (2011) Mutational probing of the forkhead domain of the transcription factor FOXL2 provides insights into the pathogenicity of naturally occurring mutations. Hum Mol Genet 20:3376–3385PubMedCrossRefGoogle Scholar
- 16.De Baere E, Dixon MJ, Small KW, Jabs EW, Leroy BP, Devriendt K, Gillerot Y, Mortier G, Meire F, Van Maldergem L, Courtens W, Hjalgrim H, Huang S, Liebaers I, Van Regemorter N, Touraine P, Praphanphoj V, Verloes A, Udar N, Yellore V, Chalukya M, Yelchits S, De Paepe A, Kuttenn F, Fellous M, Veitia R, Messiaen L (2001) Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype–phenotype correlation. Hum Mol Genet 10:1591–1600PubMedCrossRefGoogle Scholar
- 18.Beysen D, De Jaegere S, Amor D, Bouchard P, Christin-Maitre S, Fellous M, Touraine P, Grix AW, Hennekam R, Meire F, Oyen N, Wilson LC, Barel D, Clayton-Smith J, de Ravel T, Decock C, Delbeke P, Ensenauer R, Ebinger F, Gillessen-Kaesbach G, Hendriks Y, Kimonis V, Laframboise R, Laissue P, Leppig K, Leroy BP, Miller DT, Mowat D, Neumann L, Plomp A, Van Regemorter N, Wieczorek D, Veitia RA, De Paepe A, De Baere E (2008) Identification of 34 novel and 56 known FOXL2 mutations in patients with Blepharophimosis syndrome. Hum Mutat 29:E205–E219PubMedCrossRefGoogle Scholar
- 20.Moumné L, Dipietromaria A, Batista F, Kocer A, Fellous M, Pailhoux E, Veitia RA (2008) Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. Hum Mol Genet 17:1010–1019PubMedCrossRefGoogle Scholar
- 23.Schlade-Bartusiak K, Brown L, Lomax B, Bruyère H, Gillan T, Hamilton S, McGillivray B, Eydoux P (2012) BPES with atypical premature ovarian insufficiency, and evidence of mitotic recombination, in a woman with trisomy X and a translocation t(3;11)(q22.3;q14.1). Am J Med Genet A 158A:2322–2327PubMedCrossRefGoogle Scholar
- 24.Siewert AL, Stein Q, Flanagan J, Hansen KA (2008) Blepharophimosis-ptosis-epicanthus inversus syndrome and hypergonadotropic hypogonadism. Fertil Steril 90(2016):2006.e11–2006.e12Google Scholar