Journal of Endocrinological Investigation

, Volume 39, Issue 2, pp 227–233 | Cite as

Characterization of endocrine features and genotype–phenotypes correlations in blepharophimosis–ptosis–epicanthus inversus syndrome type 1

  • S. Nuovo
  • M. Passeri
  • E. Di Benedetto
  • M. Calanchini
  • I. Meldolesi
  • M. C. Di Giacomo
  • D. Petruzzi
  • M. R. Piemontese
  • L. Zelante
  • F. Sangiuolo
  • G. Novelli
  • A. Fabbri
  • F. BrancatiEmail author
Original Article



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.


Blepharophimosis–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.

Ethical approval

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

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.


  1. 1.
    Zlotogora J, Sagi M, Cohen T (1983) The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types. Am J Hum Genet 35:1020–1027PubMedPubMedCentralGoogle Scholar
  2. 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
  3. 3.
    Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA (2002) Evolution and expression of FOXL2. J Med Genet 39:916–921PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Cocquet J, De Baere E, Gareil M, Pannetier M, Xia X, Fellous M, Veitia RA (2003) Structure, evolution and expression of the FOXL2 transcription unit. Cytogenet Genome Res 101:206–211PubMedCrossRefGoogle Scholar
  5. 5.
    Ellsworth BS, Egashira N, Haller JL, Butts DL, Cocquet J, Clay CM, Osamura RY, Camper SA (2006) FOXL2 in the pituitary: molecular, genetic, and developmental analysis. Mol Endocrinol 20:2796–2805PubMedCrossRefGoogle Scholar
  6. 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
  7. 7.
    Fokstuen S, Antonarakis SE, Blouin JL (2003) FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. Am J Med Genet A 117A:143–146PubMedCrossRefGoogle Scholar
  8. 8.
    Udar N, Yellore V, Chalukya M, Yelchits S, Silva-Garcia R, Small K (2003) Comparative analysis of the FOXL2 gene and characterization of mutations in BPES patients. Hum Mutat 22:222–228PubMedCrossRefGoogle Scholar
  9. 9.
    Fraser IS, Shearman RP, Smith A, Russell P (1988) An association among blepharophimosis, resistant ovary syndrome, and true premature menopause. Fertil Steril 50:747–751PubMedGoogle Scholar
  10. 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
  11. 11.
    Méduri G, Bachelot A, Duflos C, Bständig B, Poirot C, Genestie C, Veitia R, De Baere E, Touraine P (2010) FOXL2 mutations lead to different ovarian phenotypes in BPES patients: case report. Hum Reprod 25:235–243PubMedCrossRefGoogle Scholar
  12. 12.
    Amati P, Gasparini P, Zlotogora J, Zelante L, Chomel JC, Kitzis A, Kaplan J, Bonneau D (1996) A gene for premature ovarian failure associated with eyelid malformation maps to chromosome 3q22-q23. Am J Hum Genet 58:1089–1092PubMedPubMedCentralGoogle Scholar
  13. 13.
    Beysen D, Moumné L, Veitia R, Peters H, Leroy BP, De Paepe A, De Baere E (2008) Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation. Hum Mol Genet 17:2030–2038PubMedCrossRefGoogle Scholar
  14. 14.
    Dipietromaria A, Benayoun BA, Todeschini AL, Rivals I, Bazin C, Veitia RA (2009) Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems. Hum Mol Genet 18:3324–3333PubMedCrossRefGoogle Scholar
  15. 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. 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
  17. 17.
    Nallathambi J, Moumné L, De Baere E, Beysen D, Usha K, Sundaresan P, Veitia RA (2007) A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction. Hum Genet 121:107–112PubMedCrossRefGoogle Scholar
  18. 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
  19. 19.
    Ni F, Wen Q, Wang B, Zhou S, Wang J, Mu Y, Ma X, Cao Y (2010) Mutation analysis of FOXL2 gene in Chinese patients with premature ovarian failure. Gynecol Endocrinol 26:246–249PubMedCrossRefGoogle Scholar
  20. 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
  21. 21.
    Lamba P, Fortin J, Tran S, Wang Y, Bernard DJ (2009) A novel role for the forkhead transcription factor FOXL2 in activin A-regulated follicle-stimulating hormone β subunit transcription. Mol Endocrinol 23:1001–1013PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Blount AL, Schmidt K, Justice NJ, Vale WW, Fischer WH, Bilezikjian LM (2009) FoxL2 and Smad3 coordinately regulate follistatin gene transcription. J Biol Chem 284:7631–7645PubMedPubMedCentralCrossRefGoogle Scholar
  23. 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. 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
  25. 25.
    Nelson LM (2009) Clinical practice. Primary ovarian insufficiency. N Engl J Med 360:606–614PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Verdin H, De Baere E (2012) FOXL2 impairment in human disease. Horm Res Paediatr 77:2–11PubMedCrossRefGoogle Scholar
  27. 27.
    Gersak K, Harris SE, Smale WJ, Shelling AN (2004) A novel 30 bp deletion in the FOXL2 gene in a phenotypically normal woman with primary amenorrhoea: case report. Hum Reprod 19:2767–2770PubMedCrossRefGoogle Scholar
  28. 28.
    Roth LW, Alvero R (2014) Pregnancy in a woman with premature ovarian insufficiency associated with blepharophimosis, ptosis, epicanthus inversus syndrome type I. A case report. J Reprod Med 59:87–89PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2015

Authors and Affiliations

  • S. Nuovo
    • 1
  • M. Passeri
    • 2
  • E. Di Benedetto
    • 2
  • M. Calanchini
    • 2
  • I. Meldolesi
    • 3
  • M. C. Di Giacomo
    • 4
  • D. Petruzzi
    • 5
  • M. R. Piemontese
    • 6
  • L. Zelante
    • 6
  • F. Sangiuolo
    • 1
    • 7
  • G. Novelli
    • 1
    • 7
  • A. Fabbri
    • 2
  • F. Brancati
    • 1
    • 8
    Email author
  1. 1.Unità di Genetica MedicaPoliclinico Universitario Tor VergataRomeItaly
  2. 2.Unità di Endocrinologia, Dipartimento di Medicina dei Sistemi, Polo Ospedaliero Sant’Eugenio & CTO A. AlesiniUniversità Tor VergataRomeItaly
  3. 3.Ginecologia, Consultorio GiovaniASL RM/HRomeItaly
  4. 4.U.O.C Anatomia Patologica AOR Ospedale San CarloPotenzaItaly
  5. 5.U.O. Ostetricia e Ginecologia AOR Ospedale San CarloPotenzaItaly
  6. 6.Genetica Medica, Ospedale Casa Sollievo della SofferenzaSan Giovanni RotondoItaly
  7. 7.Dipartimento di Biomedicina e PrevenzioneUniversità Tor VergataRomeItaly
  8. 8.Dipartimento di Scienze Mediche, Orali e BiotecnologicheUniversità D’AnnunzioChietiItaly

Personalised recommendations