S Nuovo1, M Passeri2, E Di Benedetto2, M Calanchini2, I Meldolesi3, M C Di Giacomo4, D Petruzzi5, M R Piemontese6, L Zelante6, F Sangiuolo1,7, G Novelli1,7, A Fabbri8, F Brancati9,10. 1. Unità di Genetica Medica, Policlinico Universitario Tor Vergata, 00133, Rome, Italy. 2. Unità di Endocrinologia, Dipartimento di Medicina dei Sistemi, Polo Ospedaliero Sant'Eugenio & CTO A. Alesini, Università Tor Vergata, 00145, Rome, Italy. 3. Ginecologia, Consultorio Giovani, ASL RM/H, 00045, Rome, Italy. 4. U.O.C Anatomia Patologica AOR Ospedale San Carlo, 85100, Potenza, Italy. 5. U.O. Ostetricia e Ginecologia AOR Ospedale San Carlo, 85100, Potenza, Italy. 6. Genetica Medica, Ospedale Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, Italy. 7. Dipartimento di Biomedicina e Prevenzione, Università Tor Vergata, 00133, Rome, Italy. 8. Unità di Endocrinologia, Dipartimento di Medicina dei Sistemi, Polo Ospedaliero Sant'Eugenio & CTO A. Alesini, Università Tor Vergata, 00145, Rome, Italy. andrea.fabbri@uniroma2.it. 9. Unità di Genetica Medica, Policlinico Universitario Tor Vergata, 00133, Rome, Italy. f.brancati@igenetica.com. 10. Dipartimento di Scienze Mediche, Orali e Biotecnologiche, Università D'Annunzio, 66013, Chieti, Italy. f.brancati@igenetica.com.
Abstract
OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Kamilla Schlade-Bartusiak; Lindsay Brown; Brenda Lomax; Hélène Bruyère; Tanya Gillan; Sara Hamilton; Barbara McGillivray; Patrice Eydoux Journal: Am J Med Genet A Date: 2012-08-06 Impact factor: 2.802
Authors: L Crisponi; M Deiana; A Loi; F Chiappe; M Uda; P Amati; L Bisceglia; L Zelante; R Nagaraja; S Porcu; M S Ristaldi; R Marzella; M Rocchi; M Nicolino; A Lienhardt-Roussie; A Nivelon; A Verloes; D Schlessinger; P Gasparini; D Bonneau; A Cao; G Pilia Journal: Nat Genet Date: 2001-02 Impact factor: 38.330
Authors: A Podfigurna-Stopa; A Czyzyk; M Grymowicz; R Smolarczyk; K Katulski; K Czajkowski; B Meczekalski Journal: J Endocrinol Invest Date: 2016-04-18 Impact factor: 4.256