A novel insertion in the FOXL2 gene in a Chilean patient with blepharophimosis ptosis epicanthus inversus syndrome type I
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Alejandro Martinez-Aguayo
Abstract
Objective: A novel insertion in the forkhead transcription factor 2 (FOXL2) was identified in a Chilean patient with blepharophimosis, ptosis, and epicanthus inversus syndrome associated with premature ovarian failure (BPES type I). A clinical and molecular characterization of a patient with BPES type I was performed.
Method: We present a 16-year-old adolescent girl with surgically treated blepharophimosis, ptosis, and epicanthus inversus that was associated with delayed puberty and secondary amenorrhea at the age of 15, indicators that suggested that the patient had BPES type I. The FOXL2 gene was analyzed by sequencing its coding region.
Results: The sequence analysis of the FOXL2 gene revealed a novel heterozygous mutation: an 11 bp duplication (c.901_911dup11) that was predicted to encode a truncated protein (p.Pro305Argfs*54).
Conclusions: A novel out-of-frame duplication following the polyalanine domain in the FOXL2 gene was identified in a Chilean patient with BPES type I. This study characterized the molecular alterations in FOXL2 and confirmed the diagnosis, thereby providing information to allow for improved genetic counseling for the patient and her family.
We are grateful for the family and the volunteers who participated in this study. This work was supported by the Clinical Laboratory Department, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile.
Conflict of interest statement: The authors have no relevant conflict of interest to disclose.
References
1. Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, et al. Evolution and expression of FOXL2. J Med Genet 2002;39:916–21.10.1136/jmg.39.12.916Suche in Google Scholar PubMed PubMed Central
2. Hersmus R, Kalfa N, de Leeuw B, Stoop H, Oosterhuis JW, et al. FOXL2 and SOX9 as parameters of female and male gonadal differentiation in patients with various forms of disorders of sex development (DSD). J Pathol 2008;215:31–8.10.1002/path.2335Suche in Google Scholar PubMed
3. Bentsi-Barnes IK, Kuo FT, Barlow GM, Pisarska MD. Human forkhead L2 represses key genes in granulosa cell differentiation including aromatase, P450scc, and cyclin D2. Fertil Steril 2010;94:353–6.10.1016/j.fertnstert.2009.09.050Suche in Google Scholar PubMed PubMed Central
4. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet 2001;27:159–66.10.1038/84781Suche in Google Scholar PubMed
5. Ottolenghi C, Pelosi E, Tran J, Colombino M, Douglass E, et al. Loss of Wnt4 and Foxl2 leads to female-to-male sex reversal extending to germ cells. Hum Mol Genet 2007;16:2795–804.10.1093/hmg/ddm235Suche in Google Scholar PubMed
6. Jaubert F, Galmiche L, Lortat-Jacob S, Fournet JC, Fellous M. Foxl-2 in gonad development and pathology. Arkh Patol 2011;73:10–3.Suche in Google Scholar
7. Verdin H, De Baere E. FOXL2 impairment in human disease. Horm Res Paediatr 2012;77:2–11.10.1159/000335236Suche in Google Scholar PubMed
8. Goswami D, Conway GS. Premature ovarian failure. Horm Res 2007;68:196–202.10.1159/000102537Suche in Google Scholar PubMed
9. Harris SE, Chand AL, Winship IM, Gersak K, Aittomaki K, et al. Identification of novel mutations in FOXL2 associated with premature ovarian failure. Mol Hum Reprod 2002;8:729–33.10.1093/molehr/8.8.729Suche in Google Scholar PubMed
10. Bodega B, Porta C, Crosignani PG, Ginelli E, Marozzi A. Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. Mol Hum Reprod 2004;10:555–7.10.1093/molehr/gah078Suche in Google Scholar PubMed
11. Gijsbers AC, D’Haene B, Hilhorst-Hofstee Y, Mannens M, Albrecht B, et al. Identification of copy number variants associated with BPES-like phenotypes. Hum Genet 2008;124:489–98.10.1007/s00439-008-0574-9Suche in Google Scholar PubMed
12. Beysen D, De Jaegere S, Amor D, Bouchard P, Christin-Maitre S, et al. Identification of 34 novel and 56 known FOXL2 mutations in patients with Blepharophimosis syndrome. Hum Mutat 2008;29:E205–19.10.1002/humu.20819Suche in Google Scholar
13. den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 2000;15:7–12.10.1002/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-NSuche in Google Scholar
14. Moumne L, Dipietromaria A, Batista F, Kocer A, Fellous M, et al. Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. Hum Mol Genet 2008;17:1010–9.10.1093/hmg/ddm373Suche in Google Scholar
15. De Baere E, Beysen D, Oley C, Lorenz B, Cocquet J, et al. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation. Am J Hum Genet 2003;72:478–87.10.1086/346118Suche in Google Scholar
16. Fokstuen S, Antonarakis SE, Blouin JL. FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients. Am J Med Genet A 2003;117A:143–6.10.1002/ajmg.a.10024Suche in Google Scholar
17. D’Haene B, Nevado J, Pugeat M, Pierquin G, Lowry RB, et al. FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions. Hum Mutat 2010;31:E1332–47.10.1002/humu.21233Suche in Google Scholar
18. Meduri G, Bachelot A, Duflos C, Bstandig B, Poirot C, et al. FOXL2 mutations lead to different ovarian phenotypes in BPES patients: case report. Hum Reprod 2010;25: 235–43.10.1093/humrep/dep355Suche in Google Scholar
19. Bell R, Murday VA, Patton MA, Jeffery S. Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2. Genet Test 2001;5:335–8.10.1089/109065701753617499Suche in Google Scholar
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Artikel in diesem Heft
- Masthead
- Masthead
- Editorials
- Editorial
- Consensus, guidelines and reviews
- Review article
- Adaptation of glucose metabolism to fasting in young children with infectious diseases: a perspective
- Images in pediatric endocrinology
- Coexistence of testicular microlithiasis with parathyroid adenoma in an obese child
- Original articles
- Remission of hypertension and electrolyte abnormalities following renal transplantation in a patient with apparent mineralocorticoid excess well documented throughout childhood
- Effects of metformin in children and adolescents with Prader-Willi syndrome and early-onset morbid obesity: a pilot study
- Glycemic control in familial vs. sporadic type 1 diabetes patients over 5 years
- Clinical and laboratory features of temporary brittle bone disease
- Age of thelarche and menarche in contemporary US females: a cross-sectional analysis
- Teriparatide (rhPTH) treatment in children with syndromic hypoparathyroidism
- Retinol and retinyl palmitate in fetal mice liver: sexual dimorphism
- Skeletal maturation and predicted adult height in children with premature adrenarche
- Homozygosity for a DTDST mutation in a child with multiple epiphyseal dysplasia
- Body composition in young patients with galactose metabolic disorders: a preliminary report
- Detection of vascular risk markers in children and adolescents with type 1 diabetes
- X-linked recessive nephrogenic diabetes insipidus: a clinico-genetic study
- Factors influencing neonatal thyroid-stimulating hormone concentrations as a measure of population iodine status
- Pediatric idiopathic intracranial hypertension and the underlying endocrine-metabolic dysfunction: a pilot study
- Patient reports
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- A pediatric patient with Cushing syndrome caused by ectopic ACTH syndrome and concomitant pituitary incidentalomas
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- Permanent neonatal diabetes mellitus in monozygotic twins achieving low-dose sulfonylurea therapy
- Hypocalcemia in a paediatric case: from the clinical features to diagnosis
- A rare case of osteogenesis imperfecta combined with complete tooth loss
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- Multiple cutaneous hemangiomas in a patient with combined pituitary hormone deficiency
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- Zellweger syndrome: prenatal and postnatal growth failure with epiphyseal stippling
- Marine-Lenhart syndrome in a young girl
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