Key

Title

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Blepharophimosis, Ptosis, and Epicanthus Inversus

NCBI

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Blepharoplasty, ptosis surgery

emedicine

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Journal of Medical Genetics

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Human Molecular Genetics free archives with search facility

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“A fork in the road to fertility”

Nature Genetics—Vol 27—Feb 2001

Haploinsufficiency of FOXL2, a new forkhead transcription factor, causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), a rare developmental disorder affecting the eyelid and sometimes the ovary. A new study implicates FOXL2 as the first human gene required for the maintenance of ovarian follicles. The discovery of FOXL2 may provide insight into the causes of idiopathic premature ovarian failure, a disease that burdens many infertile couples.

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Congenital alacrima in a patient with blepharophimosis syndrome.    2009

Athappilly GK, Braverman RS.

The University of Colorado at Denven and Health Services Center, Rocky Mountain Lions Eye Institute, Denver, CO 80045, USA. geetha.athappily@UCHSC.edu

PURPOSE: To report a case of congenital alacrima in a patient with Blepharophimosis Syndrome (BPES). METHODS: Case report of a 9-month-old female who presented with severe dry eyes. Further investigation revealed bilateral absence of lacrimal glands confirmed by CT. This unique case and its management are discussed. RESULTS: Conservative management with artificial tears and ointment did not treat the ocular surface dryness. A combination of aggressive lubrication with surgical occlusion of the lower lid punctums was required to improve the corneal surface. CONCLUSION: BPES can be associated with many ophthalmic and facial abnormalities. Review of the pubmed literature, reveals this is the first reported case of alacrima and BPES. Patient with alacrima have severe ocular surface dryness, which requires aggressive and life long lubrication and tear supplementation.

PMID: 19172509 [PubMed - in process]

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Blepharophimosis: a recommendation for early surgery in patients with severe ptosis

Beckingsale PS, Sullivan TJ, Wong VA, Oley C.Eyelid, Lacrimal and Orbital Clinic, Royal Children's Hospital, Brisbane, Queensland, Australia.PURPOSE: To determine the optimal age for surgical correction of blepharophimosis. Associated features and their effects on incidence of amblyopia were also investigated. METHODS: The study was a retrospective case series of 28 patients with blepharophimosis, ptosis and epicanthus inversus syndrome presenting to a tertiary referral eyelid, lacrimal and orbital clinic. RESULTS: Amblyopia was present in 39% of patients. Patients with coexistent strabismus had a 64% incidence of amblyopia compared to 24% for those without strabismus. Hypermetropia was present in 43% of patients and 7% were myopic. Significant astigmatism was found in 40% of patients, but these factors did not increase the risk of amblyopia. Patients with severe ptosis had lower rates of amblyopia than those with moderate ptosis but had their ptosis corrected at a median age of 2 years compared to 5 years for those with moderate ptosis. There was an 18% incidence of nasolacrimal drainage problems. A good to excellent cosmetic outcome was achieved in 86% of patients. A positive family history was noted in 75% of patients, usually with paternal inheritance. CONCLUSIONS: Patients with blepharophimosis have a high rate of amblyopia. Co-existent strabismus doubles the risk of amblyopia. Ptosis alone causes mild to moderate amblyopia only. Patients with severe ptosis should have their ptosis corrected before 3 years of age, and all other patients should undergo surgery before 5 years of age.

PMID: 12648048 [PubMed - indexed for MEDLINE]

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FOXL2-mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES); challenges for genetic counseling in female patients.
Fokstuen S, Antonarakis SE, Blouin JL.
Am J Med Genet. 2003 Mar 1;117A(2):143-6.

Division of Medical Genetics, University of Geneva Medical School and University Hospitals, Geneva, Switzerland. siv.fokstuen@hcuge.ch
Mutations in the forkhead transcription factor gene 2 (FOXL2) were recently reported to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II. Evidence was provided that BPES type I (eyelid abnormalities and female infertility) is caused by mutations resulting in a truncated FOXL2 protein. In contrast, mutant FOXL2 proteins, either with inserted aminoacids in the forkhead domain or polyalanine tract, or with novel aminoacids at the carboxyl end, were found in BPES type II, in which fertility is generally normal. We report a 32-year-old female patient with sporadic BPES and a history of menstrual cycle irregularities and periods of secondary amenorrhoea. A heterozygous frameshift mutation (c959-960insG) was found in the FOXL2 gene, resulting in a predicted FOXL2 protein with 212 novel aminoacids in the carboxyl end, suggesting BPES type II despite menstrual irregularities. The clinical presentations of our patient and of three female patients with BPES type II in the report of De Baere et al. [2001: Hum Mol Genet 10:1591-1600.] indicate phenotypic overlap between BPES type I and II. These observations do not support a clear-cut prediction of female fertility based on the FOXL2 molecular defect. As a consequence, FOXL2 mutation testing in female patients of child-bearing age with BPES should be handled with caution, and a two-step genetic counseling approach, including an initial pre-test information session, is proposed. Copyright 2003 Wiley-Liss, Inc.
PMID: 12567411 [PubMed - indexed for MEDLINE]

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Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure.

Bodega B, Porta C, Crosignani PG, Ginelli E, Marozzi A.

Department of Biology and Genetics, Medical Faculty and First Department of Obstetrics and Gynaecology, University of Milan, Italy.
Mol Hum Reprod. 2004 Aug;10(8):555-7. Epub 2004 Jun 04
Premature ovarian failure (POF) is a heterogeneous disorder whose aetiology is still unknown. Recently, the autosomal FOXL2 gene, highly expressed in the adult ovary, has been correlated with the disorder. FOXL2 mutations, causing a truncation of the FOXL2 protein in the forkhead domain or in the poly-Ala tract lead to blepharophimosis-ptosis-epicanthus-inversus syndrome associated with POF (BPES I). Interestingly, in two out of 70 idiopathic POF patients, a 30 bp deletion (898-927del) and a missense mutation (1009T-->A) were identified. To further evaluate the correlation between POF and FOXL2 mutations, 120 phenotypically normal women affected by POF were analysed by direct sequencing of the FOXL2 coding region. The analysis did not reveal any mutation in the 240 analysed chromosomes, indicating that mutations in the FOXL2 coding region are rarely associated with non-syndromic POF.
PMID: 15181179 [PubMed - in process]

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blepharophimosisThe incidence of strabismus and refractive error in patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES).
Dawson EL, Hardy TG, Collin JR, Lee JP.
Strabismus. 2003 Sep;11(3):173-7.

Moorfields Eye Hospital, City Road, London EC1V 2PD, England, U.K.
A retrospective review was carried out of 204 patients with blepharophimosis, (blepharo) ptosis and epicanthus inversus syndrome (BPES). Of these, 94 (46%) had an autosomal dominant family history of BPES. Forty (20%) had manifest strabismus. Of these, 28 (70%) had esotropia, 10 (25%) had exotropia and 2 (5%) had hypertropia. Twelve (6%) patients had nystagmus. Seventy (34%) patients had a significant refractive error requiring spectacles. Twenty-one (30%) of these patients had anisometropic hypermetropia and 24 (34%) had anisometropic myopia. Forty-three patients had bilateral amblyopia and 40 had unilateral amblyopia, with 26 (65%) of these undergoing occlusion treatment. Of these, 14 had strabismus and refractive error, 7 refractive error only, 2 strabismus only and 3 neither refractive error nor strabismus. We conclude that there is a higher incidence of strabismus and refractive error in patients with BPES than in the normal population.
PMID: 14710475 [PubMed - indexed for MEDLINE]

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Etiology of ovarian failure in blepharophimosis ptosis epicanthus inversus syndrome: FOXL2 is a conserved

Endocrinology. 2003 Jul;144(7):3237-43.

Loffler KA, Zarkower D, Koopman P.
Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Blepharophimosis ptosis epicanthus inversus syndrome (BPES) is a human disorder caused by mutations in the forkhead transcription factor gene FOXL2 and is characterized by facial dysmorphology combined in some cases with ovarian failure. To better understand the role of FOXL2 in the etiology of ovarian failure in BPES, we examined its expression in embryonic ovaries of mice, chickens, and red-eared slider turtles, representatives of three phylogenetically distant vertebrate groups that have different mechanisms of sex determination. Expression of Foxl2 was detected in early ovaries of all three species around the time of sex determination and was associated with both somatic and germ cell populations in mice. Expression was sexually dimorphic in all cases. Sequence analysis of turtle and chicken FoxL2 orthologues indicated an unusually high degree of structural conservation during evolution. FoxL2 was found to be autosomal in chickens, and therefore unlikely to represent the dominant ovarian-determining gene that has been postulated to exist as a possible explanation for female heterogamety in birds. Our observations suggest that BPES may result from early abnormalities in regulating the development of the fetal ovary, rather than premature degeneration of the postnatal or adult ovary. Further, our results suggest that FOXL2 is a highly conserved early regulator of vertebrate ovarian development.
PMID: 12810580 [PubMed - indexed for MEDLINE]