Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder caused by genetic mutations. However, the genotype-phenotype correlation remains unclear. This study aimed to identify mutations in a Chinese family with BPES and elucidate the genotype-phenotype relationship. A comprehensive clinical and molecular genetic analysis was conducted on a three-generation Chinese family with BPES, which was prospectively enrolled at the Eye Hospital of Wenzhou Medical University. Affected individuals underwent systematic phenotyping, including detailed physical and ophthalmic evaluations. Genomic DNA was isolated from peripheral blood samples and subjected to whole-exome sequencing, followed by targeted Sanger sequencing for variant validation. Candidate disease-associated variants were analyzed using in silico predictive algorithms to assess their potential structural and functional impact on encoded proteins. To further elucidate the pathogenicity of the identified mutation, functional studies were performed, including immunofluorescence-based subcellular localization assays and quantitative real-time PCR to evaluate transcriptional regulatory effects. Six affected individuals of this pedigree presented with canonical BPES features including small palpebral fissures, ptosis, epicanthus inversus, and telecanthus, without premature ovarian failure, consistent with a diagnosis of BPES type II. Whole-exome sequencing revealed a heterozygous missense mutation (c.313 A > C:p.N105H) in FOXL2, which was subsequently validated by Sanger sequencing. This variant demonstrated complete cosegregation with the BPES phenotype across all affected family members. According to ACMG guidelines, the variant was classified as Likely Pathogenic (PS1 + PM1 + PM2 + PP3). In silico pathogenicity prediction tools classified the p.N105H variant as deleterious. Immunofluorescence assays revealed aberrant nuclear aggregation of the mutant FOXL2 protein, and functional characterization via quantitative real-time PCR demonstrated no significant dysregulation (P > 0.05) of downstream targets (STAR, OSR2). This study provides functional evidence of the pathogenic FOXL2 mutation (c.313 A > C, p.N105H) in BPES type II, demonstrating its disruptive effects on protein localization while maintaining normal transcriptional activity of downstream targets. These findings expand the mutational spectrum of FOXL2 related disorders and enhance our understanding of genotype-phenotype correlations in BPES. Blepharophimosis syndrome (BPES) is a relatively rare genetic condition that primarily affects eyelid formation and results in a distinctive facial appearance present at birth. This condition was first described by Komoto in 1921. The condition is characterized by the existence of a reduced horizontal opening of the eyelid (blepharophimosis), drooping of the upper eyelid (ptosis), increased distance between the inner corners of the eyes (telecanthus), and an upward fold of skin near the inner corner of the eye, where the medial eyelid skin fold appears more prominent in the lower eyelid, extending across the canthus and tapering into the upper eyelid (epicanthus inversus). These congenital features define the syndrome, hence the acronym BPES (see Image. Male Child with Blepharophimosis Syndrome). Blepharophimosis syndrome is an autosomal dominant disease affecting the eyelids and mid-face structures. These characteristics significantly impact the patient's vision and facial appearance. BPES can also be associated with additional systemic defects, specifically premature ovarian insufficiency in females, resulting in BPES type I. Most cases are caused by mutations in FOXL2 on chromosome 3q23. The structural defects observed in BPES are caused by the interruption of the development of the eyelid and related tissues during embryogenesis. The course of BPES is contingent upon the specific subtype and severity, resulting in varying outcomes. Some persons may encounter substantial visual impairment caused by ptosis, whereas others may be concerned with cosmetic issues. The condition has no propensity for dissemination but remains limited to the congenital structural defects. Nevertheless, if ptosis is not addressed, subsequent complications such as amblyopia may result, underscoring the importance of prompt detection and surgery. There are 2 main types of BPES. Each type harbors the 4 classic clinical signs—blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Type I is associated with premature ovarian insufficiency, whereas type II is characterized by the classic facial features alone. These features are associated with a high incidence of amblyopia if not correctly managed. Both types require surgical treatment early in life for normal vision development (see Image. Male Child After Surgery for Blepharophimosis Syndrome).

To investigate the molecular pathogenesis of a large group of Han Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), and to evaluate the correlation between the phenotype and genotype for these patients. Seventy-six affected individuals, including 45 patients from 17 pedigrees and 31 sporadic patients, were recruited with their family members. All participants underwent complete clinical examinations and were classified as having type I or II based on whether they had premature ovarian failure. The patients' genomic DNA was extracted. A genetic test was performed with direct sequencing of the coding regions of the forkhead transcriptional factor 2 (FOXL2) gene. Variations were analyzed using online databases and programs. Genotype-phenotype correction was investigated. Seventy-six affected and 75 unaffected individuals underwent clinical evaluations and genetic testing. Only one family was diagnosed with type I; the others could not be classified because of a lack of female patients or a definite history of premature ovarian failure. Twenty-seven variations were identified, including 12 novel and 15 previously reported variations. Six variations were detected repeatedly in different nonconsanguineous pedigrees. Four indel variations, located in the alanine/proline-rich region of the FOXL2 gene, presented with a relatively higher frequency. Two rare double variations were detected in two sporadic patients. FOXL2 gene variations were not detected in five sporadic patients. The phenotype varied among different families and patients, although they carried the same variations. We identified 12 novel variations in the FOXL2 gene that would expand the spectrum of the FOXL2 variation database. In addition, we found that the alanine/proline-rich region is a variation hotspot in the FOXL2 gene. The genotype-phenotype correlation is not easy to establish due to clinical and genetic heterogeneity.

To describe the experiences of three women with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) who desired to pursue planned oocyte cryopreservation. Case series. An academic institution and a private clinic. Three nulligravid women aged 23, 25, and 34 years who desired to pursue planned oocyte cryopreservation. Two women had BPES diagnosed when they were infants and one had BPES diagnosed after presenting to discuss oocyte cryopreservation. All three women underwent ovarian stimulation. One woman underwent three oocyte retrievals. Vitrification of metaphase II oocytes. One woman had a total of eight metaphase II oocytes vitrified. In addition, she underwent genetic testing that confirmed type 1 BPES. The other two women, who had BPES diagnosed when they were newborns, each underwent two cycles of ovarian stimulation. Neither of these two women responded to ovarian stimulation and both cycles were cancelled before oocyte retrieval. BPES is a rare condition that can lead to primary ovarian insufficiency. Early identification of this condition is important to allow for timely reproductive counseling so that oocyte cryopreservation can be offered at a young age before oocyte depletion. Careful counseling is critical for these patients, because this case series demonstrated that not all women with BPES will respond to stimulation. Further, outcomes with cryopreserved oocytes have not yet been described in women with BPES.

FOXL2 gene mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and may be associated with premature ovarian insufficiency (POI). Two types of BPES were described in the literature. BPES type 2 is a simple association of inherited developmental defects of the eyelid area, while in type 1 female patients additionally suffer from POI. The following case study is the first report of endocrine impairments typical for menopausal transition in young female with NG_012454.1:g.138665342G > A, c.223C > T p.(Leu75Phe), mutation in FOXL2 gene. This mutation has been reported in the literature before, however until now, it was never linked to BPES type 1. An 18-year-old nulliparous woman suspected of secondary amenorrhea was referred to our Endocrinology Outpatient Clinic. Blood tests revealed decreased levels of AMH (anti-Mullerian hormone) and increased levels of gonadotropins, suggesting menopausal transition. Her past medical history was remarkable for several ophthalmic defects that has required surgical interventions. BPES syndrome had not been suspected before, although the patient had reported a similar phenotype occurring in her father, sister and half-sister. Venous blood samples were collected from the female proband and from her three family members. Whole-exome sequencing and deep amplicon sequencing were performed. A potential pathogenic variant in the FOXL2 gene was revealed. Namely, the c.223C > T p.(Leu75Phe) missense variant was detected. The authors found mutations, c.223C > T p.(Leu75Phe) in the FOXL2 gene in a young woman with hormonal disorders suggesting menopausal transition. These results indicate that the possibility of different phenotypes should be considered in patients with a similar genetic mutation.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is due to heterozygous FOXL2 intragenic mutations in about 70% of the patients, whereas total or partial gene deletions account for a minority of cases. Alteration of FOXL2 regulatory elements has been rarely described in patients with BPES. In this study, a prepubertal girl with BPES due to a 197-kb de novo deletion of the regulatory elements upstream of FOXL2 is reported. This girl presented with additional clinical features such as a soft cleft palate and microcephaly; thus, this copy number variant might have other somatic effects. The present deletion encompasses 2 coding genes (MRPS22 and COPB2), whose homozygous mutations have been associated with microcephaly. In our case, the sequences of the non-deleted allele were normal, ruling out a compound genetic defect. Normal levels of new biomarkers of ovarian reserve (anti-müllerian hormone, inhibin B) likely indicate an early diagnosis of type 2 BPES, but an evolutive gonadal damage will be excluded only by long-term follow-up. Additional reports of microdeletions upstream of FOXL2 are needed to better define the underlying genetic mechanism and the related phenotypic spectrum; the ability of the new hormonal markers to predict ovarian function in adolescence and adulthood should be confirmed.