The Genetic and Clinical Features of FOXL2-Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 (FOXL2) gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.

A rare association of blepharophimosis-ptosis-epicanthus inversus case with congenital nasolacrimal duct obstruction.

PURPOSE: The aim of reporting this case is to describe a rare combination of blepharophimosis-ptosis-epicanthus inversus syndrome with congenital nasolacrimal duct obstruction. A variety of lacrimal anomalies have been seen in blepharophimosis-ptosis-epicanthus inversus syndrome but the occurrence of nasolacrimal duct obstruction is rare. METHOD: The blepharophimosis-ptosis-epicanthus inversus syndrome is an autosomal dominant rare genetic defect with clinical manifestation of dysplasia of the eyelids, palpebral fissures, flat nasal bridge, and ptosis. A 20-month-old boy was referred with the complaints of watering and discharge from his right eyes since birth. On examination, the child had all the features of blepharophimosis-ptosis-epicanthus inversus syndrome with right congenital nasolacrimal duct obstruction in line with the published reports. RESULT: On endoscopic probing and irrigation, the probe could not be visualized into the inferior meatus. On dacryoendoscopy, the membranous part of the nasolacrimal duct was found to be completely obliterated with no light transmission into the nose indicating a malformed nasolacrimal duct. The child was managed by endoscopic dacryocystorhinostomy. We could find only one case report published so far on the combination of congenital nasolacrimal duct obstruction with blepharophimosis-ptosis-epicanthus inversus syndrome. This study adds one more case of blepharophimosis-ptosis-epicanthus inversus syndrome with congenital nasolacrimal duct obstruction and adjuvant use of dacryoendoscopy.

Hypopituitarism in Patients with Blepharophimosis and FOXL2 Mutations.

BACKGROUND: FOXL2 is the gene involved in blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). There have been few single case reports of growth hormone deficiency (GHD) with this syndrome, and Foxl2 is known to be involved in pituitary development in mice. Our aim was to analyze the prevalence of FOXL2 gene alteration in a series of patients with congenital hypopituitarism and eyelid anomalies. METHODS: FOXL2 was analyzed in 10 patients with hypopituitarism (ranging from isolated GHD to complete pituitary hormone deficiency) and eyelid anomalies (typical BPES in 4 patients and milder anomalies in 6 patients). In patients with an FOXL2 mutation, we ruled out other possible molecular explanations by analyzing a panel of 20 genes known to be associated with hypopituitarism, and a candidate gene approach was used for patients without an FOXL2mutation. RESULTS: Three patients had an FOXL2mutation. All 3 had typical BPES. Their pituitary phenotype varied from GHD to complete pituitary hormone deficiency and their pituitary morphology ranged from normal to an interrupted pituitary stalk. No mutations were found in genes previously associated with hypopituitarism. CONCLUSION: Our study shows that some patients with BPES have hypopituitarism with no molecular explanation other than FOXL2 mutation. This points toward an involvement of FOXL2 in human pituitary development.

A novel FOXL2 mutation in two infertile patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

BACKGROUND: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare, autosomal dominant disease. There are two clinical types of BPES: type I patients have eyelid abnormalities accompanied by infertility in affected females, while type II patients only display eyelid malformations. Previous studies have reported that the forkhead box L2 (FOXL2) gene mutations cause BPES. PURPOSE: To identify plausible FOXL2 mutation in a Chinese family with BPES and infertility METHODS: Mutational screening of FOXL2 was performed in the affected members and 223 controls. Functional characterization of the novel mutation identified was carried out in vitro by luciferase reporter assay and subcellular localization experiment. RESULTS: A novel heterozygous mutation c.188 T > A (p.I63N) in FOXL2 was identified in two BPES patients in this family. The mutation abolished the transcriptional repression of FOXL2 on the promoters of CYP19A1 and CCND2 genes, as shown by luciferase reporter assays. However, no dominant-negative effect was observed for the mutation, and it did not impact FOXL2 protein nuclear localization and distribution. CONCLUSIONS: The mutation c.188 T > A (p.I63N) in FOXL2 might be causative for BPES and infertility in this family and further amplified the spectrum of FOXL2 mutations.

Chronic Otitis Media Associated with Cholesteatoma in a Case of the Say-Barber-Biesecker-Young-Simpson Variant of Ohdo Syndrome.

BACKGROUND The Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome is characterized by congenital hypothyroidism, facial dysmorphism, postaxial polydactyly, and mental retardation. The SBBYS variant of Ohdo syndrome is extremely rare with only 19 cases previously reported in the literature. A case is presented of chronic otitis media associated with cholesteatoma in a six-year-old boy with the SBBYS variant of Ohdo syndrome. CASE REPORT A 6-year-old boy presented with perforation of the tympanic membrane and a cholesteatoma in the mesotympanic-attic region associated with chronic otitis media. The child had previously been diagnosed with the SBBYS variant of Ohdo syndrome. Following computed tomography (CT) and magnetic resonance imaging (MRI), tympanoplasty was performed with removal of the lesion. CONCLUSIONS This is the first case described in the literature of chronic otitis media associated with cholesteatoma in a patient with the SBBYS variant of Ohdo syndrome. This case demonstrates the importance of specialist otolaryngology referral for patient management.

Novel FOXL2 mutations cause blepharophimosis-ptosis-epicanthus inversus syndrome with premature ovarian insufficiency.

BACKGROUND: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a malformation of the eyelids. Forkhead Box L2 (FOXL2) is the only gene known to be associated with BPES. METHODS: We identified two Han Chinese BPES families with premature ovarian insufficiency (POI). Sanger sequencing and in vitro functional analysis were performed to identify the genetic cause. RESULTS: Sanger sequencing identified two novel mutations (c.462_468del, c.988_989insG) in FOXL2, one in each family. The in vitro functional analysis confirmed that both novel mutations were associated with impaired transactivation of downstream genes. Specifically, the single-base insertion, c.988_989insG, led to subcellular mislocalization and aggregation of the encoded protein, which validated the hypothesis that the two novel FOXL2 mutations are deleterious and associated with POI in the two BPES families. CONCLUSION: The novel mutations identified in the present study will enhance the present knowledge of the mutation spectrum of FOXL2. The in vitro experiments provide further insights into the molecular mechanism by which the two new variants mediate disease pathogenesis and may contribute to elucidating the genotype-phenotype correlation between the two novel FOXL2 mutations and POI.

Interstitial deletion 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with clubfoot, blepharophimosis, arthrogryposis, and multiple congenital abnormalities.

Interstitial deletions of the short and long arms of chromosome 5 are rare cytogenetic abnormalities. The 5p distal deletion is a genetic disorder characterized by a high-pitched cat-like cry, microcephaly, epicanthal folds, micrognathia, severe intellectual disability and motor delays. Previously, more than 46 patients with the 5q deletion have been reported. Here, we report de novo interstitial deletions involving 5p14.1-p15.2 and 5q14.3-q23.2 in a patient with multiple congenital abnormalities, including blepharophimosis, arthrogryposis, short neck, round face, pelvic kidney, agenesis of the corpus callosum, and clubfoot. The deletions were characterized using GTG banding and aCGH microarray analysis. Concurrent 5p and 5q interstitial deletions in humans have not been previously reported. We also discussed the relationship between the 5q deleted region and clubfeet.

Autism spectrum disorder in Say-Barber-Biesecker-Young-Simpson syndrome.

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), also known as Ohdo syndrome SBBYS type, is a rare genetic disorder characterised by dysmorphic facial features and severe intellectual disability, as well as cardiac, dental and hearing abnormalities. There has been little psychiatric or psychological description of children with SBBYSS, although previous reports noted repetitive self-injurious behaviours, sensitivity to light and noise and severe deficits in communication. In this report, a 4-year-old male with SBBYSS is described with a focus on psychiatric and psychological assessment, including formal testing for autism spectrum disorder (ASD). Results of multiple behavioural assessment scales are reported. Testing revealed characteristic ASD features, and the patient met criteria for ASD diagnosis in the context of SBBYSS. His behaviours improved with Applied Behavioural Analysis therapy and communication skills training. This is the first documented case of ASD reported alongside SBBYSS. These results suggest ASD may be a clinical feature of SBBYSS.

[Clinical diagnose and significance of congenital sensorineural hearing loss combined with BPES].

To analyze congenital sensorineural hearing loss combined with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). For the case of cochlear implantation to child with congenital sensorineural deafness combined BPES, accomplish routine examination and assessment, combining with literature to analyze the clinical diagnosis of this disease and its significance. Sensorineural hearing loss is a common congenital diseases with neonatal incidence of 1 per thousand - 3 per thousand, 50%-70% of deafness is associated with genetic factors, the incidence of congenital sensorineural hearing loss combined with eye disease is about 40%-60%, mainly reflected in ametropia and retinopathy. BPES's main clinical manifestations is blepharophimosis, ptosis, epicanthus inversus, and telecanthus. BPES is a rare autosomal dominant disease caused by FOXL 2 gene mutation, sometimes associated with retarded growth, delayed development, congenital heart disease, and microcephaly. Suffering from both sensorineural hearing loss and BPES is rare in reported literature. This case is diagnosed by clinical examination, without visual impairment. Facial nerve dysplasia has been found during the surgery. For congenital deafness patients with eye disease or other diseases, timely and correct diagnosis has important clinical significance, which can improve the diagnostic rate and make it coming true to early intervention, and then, effectively improve the quality of the patients. There are few literature reports, of patients with two kinds of genetic diseases. Our inference is that the cases are rare or the patients has visited different departments and ignored the other systems' signs. Therefore, in such doubtful cases, we should do the professional comprehensive examination in daily clinical work in order to avoid missed diagnosis or delayed treatment and intervention. By analyzing this case, the patient may also suffer from facial nerve dysplasia. Preoperatively viewing CT scan and operatively facial nerve monitor being used can avoid the occurrence of surgical complications.

Co-occurrence of congenital hydronephrosis and FOXL2-associated blepharophimosis, ptosis, epicanthus inversus syndrome (BPES).

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is an autosomal dominantly inherited congenital malformation of the eyelids. Diagnostic criteria include blepharophimosis, ptosis, epicanthus inversus and telecanthus. Type І BPES has additional features of premature ovarian failure and female infertility, while type ІІ occurs isolated. We report a two-year old male child with typical features of BPES and bilateral congenital hydronephrosis. The child, first-born to non-consanguineous parents, presented to us with hypertension. Congenital hydronephrosis and reduced renal function were confirmed by renal dynamic scan. Pyeloplasty and stent placement were performed with subsequent resolution of hypertension. On follow up, growth and development are appropriate for age. His father has similar but less severe features of BPES. Sequencing of the FOXL2 gene revealed a heterozygous FOXL2 mutation c.672_701dup, which is a recurrent 30-bp duplication leading to expansion of the polyalanine tract (p.Ala225_Ala234dup), in both father and son. Additional atypical clinical features have been reported previously in BPES patients with this mutation. However, this is the first report of a renal congenital anomaly in a BPES patient with this or other mutations. Although a pleiotropic effect of the FOXL2 mutation cannot be excluded, the co-occurrence of congenital hydronephrosis and BPES may represent two different entities.

Pregnancy in a woman with premature ovarian insufficiency associated with blepharophimosis, ptosis, epicanthus inversus syndrome type I. A case report.

BACKGROUND: Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) type I is a rare disorder that causes a recognizable pattern of eye abnormalities and is associated with premature ovarian insufficiency. There is no data to guide the treatment of these patients when presenting with infertility. CASE: A 30-year-old, nulligravid woman with premature ovarian insufficiency associated with BPES type I presented to care secondary to a desire to conceive. Ovarian stimulation with gonadotropins was performed, and the patient conceived and delivered viable twins. CONCLUSION: It is not known whether premature ovarian insufficiency associated with BPES type I follows the same clinical course as idiopathic premature ovarian insufficiency. In patients with BPES type I who present with infertility, ovarian stimulation with gonadotropins may be a reasonable therapeutic option.

Clinical, radiologic, and genetic features in blepharophimosis, ptosis, and epicanthus inversus syndrome in the Indian population.

PURPOSE: To study the clinical, radiologic, and genetic features in Indian Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) patients. METHODS: A total of 33 clinically well characterized BPES cases who presented between 2009 to 2011 were recruited. Clinical evaluation consisted of ophthalmic and orthoptic examination. For orbital indices, computed tomography (CT) scan of orbits was performed. Genetic studies included cytogenetic analysis and molecular analysis of FOXL2 gene. RESULTS: Significant clinical findings included a high incidence of refractive error in 94%, amblyopia in 60%, and strabismus in 40% of BPES cases. Orbital radiologic indices on CT scan in BPES were found to be comparable to the control group. On karyotyping, 8 out of 33 (24%) cases harbored chromosomal abnormalities. These abnormalities included 46,XY;del(3qter), 46,XY;del(3q26.3), 46,XX;del(3q24-25), and 46,XY;del(3q26qter). On molecular analysis, a novel mutation consisting of heterozygous substitution at c1635 that replaced cytosine by thymidine was detected. CONCLUSIONS: To the best of our knowledge, this is the first study on clinical features in BPES patients of Indian origin. A high incidence of refractive error, strabismus, and amblyopia was found in BPES cases. Orbital imaging confirmed that clinical features are limited to soft tissue abnormalities, with no underlying bony changes. Cytogenetic studies showed that most chromosomal abnormalities in the Indian population are in the region of the long arm of chromosome 3. Results of molecular analysis indicate that there may be loci other than the FOXL2 gene, which are affected in BPES cases. Our study expands the existing mutation spectrum of FOXL2 gene.

The difficult nosology of blepharophimosis-mental retardation syndromes: report on two siblings.

Blepharophimosis-mental retardation syndromes (BMRS) include a group of clinically and etiologically heterogeneous conditions, which can occur as isolated features or as part of distinct disorders displaying multiple congenital anomalies. We report on two siblings, a 6-year-old girl and an 18-month-old male, presenting with overlapping clinical findings. Major characteristics included facial dysmorphisms with upward slanted palpebral fissures, blepharophimosis, telecanthus, hypertelorism, posteriorly rotated and abnormal ears, and micrognathia. Ectodermal abnormalities consisted of fine hair, sparse eyebrows, and thin skin. Both patients had feeding difficulties with gastro-esophageal reflux and growth retardation. Psychomotor skills were severely delayed with no verbal capacity. The male sib also displayed low growth hormone (GH) levels, while the older sister had low cholesterol and mildly elevated TSH levels. Numerous metabolic/genetic investigations, including cholesterol precursors, dosage, and high-resolution array-CGH, were negative. BMR syndromes, including Dubowitz syndrome, Marden-Walker syndrome, Ohdo/Ohdo-like syndromes, and the cholesterol storage disorders were considered. We concluded that these two patients are affected by a possible autosomal recessive condition within the heterogeneous clinical spectrum of BMRS, fitting with the Young-Simpson syndrome subtype.

De novo interstitial deletion of 3q22.3-q25.2 encompassing FOXL2, ATR, ZIC1, and ZIC4 in a patient with blepharophimosis/ptosis/epicanthus inversus syndrome, Dandy-Walker malformation, and global developmental delay.

We report a case carrying a de novo interstitial deletion of chromosome 3q22-q25. The clinical phenotype of this case included blepharophimosis/ptosis/epicanthus inversus syndrome, Dandy-Walker malformation, and global developmental delay. Contiguous heterozygous deletion of FOXL2, ATR, ZIC1, and ZIC4 was postulated as the causative mechanism of the clinical phenotype. The association of blepharophimosis, ptosis, and epicanthus inversus syndrome with developmental delay or mental retardation may be an indication for the use of brain imaging and chromosomal analysis capable of detecting chromosomal rearrangements encompassing several candidate genes.

Novel findings in the Marden-Walker syndrome.

Reports about the Marden-Walker syndrome mainly consist of sporadic cases. We describe a 14-year-old girl with the Marden-Walker syndrome who presented with a huge scalp hematoma. The case and the corresponding images demonstrate an association with a defective hemostasis, skin hyperlaxity, and impaired wound healing.

Blepharophimosis mental retardation syndrome Say-Barber/Biesecker/Young-Simpson type - new findings with neuroimaging.

We report on a female patient with blepharophimosis mental retardation syndrome of Say/Barber/Biesecker/Young-Simpson (SBBYS) type. Main findings in her were marked developmental delay, blepharophimosis, ptosis, cleft palate, external auditory canal stenosis, small and malformed teeth, hypothyroidism, hearing impairment, and joint limitations. We performed diffusion tensor magnetic resonance imaging (MRI) and tractography of the brain which showed inappropriate myelination and disturbed white matter integrity. Cytogenetic analysis, subtelomeric fluorescence in situ hybridization and comparative genomic hybridization failed to identify an abnormality. It remains uncertain whether the MRI findings are specific to the present patient or form part of the SBBYS syndrome.

A clinical dilemma: the potential use of egg freezing to preserve fertility in a young patient at risk of developing premature ovarian failure.

Following diagnosis of premature ovarian failure (POF), few women become pregnant spontaneously and the only fertility treatment that can be offered is oocyte donation. With advances in fertility technology, timely preservation of female fertility in the form of egg freezing is a topical area, and one of which patients are increasingly aware. Women with a family history of POF may be especially concerned about future fertility. We describe a case where a consultation was sought in the POF clinic for this issue.