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The phenotypes associated with MED12 pathogenic variants are diverse. Male patients usually have missense variants, but the effects of base substitutions on mRNA splicing have not been investigated. Here, we report a Japanese brother with intellectual disability, characteristic facial appearance with blepharophimosis, cleft palate, Fallot tetralogy, vesicoureteral reflux, and deafness. A known missense pathogenic variant was detected in MED12, NM_005120.3:c.887G>A p.(Arg296Gln), and X-linked Ohdo syndrome was diagnosed in combination with their phenotype. mRNA splicing of MED12 was evaluated qualitatively and quantitatively using long-range PCR-based targeted RNA sequencing (reverse transcribed long amplicon sequencing), and it was shown that this missense variant simultaneously causes aberrant splicing of the 42-bp in-frame deletion in exon 7, r.847_888del, which accounts for approximately 30% of the mRNAs in both siblings. The X chromosome inactivation study showed that the X chromosome carrying the mutant allele was 100% inactivated in the carrier mothers. mRNA level analysis is essential for the accurate interpretation of the effects of variants. In this case, the MED12 protein function may be reduced by more than just an amino acid substitution, resulting in the patients with the most severe phenotype of MED12-related syndrome in males., (© 2024 Wiley Periodicals LLC.)

Nablus mask-like facial syndrome (NMLFS) is a rare condition characterized by unique facial features, initially described in a 4-year-old boy from Nablus, Palestine. These features include expressionless facial appearance, tight facial skin, blepharophimosis, sparse eyebrows, and a flat nose. Genetic studies have identified a deletion of 8q22.1 as the cause of the syndrome, however while 26 patients have been reported with the deletion, only 13 displayed the characteristic facial features. Here we report on a 35-year-old male with 8q21.3-q22.1 deletion identified by whole exome sequencing and Chromosomal microarray analysis (CMA) that presents with typical and atypical features, including neurodevelopmental disorder, mild facial features, and myopathy, which has not been described in a patient with NMLFS to date. Further research will be required to understand the underlying pathogenetic mechanism of this rare genetic disorder., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

CDK9 has been considered a candidate gene involved in the CHARGE-like syndrome in a pair of cousins. We report an 8-year-old boy with a strikingly similar phenotype including facial asymmetry, microtia with preauricular tags and bilateral hearing loss, cleft lip and palate, cardiac dysrhythmia, and undescended testes. Joint contracture, no finger flexion creases, and large halluces were the same as those of a previously reported patient with homozygous CDK9 variants. The ocular phenotype included blepharophimosis, lacrimal duct obstruction, eyelid dermoids, Duane syndrome-like abduction deficit, and congenital cataracts. Optical coherence tomography and electroretinography evaluations revealed severe retinal dystrophy had developed at an early age. Trio-based whole-exome sequencing identified compound heterozygous variants in CDK9 [p.(A288T) of maternal origin and p.(R303C) of paternal origin] in the patient. Variants' kinase activities were reduced compared with wild type. We concluded that CDK9 biallelic variants cause a CHARGE-like malformation syndrome with retinal dystrophy as a distinguishing feature., (© 2021. The Author(s).)

X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in MED12 gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G > A substitution in exon 7 of the MED12 gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of MED12 -related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations.

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

Blepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder., (© 2020 Wiley Periodicals LLC.)

Background/aims: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease caused by FOXL2 gene mutations, and it is clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). Functional study of novel mutations is especially critical for female patients, as it may allow the prediction of infertility and early planning of an appropriate therapy., Methods: A clinical and molecular genetic investigation was performed in all members of a Chinese family with BPES. Genomic DNA was extracted, and the FOXL2 coding region was sequenced. Subcellular localization was performed by confocal microscopy. Transactivation studies were performed by real-time PCR, dual luciferase reporter assays and electrophoretic mobility shift assays., Results: A novel deletion mutation (C.634_641 del, CCCATGC) between the forkhead domain and the polyalanine domain was found, resulting in a frameshift mutation and a truncated protein. Functional studies showed a strong cytoplasmic mislocalization and abnormal transactivation activity, implying a type I kind mutation with a large chance of infertility., Conclusion: This study identifies that this mutation indicates the probability of developing into POF and shows the importance and necessity of early recognition of BPES type through mutation testing for female patients. Prompt personalized therapy and follow-up is of great clinical significance for female patients carrying this kind of mutation., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background: Blepharophimosis syndrome (BPES) is characterized by eyelid malformation with occasional premature ovarian failure. Mutations in FOXL2 underlie a fraction of BPES cases., Objective: We aimed to investigate the genetic basis of BPES in 26 Chinese families that included 78 patients., Methods: We performed ophthalmological examinations on each family member. We used Sanger sequencing to screen FOXL2 exons and their flanking sequences. We also performed bioinformatics studies, structural modeling and pathogenicity evaluations on all identified variations. Literature was reviewed and genotype-phenotype correlation analysis was performed., Results: The patients had typical manifestations of BPES. Ten mutations were identified in ten of the twenty-six families. Among these, seven were novel mutations. These included the six truncating mutations, p.Glu69*, p.Gly256Glyfs*14, p.Ala14Serfs*135, p.Pro333Profs*200, p.Pro290Leufs*70, and p.Pro157Profs*91, and one missense mutation, p.Tyr59Cys. The mutations were scattered within the gene, and no mutational hotspots were found. Genotype-phenotype correlation analysis showed that frameshift or nonsense mutations were correlated with type I BPES, while in-frame or missense mutations were associated with type II BPES., Conclusion: We report the largest BPES cohort in China thus far as well as seven novel mutations in FOXL2. The identification of novel mutations has not only expanded the mutational spectrum of the gene (which is valuable for mutation detection-based screening) but also suggests that most mutations within the Chinese population may not have been characterized yet., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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., (© 2017 Wiley Periodicals, Inc.)

Mutations in KAT6B gene are responsible for Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GPS), with most mutations occurring in exon 18. A 4-year-old Chinese boy presented with short stature but no other clinical features of SBBYSS or GPS had a de novo novel nonsense pathogenic mutation in exon 14 of the KAT6B gene at position c.2636T>A (p.Leu879X). The correlation analysis of genotype-phenotype indicated distinctive clinical features (short stature, growth hormone deficiency, and delayed bone age) compared with the classical mutations of KAT6B gene. To the best of our knowledge, this is the first report of KAT6B gene mutation in any Chinese individual. This work expands the mutant phenotypic spectrum of the KAT6B gene.

In a 46 XY individual, the presence of the Y chromosome harboring the testis-determining factor (SRY) triggers testis determination and differentiation. In a 46 XX individual, the absence of SRY and the activation of genes associated with the female pathway lead to ovarian development. The latter process has long been considered as a default pathway. However, recent studies have cast doubts on this dogma. Here, after a brief overview of the main steps of ovarian development, we focus on three genes WNT4, RSPO1 and FOXL2 that are essential for ovarian determination, differentiation and/or maintenance. Special attention is paid to FOXL2 whose mutations are responsible for the blepharophimosis syndrome, often associated with female infertility, and for cancer. We highlight the cooperation of WNT4, RSPO1 and FOXL2 within a regulatory network and the need for further research to better understand their role in defining and maintaining ovarian identity., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GTPTS) are clinically similar disorders with some overlapping features. Although they are currently considered to be distinct clinical entities, both were found to be caused by de novo truncating sequence variants in the KAT6B (lysine acetyltransferase 6B) gene, strongly suggesting that they are allelic disorders. Herein, we report the clinical and genetic findings in a girl presenting with a serious multiple congenital anomaly syndrome with phenotypic features overlapping both SBBYSS and GTPTS; pointing out that the clinical distinction between these disorders is not exact and there do exist patients, in whom conventional clinical classification is problematic. Genetic analyses revealed a truncating c.4592delA (p.Asn1531Thrfs*18) variant in the last KAT6B exon. Our findings support that phenotypes associated with typical KAT6B disease-causing variants should be referred to as 'KAT6B spectrum disorders' or 'KAT6B related disorders', rather than their current SBBYSS and GTPTS classification., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. We performed various experiments, e.g. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions.

Intellectual disability (ID) is estimated to affect 1-3% of the general population and is a common reason for referrals to pediatric and adult geneticists, as well as neurologists. There are many genetic and non-genetic causes of ID; X-linked forms are identifiable through their characteristic inheritance pattern. Current testing methods have been able to identify over 100 genes on the X chromosome responsible for X-linked intellectual disability (XLID) syndromes. MED12 [MIM *300188] (mediator complex subunit 12) mutations have been linked to numerous XLID syndromes, including Lujan, FG, and Ohdo, and MED12 is included in many XLID panels. MED12 is located at Xq13.1 and its product has roles in transcriptional activation and repression. We describe two affected male siblings and their unaffected mother with a novel missense mutation in MED12, c.4147G>A (p.Ala1383Thr). The siblings share some features of Ohdo syndrome, including feeding difficulties, microcephaly, and speech delay. However, additional attributes such as hypertonia, eosinophilic esophagitis, penile chordee, and particular facial dysmorphisms depart sufficiently from individuals previously described such that they appear to represent a new and expanded phenotype. This case lends credence to the evolving theory that the subtypes of Ohdo, and perhaps other MED12 disorders, reflect a spectrum of characteristics, rather than distinct syndromes. As XLID panel testing and whole exome sequencing (WES) becomes a standard of care for affected males, further MED12 mutations will broaden the phenotype of these intriguing disorders and challenge clinicians to rethink the current diagnostic boundaries., (© 2015 Wiley Periodicals, Inc.)

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Background: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease. Mutations in the forkhead box L2 (FOXL2) gene cause two types of BPES distinguished by the presence (type I) and absence (type II) of premature ovarian failure (POF). The purpose of this study was to identify possible mutations in FOXL2 in two Chinese families with BPES., Methods: Two large autosomal dominant Chinese BPES families were enrolled in this study. Genomic DNA was obtained from the leukocytes in peripheral venous blood. Four overlapping sets of primers were used to amplify the entire coding region and nearby intron sequences of the FOXL2 gene for mutations detection using polymerase chain reaction (PCR) and sequencing analyses. The sequencing results were analyzed using DNAstar software., Results: All patients of the two families demonstrated typical features of BPES type II, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus without female infertility (POF). A novel FOXL2 heterozygous indel mutation c.675_690delinsT, including a 16-bp deletion and a 1-bp(T) insertion (p.Ala226_Ala230del), which would result in deletion of 5 alanine residues of a poly-alanine (poly-Ala) tract in the protein, was identified in all affected members of family A. A novel heterozygous missense mutation (c.223C > T, p.Leu75Phe) was identified in family B., Conclusions: Two novel FOXL2 mutations were identified in Chinese families with BPES. Our results expand the spectrum of FOXL2 mutations and provide additional structure-function insights into the FOXL2 protein.

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by small palpebral fissures and other craniofacial malformations, often with (type I) but could also without (type II) premature ovarian failure. While mutations of the forkhead transcription factor FOXL2 are associated with and likely be responsible for many BPES cases, how FOXL2 affects craniofacial development remain to be understood. Through a large-scale piggyBac (PB) insertion mutagenesis, we have identified a mouse mutant carrying a PB insertion ∼160 kb upstream of the transcription start site (TSS) of Foxl2. The insertion reduces, but not eliminates, the expression of Foxl2. This mutant, but not its revertant, displays BPES-like conditions such as midface hypoplasia, eyelid abnormalities and female subfertility. Further analysis indicates that the mutation does not affect mandible, but causes premature fusion of the premaxilla-maxilla suture, smaller premaxilla and malformed maxilla during midface development. We further identified an evolutionarily conserved fragment near the insertion site and observed enhancer activity of this element in tissue culture cells. Analyses using DNase I hypersensitivity assay and chromosome conformation capture assay in developing maxillary and periocular tissues suggest that the DNA region near the insertion site likely interacts with Foxl2 TSS. Therefore, this mutant presents an excellent animal model for mechanistic study of BPES and regulation of Foxl2., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Blepharophimosis-ptosis-epicanthus inversus syndrome is an autosomal dominant condition because of mutations or deletions of the FOXL2 gene. Microcephaly is not associated with FOXL2 mutations but has been reported in individuals with chromosome 3q deletions, which include the FOXL2 gene and other contiguous genes. The ATR gene has been reported as a candidate gene for microcephaly in individuals with contiguous deletion of chromosome 3q involving the FOXL2 gene., Patient: We describe a girl with blepharophimosis-ptosis-epicanthus inversus syndrome along with acquired microcephaly and intellectual disability., Results: Our patient had a deletion of chromosome 3q22.2q23, which does not include the ATR gene but does include the PIK3CB gene as a candidate gene for microcephaly., Conclusion: We propose that the PIK3CB gene included in our patient's chromosome 3q deletion may be the gene responsible for microcephaly and other patients with blepharophimosis-ptosis-epicanthus inversus syndrome because of a chromosome 3q deletion., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) have both recently been shown to be caused by distinct mutations in the histone acetyltransferase KAT6B (a.k.a. MYST4/MORF). All variants are de novo dominant mutations that lead to protein truncation. Mutations leading to GPS occur in the proximal portion of the last exon and lead to the expression of a protein without a C-terminal domain. Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense-mediated decay, or more distally in the last exon. Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis, and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities. Several features occur in both, such as intellectual disability, congenital heart defects, and genital and patellar anomalies. We propose that haploinsufficiency or loss of a function mediated by the C-terminal domain causes the common features, whereas gain-of-function activities would explain the features unique to GPS. Further molecular studies and the compilation of mutations in a database for genotype-phenotype correlations (www.LOVD.nl/KAT6B) might help tease out answers to these questions and understand the developmental programs dysregulated by the different truncations., (© 2012 Wiley Periodicals, Inc.)

We identified a novel 6.33 Mb deletion of 1q21.3q23.3 (hg18; chr1: 153035245-159367106) in two siblings presenting with blepharophimosis, ptosis, microbrachycephaly, severe psychomotor, and intellectual disability. Additional common features include small corpus callosum, normal birth length and head circumference, postnatal growth restriction, low anterior hairline, upturned nose, bilateral preauricular pits, widely spaced teeth, gingival hypertrophy, left ventricular dilatation with decreased biventricular systolic function, delayed bone age, 5th finger clinodactyly, short 3rd digit, hyperconvex nails, obstructive and central sleep apnea, and bilateral heel contractures. Fluorescence in situ hybridization (FISH) performed in the mother of both children showed an apparently balanced, intrachromosomal insertional translocation of 1q21.3q23.3 to 1q42.12. The sibling recurrence likely arose by a maternal meiotic crossing over on the rearranged chromosome 1 between the deleted region and the insertion. We hypothesize that the decreased cardiac function and contractures may be related to LMNA haploinsufficiency. This case illustrates the importance of FISH when attempting to determine inheritance of a copy-number variation and emphasize the value of evaluating known haploinsufficiency phenotypes for genes in deleted regions., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a developmental disease characterized by a complex eyelid malformation associated or not with premature ovarian failure (POF). BPES is essentially an autosomal dominant disease, due to mutations in the forkhead box L2 (FOXL2) gene, encoding a forkhead transcription factor. More than one hundred unique FOXL2 mutations have been described in BPES in different populations, many of which are missense mutations in the forkhead domain. Here, we report on a very severe form of BPES resulting from a missense mutation outside the forkhead domain., Methods: A clinical and molecular genetic investigation was performed in affected and unaffected members of an Iranian family with BPES. The FOXL2 coding region was sequenced in an index case. Targeted mutation testing was performed in 8 family members., Results: We have identified a heterozygous FOXL2 missense mutation c.650C→G (p.Ser217Cys) co-segregating with disease in members of a three-generation family with BPES type II. Only few missense mutations have been reported outside the forkhead domain so far. They were all found in mild BPES, in line with in vitro studies demonstrating mostly normal localization and normal or increased transactivation properties of the mutant proteins. Unlike previous studies, affected members of the family studied here showed a severe BPES phenotype, with bilateral amblyopia due to uncorrected ptosis., Conclusions: This is the first study demonstrating a severe BPES phenotype resulting from a FOXL2 missense mutation outside the forkhead domain, expanding our knowledge about the phenotypic consequences of missense mutations outside the forkhead domain in BPES.

Purpose: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant complex eyelid malformation. The authors aim to offer an explanation for the lower eyelid malformation and propose a novel surgical approach to correct it., Methods: An observational and interventional case series of 10 consecutive, molecularly proven BPES patients who underwent surgical repair of the lower eyelid malformation. During surgery detailed anatomical examination and surgical repositioning of the medial canthal tendon was performed. All the patients were followed up regularly after the surgery and assessed for epiphora., Results: All patients exhibited a marked asymmetry in the attachment of the lower and upper eyelid to the medial canthal tendon, with the lower eyelid being much less attached. This resulted in an abnormal downward concavity with a temporal ectropion and a temporally displaced lower eyelid. Consequently, the inferior punctum was displaced temporally. All patients underwent a novel surgical technique to remediate this, namely, inserting a 4.0 nylon suture between the tarsal plate of the lower eyelid and the medial canthal tendon during telecanthus surgery. This simple additional surgical step corrected not only the position of the lower eyelid but also its abnormal downward concavity, the temporal ectropion and the lateral displacement of the inferior punctum. None of the authors' patients had lasting epiphora., Conclusion: Lateral displacement of the inferior punctum is an important hallmark in the diagnosis of BPES. The authors demonstrate an anatomical explanation for the complex lower eyelid malformation and also propose a novel surgical technique to correct this. During surgical repair of the telecanthus and blepharophimosis, specific attention should be paid to reattachment of the lower eyelid to the medial canthal tendon. This understanding improves clinical diagnosis and surgical treatment of BPES patients.

Notch signaling is pivotal for the morphogenesis and homeostasis of many tissues. We found that aberrant Notch activation in mouse neural-crest-derived periocular mesenchymal cells (POMCs), which contribute to the formation of corneal and eyelid stroma, results in blepharophimosis. Compound transgenic mice overexpressing the Notch1 intracellular domain (N1-ICD) in POMCs (POMC(N1-ICD)) showed relatively minor effects on the cornea, but increased cell apoptosis and decreased cell proliferation during eyelid morphogenesis. Eyelid closure at E15.5 and eyelid formation at birth were incomplete. In further analyses, overexpression of N1-ICD impaired eyelid levator smooth muscle formation by downregulating the transcription factor FoxL2. This is similar to the effect of haploinsufficiency of FOXL2 in humans, which results in type II BPES (blepharophimosis, ptosis and epicanthus inversus syndrome). In vitro studies showed that FoxL2 expression is augmented by a low dose of N1-ICD but was downregulated by a high dose, depending on the extent of Hes-1 and Hey-1 activation. Moreover, transfection of CMV-FoxL2 enhanced α-SMA promoter activity. These data strongly imply that a physiologically low level of Notch1 is crucial for proper FoxL2 expression in POMCs, which is, in turn, essential for Müeller muscle formation and normal eyelid development.

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.

Deletions of the distal 3q22.3 region encompassing the gene forkhead transcription factor FOXL2 (FOXL2) usually result in intellectual disability (ID) and the highly recognizable blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). We encountered three patients with molecularly defined interstitial deletions distal to the FOXL2 gene. They present with remarkably similar manifestations comprising variable ID, a coarse facial appearance, including prominent nose and eyebrows, hypogonadism and skin pigmentation abnormalities, and they share an approximately 8.8 Mb overlapping 3q24q25 deletion. Interestingly, one of the present patients was described previously in a clinical report with emphasis on her clinical similarity to the Wisconsin syndrome, suggesting that Wisconsin syndrome might be caused by a (micro) deletion within the 3q24q25 region., (Copyright © 2010 Wiley-Liss, Inc.)

Purpose: Twist2 is a member of a family of bHLH transcription factors critical for normal mesenchymal proliferation and differentiation. In this study, the authors analyzed the role of Twist2 in the eye and cornea through examination of a Twist2 loss-of-function mouse mutant., Methods: Twist2 expression during eye development in the mouse was investigated using RT-PCR and mRNA slide in situ hybridization. Lineage tracing was performed using Cre reporter mice. Morphometric analyses were performed, and cell proliferation and cell death were investigated by immunohistochemistry using Ki67 and cleaved caspase 3 antibodies, respectively., Results: In the mouse, Twist2 is expressed first in the periocular mesenchyme and subsequently in the corneal stroma and endothelium of the developing eye. Loss of Twist2 function leads to corneal thinning and a reduced population of stromal keratocytes. The reduction in the stromal cell population can be traced back to embryonic stages during which the proliferation of stromal progenitor cells is impaired and to the reduced number of proliferating cells in the corneal limbus postnatally. Adult Twist2-null mice display enophthalmia and blepharophimosis. Corneal thinning in mutant mice is not accompanied by glaucoma, an association reported in human patients., Conclusions: Twist2 is required for normal corneal keratocyte proliferation and eyelid morphogenesis in the mouse. Loss of Twist2 function leads to corneal thinning because of the reduction in stromal keratocyte proliferation.

Epidermal nevus syndrome is a clinically variable and genetically heterogeneous group of mosaic conditions characterized by the concurrence of extensive epidermal nevus with additional cutaneous and extracutaneous manifestations. This term groups together well-characterized clinical entities, as well as dozens of apparently unique associations, which need further delineation. We report on a 23-year-old woman presenting the previously undescribed combination of widespread eccrine proliferation, multiple facial and oral pox-like lesions, gingival synechiae, blepharophimosis, body asymmetry, and mental retardation. The patient has a healthy monozygotic twin. The eccrine proliferation is intermingled with areas of unaffected skin with a linear/segmental distribution on the limbs. The clinical presentation of such a complex phenotype fits well with the genetic mosaicism theory. The histologic findings, consisting of proliferation of immature to well-formed eccrine duct-like structures located in the deep dermis and interspersed with an abundant fibrous stroma constituted of horizontally oriented collagen fibers, seem a possible hallmark of this condition.

Background: Blepharophimosis ptosis epicanthus inversus syndrome (BPES) is a rare congenital ophthalmic disorder, characterized by congenital eyelid malformation including bilateral ptosis, shortening of the horizontal eyelid fissure, epicanthus inversus, and increased distance between the inner canthi. In this research, we studied the histological structure and ultrastructure of medial canthal ligament of patients with BPES., Methods: Thirty patients with BPES who received plastic surgery at the Zhongshan Ophthalmic Center from March 2006 to January 2008 were studied. There were 17 males and 13 females with an average age of (8.73 +/- 3.37) years (3 - 31 years). The medial canthal ligaments of patients were collected during the plastic surgery to analyze the histological structure by hematoxylin and eosin (HE), Congo red, van Gieson's (VG), Masson trichrome and aldehyde-fuchsin staining. The ultrastructures of the medial canthal ligaments were also analyzed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Fifteen samples of medial canthal ligament from healthy persons with an average age of (9.02 +/- 3.12) years (6 - 30 years) were collected as a control group., Results: Morphological and histological study showed that the medial canthal ligaments of BPES patients were composed of collagen fibers, a few elastic fibers and striated muscles. The collagen fibers assemblies were disorganized and the fibrous connective tissues were undergoing hyaline degeneration. The karyopycnosis of fibroblasts was located among the collagen fibrils and the numbers of fibroblasts were decreased. Ultrastructural study with SEM showed that the collagen fibers were larger than normal, irregular and loose. Parts of the collagen fibers were broken and had a coarse surface. Ultrastructural study with TEM showed that the fibroblasts had less cytoplasm, fewer organelles and the nucleus displayed pyknosis., Conclusions: The medial canthal ligament in BPES patients is composed chiefly of collagen fibers. The collagen fibers of medial canthal ligaments in BPES patients are disorganized and hyaline degeneration is present. The study revealed that the medial canthal ligament of BPES patients might have congenital dysplasia.

The FOXL2 gene is one of 10 forkhead genes, the mutations of which lead to human developmental disorders, often with ocular manifestations. Mutations in FOXL2 are known to cause blepharophimosis syndrome (BPES), an autosomal dominant eyelid malformation associated (type I) or not (type II) with ovarian dysfunction, leading to premature ovarian failure (POF). In addition, a few mutations have been described in patients with isolated POF. Here, we review all currently described FOXL2 sequence variations and genomic rearrangements in BPES and POF. Using a combined mutation detection approach, it is possible to identify the underlying genetic defect in a major proportion (88%) of typical BPES patients. Of all genetic defects found in our BPES cohort, intragenic mutations represent 81%. They include missense changes, frameshift and nonsense mutations, in-frame deletions, and duplications, that are distributed along the single-exon gene. Genomic rearrangements comprising both deletions encompassing FOXL2 and deletions located outside its transcription unit, represent 12% and 5% of all genetic defects in our BPES cohort, respectively. One of the challenges of genetic testing in BPES is the establishment of genotype-phenotype correlations, mainly with respect to the ovarian phenotype. Genetic testing should be performed in the context of genetic counseling, however, and should be systematically complemented by a multidisciplinary clinical follow-up. Another challenge for health care professionals involved in BPES is the treatment of the eyelid phenotype and the prevention or treatment of POF., ((c) 2008 Wiley-Liss, Inc.)

We describe a patient with the clinical spectrum of Young-Simpson syndrome. This rare genetic disorder is characterized by congenital hypothyroidism, mental retardation and blepharophimosis. Young-Simpson syndrome is, at present, poorly known to endocrinologists and pediatricians, and should be included in the differential diagnosis of congenital hypothyroidism. It is important to underline that the association of congenital hypothyroidism, blepharophimosis and ptosis allows an exact clinical diagnosis, since the majority of other clinical aspects are common to other disorders.

We report a series of eight patients with the Say/Barber/Biesecker/Young-Simpson (SBBYS) type of Ohdo syndrome, which is the largest cohort described to date. We expand on the type, frequency and severity of the clinical characteristics in this condition; comment on the natural history of Ohdo syndrome and further refine previously published diagnostic criteria. Cytogenetic investigations and microarray CGH analysis undertaken in this cohort of patients failed to identify a chromosomal aetiology. It remains possible that this rare condition is heterogeneous and therefore caution must be undertaken during counselling until the underlying genetic mechanism(s) is (are) identified.

We report on a young female patient with the clinical features of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES, OMIM 110100) and a balanced chromosome translocation 46, XX, t(2;3)(q33;q23)dn.BPES is a rare autosomal dominant congenital disorder characterized by the eponymous oculo-facial features that are, in female patients, associated either with (type 1 BPES) or without (type 2 BPES) premature ovarian failure. Both types of BPES are caused by heterozygous mutations in the FOXL2 gene, which is located in chromosome band 3q23. Chromosome aberrations such as balanced rearrangements have only rarely been observed in BPES patients but can provide valuable information about regulatory regions of FOXL2. The translocation in this patient broadens our knowledge of pathogenic mechanisms in BPES and highlights the importance of conventional cytogenetic investigations in patients with negative results of FOXL2 mutation screening as a prerequisite for optimal management and genetic counseling.

Blepharophimosis is a rare congenital anomaly of the palpebral fissure which is often associated with mental retardation and additional malformations. We report on a boy with blepharophimosis, ptosis and severe mental retardation carrying an unbalanced 4;10 translocation with terminal duplication of 10q [dup(10)(q25.1-->qter)] and monosomy of a small terminal segment of chromosome 4q [del(4)(34.3-->qter)]. Detailed clinical examination and review of the literature showed that the phenotype of the patient was mainly determined by the dup(10q). This paper reviews the chromosomal aberrations associated with BMR (blepharophimosis mental retardation) phenotypes. Searching different databases and reviewing the literature revealed 14 microscopically visible aberrations (among them UPD(14)pat) and two submicroscopic rearrangements causing blepharophimosis and mental retardation (BMR) syndrome. Some of these rearrangements-like the terminal dup(10q) identified in our patient or interstitial del(2q)-are associated with clearly defined phenotypes and can be well distinguished from each other on basis of clinical examination. This paper should assist clinicians and cytogeneticists when evaluating patients with BMR syndrome.

Objective: To explore the clinical effect of combining medial and lateral canthoplasty with blepharoptosis correction at one-stage for congenital blepharophimosis syndrome., Methods: From January 2002 to May 2006, 26 patients (52 sides) with congenital blepharophimosis syndrome were treated. There were 16 males and 10 females, aging from 3 to 35 years (mean 8.5 years). They were all bilateral blepharoptosis significantly. The palpebral muscle force was 0-3 mm; the transverse dimension and vertical dimension of the palpebral tissue were 13-22 mm and 2-4 mm; the intercanthal distance was 33-44 mm; the levator function was 1-3 mm., Results: Twenty-six patients underwent medial canthoplasty and blepharoptosis correction of them. 12 patients were also given lateral canthoplasty at one-stage. The postoperative transverse dimension and vertical dimension of the palpebral tissue were 6-8 mm and 24-32 mm, respectively. The intercanthal distance was 29-34 mm. The levator function was 4-6 mm. The supratarsal fold in the upper lid was natural. With a follow up of 3 months to 4 years. all patients were satisfied with their results., Conclusion: One-stage surgical treatment of combining medial and lateral canthoplasty with blepharoptosis correction can achieve good result for blepharophimosis syndrome with a shortened treatment time.

Background: So far, most of the surgical techniques for congenital blepharophimosis syndrome are two-stage procedures. In this study, we investigated a modified one-stage procedure to reduce the suffering of patients., Methods: From 2003 to 2005, we adopted an one-stage technique combining blepharoptosis correction with medial canthoplasty in 16 patients with congenital blepharophimosis syndrome (10 male, 6 female; aged from 6 to 21). All the patients had bilateral severe blepharoptosis, epicanthus inversus, and flat dorsum nasi. The movement of the upper lid was 0 to 3 mm, vertical length of the eye fissure 2 to 4 mm, horizontal length 13 to 22 mm, and the distance between the eyes was 35 to 39 mm. The patients were followed up for one half to 2 years after the operation., Results: In all the patients, after the operation, the horizontal length of the eyelid > 25 mm, the vertical length > 6 mm. and the distance between the eyes < 35 mm. The appearance of their double eyelids was satisfying., Conclusion: The modified one-stage technique combining blepharoptosis correction with medial canthoplasty can achieve favorable outcomes for patients with congenital blepharophimosis syndrome.

This case describes the novel coexistence of sporadic blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and bilateral type I Duane syndrome in a female infant, with a FOXL2 mutation. Mutational analysis of FOXL2 demonstrated a 30-nucleotide duplication (c.672(-)701dup30) within the polyalanine tract of FOXL2. The association of BPES and Duane syndrome represents a novel phenotype which may suggest a greater pleiotropic effect of FOXL2 in development. During the period of the 4-8th week of embryonic development, the cranial nerves, their nuclei and the corresponding innervation to the extraocular muscles develop, the extraocular muscles undergo development and differentiation. This coincides with the period of time that FOXL2 is expressed strongly in the developing eyelids and the surrounding tissues. Forkhead genes are transcription factors and likely to be involved in signal transduction pathways. This case expands the spectrum of FOXL2 mutations associated with BPES.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant syndrome in which eyelid malformation is associated with (type I BPES) or without premature ovarian failure (type II BPES). Mutations of a putative winged helix/forkhead transcription factor FOXL2 account for both types of BPES. We report on a 16-year-old adolescent girl with blepharophimosis and ptosis. Subsequently she developed oligomenorrhea, secondary amenorrhea for 6 months, and an extremely large cyst of one ovary. The cyst contained 8 l of cyst fluid and histopathology displayed a large corpus luteum cyst. Following laparotomy, gonadotropin levels were elevated (LH 17.2 U/l, FSH 29.4 U/l) and estradiol levels decreased (67 pmol/l). Because of clinical aspects of BPES and abnormal ovarian function we suspected a mutation of her FOXL2 gene and found a new in-frame mutation (904&#95;939dup36) on one allele, leading to a 12 alanine expansion within the polyalanine domain. We conclude that the FOXL2 mutation 904&#95;939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst. In contrast to known FOXL2 mutations with polyalanine expansions and association with BPES type II, clinical aspects of our girl may indicate some degree of ovarian dysfunction that might finally lead to BPES type I with premature ovarian failure.

We report on a 3-year-old girl with Michels syndrome, a rare condition characterized by craniosynostosis, blepharophimosis, ptosis, epicanthus inversus, cleft lip/palate, abnormal supra-umbilical abdominal wall, and mental deficiency. The phenotypic findings are compared with the six previously reported Michels cases, and with patients referred to as Carnevale, OSA, and Malpuech syndromes. Michels syndrome is characterized by cleft lip and palate, anterior chamber anomalies, blepharophimosis, epicanthus inversus, and craniosynostosis. Carnevale syndrome shows hypertelorism, downslanting palpebral fissures, ptosis, strabismus synophrys, large and fleshy ears, and lozenge-shaped diastasis around the umbilicus. OSA syndrome resembles Carnevale, with humeroradial synostoses, and spinal anomalies as extra features. Malpuech syndrome shows IUGR, hypertelorism, cleft lip and palate, micropenis, hypospadias, renal anomalies, and caudal appendage. All are autosomal recessive. Despite the presence of apparently distinctive key features, it appears that these four entities share multiple similarities in the facial Gestalt and the pattern of MCA. Those similarities lead us to postulate that they belong to the same spectrum, which could be referred to as "3MC syndrome" (Malpuech-Michels-Mingarelli-Carnevale syndrome)., ((c) 2005 Wiley-Liss, Inc.)

We present a boy with blepharophimosis, ptosis, epicanthus inversus, microcephaly, mild mental retardation, and growth delay. Chromosomal analysis revealed a male karyotype with an interstitial deletion in the long arm of chromosome 3. DNA-analysis showed that the deletion is of maternal origin and encompasses the region between markers D3S1535 and D3S1593. The deletion contains not only the FOXL2 gene, but also the gene encoding ataxia-telangiectasia and Rad3-related protein (ATR). Mutations in FOXL2 have been shown to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). ATR has been identified as a candidate gene for Seckel syndrome, an autosomal recessive syndrome that comprises growth retardation, microcephaly, and mental retardation. We hypothesize that our patient has a contiguous gene syndrome and that the non-BPES-associated abnormalities (microcephaly, mild mental retardation, and growth delay) are the result of the deletion of the maternal ATR gene. However, it has not yet been excluded that haploinsufficiency of some other gene in this region plays a role., (Copyright 2005 Wiley-Liss, Inc.)

Here, we report on a Venezuelan child with manifestations of van den Ende-Gupta syndrome, including blepharophimosis, arachnodactyly, and congenital contractures. We also review cases from the literature., ((c) 2005 Wiley-Liss, Inc.)