DEFENSIVE Stroke Scale: Novel Diagnostic Tool for Predicting Posterior Circulation Infarction in the Emergency Department.

BACKGROUND: Dizziness is the most common posterior circulation symptom; however, diagnosing a posterior circulation infarction is difficult due to a lack of typical symptoms. We aimed to investigate the frequency of misdiagnosis of a posterior circulation infarction in patients who presented with dizziness and to develop a new stroke scale that increased the diagnostic accuracy for stroke among these subjects. METHODS: We retrospectively analyzed consecutive data from subjects hospitalized with ischemic stroke who presented with dizziness (the developmental phase). Based on these results, we created a novel stroke scale, which was used as a diagnostic procedure in the prospective validation phase. We compared the rate of misdiagnosis of ischemic stroke between phases. RESULTS: During the development phase, 115 subjects were hospitalized for ischemic stroke accompanied by dizziness. Six ischemic stroke subjects were not properly diagnosed (6/115, 5.2%). We created the new DisEquilibrium, Floating sEnsation, Non-Specific dizziness, Imbalance, and VErtigo (DEFENSIVE) stroke scale to prevent underdiagnosis of a posterior circulation infarction. During the validation phase, 949 subjects with dizziness were examined with the DEFENSIVE stroke scale; among these subjects, 100 were hospitalized for ischemic stroke accompanied by dizziness. No subject with ischemic stroke was overlooked. The new DEFENSIVE stroke scale had a sensitivity of 100% and decreased the rate of improper diagnosis of stroke (5.2% versus 0%; P = .022). CONCLUSIONS: Our new stroke recognition instrument for a posterior circulation infarction presenting with dizziness and related symptoms (the DEFENSIVE stroke scale) is easy to administer and has good diagnostic accuracy.

Say-Barber-Biesecker-Young-Simpson syndrome and Genitopatellar syndrome: Lumping or splitting?

The Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are 2 rare but clinically well-described diseases caused by de novo heterozygous sequence variants in the KAT6B gene. Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities, and patellar hypoplasia/agenesis. In addition, congenital heart defects, dental abnormalities, hearing loss, and thyroid anomalies are common to both phenotypes. This broad clinical overlap led some authors to propose the concept of KAT6B spectrum disorders. On the other hand, some clinical features could help to differentiate the 2 disorders. Furthermore, it is possible to establish a genotype-phenotype correlation when considering the position of the sequence variant along the gene, supporting the notion of the 2 disorders as really distinct entities.

A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing.

Mutations of the histone acetyltransferase-encoding KAT6B gene cause the Say-Barber-Biesecker/Young-Simpson (SBBYS) type of blepharophimosis-"mental retardation" syndromes and the more severe genitopatellar syndrome. The SBBYS syndrome-causing mutations are clustered in the large exon 18 of KAT6B and almost exclusively lead to predicted protein truncation. An atypical KAT6B mutation, a de novo synonymous variant located in exon 16 (c.3147G>A, p.(Pro1049Pro)) was previously identified in three unrelated patients. This exonic mutation was predicted in silico to cause protein truncation through aberrant splicing. Here, we report three additional unrelated children with typical SBBYS syndrome and the KAT6B c.3147G>A mutation. We show on RNA derived from patient blood that the mutation indeed induces aberrant splicing through the use of a cryptic exonic splice acceptor site created by the sequence variant. Our results thus identify the synonymous variant c.3147G>A as a splice site mutation and a mutational hot spot in SBBYS syndrome.

Etiology of craniofacial malformations in mouse models of blepharophimosis, ptosis and epicanthus inversus syndrome.

Blepharophimosis, ptosis, epicanthus-inversus syndrome (BPES) is an autosomal dominant genetic disorder characterized by narrow palpebral fissures and eyelid levator muscle defects. BPES is often associated to premature ovarian insufficiency (BPES type I). FOXL2, a member of the forkhead transcription factor family, is the only gene known to be mutated in BPES. Foxl2 is essential for maintenance of ovarian identity, but the developmental origin of the facial malformations of BPES remains, so far, unexplained. In this study, we provide the first detailed account of the developmental processes leading to the craniofacial malformations associated to Foxl2. We show that, during development, Foxl2 is expressed both by Cranial Neural Crest Cells (CNCCs) and by Cranial Mesodermal Cells (CMCs), which give rise to skeletal (CNCCs and CMCs) and muscular (CMCs) components of the head. Using mice in which Foxl2 is selectively inactivated in either CNCCs or CMCs, we reveal that expression of Foxl2 in CNCCs is essential for the development of extraocular muscles. Indeed, inactivation of Foxl2 in CMCs has only minor effects on muscle development, whereas its inactivation in CNCCs provokes a severe hypoplasia of the levator palpabrae superioris and of the superior and inferior oblique muscles. We further show that Foxl2 deletion in either CNCCs or CMCs prevents eyelid closure and induces subtle skeletal developmental defects. Our results provide new insights in the complex developmental origin of human BPES and could help to understand the origin of other ocular anomalies associated to this syndrome.

Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain.

Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms--such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)--were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease.

Cleft palate and keratoconus in a child affected by fetal alcohol syndrome: an accidental association?

This report describes the case of a 9-year-old girl affected by fetal alcohol syndrome who presented at birth with blepharophimosis and a cleft palate, which was submitted to surgery. She was referred to our hospital for a visual acuity reduction, where a diagnosis of keratoconus was made. This case highlights the rarity of the association between fetal alcohol syndrome and cleft palate and the previously unreported association involving fetal alcohol syndrome-keratoconus and cleft palate-keratoconus.

Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development.

FOXL2 mutations cause gonadal dysgenesis or premature ovarian failure (POF) in women, as well as eyelid/forehead dysmorphology in both sexes (the 'blepharophimosis-ptosis-epicanthus inversus syndrome', BPES). Here we report that mice lacking Foxl2 recapitulate relevant features of human BPES: males and females are small and show distinctive craniofacial morphology with upper eyelids absent. Furthermore, in mice as in humans, sterility is confined to females. Features of Foxl2 null animals point toward a new mechanism of POF, with all major somatic cell lineages failing to develop around growing oocytes from the time of primordial follicle formation. Foxl2 disruption thus provides a model for histogenesis and reproductive competence of the ovary.

Etiology of ovarian failure in blepharophimosis ptosis epicanthus inversus syndrome: FOXL2 is a conserved, early-acting gene in vertebrate ovarian development.

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.

Orbicularis myectomy with levator advancement in Schwartz-Jampel syndrome.

PURPOSE: Schwartz-Jampel syndrome is a disorder of continuous myotonia causing blepharospasm, acquired ptosis, and blepharophimosis. We report the management of the associated eyelid anomalies with orbicularis oculi myectomy, levator aponeurosis resection, and lateral canthopexy. METHODS: Interventional case reports. Two patients with Schwartz-Jampel syndrome presented with blepharospasm, acquired ptosis, and blepharophimosis. Orbicularis myectomy, levator aponeurosis resection, and lateral canthopexy were performed to relieve the blepharospasm and to correct the ptosis and blepharophimosis. RESULTS: Significant functional and cosmetic improvements were achieved by increasing the palpebral fissure height and length while greatly decreasing the blepharospasm of the patients. No recurrence of the blepharospasm or eyelid anomalies has been noted after 1 and 15 years of follow-up, respectively. CONCLUSION: The blepharospasm and eyelid alterations caused by Schwartz-Jampel syndrome should be treated to provide functional and cosmetic improvements. Our technique of myectomy, levator resection, and lateral canthopexy provides an excellent, long-lasting result.

Levator aponeurosis surgery in Schwartz-Jampel syndrome.

Schwartz-Jampel syndrome is a rare disorder with prominent palpebral fissure changes. These changes are complex and have been described as ptosis, blepharophimosis, and blepharospasm. Two new cases of the Schwartz-Jampel syndrome and the results of elevating the upper eyelid margin with levator aponeurosis surgery are presented, along with a review of the literature.