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American Journal of Human Genetics Jun 2016Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report...
Duane retraction syndrome (DRS) is a congenital eye-movement disorder defined by limited outward gaze and retraction of the eye on attempted inward gaze. Here, we report on three heterozygous loss-of-function MAFB mutations causing DRS and a dominant-negative MAFB mutation causing DRS and deafness. Using genotype-phenotype correlations in humans and Mafb-knockout mice, we propose a threshold model for variable loss of MAFB function. Postmortem studies of DRS have reported abducens nerve hypoplasia and aberrant innervation of the lateral rectus muscle by the oculomotor nerve. Our studies in mice now confirm this human DRS pathology. Moreover, we demonstrate that selectively disrupting abducens nerve development is sufficient to cause secondary innervation of the lateral rectus muscle by aberrant oculomotor nerve branches, which form at developmental decision regions close to target extraocular muscles. Thus, we present evidence that the primary cause of DRS is failure of the abducens nerve to fully innervate the lateral rectus muscle in early development.
Topics: Animals; Duane Retraction Syndrome; Embryo, Mammalian; Female; Hearing Loss; Humans; Labyrinth Diseases; MafB Transcription Factor; Male; Mice; Mice, Knockout; Oculomotor Muscles; Pedigree
PubMed: 27181683
DOI: 10.1016/j.ajhg.2016.03.023 -
Medicine Sep 2018Blepharoptosis (ptosis) is a common but often overlooked sign that may serve as a sign/manifestation of other conditions, ranging from a mild and purely cosmetic... (Review)
Review
Blepharoptosis (ptosis) is a common but often overlooked sign that may serve as a sign/manifestation of other conditions, ranging from a mild and purely cosmetic presentation to a severe and occasionally progressive disorder. Ptosis may show an acute onset or may manifest as a chronic disorder. Its presentation may vary: unilateral versus bilateral, progressive versus non-progressive, isolated versus complex which occurs in association with other symptoms, and congenital versus acquired (often concomitant with neuromuscular disorders).Congenital ptosis includes the isolated type-the congenital cranial dysinnervation disorders, which are further, distinguished into different subtypes such as Horner syndrome (HS), and ptosis as a sign/manifestation of various congenital malformation syndromes.In this article, we review the primary causes of ptosis occurring in childhood, and its various clinical presentations, including a short report on selected cases observed in our institution: a classical isolated familial ptosis comprising 14 members over 5 generations, 3 sibling with isolated congenital ptosis who in addition suffered by episodes of febrile seizures, a patient with Duane retraction syndrome who presented congenital skin and hair anomalies, and a girl with HS who showed a history of congenital imperforate hymen. A flowchart outlining the congenital and acquired type of ptosis and the clinical approach to the management and treatment of children with this anomaly is reported.
Topics: Blepharoptosis; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Male
PubMed: 30200099
DOI: 10.1097/MD.0000000000012124 -
Indian Journal of Ophthalmology May 2015
Topics: Accommodation, Ocular; Duane Retraction Syndrome; Esotropia; Eye Movements; Female; Humans; Male; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Vision, Binocular
PubMed: 26139819
DOI: 10.4103/0301-4738.159908 -
Saudi Journal of Ophthalmology :... 2021Consecutive exotropia is considered as a rare complication after medial rectus recession that is performed for cases of esotropic Duane syndrome. Here, we present a case...
Consecutive exotropia is considered as a rare complication after medial rectus recession that is performed for cases of esotropic Duane syndrome. Here, we present a case of 5-year-old female initially presented with the limitation of abduction, narrowing of the palpebral fissure, and globe retraction of the left eye along with a mild left face turn. She was diagnosed with Duane syndrome Type 1. She was treated with the medial rectus recession (6.5 mm). Postsurgery, she developed a consecutive exotropia. This was managed successfully with the ipsilateral lateral rectus recession (8 mm). Following this surgery, the patient was orthoptic in the primary position and her abnormal head posture was markedly improved.
PubMed: 35391814
DOI: 10.4103/1319-4534.337851 -
Structure of SALL4 zinc finger domain reveals link between AT-rich DNA binding and Okihiro syndrome.Life Science Alliance Mar 2023Spalt-like 4 (SALL4) maintains vertebrate embryonic stem cell identity and is required for the development of multiple organs, including limbs. Mutations in SALL4 are...
Spalt-like 4 (SALL4) maintains vertebrate embryonic stem cell identity and is required for the development of multiple organs, including limbs. Mutations in SALL4 are associated with Okihiro syndrome, and SALL4 is also a known target of thalidomide. SALL4 protein has a distinct preference for AT-rich sequences, recognised by a pair of zinc fingers at the C-terminus. However, unlike many characterised zinc finger proteins, SALL4 shows flexible recognition with many different combinations of AT-rich sequences being targeted. SALL4 interacts with the NuRD corepressor complex which potentially mediates repression of AT-rich genes. We present a crystal structure of SALL4 C-terminal zinc fingers with an AT-rich DNA sequence, which shows that SALL4 uses small hydrophobic and polar side chains to provide flexible recognition in the major groove. Missense mutations reported in patients that lie within the C-terminal zinc fingers reduced overall binding to DNA but not the preference for AT-rich sequences. Furthermore, these mutations altered association of SALL4 with AT-rich genomic sites, providing evidence that these mutations are likely pathogenic.
Topics: Humans; Duane Retraction Syndrome; Mutation; Transcription Factors; Zinc Fingers
PubMed: 36635047
DOI: 10.26508/lsa.202201588 -
Oman Journal of Ophthalmology 2023Achondroplasia is an autosomal dominant congenital disorder of endochondral ossification, induced by abnormal activity of fibroblast growth factor receptor 3. Affected...
Achondroplasia is an autosomal dominant congenital disorder of endochondral ossification, induced by abnormal activity of fibroblast growth factor receptor 3. Affected individuals have short stature and often present with neurological and skeletal complications. Most have normal intelligence. Ocular association with achondroplasia include simple microphthalmos, congenital-onset glaucoma with presumed Axenfeld-Rieger anomaly, telecanthus, exotropia, inferior oblique overaction, angle anomalies, Duane retraction syndrome, cone-rod dystrophy, fundus albipunctatus, chorioretinal coloboma, macular coloboma, keratoconus, and developmental cataract. A 6-year-old achondroplasia boy with developmental delay had a high axial length (high myopia) in both eyes. This child had a left eye subluxated cataractous lens, while the other eye showed mild lens changes. All achondroplasia patients should be routinely screened in detail for lens and other ophthalmological anomalies so that they can undergo timely intervention and management.
PubMed: 38059098
DOI: 10.4103/ojo.ojo_42_23 -
Oman Journal of Ophthalmology Sep 2014A 5-year-old girl presented with bilateral familial vertical Duane retraction syndrome with alternating esotropia, elevation deficit, Marcus gunn phenomenon, and facial...
A 5-year-old girl presented with bilateral familial vertical Duane retraction syndrome with alternating esotropia, elevation deficit, Marcus gunn phenomenon, and facial hypoplasia. Abnormal adducting downshoots on attempting abduction suggestive of a synergistic convergence were noted. Hypothesis suggests aberrant innervations or peripheral anatomic connections between inferior and medial recti.
PubMed: 25378878
DOI: 10.4103/0974-620X.142596 -
Scientific Reports Aug 2019Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by...
Thalidomide is widely used for several diseases; however, it causes malformations in embryos exposed during pregnancy. The complete understanding of the mechanisms by which thalidomide affects the embryo development has not yet been obtained. The phenotypic similarity makes TE a phenocopy of syndromes caused by mutations in ESCO2, SALL4 and TBX5 genes. Recently, SALL4 and TBX5 were demonstrated to be thalidomide targets. To understand if these genes act in the TE development, we sequenced them in 27 individuals with TE; we verified how thalidomide affect them in human pluripotent stem cells (hPSCs) through a differential gene expression (DGE) analysis from GSE63935; and we evaluated how these genes are functionally related through an interaction network analysis. We identified 8 variants in ESCO2, 15 in SALL4 and 15 in TBX5. We compared allelic frequencies with data from ExAC, 1000 Genomes and ABraOM databases; eight variants were significantly different (p < 0.05). Eleven variants in SALL4 and TBX5 were previously associated with cardiac diseases or malformations; however, in TE sample there was no association. Variant effect prediction tools showed 97% of the variants with potential to influence in these genes regulation. DGE analysis showed a significant reduction of ESCO2 in hPSCs after thalidomide exposure.
Topics: Abnormalities, Multiple; Acetyltransferases; Brazil; Cell Line; Chromosomal Proteins, Non-Histone; Craniofacial Abnormalities; Datasets as Topic; Duane Retraction Syndrome; Ectromelia; Female; Gene Expression Profiling; Gene Frequency; Genetic Predisposition to Disease; Heart Defects, Congenital; Heart Septal Defects, Atrial; Humans; Hypertelorism; Leprosy; Lower Extremity Deformities, Congenital; Male; Mutation; Pluripotent Stem Cells; Polymorphism, Single Nucleotide; Pregnancy; Pregnancy Complications; Protein Interaction Maps; T-Box Domain Proteins; Teratogenesis; Thalidomide; Transcription Factors; Upper Extremity Deformities, Congenital
PubMed: 31388035
DOI: 10.1038/s41598-019-47739-8 -
Journal of AAPOS : the Official... Oct 2014Superior rectus transposition with or without medial rectus recession has been advocated for the treatment of abducens nerve palsy and esotropic Duane syndrome. Early...
BACKGROUND
Superior rectus transposition with or without medial rectus recession has been advocated for the treatment of abducens nerve palsy and esotropic Duane syndrome. Early reports have focused mainly on postoperative ocular alignment, but there is concern that superior rectus transposition may induce torsional misalignment. The purpose of this study was to evaluate torsional outcomes after superior rectus transposition surgery using prospective preoperative and postoperative torsional assessments.
METHODS
Prospective measurements were performed on all patients undergoing superior rectus transposition. Preverbal infants were assessed using fundus torsion evaluating the position of the fovea relative to the optic nerve; older children/adults underwent double Maddox rod (DMR) assessment of torsion.
RESULTS
A total of 11 subjects met the study inclusion criteria. The etiology of strabismus was an abducens nerve palsy (n = 7) or Duane syndrome (n = 4). For the subjects evaluated by fundus torsion (n = 4), there was no significant change in torsion for 3 (75%). For those subjects undergoing DMR (n = 7), there was a significant change in subjective torsion (4.7 ± 3.8°excyclotorsion vs 0.0° ± 5.0° excyclotorsion; P = 0.004). Esotropic deviation improved significantly for all subjects (39(Δ) ± 23(Δ) vs 6.5(Δ) ± 13(Δ); P = 0.001) and no significant mean vertical deviation postoperatively, although 1 patient had a clinically significant postoperative hypertropia measuring 14(Δ). Abduction also improved significantly (-4.2 ± 0.9 vs -2.8 ± 1, P = 0.0001).
CONCLUSIONS
In this patient series, superior rectus transposition with medial rectus recession did not have clinically significant induction of torsional diplopia as a result of the procedure.
Topics: Abducens Nerve Diseases; Adolescent; Aged; Child; Diagnostic Techniques, Ophthalmological; Diplopia; Duane Retraction Syndrome; Female; Humans; Infant; Male; Middle Aged; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Prospective Studies; Strabismus; Torsion Abnormality; Vision, Binocular; Visual Acuity
PubMed: 25266834
DOI: 10.1016/j.jaapos.2014.06.008 -
BMC Medical Genomics Feb 2023SALL4, a member of the SALL genes family, encodes a zinc-finger transcriptional factor that either activates or represses gene transcription depending on cell type...
BACKGROUND
SALL4, a member of the SALL genes family, encodes a zinc-finger transcriptional factor that either activates or represses gene transcription depending on cell type during embryonic development. SALL4 mutations cause extremely variable conditions including Duane-radial ray (DRR), Okihiro, Holt-oram, Acro-renal ocular and IVIC syndromes, all with autosomal dominant inheritance pattern. However, all these syndromes with different terminologies are actually the same entity termed SALL4 related disorders.
CASE PRESENTATION
Herein, we examine an Iranian patient suspected to DRR syndrome which has not been previously described in the population. Whole-exome sequencing (WES) was performed to examine pathogenic genes in the proband. Subsequently, Sanger sequencing was used to confirm the mutation found. To elucidate the effects of the identified mutation, clinical data of patient was collected. Morever, the possible impact of the mutation found on the corresponding protein was evaluated using bioinformatics tools. WES identifed a novel de novo heterozygous nonsense mutation in exon 2 of SALL4 gene (c.712 C > T:p.Q238X). Subsequently, segregation and phenotype-genotype correlation analysis as well as in-silico approaches confirmed the autosomal dominance inheritance and disease-causing nature of the identified mutation. In addition, studied patient had features not described previously, including kyphoscoliosis, dimple presacral sinus, barrel chest and artric disc (C6-C7). These manifestations could be additional characteristics of the growing phenotypic spectrum of SALL4 related disorders.
CONCLUSION
Our findings could extend the pathogenic mutations and phenotypic spectrum of SALL4 related disorders. Such reports can also aid to conduct genetic counseling, prenatal diagnosis and clinical management for individuals at high risk of SALL4 related disorders.
Topics: Humans; Duane Retraction Syndrome; Codon, Nonsense; Iran; Transcription Factors; Mutation; Pedigree
PubMed: 36829172
DOI: 10.1186/s12920-023-01467-1