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Clinical Imaging 2016Functional single ventricle (FSV) encompasses a spectrum of severe congenital heart disease. Patients with FSV are living longer than decades prior resulting in more... (Review)
Review
Functional single ventricle (FSV) encompasses a spectrum of severe congenital heart disease. Patients with FSV are living longer than decades prior resulting in more frequent imaging both for surgical planning and functional evaluation. At each stage of surgical intervention, imaging plays a critical role in detecting postoperative complications and preprocedural planning. This article describes the unique imaging findings, including complications, that are most important to the referring physician or surgeon at each surgical stage of FSV management. A description of lesions that embody the diagnosis of FSV is also included.
Topics: Angiography; Cleft Palate; Ear, External; Echocardiography; Fontan Procedure; Heart Defects, Congenital; Heart Ventricles; Humans; Magnetic Resonance Angiography; Microcephaly; Micrognathism; Multidetector Computed Tomography; Palliative Care; Postoperative Complications; Pulmonary Artery; Retrospective Studies; Surgery, Computer-Assisted; Treatment Outcome; Tricuspid Atresia
PubMed: 27568070
DOI: 10.1016/j.clinimag.2016.08.003 -
Brazilian Dental Journal 2015Tutankhamun was a Pharaoh of the 18th Dynasty (New Kingdom) in ancient Egypt. Medical and radiological investigations of his skull revealed details about the jaw and...
Tutankhamun was a Pharaoh of the 18th Dynasty (New Kingdom) in ancient Egypt. Medical and radiological investigations of his skull revealed details about the jaw and teeth status of the mummy. Regarding the jaw relation, a maxillary prognathism, a mandibular retrognathism and micrognathism have been discussed previously. A cephalometric analysis was performed using a lateral skull X-ray and a review of the literature regarding King Tutankhamun´s mummy. The results imply diagnosis of mandibular retrognathism. Furthermore, third molar retention and an incomplete, single cleft palate are present.
Topics: Adolescent; Adult; Egypt, Ancient; History, Ancient; Humans; Male; Mummies; Tooth; Young Adult
PubMed: 26963220
DOI: 10.1590/0103-6440201300431 -
American Journal of Medical Genetics.... Aug 2022The phenotypic spectrum of SOX11-related Coffin-Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear...
The phenotypic spectrum of SOX11-related Coffin-Siris syndrome (CSS) is expanding with reports of new associations. SOX11 is implicated in neurogenesis and inner ear development. Cochlear nerve deficiency, absence or hypoplasia, is commonly associated with cochlear canal stenosis or with CHARGE syndrome, a monogenic condition that affects inner ear development. SOX11 is a transcription factor essential for neuronal identity, highly correlated with the expression of CHD7, which regulates SOX11. We present two unrelated probands, each with novel de novo SOX11 likely pathogenic variants and phenotypic manifestations of CSS including global developmental delay, growth deficiency, and hypoplastic nails. They have unilateral sensorineural hearing loss due to cochlear nerve deficiency confirmed on MRI. SOX11 is implicated in sensory neuron survival and maturation. It is highly expressed in the developing inner ear. Homozygous ablation of SOX11 in a mouse model resulted in a reduction in sensory neuron survival and decreased axonal growth. A heterozygous knockout mice model had hearing impairment with grossly normal inner ear structures like the two probands reported. We propose cochlear nerve deficiency as a new phenotypic feature of SOX11-related CSS. Magnetic resonance imaging is useful in delineating the cochlear nerve deficiency and other CSS-related brain malformations.
Topics: Abnormalities, Multiple; Animals; CHARGE Syndrome; Cochlear Nerve; Face; Hand Deformities, Congenital; Hearing Loss, Sensorineural; Intellectual Disability; Mice; Micrognathism; Neck; SOXC Transcription Factors
PubMed: 35642566
DOI: 10.1002/ajmg.a.62851 -
Journal of Orofacial Orthopedics =... Jan 2015Micro- and retrognathia of mandibular origin may lead to life-threatening respiratory problems in connection with glossoptosis immediately after birth. Prenatal...
OBJECTIVE
Micro- and retrognathia of mandibular origin may lead to life-threatening respiratory problems in connection with glossoptosis immediately after birth. Prenatal screening for this malformation is therefore increasingly important. Today this is accomplished by predominantly subjective standards. Objective criteria have been proposed but have not become established. We therefore made an effort to develop indices that would identify major skeletal discrepancies or micrognathia in as straightforward a fashion as possible during routine prenatal sonography.
MATERIALS AND METHODS
Series of fetal jaw sonograms (Toshiba Aplio MX®) were obtained in 313 women with normal pregnancies from weeks 19-29 of gestation. Upper- and lower-jaw landmarks were interactively located on screen and evaluated for reproducibility. Linear parameters representative of maxillary and mandibular length (SpA'-SpP' and Rami-SymMe) were measured and related to femur length and gestational age. Based on these data, indices for maxillary, and mandibular length were derived and analyzed.
RESULTS
High correlations were identified for mandibular length both with gestational age (R = 0.845; R(2) = 0.713) and with femur length (correlation coefficients (R) = 0.839; coefficients of determination (R(2)) = 0.704). For maxillary length, the respective correlation coefficients were 0.691 (R(2) = 0.477) and 0.656 (R(2) = 0.430). Estimates of mandibular and maxillary length based on gestational age and femur length were obtained by regression analysis. The mean bimaxillary length ratio was 0.628 ± 0.043.
CONCLUSION
Maxillary and mandibular growth can be objectively evaluated via indices. It is conceivable to develop this approach into a sensitive and reliable method of prenatal jaw screening for major skeletal anomalies and congenital malformations.
Topics: Anthropometry; Female; Germany; Humans; Image Interpretation, Computer-Assisted; Male; Mandible; Micrognathism; Reference Values; Reproducibility of Results; Retrognathia; Sensitivity and Specificity; Ultrasonography, Prenatal
PubMed: 25613383
DOI: 10.1007/s00056-014-0257-1 -
European Journal of Human Genetics :... Aug 2018Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to... (Meta-Analysis)
Meta-Analysis Review
Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.
Topics: Abnormalities, Multiple; Face; Germ-Line Mutation; Hand Deformities, Congenital; Humans; Intellectual Disability; Meningeal Neoplasms; Meningioma; Micrognathism; Neck; Neurilemmoma; Phenotype; Polymorphism, Single Nucleotide; SMARCB1 Protein
PubMed: 29706634
DOI: 10.1038/s41431-018-0143-1 -
JCI Insight May 2022The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is,...
The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.
Topics: Animals; Chromosomal Proteins, Non-Histone; Congenital Microtia; DNA Replication; Growth Disorders; Humans; Mice; Micrognathism; Minichromosome Maintenance Proteins; Patella; Saccharomyces cerevisiae
PubMed: 35603789
DOI: 10.1172/jci.insight.155648 -
International Journal of Oral Science Oct 2022Micrognathia is a severe craniofacial deformity affecting appearance and survival. Previous studies revealed that multiple factors involved in the osteogenesis of...
Micrognathia is a severe craniofacial deformity affecting appearance and survival. Previous studies revealed that multiple factors involved in the osteogenesis of mandibular bone have contributed to micrognathia, but concerned little on factors other than osteogenesis. In the current study, we found that ectopic activation of Fgf8 by Osr2-cre in the presumptive mesenchyme for masseter tendon in mice led to micrognathia, masseter regression, and the disrupted patterning and differentiation of masseter tendon. Since Myf5-cre;Rosa26R-Fgf8 mice exhibited the normal masseter and mandibular bone, the possibility that the micrognathia and masseter regression resulted directly from the over-expressed Fgf8 was excluded. Further investigation disclosed that a series of chondrogenic markers were ectopically activated in the developing Osr2-cre;Rosa26R-Fgf8 masseter tendon, while the mechanical sensing in the masseter and mandibular bone was obviously reduced. Thus, it suggested that the micrognathia in Osr2-cre;Rosa26R-Fgf8 mice resulted secondarily from the reduced mechanical force transmitted to mandibular bone. Consistently, when tenogenic or myogenic components were deleted from the developing mandibles, both the micrognathia and masseter degeneration took place with the decreased mechanical sensing in mandibular bone, which verified that the loss of mechanical force transmitted by masseter tendon could result in micrognathia. Furthermore, it appeared that the micrognathia resulting from the disrupted tenogenesis was attributed to the impaired osteogenic specification, instead of the differentiation in the periosteal progenitors. Our findings disclose a novel mechanism for mandibular morphogenesis, and shed light on the prevention and treatment for micrognathia.
Topics: Mice; Animals; Micrognathism; Masseter Muscle; Mandible; Osteogenesis
PubMed: 36257937
DOI: 10.1038/s41368-022-00196-y -
Journal of Glaucoma Jan 2018Cerebro-costo-mandibular syndrome (CCMS) is a rare hereditary disorder characterized by micrognathia, posterior rib gaps, and secondary developmental delay. Patients...
Cerebro-costo-mandibular syndrome (CCMS) is a rare hereditary disorder characterized by micrognathia, posterior rib gaps, and secondary developmental delay. Patients often require ventilation and feeding support throughout life. We describe the first reported ophthalmic findings of CCMS and propose that defects in choroidal permeability lead to chronic macular edema and refractory aqueous misdirection syndrome. Here we discuss the medical and surgical management concerns of recurrent angle closure and raised intraocular pressure in a CCMS patient.
Topics: Atropine; Chronic Disease; Consanguinity; Female; Glaucoma, Angle-Closure; Glucocorticoids; Gonioscopy; Humans; Intellectual Disability; Intraocular Pressure; Iris; Laser Coagulation; Lens, Crystalline; Macular Edema; Micrognathism; Mydriatics; Ribs; Tomography, Optical Coherence; Triamcinolone Acetonide; Visual Acuity; Vitrectomy; Young Adult
PubMed: 29117007
DOI: 10.1097/IJG.0000000000000815 -
American Journal of Medical Genetics.... Sep 2023Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia,...
Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.
Topics: Male; Humans; DNA-Binding Proteins; Muscle Hypotonia; Transcription Factors; Face; Abnormalities, Multiple; Micrognathism; Intellectual Disability; Hand Deformities, Congenital; Neck
PubMed: 37654076
DOI: 10.1002/ajmg.c.32056 -
Journal of Medical Genetics Nov 2022A neurodevelopmental syndrome was recently reported in four patients with heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The...
BACKGROUND
A neurodevelopmental syndrome was recently reported in four patients with heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome.
METHODS
We newly identified 17 patients with variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes.
RESULTS
All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS.
CONCLUSION
These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to haploinsufficiency in neurogenesis and multiple other developmental processes.
Topics: Humans; Micrognathism; Hand Deformities, Congenital; Intellectual Disability; Neurodevelopmental Disorders; Syndrome; Phenotype; DNA; SOXC Transcription Factors
PubMed: 35232796
DOI: 10.1136/jmedgenet-2021-108375