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Disease Models & Mechanisms Jun 2022Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular...
Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular syndrome (CCMS). We show that Snrpb heterozygous mouse embryos arrest shortly after implantation. Additionally, heterozygous deletion of Snrpb in the developing brain and neural crest cells models craniofacial malformations found in CCMS, and results in death shortly after birth. RNAseq analysis of mutant heads prior to morphological defects revealed increased exon skipping and intron retention in association with increased 5' splice site strength. We found increased exon skipping in negative regulators of the P53 pathway, along with increased levels of nuclear P53 and P53 target genes. However, removing Trp53 in Snrpb heterozygous mutant neural crest cells did not completely rescue craniofacial development. We also found a small but significant increase in exon skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations. This article has an associated First Person interview with the first author of the paper.
Topics: Animals; Craniofacial Abnormalities; Humans; Intellectual Disability; Mice; Micrognathism; Morphogenesis; Neural Crest; Ribs; Tumor Suppressor Protein p53; snRNP Core Proteins
PubMed: 35593225
DOI: 10.1242/dmm.049544 -
Genetics in Medicine : Official Journal... Aug 2022Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally...
PURPOSE
Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes.
METHODS
Clinical data was collected through an extensive web-based survey.
RESULTS
We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%).
CONCLUSION
Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes.
Topics: Abnormalities, Multiple; Chromosomal Proteins, Non-Histone; Face; Genetic Association Studies; Hand Deformities, Congenital; Humans; Intellectual Disability; Micrognathism; Neck; Phenotype
PubMed: 35579625
DOI: 10.1016/j.gim.2022.04.010 -
Case Reports in Dentistry 2022Sanjad-Sakati syndrome (SSS) is a rare autosomal recessive congenital disorder. The present case report is aimed at describing the orofacial manifestations and dental...
Sanjad-Sakati syndrome (SSS) is a rare autosomal recessive congenital disorder. The present case report is aimed at describing the orofacial manifestations and dental management of a 4-year seven-month-old, Tunisian boy with SSS. The patient has typical dysmorphic facial features and growth retardation. Intraoral examination revealed micrognathic mandible and maxilla, an arched palate, and small dental arches with an open bite. All the maxillary and mandibular teeth were decayed due to the poor oral hygiene, plaque accumulation, and enamel hypoplasia. Oral rehabilitation involved pulpotomies and root canal therapies on decayed teeth. Resin composite restorations were performed on maxillary and mandibular incisors, and stainless-steel crowns were placed on maxillary and mandibular first and second primary molars. Dental treatment of children with SSS should improve their quality of life and their general health. Undeveloped dental arches associated with dental anomalies as well as learning deficit make very difficult of the oral rehabilitation of such patients.
PubMed: 35493399
DOI: 10.1155/2022/9585460 -
Human Genetics Nov 2022Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular...
Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2-10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700s. These haplotype and genealogical data suggest that these families and the remaining "unrelated" samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.
Topics: Carrier Proteins; Hemangioma, Cavernous, Central Nervous System; Humans; Intellectual Disability; Micrognathism; Mutation; Pedigree; Proto-Oncogene Proteins; Ribs; Sequence Deletion
PubMed: 35488064
DOI: 10.1007/s00439-022-02458-5 -
Pediatric Rheumatology Online Journal Apr 2022This retrospective, cross-sectional study aimed to assess the pharyngeal airway dimensions of patients with juvenile idiopathic arthritis (JIA) and moderate/severe...
BACKGROUND
This retrospective, cross-sectional study aimed to assess the pharyngeal airway dimensions of patients with juvenile idiopathic arthritis (JIA) and moderate/severe JIA-related dentofacial deformity (mandibular retrognathia/micrognathia), and compare the results with JIA patients with a normal mandibular appearance and a group of non-JIA patients.
METHODS
Seventy-eight patients were retrospectively included in a 1:1:1 manner as specified below. All patients had previously been treated at the Section of Orthodontics, Aarhus University, Denmark. All had a pretreatment cone beam computed tomography (CBCT). Group 1 (JIA+); 26 JIA patients with severe arthritis-related dentofacial deformity and mandibular retrognathia/micrognathia. Group 2 (JIA-); 26 JIA patients with normal mandibular morphology/position. Group 3 (Controls); 26 non-JIA subjects. Dentofacial morphology and upper airway dimensions, excluding the nasal cavity, were assessed in a validated three-dimensional (3D) fashion. Assessment of dentofacial deformity comprised six morphometric measures. Assessment of airway dimensions comprised nine measures.
RESULTS
Five morphometric measures of dentofacial deformity were significantly deviating in the JIA+ group compared with the JIA- and control groups: Posterior mandibular height, anterior facial height, mandibular inclination, mandibular occlusal inclination, and mandibular sagittal position. Five of the airway measurements showed significant inter-group differences: JIA+ had a significantly smaller nasopharyngeal airway dimension (ad2-PNS), a smaller velopharyngeal volume, a smaller minimal cross-sectional area and a smaller minimal hydraulic diameter than JIA- and controls. No significant differences in upper airway dimensions were seen between JIA- and controls.
CONCLUSION
JIA patients with severe arthritis-related dentofacial deformity and mandibular micrognathia had significantly restricted upper airway dimensions compared with JIA patients without dentofacial deformity and controls. The restrictions of upper airway dimension seen in the JIA+ group herein were previously associated with sleep-disordered breathing in the non-JIA background population. Further studies are needed to elucidate the role of dentofacial deformity and restricted airways in the development of sleep-disordered breathing in JIA.
Topics: Arthritis, Juvenile; Cross-Sectional Studies; Dentofacial Deformities; Humans; Micrognathism; Retrognathia; Retrospective Studies; Sleep Apnea Syndromes; Temporomandibular Joint Disorders
PubMed: 35477405
DOI: 10.1186/s12969-022-00691-w -
BMJ Case Reports Apr 2022
Topics: Humans; Maxilla; Maxillary Sinus; Micrognathism; Sjogren's Syndrome
PubMed: 35393283
DOI: 10.1136/bcr-2022-249659 -
BMJ Case Reports Mar 2022A female patient in her early 20s, with a known diagnosis of hemifacial microsomia (unilateral microtia and mandibular hypoplasia) accompanied with an unoperated cleft...
A female patient in her early 20s, with a known diagnosis of hemifacial microsomia (unilateral microtia and mandibular hypoplasia) accompanied with an unoperated cleft palate, came for an infected mandibular distraction plate removal. The anticipated difficult airway and lack of enough literature about what to expect in such a scenario, along with the psychological impact on the patient, made this case challenging and thought-provoking. Inability to perform the awake tracheal intubation because of the uncooperative patient, along with the difficult fibreoptic owing to narrowed nostrils, offered an extra set of challenges.
Topics: Adult; Cleft Palate; Facial Asymmetry; Female; Goldenhar Syndrome; Humans; Mandible; Micrognathism
PubMed: 35338041
DOI: 10.1136/bcr-2021-247858 -
Journal of Clinical Sleep Medicine :... Jul 2022Craniofacial malformations with micrognathia cause high grades of obstructive sleep apnea (OSA) measured by polysomnography (PSG). Mandibular distraction osteogenesis is...
STUDY OBJECTIVES
Craniofacial malformations with micrognathia cause high grades of obstructive sleep apnea (OSA) measured by polysomnography (PSG). Mandibular distraction osteogenesis is a novel procedure for upper airway obstruction relief. Our primary objective was to describe the utilization of PSGs to improve obstruction in patients undergoing mandibular distraction.
METHODS
This is a retrospective study. Patients with micrognathia and severe upper airway obstruction, presenting with severe OSA diagnosed by PSG, were included from a single tertiary care center between 2015 and 2019. PSGs were done (1) prior to surgery, (2) once the cosmetic goal was achieved (Post-Op 1), and (3) if residual moderate-to-severe OSA was seen, every 2 nights until mild or no OSA was achieved (Post-Op 2).
RESULTS
Thirteen patients were included. The median age at surgery was 1.1 months (10 days-3 months). All 13 patients had baseline severe OSA, with a median obstructive apnea-hypopnea index of 33 events/h and a median O nadir of 73%. Post-Op 1 PSG was done at a median of 6 days after surgery. Median first postoperative obstructive apnea-hypopnea index in all 13 patients was 6.8 events/h, with a median O nadir of 87%. A median additional distraction of 3 mm was needed beyond the traditionally recommended advancement. Long-term follow-up studies at or after 1 year were done in 5 patients, all showing persistent nonsevere OSA.
CONCLUSIONS
This is the first case series utilizing PSGs as a guide for mandibular distraction osteogenesis in patients with micrognathia showing the need for jaw overcorrection to achieve resolution of OSA.
CITATION
Kochhar R, Modi V, de Silva N, et al. Polysomnography-guided mandibular distraction osteogenesis in Pierre Robin sequence patients. . 2022;18(7):1749-1755.
Topics: Airway Obstruction; Humans; Infant; Mandible; Micrognathism; Osteogenesis, Distraction; Pierre Robin Syndrome; Polysomnography; Retrospective Studies; Sleep Apnea, Obstructive; Treatment Outcome
PubMed: 35332870
DOI: 10.5664/jcsm.9960 -
Genetics in Medicine : Official Journal... Jun 2022This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.
PURPOSE
This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.
METHODS
Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.
RESULTS
In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported.
CONCLUSION
ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required.
Topics: Cataract; Child; Dwarfism; Female; Fetal Growth Retardation; Hepatoblastoma; Humans; Intellectual Disability; Liver Neoplasms; Male; Micrognathism; Phenotype; Syndrome
PubMed: 35300924
DOI: 10.1016/j.gim.2022.02.005 -
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