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International Journal of Oral and... Apr 2023The aims of this cohort study were to compare the mandibular morphology between patients with Robin sequence (RS) and controls, and to examine the effects of mandibular...
The aims of this cohort study were to compare the mandibular morphology between patients with Robin sequence (RS) and controls, and to examine the effects of mandibular distraction osteogenesis (MDO) using different vectors. Measurements of the mandibles of 80 patients with RS and 46 controls aged< 90 days were made using computed tomography. The data were compared among isolated RS patients (n = 58), syndromic RS patients (n = 22), and controls. Patients with RS exhibited significantly shorter ramus and body lengths and larger symphyseal angles than controls (all P < 0.001). Patients with isolated RS had shorter body lengths (P < 0.001), while syndromic patients had shorter ramus and body lengths (both P < 0.001) than controls. Seventy RS patients underwent MDO. Pre-MDO (n = 37) and post-MDO (n = 29) mandibular measurements were compared between patients undergoing MDO with a vertical vector and those undergoing MDO with a horizontal vector. Polysomnography data from part of the cohort highlighted the effectiveness of both vectors. MDO with a horizontal vector conferred 11% and 36% increases in ramus and body length, respectively, while these increases were 34% and 27.5%, respectively, with a vertical vector. MDO with a vertical vector was effective in lengthening ramus and body components and should be considered in the presence of ramus hypoplasia.
Topics: Humans; Infant; Cohort Studies; Retrospective Studies; Pierre Robin Syndrome; Osteogenesis, Distraction; Mandible; Polymers; Treatment Outcome; Airway Obstruction
PubMed: 35985910
DOI: 10.1016/j.ijom.2022.07.007 -
American Journal of Medical Genetics.... Jun 2024Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex,...
Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. The classic finding of fifth digit hypo- or aplasia is seen variably. ARID2, previously described, is one of the less frequently observed gene changes in CSS. Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. We report here a cohort of 17 individuals with ARID2 variants from the Coffin-Siris/BAF clinical registry and detail their medical challenges as well as developmental progress. Feeding difficulties, hypotonia, and short stature occur often, and hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer. Individuals appear to have mild to moderate intellectual impairment and may carry additional diagnoses such as ADHD. Further phenotypic description of this gene will aid clinicians caring for individuals with this rarer form of CSS.
Topics: Humans; Micrognathism; Intellectual Disability; Neck; Hand Deformities, Congenital; Face; Phenotype; Male; Female; Transcription Factors; Abnormalities, Multiple; Child; Child, Preschool; Infant; Mutation; Adolescent; DNA-Binding Proteins; Genetic Predisposition to Disease
PubMed: 38243407
DOI: 10.1002/ajmg.a.63540 -
The Cleft Palate-craniofacial Journal :... Mar 2020The purpose of this investigation was to assess the and the ogy of individuals with Treacher Collins syndrome (TCS) when compared to vertical skeletal class II...
OBJECTIVES
The purpose of this investigation was to assess the and the ogy of individuals with Treacher Collins syndrome (TCS) when compared to vertical skeletal class II individuals. It is our hypothesis that the upper airways of individuals with TCS are reduced in view of the skeletal pattern and the maxillomandibular dysmorphologies.
MATERIALS AND METHODS
Cone-beam computed tomography scans of 26 individuals had the pharyngeal volume (V) and minimal cross-sectional area (mCSA) evaluated. Study group (TCS) was formed by 13 scans of patients with TCS (7 males and 6 females; 20.2 ± 4.7 years). Control group (CG) assembled 13 scans of nonaffected individuals with the same type of skeletal pattern (2 males and 11 females; 26.6 ± 5.4 years). Cephalometric data of maxillomandibular position, maxillomandibular dimensions, and growth pattern were assessed. Statistical analysis ( ≤ .05) included Student test and Pearson correlation coefficient.
RESULTS
Although reduced, pharyngeal V and mCSA of TCS were not statistically different from the CG. On both groups, mCSA was mostly at the oropharyngeal level. Individuals with TCS presented retrognathic chin, reduced maxillomandibular dimensions, and increased clockwise rotation of the palatal plane. Maxillary and mandibular lengths were correlated with pharyngeal V and mCSA.
CONCLUSIONS
The pharyngeal dimensions of individuals with TCS are impacted by the micrognathia and retrognathia. In association with the skeletal pattern, the reduction of the airways, although not statistically significant, may explain the increased prevalence of airways disorder in this syndrome.
Topics: Cephalometry; Cone-Beam Computed Tomography; Female; Humans; Imaging, Three-Dimensional; Male; Mandible; Mandibulofacial Dysostosis; Maxilla; Pharynx
PubMed: 31801369
DOI: 10.1177/1055665619885555 -
Disease Models & Mechanisms Aug 2022Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes...
Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (orofaciodigital syndrome 14), we identified disruptions in the FGF23-PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. Although pharmacological intervention with the U.S. Food and Drug Administration (FDA)-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target SPRY2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in molecular, cellular and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options.
Topics: Cilia; Ciliopathies; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Micrognathism; Phenotype; Proteins
PubMed: 35818799
DOI: 10.1242/dmm.049611 -
American Journal of Medical Genetics.... Sep 2022Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12... (Review)
Review
Coffin-Siris syndrome (CSS) is an autosomal dominant neurodevelopmental syndrome that can present with a variety of structural birth defects. Pathogenic variants in 12 genes have been shown to cause CSS. Most of these genes encode proteins that are a part of the mammalian switch/sucrose non-fermentable (mSWI/SNF; BAF) complex. An association between genes that cause CSS and congenital diaphragmatic hernia (CDH) has been suggested based on case reports and the analysis of CSS and CDH cohorts. Here, we describe an unpublished individual with CSS and CDH, and we report additional clinical information on four published cases. Data from these individuals, and a review of the literature, provide evidence that deleterious variants in ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, and SMARCC2, which are associated with CSS types 1-8, respectively, are associated with the development of CDH. This suggests that additional genetic testing to identify a separate cause of CDH in an individual with CSS may be unwarranted, and that comprehensive genetic testing for individuals with non-isolated CDH should include an evaluation of CSS-related genes. These data also suggest that the mSWI/SNF (BAF) complex may play an important role in diaphragm development.
Topics: Abnormalities, Multiple; Chromosomal Proteins, Non-Histone; DNA Helicases; DNA-Binding Proteins; Face; Hand Deformities, Congenital; Hernias, Diaphragmatic, Congenital; Humans; Intellectual Disability; Micrognathism; Neck; Nuclear Proteins; Transcription Factors
PubMed: 35796094
DOI: 10.1002/ajmg.a.62889 -
American Journal of Medical Genetics.... Jan 2022Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates....
Robin sequence (RS), the triad of micrognathia, glossoptosis, and airway obstruction, is a major cause of respiratory distress and feeding difficulties in neonates. Robin sequence can be associated with other medical or developmental comorbidities in ~50% of cases ("syndromic" RS). As well, RS is variably associated with cleft palate (CP). Previous studies have not investigated differences in clinical characteristics of children with RS based on presence or absence of CP. We retrospectively reviewed 175 children with RS and compared genetic diagnoses, medical and developmental comorbidities, severity of airway obstruction, and feeding outcomes between those with and without CP. Strikingly, 45 of 45 (100%) children with RS without CP were classified as syndromic due to presence of comorbidities unrelated to RS, while 83 of 130 (64%) children with RS with CP were classified as syndromic. Among 128 children with syndromic RS, there were no differences in severity of airway obstruction, surgical intervention rate or type, or feeding outcome at 12 months based on CP status. Our findings support the conclusion that the pathogenesis of RS without CP is distinct from RS with CP and more likely to cause additional medical or developmental problems. Alternatively, children with RS without CP and without additional anomalies present may be under recognized.
Topics: Airway Obstruction; Child; Cleft Palate; Humans; Infant, Newborn; Micrognathism; Pierre Robin Syndrome; Retrospective Studies
PubMed: 34569146
DOI: 10.1002/ajmg.a.62515 -
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 -
Clinical Genetics Aug 2020Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged...
Variants in the FIG4 gene, which encodes a phosphatidylinositol-3,5-bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi-allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot-Marie-Tooth disease type-4J (CMT4J) and Yunis-Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant-onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.
Topics: Age of Onset; Charcot-Marie-Tooth Disease; Child; Child, Preschool; Cleidocranial Dysplasia; Dystonia; Ectodermal Dysplasia; Female; Flavoproteins; Genetic Predisposition to Disease; Genotype; Humans; Limb Deformities, Congenital; Male; Micrognathism; Muscle Hypotonia; Mutation; Pedigree; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 32385905
DOI: 10.1111/cge.13771 -
Journal of Medical Genetics Aug 2022Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication...
INTRODUCTION
Replication of the nuclear genome is an essential step for cell division. Pathogenic variants in genes coding for highly conserved components of the DNA replication machinery cause Meier-Gorlin syndrome (MGORS).
OBJECTIVE
Identification of novel genes associated with MGORS.
METHODS
Exome sequencing was performed to investigate the genotype of an individual presenting with prenatal and postnatal growth restriction, a craniofacial gestalt of MGORS and coronal craniosynostosis. The analysis of the candidate variants employed bioinformatic tools, structural protein analysis and modelling in budding yeast.
RESULTS
A novel homozygous missense variant NM_016095.2:c.341G>T, p.(Arg114Leu), in was identified. Both non-consanguineous healthy parents carried this variant. Bioinformatic analysis supports its classification as pathogenic. Functional analyses using yeast showed that this variant increases sensitivity to nicotinamide, a compound that interferes with DNA replication processes. The phylogenetically highly conserved residue p.Arg114 localises at the docking site of CDC45 and MCM5 at GINS2. Moreover, the missense change possibly disrupts the effective interaction between the GINS complex and CDC45, which is necessary for the CMG helicase complex (Cdc45/MCM2-7/GINS) to accurately operate. Interestingly, our patient's phenotype is strikingly similar to the phenotype of patients with -related MGORS, particularly those with craniosynostosis, mild short stature and patellar hypoplasia.
CONCLUSION
is a new disease-associated gene, expanding the genetic aetiology of MGORS.
Topics: Cell Cycle Proteins; Chromosomal Proteins, Non-Histone; Congenital Microtia; Craniosynostoses; Growth Disorders; Humans; Micrognathism; Patella; Saccharomyces cerevisiae
PubMed: 34353863
DOI: 10.1136/jmedgenet-2020-107572 -
The Journal of Craniofacial Surgery May 2022Maxillary hypoplasia is common in patients with cleft lip and palate (CL/P), and its etiology is incompletely understood. The purpose of this study is to evaluate facial...
Maxillary hypoplasia is common in patients with cleft lip and palate (CL/P), and its etiology is incompletely understood. The purpose of this study is to evaluate facial suture patency in patients with CL/P and maxillary hypoplasia. The authors hypothesize that patients with CL/P will demonstrate higher rates of premature midfacial suture fusion in comparison to unaffected controls. Skeletally mature patients with CL/P and midface hypoplasia were identified, along with a cohort of unaffected age- and sex-matched controls. High-resolution facial computed tomography scans were evaluated for the presence of facial suture fusion. Utilizing a previously published suture fusion grading scale, the facial sutures were classified as open, partially open, closed, or pathologically absent. Thirty-one CL/P patients with midface hypoplasia were identified, with age and sex-matched controls. The frequency of intermaxillary suture fusion did not differ between patients with CL/P and unaffected controls (P > 0.05.) Pathologic absence of the midpalatal suture was more commonly present in patients with CL/ P and midface hypoplasia in comparison to unaffected controls (P < 0.05.) The role of midfacial sutures in the development of midfacial hypoplasia seen in CLP has not previously been studied or described. Our data show that the midpalatal suture is frequently pathologically absent in patients with CL/P and maxillary hypoplasia. The authors did not identify statistically significant differences in other midfacial sutures between patients with CL/P and controls, leading us to conclude that midfacial sutures may not play a key role in the development of midfacial hypoplasia.
Topics: Child; Cleft Lip; Cleft Palate; Face; Humans; Maxilla; Micrognathism; Sutures
PubMed: 35034086
DOI: 10.1097/SCS.0000000000008469