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European Journal of Human Genetics :... Jul 2024Biallelic pathogenic variants in CDC45 are associated with Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), which also includes short stature and...
Biallelic pathogenic variants in CDC45 are associated with Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), which also includes short stature and absent/hypoplastic patellae. Identified variants act through a hypomorphic loss of function mechanism, to reduce CDC45 activity and impact DNA replication initiation. In addition to missense and premature termination variants, several pathogenic synonymous variants have been identified, most of which cause increased exon skipping of exon 4, which encodes an essential part of the RecJ-orthologue's DHH domain. Here we have identified a second cohort of families segregating CDC45 variants, where patients have craniosynostosis and a reduction in height, alongside common facial dysmorphisms, including thin eyebrows, consistent with MGORS7. Skipping of exon 15 is a consequence of two different variants, including a shared synonymous variant that is enriched in individuals of East Asian ancestry, while other variants in trans are predicted to alter key intramolecular interactions in α/β domain II, or cause retention of an intron within the 3'UTR. Our cohort and functional data confirm exon skipping is a relatively common pathogenic mechanism in CDC45, and highlights the need for alternative splicing events, such as exon skipping, to be especially considered for variants initially predicted to be less likely to cause the phenotype, particularly synonymous variants.
Topics: Humans; Exons; Cell Cycle Proteins; Craniosynostoses; Female; Male; Alternative Splicing; Pedigree; Growth Disorders; Micrognathism; Patella; Congenital Microtia
PubMed: 38467731
DOI: 10.1038/s41431-024-01583-1 -
The Journal of Craniofacial Surgery Jun 2024The aim of this cross-sectional study was to evaluate, via cone-beam computed tomography, the long-term postoperative outcome in children treated with mandibular...
AIM
The aim of this cross-sectional study was to evaluate, via cone-beam computed tomography, the long-term postoperative outcome in children treated with mandibular distraction osteogenesis.
MATERIALS AND METHODS
All young patients treated with mandibular distraction osteogenesis (MDO), during a 16-year period, at the University Department of Oral and Maxillofacial Surgery of a Pediatric Hospital, were recalled, and various clinical and radiographic parameters were recorded.
RESULTS
Eleven patients were included: 5 with hemifacial microsomia (HFM) and 6 with mandibular micrognathia. In all cases, MDO had been successful in regular follow-up and decannulation, soon after MDO, was achieved in all tracheostomy cases. The long-term result in cases of HFM was found stable, functionally and esthetically accepted, although less satisfactory than in regular follow-up; in micrognathia patients, relapse of different degrees was registered in 4 of 6 cases, without any need for tracheostomy though. Detailed and accurate information was obtained by cone-beam computed tomography (CBCT). The shape of the regenerated bone was irregular in HFM cases and relatively normal in the micrognathia cases. Quality of the regenerated bone was normal in all patients. The irregular shape registered in HFM cases did not compromise a safe orthognathic operation.
CONCLUSIONS
Distraction osteogenesis remains an early treatment choice in cases of mandibular deformities. Long-term findings showed that there is a degree of relapse with growth, which was more obvious in mandibular micrognathia cases. Computed tomography contributes to detailed evaluation of changes at the distraction site.
Topics: Humans; Osteogenesis, Distraction; Cone-Beam Computed Tomography; Female; Child; Male; Adolescent; Cross-Sectional Studies; Mandible; Treatment Outcome; Micrognathism; Facial Asymmetry; Child, Preschool
PubMed: 38376164
DOI: 10.1097/SCS.0000000000010044 -
Journal of Cranio-maxillo-facial... Apr 2024The aim of this study is to present a sequential strategy of soft-tissue, non-osteogenic distraction with a novel device, followed by microvascular bony reconstruction...
The aim of this study is to present a sequential strategy of soft-tissue, non-osteogenic distraction with a novel device, followed by microvascular bony reconstruction for severe cases of mandibular hypoplasia. The case of a 21-year-old woman with Goldenhar syndrome is presented, whose mandible remained severely hypoplastic despite previous attempts at distraction and was not suitable for further osteogenic distraction. Soft tissue deficiency and pin track scarring prevented free fibular transfers. A personalized distractor, anchored to the cranium and the mandibular symphysis, was designed to expand the soft tissues while allowing for physiological temporomandibular joint (TMJ) movement without compression forces. Internal distractors were placed along the osteotomies to prevent condylar luxation. After completion of the soft tissue distraction, the native mandible was resected except for the condyles and reconstructed with two free fibula flaps. This report represents the proof of concept of a sequential approach to severe lower face soft-tissue and bone deficiency, which preserves TMJ function and avoids the transfer of poorly matched skin to the face.
Topics: Female; Humans; Young Adult; Adult; Goldenhar Syndrome; Mandible; Plastic Surgery Procedures; Micrognathism; Skull; Osteogenesis, Distraction
PubMed: 38369394
DOI: 10.1016/j.jcms.2024.01.023 -
Journal of the College of Physicians... Feb 2024To evaluate the correlation of cerebrospinal fluid total protein and serum neutrophil-to-lymphocyte ratio with the clinical outcomes and the various clinical and...
OBJECTIVE
To evaluate the correlation of cerebrospinal fluid total protein and serum neutrophil-to-lymphocyte ratio with the clinical outcomes and the various clinical and electrophysiological variants of Guillain-Barre syndrome.
STUDY DESIGN
Cross-sectional study. Place and Duration of the Study: Department of Neurology, Mayo Hospital and King Edward Medical University, Lahore, Pakistan, from November 2022 to April 2023.
METHODOLOGY
Fourty-six Guillain-Barre syndrome patients, aged 12-70 years, were included in the study diagnosed by using the Brighton's criteria. Functional disability and respiratory insufficiency were assessed by using the modified Hughes disability score and the Erasmus Guillain-Barre syndrome respiratory insufficiency score, respectively. Serum neutrophil-to-lymphocyte ratio and cerebrospinal fluid total protein were calculated for each patient at the time of admission.
RESULTS
Axonal variants had a higher mean neutrophil-to-lymphocyte ratio (5.29 ± 4.38) than demyelinating variants (4.71 ± 3.4) and Miller-Fischer syndrome (3 ± 2.828). This ratio was positively correlated with the modified Hughes's disability score (r = 0.790, p = 0.001) and the Erasmus Guillain-Barre syndrome respiratory insufficiency score (r = 0.936, p = 0.002). Mean cerebrospinal fluid total protein was higher for demyelinating (218 ± 136 mg/dl) than axonal variants (86 ± 56 mg/dl) and Miller-Fischer syndrome (34 ± 21 mg/dl). However, higher modified Hughes disability score (4-6) (r = 0.020, p = 0.117) and a high Erasmus Guillain-Barre syndrome respiratory insufficiency score (5-7) (r = 0.115, p = 0.302) did not significantly affect mean cerebrospinal fluid total proteins.
CONCLUSION
Serum neutrophil-to-lymphocyte ratio can be regarded as a reliable biomarker to assess disease severity and clinical outcome in Guillain-Barre syndrome. Cerebrospinal fluid total protein is a poor predictor of the prognosis and severity of Guillain-Barre syndrome.
KEY WORDS
Guillain-Barre syndrome (GBS), Clinical outcome, Cerebrospinal fluid total protein (CSF-TP), Neutrophil-to-lymphocytic ratio (NLR), Prognostic biomarker.
Topics: Humans; Guillain-Barre Syndrome; Neutrophils; Cross-Sectional Studies; Biomarkers; Lymphocytes; Respiratory Insufficiency; Chromosome Deletion; WAGR Syndrome; Abnormalities, Multiple; Limb Deformities, Congenital; Mandibulofacial Dysostosis; Micrognathism; Chromosomes, Human, Pair 11
PubMed: 38342870
DOI: 10.29271/jcpsp.2024.02.187 -
Genes Dec 2023Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb... (Review)
Review
Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb deformities, mandibular hypoplasia, hypoplasia or absence of thumbs, microretrognathia, and ankylosis of the temporomandibular joint. The prevalence is very rare and the literature describes only about a hundred cases of Nager syndrome. There is evidence of autosomal dominant and autosomal recessive inheritance for Nager syndrome, suggesting genetic heterogeneity. The majority of the described causes of Nager syndrome include pathogenic variants in the gene, which encodes a component of the spliceosome; therefore, the syndrome belongs to the spliceosomopathy group of diseases. The diagnosis is made on the basis of physical and radiological examination and detection of mutations in the gene. Due to the diversity of defects associated with Nager syndrome, patients require multidisciplinary, complex, and long-lasting treatment. Usually, it starts from birth until the age of twenty years. The surgical procedures vary over a patient's lifetime and are related to the needed function. First, breathing and feeding must be facilitated; then, oral and facial clefts should be addressed, followed by correcting eyelid deformities and cheekbone reconstruction. In later age, a surgery of the nose and external ear is performed. Speech and hearing disorders require specialized logopedic treatment. A defect of the thumb is treated by transplanting a tendon and muscle or transferring the position of the index finger. In addition to surgery, in order to maximize a patient's benefit and to reduce functional insufficiency, complementary treatments such as rehabilitation and physiotherapy are recommended. In our study, we describe eight patients of different ages with various cases of Nager syndrome. The aim of our work was to present the actual genetic knowledge on this disease and its treatment procedures.
Topics: Child; Humans; Young Adult; Adult; Mandibulofacial Dysostosis; Cleft Palate; Micrognathism; Syndrome; RNA Splicing Factors
PubMed: 38254920
DOI: 10.3390/genes15010029 -
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 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jan 2024To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS).
OBJECTIVE
To explore the genetic basis of two children with unexplained psychomotor developmental delay and facial dysmorphisms suggestive of Coffin-Siris syndrome (CSS).
METHODS
A boy and a girl suspected for CSS at the 980th Hospital of the People's Liberation Army Joint Service Support Force respectively in July 2019 and January 2021, and seven members from their families, were selected as the study subjects. Clinical data and family history of the children were collected, and detailed physical examination was carried out, in addition with laboratory and related auxiliary examinations. Potential variants and copy number variations (CNVs) were detected by whole exome sequencing (WES) and copy number variation sequencing (CNV-seq).
RESULTS
Child 1, an 8-month-old female, had featured microcephaly, atrial septal defect, curving of fifth finger/toe, and low limb muscle tone. Child 2 was a 2.5-year-old male with language delay, social impairment, dense hair but no curving of the fifth fingers. Genetic testing revealed that child 1 had loss of heterozygosity for exons 8 to 21 of the ARID1B gene, which was unreported previously. Family verification showed that both of her parents were of the wild type. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG) and American Society of Molecular Pathology (AMP), the variant was rated as pathogenic (PVS1+PS2+PM2-supporting). Child 2 was found to harbor a heterozygous c.4263-6 (IVS17) T>G variant of the ARID1B gene. Transcriptome sequencing confirmed that the variant can affect the normal splicing, resulting in retention of a 5 bp sequence in intron 17. Family verification showed that both of his parents were of the wild type. Based on the guidelines from the ACMG, the variant was rated as pathogenic (PS2+PM2-supporting+PP3+PS3).
CONCLUSION
WES and RNA-seq have confirmed the diagnosis of CSS in both children. Discovery of the novel variants has expanded the spectrum of pathogenic mutations underlying CSS, and provided a basis for the genetic counseling.
Topics: Child, Preschool; Female; Humans; Infant; Male; Abnormalities, Multiple; DNA Copy Number Variations; DNA-Binding Proteins; Intellectual Disability; Micrognathism; Mutation; Transcription Factors
PubMed: 38171562
DOI: 10.3760/cma.j.cn511374-20221026-00721 -
Journal of Ultrasound in Medicine :... Mar 2024To prospectively evaluate the prognosis of fetuses diagnosed with micrognathia using prenatal ultrasound screening.
OBJECTIVE
To prospectively evaluate the prognosis of fetuses diagnosed with micrognathia using prenatal ultrasound screening.
METHODS
Between January 2019 and December 2022, a normal range of IFA to evaluate the facial profile in fetuses with micrognathia in a Chinese population between 11 and 20 gestational weeks was established, and the pregnancy outcomes of fetal micrognathia were described. The medical records of these pregnancies were collected, including family history, maternal demographics, sonographic findings, genetic testing results, and pregnancy outcomes.
RESULTS
Ultrasound identified 25 patients with fetal micrognathia, with a mean IFA value of 43.6°. All cases of isolated fetal micrognathia in the initial scans were non-isolated in the following scans. A total of 78.9% (15/19) cases had a genetic cause confirmed, including 12 with chromosomal abnormalities and 3 with monogenic disorders. Monogenic disorders were all known causes of micrognathia, including two cases of campomelic dysplasia affected by SOX9 mutations and one case of mandibulofacial dysostosis with an EFTUD2 mutation. In the end, 19 cases were terminated, 1 live birth was diagnosed as Pierre Robin syndrome, and 5 cases were lost to follow-up.
CONCLUSION
IFA is a useful indicator and three-dimensional ultrasound is a significant support technique for fetal micrognathia prenatal diagnosis. Repeat ultrasound monitoring and genetic testing are crucial, with CMA recommended and Whole exome sequencing performed when normal arrays are reported. Isolated fetal micrognathia may be an early manifestation of monogenic disorders.
Topics: Pregnancy; Female; Humans; Micrognathism; Prospective Studies; Ultrasonography, Prenatal; Prenatal Diagnosis; Fetus; Peptide Elongation Factors; Ribonucleoprotein, U5 Small Nuclear
PubMed: 38164991
DOI: 10.1002/jum.16379 -
Acta Anaesthesiologica Scandinavica Apr 2024We investigated how syndromic versus nonsyndromic forms of micrognathia impacted difficult intubation outcomes in children. Primary outcome was the first-attempt success...
BACKGROUND
We investigated how syndromic versus nonsyndromic forms of micrognathia impacted difficult intubation outcomes in children. Primary outcome was the first-attempt success rate of tracheal intubation, secondary outcomes were number of intubation attempts and complications. We hypothesized that syndromic micrognathia would be associated with lower first-attempt success rate.
METHODS
In micrognathic patients enrolled in the Pediatric Difficult Intubation Registry (08/2012-03/2019) we retrospectively compared demographic and clinical characteristics between children with nonsyndromic and syndromic micrognathia using standardized mean differences (SMD) and assessed the association of the presence of syndrome with the primary and secondary outcomes using propensity score matching analysis with and without matching for airway assessment findings.
RESULTS
Nonsyndromic patients (628) were less likely to have additional airway abnormalities. Syndromic patients (216) were less likely to have unanticipated difficult intubation (2% vs. 20%, SMD 0.59). First-attempt success rates of intubation were: 38% in the syndromic versus 34% in the nonsyndromic group (odds ratio [OR] 1.18; 95% confidence intervals [95% CI] 0.74, 1.89; p = .478), and 37% versus 37% (OR 0.99; 95% CI 0.66, 1.48; p = .959). Median number of intubation attempts were 2 (interquartile range [IQR]: 1, 3; range: 1, 8) versus 2 (IQR: 1, 3; range 1, 12) (median regression coefficient = 0; 95% CI: -0.7, 0.7; p = .999) and 2 (IQR: 1, 3; range: 1, 12) versus 2 (IQR: 1, 3; range 1, 8) (median regression coefficient = 0; 95% CI: -0.5, 0.5; p = .999). Complication rates were 14% versus 22% (OR 0.6; 95% CI 0.34, 1.04; p = .07) and 16% versus 21% (OR 0.71; 95% CI 0.43, 1.17; p = .185).
CONCLUSIONS
Presence of syndrome was not associated with lower first-attempt success rate on intubation, number of intubation attempts, or complication rate among micrognathic patients difficult to intubate, despite more associated craniofacial abnormalities. Nonsyndromic patients were more likely to have unanticipated difficult intubations, first attempt with direct laryngoscopy.
Topics: Child; Humans; Retrospective Studies; Micrognathism; Intubation, Intratracheal; Laryngoscopy; Registries
PubMed: 38164092
DOI: 10.1111/aas.14369 -
Human Genetics Jan 2024Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular...
Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.
Topics: Adult; Humans; Child; Intellectual Disability; Abnormalities, Multiple; Micrognathism; Hand Deformities, Congenital; Neck; Phenotype; DNA Helicases; Nuclear Proteins; Transcription Factors; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Face
PubMed: 38117302
DOI: 10.1007/s00439-023-02622-5