Nonsyndromic Cases Research Articles

Comparison of syndromic and non-syndromic craniosynostosis cases followed in a tertiary pediatric intensive care unit: a case control study.

Craniosynostosis, marked by premature skull suture closure, manifests as isolated or syndromic cases. While isolated cases are more common, syndromic craniosynostoses are associated with a range of complications. This study aims to compare postoperative outcomes in isolated and syndromic craniosynostosis, hypothesizing greater complications in the latter. A case-control study was conducted with 30 pediatric patients with isolated (Group C) and syndromic (Group S) craniosynostosis undergoing surgery. Data on demographics, operative details, blood product transfusions, and postoperative complications were analyzed. Statistical analysis employed Chi-square, Fisher exact tests, and Mann-Whitney U tests. Perioperative bleeding and postoperative packed red blood cell (PRBC) transfusions were significantly higher in isolated cases. Morbidity analysis, including reoperation, massive bleeding, infection, hydrocephalus, and seizures indicated higher rates in syndromic cases. The rates of postoperative morbidities were 30% in syndromic and 10% in isolated cases (p = 0.053). Correlations revealed a low positive association between body weight and both PICU and hospital stays. Additionally, a low positive correlation was found between perioperative PRBC transfusion amount and PICU length of stay. The total number of morbidities showed a moderate positive correlation with PICU length of stay and a low positive correlation with hospital length of stay. Isolated craniosynostosis cases exhibited higher perioperative bleeding and PRBC transfusions, potentially influenced by surgery at an earlier age. Although complications tended to be elevated in syndromic cases, no significant differences were observed. This study underscores the necessity for meticulous perioperative care, emphasizing individualized approaches considering age-related factors and associated complications in managing craniosynostosis cases.

Maternal factors increase risk of orofacial cleft: a meta-analysis

Orofacial clefts are among the most prevalent birth defects, with severe medical and psychosocial consequences. Cleft lip with or without cleft palate (CL ± P) and cleft palate only (CPO) affect on average nearly 1/700 births worldwide. The cause of most non-syndromic cases is unknown. Maternal factors and disorders are assumed to modify the risk of orofacial clefting. In the present study, we performed a systematic review and meta-analysis to analyze the effects of maternal underweight, obesity, hypertension, diabetes, as well as smoking, and alcohol consumption on the development of orofacial clefts. As CL ± CP and CPO have distinct pathogenetic backgrounds, these cleft subtypes were assessed separately. Altogether, 5,830 studies were identified and 64 of them met the inclusion and exclusion criteria. Obesity significantly elevated the odds of clefting (OR = 1.28, CI:1.08–1.51) (ORCL±CP = 1.23, CI:1.01–1.50; ORCPO = 1.31, CI:0.97–1.77). Maternal underweight also significantly increased the odds of clefting (OR = 1.21 CI:1.06–1.38). In mothers with type 1 diabetes, the odds of cleft development were significantly elevated (OR = 1,75, CI:1.45–2.12). Essential hypertension was also associated with higher odds of developing cleft (OR = 1.55, CI:1.18–2.03). Smoking during pregnancy significantly elevated the odds of cleft development (OR = 1.55, CI:1.34–1.79) (ORCL±CP = 1.58, CI:1.36–1.83; ORCPO = 1.50, CI:1.15–1.96). Passive smoking was even more damaging than active tobacco use, but alcohol consumption had no effect. In conclusion, this study clearly showed the importance of maintaining normal maternal body weight and emphasized the importance of hypertension and type 1 diabetes care in the first months of pregnancy. It also highlighted similarnegative effects of passive and active smoking, while alcohol consumption did not seem to be a significant risk factor for cleft development. However, there is a complete lack of available studies on the interactions of these factors, which is an essential direction for improving prevention.

A study of the cerebral venous drainage patterns in craniosynostosis: nonsyndromic cases and the induction effect of Virchow's law on venous sinuses.

Surgical intervention is commonly necessary for craniosynostosis. One of the preoperative concerns revolves around the cerebral venous drainage pattern and its potential involvement during surgery. Although there have been reports regarding venous drainage patterns in syndromic craniosynostosis, studies of nonsyndromic cases have been rare. In the present study, the aim was to study venous drainage patterns in nonsyndromic craniosynostosis. Nonsyndromic cases at a single institute were retrospectively reviewed, and cerebral venous drainage in the posterior (transverse sinus [TS]) and anterior (cavernous sinus [CS] and para-CS [ParaCS]) venous routes was systematically investigated. The occipital sinus (OS) and emissary veins were also evaluated. A total of 89 nonsyndromic cases were evaluated, including 12 right coronal synostosis (RCS), 14 left coronal synostosis (LCS), 15 bilateral coronal synostosis (BCS), 36 sagittal synostosis, 6 metopic synostosis, and 6 combined metopic-sagittal synostosis cases. All venous studies were performed using MR venography. There was a significant difference among all six groups in TS dominance (p = 0.0108). In unilateral coronal synostosis (UCS; including RCS and LCS) cases, 76.9% had TS dominance on the opposite side of the synostotic suture (20 of 26 UCS, including 10 of 12 RCS and 10 of 14 LCS). There was a significant difference in the incidence of OS, with the highest incidence observed in the BCS group (33.3%, p = 0.027). CS/ParaCS venous drainage was observed in 94.4% of cases on the right side and 95.5% on the left side, showing no significant difference among the groups on both sides. No visible emissary vein was observed in any of the groups. A significantly higher predominance of left TS was found in RCS cases, in contrast with the typical right-side predominance seen in the normal population. In addition, the majority of UCS cases exhibited TS dominance on the opposite side of the synostotic suture. Furthermore, the present results showed a significant difference in the prevalence of OS, which was predominantly observed in BCS cases. These findings could be explained by the induction effect on venous sinuses by the compensatory growth of the skull according to Virchow's law, suggesting that synostotic sutures induce compensatory skull expansion in regions farthest (diagonally) from the affected sutures, thereby enlarging nearby venous sinuses.

Genetic heterogeneity in autosomal recessive hearing loss: a survey of Brazilian families.

Hearing loss is a frequent sensory impairment type in humans, with about 50% of prelingual cases being attributed to genetic factors. Autosomal recessive hearing loss (ARHL) exhibits great locus heterogeneity and is responsible for 70%-80% of hereditary nonsyndromic cases. A total of 90 unrelated Brazilian individuals were selected for having hearing loss of presumably autosomal recessive inheritance, either born from consanguineous marriages or belonging to families with two or more affected individuals in the sibship and most cases were of normal hearing parents. In all cases, common pathogenic variants in GJB2 (c.35delG), GJB6 [del(GJB6-D13S1830) and del(GJB6-D13S1854)] and MT-RNR1 (m.1555A>G) were discarded and most were previously assessed by complete Sanger sequencing of GJB2. Their genetic material was analyzed through next-generation sequencing, targeting 99 hearing loss-related genes and/or whole exome sequencing. In 32 of the 90 probands (36,7%) causative variants were identified, with autosomal recessive inheritance confirmed in all, except for two cases due to dominant variants (SIX1 and P2RX2). Thirty-nine different causative variants were found in 24 different known hearing loss-associated genes, among which 10 variants are novel, indicating wide genetic heterogeneity in the sample, after exclusion of common pathogenic variants. Despite the genetic heterogeneity, some genes showed greater contribution: GJB2, CDH23, MYO15A, OTOF, and USH2A. The present results confirmed that next-generation sequencing is an effective tool for identifying causative variants in autosomal recessive hearing loss. To our knowledge, this is the first report of next-generation sequencing being applied to a large cohort of pedigrees with presumable autosomal recessive hearing loss in Brazil and South America.

Visual Prognosis in Craniosynostosis Patients: A 20-year Retrospective Cohort Study at a Tertiary Referral Center in Thailand

Objective: This study aims to evaluate the visual prognosis in craniosynostosis patients in order to identify ophthalmologic manifestations in craniosynostosis patients and strabismus surgery outcomes in these patients. Materials and Methods: The medical record charts of craniosynostosis patients were reviewed retrospectively from January 2000 to June 2023. All the relevant patient data, such as age, sex, visual acuity, ophthalmologic examinations, and strabismus surgery outcomes were recorded. Results: In total, 123 patients were included in the study, among whom 65 (52.84%) were male. Overall, there were 70 cases (56.91%) of non-syndromic craniosynostosis, and 53 cases of syndromic craniosynostosis, comprising Crouzon syndrome (15 cases), Apert syndrome (8 cases), Pfeiffer syndrome (2 cases), and other syndromes (28 cases). The mean age at first examination was 3.11 years old. Out of 107 cases with visual impairment at the first visit, 92 (85.98%) showed no visual impairment at the last visit. Among the 87 patients with strabismus, 28 (32.18%) had strabismus at the primary position, with exotropia being the most common type (18 cases). Eight cases underwent strabismus surgery, and 4 cases achieved success (deviation < 10 prism diopters). Other ophthalmologic manifestations were lagophthalmos, exposure keratopathy, ptosis, proptosis, and nasolacrimal duct obstruction. Conclusion: Among the craniosynostosis cases, 85.98% had no visual impairment, with the common ophthalmologic manifestations being refractive errors, strabismus, lagophthalmos, and exposure keratopathy. The syndromic craniosynostosis cases showed worse visual outcomes and a higher incidence of ocular diseases than non-syndromic cases. The success rate for strabismus surgery in craniosynostosis patients was 50%.

Genetic Insights Into Hypothalamic Hamartoma: Unraveling Somatic Variants.

Hypothalamic hamartomas (HHs) are rare developmental brain lesions associated with drug-resistant epilepsy and often subjected to epilepsy surgery. Brain somatic variants in genes affecting the Sonic hedgehog (Shh) and primary cilia signaling pathways have been implicated in approximately 50% of nonsyndromic HH cases. This study aims to characterize a new cohort of 9 HH cases and elucidate their genetic etiology. We recruited 9 HH cases including 8 nonsyndromic cases of which 4 were type IV HH. Genomic DNA was extracted from peripheral blood and surgical brain tissues, and somatic variants were investigated using high-depth whole-exome sequencing. Pathogenic somatic variants in known HH genes (GLI3, OFD1, and PRKACA) were identified in 7 of the 9 cases. In addition, a 2-hit mutational event comprising a germline variant (predicted to impair kinase activity) and a somatic loss-of-heterozygosity was identified in TNK2, a gene encoding a brain-expressed tyrosine kinase. Our findings reinforce the role of somatic variants in Shh and cilia genes in HH cases while also shedding light on TNK2 as a potential novel disease-causing gene. This study emphasizes the increasing importance of brain mosaicism in epilepsy disorders and underscores the critical role of genetic diagnosis derived from resected brain tissue.

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

BackgroundThe plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or ‘endozepine’) increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.MethodsWe measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.ResultsCirculating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.ConclusionThese findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

The impact of neurosurgery on the neuropsychological development of patients with craniosynostosis: A scoping review

Introduction: Neuropsychological assessment evaluates the cognitive profile by identifying deficits and enabling monitoring. At HRAC-USP, patients with craniosynostoses undergo this assessment due to impacts on neuropsychomotor development (DNPM). These conditions may cause cranial fusion, restricting brain growth and adversely affecting cognitive functions. Evaluation is crucial for guiding therapeutic and surgical approaches and ensuring better outcomes. Objective: To identify how surgical procedures impact the neuropsychological profile of patients with syndromic and isolated craniosynostoses through a scoping review. Methodology: This scoping review was conducted in March 2024 using PubMed, Embase, BVS/Lilacs, and Scopus databases; 1,215 articles were found and 18 original articles (E1-18) in English were selected that addressed the question: "What is the impact of surgery on neuropsychological aspects in patients with craniosynostoses?" Results: Studies on craniosynostosis highlighted the predominance of isolated cases (83.3%), with surgeries performed before one year of age associated with better cognitive outcomes. The cranial expansion technique (38.8%) was effective in non-syndromic cases, while cranial remodeling showed varied results. After surgery, there were overall improvements in DNPM, but also risks of language delay and motor deficits, especially in patients operated on at older ages. Conclusion: Surgery for craniosynostosis can improve neuropsychological outcomes, especially when performed early and with appropriate surgical techniques. More invasive procedures may lead to better outcomes, including increased Total Intelligence Quotient and better academic performance. It is crucial to consider such factors to optimize outcomes, reduce neurodevelopmental risks, and continuously monitor language and executive functions.

Cochlear implantation in syndromic patients: difficulties and lessons learnt.

Identify the prevalence of syndromes in a cohort of patients who underwent cochlear implantation, to report on the presence of inner and middle ear malformations and highlight the surgical difficulties encountered. Observational, retrospective study. Tertiary referral children's hospital pediatric cochlear implant program. An IRB-approved retrospective chart review of children undergoing cochlear implantation at a tertiary academic medical center, from 2018 to 2023. Preoperative imaging data of syndromic patients in that cohort with special attention to the presence of inner ear or middle ear malformations were collected. Abnormal intraoperative findings and difficulties reported by the surgeons were also noted. 1024 children were unilaterally implanted for bilateral profound hearing loss. There were 45 cases diagnosed with associated syndromes (4.3%). The commonest syndromes were Jervell and Lange Nielsen (JLN) syndrome followed by Waardenberg syndrome (WS), in a prevalence of 34% and 32% respectively. These syndromes had no associated inner ear malformations (IEM). Less common syndromes included Branchio-oto-renal (BOR) syndrome, CHARGE association and Treacher Collins syndrome, 3 cases each, and keratosis icthyosis deafness syndrome (KID), Usher syndrome and Albino, 2 cases each and an H syndrome case. There were 9 cases (20%) with IEM, with 6 cases of perilymph gusher. Two cases had middle ear anomalies and one case had a facial nerve course abnormality. The outcome of these cases was similar to non-syndromic cases. Children with syndromic HL should be dealt with on a case by case scenario to diagnose inner and middle ear malformations. Additional disabilities can affect the rehabilitation procedures. All children with congenital hearing loss should undergo pediatric, cardiologic, ophthalmologic and nephrologic examination in order to exclude the syndromic etiology of hearing loss.

Database-assisted screening of autism spectrum disorder related gene set

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social and communication difficulties, along with repetitive behaviors. While genetic factors play a significant role in ASD, the precise genetic landscape remains complex and not fully understood, particularly in non-syndromic cases. The study performed an in silico comparison of three genetic databases. ClinVar, SFARI Gene, and AutDB were utilized to identify relevant gene subset and genetic variations associated with non-syndromic ASD. Gene set enrichment analysis (GSEA) and protein–protein interaction (PPI) network analysis were conducted to elucidate the biological significance of the identified genes. The integrity of ASD-related gene subset and the distribution of their variations were statistically assessed. A subset of twenty overlapping genes potentially specific for non-syndromic ASD was identified. GSEA revealed enrichment of biological processes related to neuronal development and differentiation, synaptic function, and social skills, highlighting their importance in ASD pathogenesis. PPI network analysis demonstrated functional relationships among the identified genes. Analysis of genetic variations showed predominance of rare variants and database-specific distribution patterns. The results provide valuable insights into the genetic landscape of ASD and outline the genes and biological processes involved in the condition, while taking into account that the study relied exclusively on in silico analyses, which may be subject to biases inherent to database methodologies. Further research incorporating multi-omics data and experimental validation is warranted to enhance our understanding of non-syndromic ASD genetics and facilitate the development of targeted research, interventions and therapies.

Pattern of Cleft Lip and Palate Clefts at a Tertiary Care Hospital in Saudi Arabia.

Clefts of the lip and palate (CL/P) and cleft palate (CP) are the most common craniofacial congenital anomalies. Clefts are classified as syndromic and nonsyndromic. Nonsyndromic clefts have no known genetic causes. This study combines prospective and retrospective studies to review the patterns of CL/P and CP and associated syndromes and conditions in patients registered for CL/P surgery at a tertiary care pediatric center in our tertiary care hospital in Saudi Arabia. It included patient data from May 2015 through April 2023. Patient record forms and SPSS (IBM version 20.0) were used to collect and analyze data. A significance level of 5% was used, with p ≤ 0.05 considered statistically significant. Of the 319 patients who met our inclusion criteria, 175 were male. Of the total, 99 had a left unilateral isolated cleft lip, 61 had a right unilateral isolated cleft lip, 69 had a bilateral cleft lip, and 90 had an isolated CP. Of the total, 140 had CL/P. Around 242 were nonsyndromic. The Chi-square test revealed a significant association between the prevalence of isolated CP and CLP and gender. The prevalence of left unilateral isolated cleft lip and bilateral and isolated CP was significantly associated with syndromic and nonsyndromic cases. Males are more likely to be affected by orofacial clefts, which is consistent with the global trend. Isolated CP was the most common orofacial cleft. Within the sample, syndromes' association with orofacial clefts was significantly weaker than that of isolated and bilateral clefts.

Treatment and genetic analysis of multiple supernumerary and impacted teeth in an adolescent patient

BackgroundMultiple supernumerary teeth, combined with numerous impacted teeth, can lead to various malocclusions, posing significant treatment challenges. While certain genes associated with syndromic cases of multiple supernumerary and impacted teeth have been identified, the etiologies of non-syndromic cases still largely remain elusive.Case presentationHere, we report a treatment of a 12-year-old boy who presented with 10 supernumerary teeth and 6 impacted teeth, accompanied by a genetic analysis to explore the underlying etiology. During the treatment, fifteen teeth were extracted, and various skilled techniques, including the closed-eruption technique and the application of by-pass arches, were utilized. Post-treatment, traction was successful for all the impacted teeth, without any tooth mobility or reduction in gingival height. Space closure, well-aligned teeth, and excellent functional occlusion were achieved. Furthermore, comprehensive genetic analysis was conducted through whole-exome sequencing on the patient and his parents, which revealed a potential link between the patient’s numerous supernumerary teeth and abnormal mineralization. Notably, the p.Ser496Pro variant in the TCF7L2 gene was identified as a potential candidate variant in this patient.ConclusionsOverall, our findings not only report the treatment of a rare case involving multiple supernumerary and impacted teeth but also offer valuable insights into the molecular basis of supernumerary teeth.

Orofacial Clefts and Maternal Risk Factors: A Population-Based Case-Control Study.

Orofacial clefts (OFCs) are some of the most common congenital anomalies worldwide. The aim of this case-control study was to evaluate the association of OFCs with selected maternal characteristics. Data on isolated non-syndromic cases of OFCs were extracted from the population-based registry of congenital anomalies of Tuscany. A sample of live-born infants without any congenital anomaly was used as the control group. We investigated the association with sex and some maternal characteristics: age, body mass index, smoking, and education. Adjusted odds ratios (OR) were calculated using a logistic regression model. Analyses were performed for the total OFCs and separately for cleft lip (CL) and cleft palate (CP). Data on 219 cases and 37,988 controls were analyzed. A higher proportion of males (57.9%) was observed, particularly for CL. A decreasing trend among the maternal age classes was observed (OR:0.81 (95%CI 0.70-0.94)). Underweight mothers had a higher prevalence of OFCs, in particular for CL (OR:1.88 (95%CI 1.08-3.26)). We found an association of OFCs with lower maternal age. The association with maternal age remains controversial and further epidemiological evidence is needed through multicenter studies. We observed that CL was more common in underweight mothers, suggesting actions of primary prevention.

High prevalence of m.1555A > G in patients with hearing loss in the Baikal Lake region of Russia as a result of founder effect

Mitochondrial forms account approximately 1–2% of all nonsyndromic cases of hearing loss (HL). One of the most common causative variants of mtDNA is the m.1555A > G variant of the MT-RNR1 gene (OMIM 561000). Currently the detection of the m.1555A > G variant of the MT-RNR1 gene is not included in all research protocols. In this study this variant was screened among 165 patients with HL from the Republic of Buryatia, located in the Baikal Lake region of Russia. In our study, the total contribution of the m.1555A > G variant to the etiology of HL was 12.7% (21/165), while the update global prevalence of this variant is 1.8% (863/47,328). The m.1555A > G variant was notably more prevalent in Buryat (20.2%) than in Russian patients (1.3%). Mitogenome analysis in 14 unrelated Buryat families carrying the m.1555A > G variant revealed a predominant lineage: in 13 families, a cluster affiliated with sub-haplogroup A5b (92.9%) was identified, while one family had the D5a2a1 lineage (7.1%). In a Russian family with the m.1555A > G variant the lineage affiliated with sub-haplogroup F1a1d was found. Considering that more than 90% of Buryat families with the m.1555A > G variant belong to the single maternal lineage cluster we conclude that high prevalence of this variant in patients with HL in the Baikal Lake region can be attributed to a founder effect.

Characterization of stromal calcifications in odontogenic keratocyst: a multicentric study.

Odontogenic keratocysts (OKCs) are locally aggressive cysts that exhibit typical histopathological features and have a propensity for recurrence. Though histological variations are observed in OKCs, hard tissue formation and metaplastic changes are rare, and the underlying pathogenesis is not well understood. This study aimed to characterize stromal calcifications andanalyze their association with odontogenic components in non-syndromic and syndrome-associated cases of OKCs. We analyzed 153 cases of OKCs from healthcare institutes in India and Japan. The epithelial and stromal features were evaluated, and the relationship of calcifications with odontogenic rests was determined. Immunohistochemistry for cytokeratin-19 and special stains including Masson Trichrome and Van Gieson, were used for identification of odontogenic rests and calcifications respectively. Stromal calcifications were observed in 29.41% OKCs. The calcification patterns included irregular dystrophic, dentinoid with linear or calcospherite-type mineralization, and psammoma calcifications. Psammoma and dentinoid calcifications were found in the proximity of cytokeratin-19-positive odontogenic rests or satellite cysts, whereas majority cases with dystrophic calcifications did not exhibit co-localization with stromal odontogenic components. Distinct patterns of calcifications were observed in OKCs. Calcifications found in proximity of the odontogenic rests were possibly indicative of an inductive or host-mediated response.

Clinical Genetic Testing for Hearing Loss: Implications for Genetic Counseling and Gene-Based Therapies.

Genetic factors contribute significantly to congenital hearing loss, with non-syndromic cases being more prevalent and genetically heterogeneous. Currently, 150 genes have been associated with non-syndromic hearing loss, and their identification has improved our understanding of auditory physiology and potential therapeutic targets. Hearing loss gene panels offer comprehensive genetic testing for hereditary hearing loss, and advancements in sequencing technology have made genetic testing more accessible and affordable. Currently, genetic panel tests available at a relatively lower cost are offered to patients who face financial barriers. In this study, clinical and audiometric data were collected from six pediatric patients who underwent genetic panel testing. Known pathogenic variants in MYO15A, GJB2, and USH2A were most likely to be causal of hearing loss. Novel pathogenic variants in the MYO7A and TECTA genes were also identified. Variable hearing phenotypes and inheritance patterns were observed amongst individuals with different pathogenic variants. The identification of these variants contributes to the continually expanding knowledge base on genetic hearing loss and lays the groundwork for personalized treatment options in the future.

Exome sequencing of 1190 non-syndromic clubfoot cases reveals HOXD12 as a novel disease gene

BackgroundClubfoot, presenting as a rigid inward and downward turning of the foot, is one of the most common congenital musculoskeletal anomalies. The aetiology of clubfoot is poorly understood and variants...

AXIN1 mutations in nonsyndromic craniosynostosis.

Occurring once in every 2000 live births, craniosynostosis (CS) is the most frequent cranial birth defect. Although the genetic etiologies of syndromic CS cases are well defined, the genetic cause of most nonsyndromic cases remains unknown. The authors analyzed exome or RNA sequencing data from 876 children with nonsyndromic CS, including 291 case-parent trios and 585 additional probands. The authors also utilized the GeneMatcher platform and the Gabriella Miller Kids First genome sequencing project to identify additional CS patients with AXIN1 mutations. The authors describe 11 patients with nonsyndromic CS harboring rare, damaging mutations in AXIN1, an inhibitor of Wnt signaling. AXIN1 regulates signaling upstream of key mediators of osteoblast differentiation. Three of the 6 mutations identified in trios occurred de novo in the proband, while 3 were transmitted from unaffected parents. Patients with nonsyndromic CS were highly enriched for mutations in AXIN1 compared to both expectation (p = 0.0008) and exome sequencing data from > 76,000 healthy controls (p = 2.3 × 10-6), surpassing the thresholds for genome-wide significance. These findings describe the first phenotype associated with mutations in AXIN1, with mutations identified in approximately 1% of nonsyndromic CS cases. The results strengthen the existing link between Wnt signaling and maintenance of cranial suture patency and have implications for genetic testing in families with CS.

Nonsyndromic Craniosynostosis Correlation Between Ethnicity, Race, and Pattern of Affected Suture Type: Meta-Analysis.

Previous studies have sought to analyze risk factors associated with craniosynostosis and while syndromic craniosynostosis is often linked to genetic mutations, the factors impacting nonsyndromic cases are less investigated. The aim of current meta-analysis is to evaluate the relationship between ethnicity and suture type in nonsyndromic craniosynostosis patients. The search term "craniosynostosis [Title/Abstract] AND (race [Title/Abstract] OR ethnicity [Title/Abstract])) NOT (syndrome [Title/Abstract])" was used to search the PubMed, Cochrane, and MEDLINE databases. Analyses were conducted separately for each racial and ethnic group for each suture type cohort. Odds ratios were conducted for each suture cohort and confounders were adjusted using linear mixed-effect models. Because of the homogeneity of the populations and categorical nature of the classification, binary logistic regression was run on aggregate data. The literature search yielded 165 articles. After reviewing titles, abstracts, and manuscript contents of these articles, 5 studies were ultimately included in a meta-analysis. Studies with missing data for a particular cohort or variable were excluded from the respective analysis. Hispanic children had higher odds of sagittal suture involvement (OR: 1.53, P <0.001), whereas Asian had coronal suture (OR: 2.47, P <0.001). Both Asian and African American children had significantly lower odds of sagittal suture involvement (OR: 0.50, P <0.001 and OR: 0.7, P =0.04, respectively). The relationship between ethnicity and craniosynostosis has been suggested as a risk factor, but without definitive conclusion. Present meta-analysis findings demonstrated association between ethnicity and suture type, however further research with larger scale and geographically varied data is warranted.

Contiguous Gene Syndromes and Hearing Loss: A Clinical Report of Xq21 Deletion and Comprehensive Literature Review.

Given the crucial role of the personalized management and treatment of hearing loss (HL), etiological investigations are performed early on, and genetic analysis significantly contributes to the determination of most syndromic and nonsyndromic HL cases. Knowing hundreds of syndromic associations with HL, little comprehensive data about HL in genomic disorders due to microdeletion or microduplications of contiguous genes is available. Together with the description of a new patient with a novel 3.7 Mb deletion of the Xq21 critical locus, we propose an unreported literature review about clinical findings in patients and their family members with Xq21 deletion syndrome. We finally propose a comprehensive review of HL in contiguous gene syndromes in order to confirm the role of cytogenomic microarray analysis to investigate the etiology of unexplained HL.