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At least 19 recordsLinked to original sources
PubMed2026

Clinical and molecular characterization of TCF12 variants in an Asian pediatric cohort with craniosynostosis.

BACKGROUND: Craniosynostosis is a genetically heterogeneous craniofacial disorder caused by the premature fusion of one or more cranial sutures. Pathogenic variants in TCF12, encoding a basic helix-loop-helix (bHLH) transcription factor, represent a major cause of autosomal dominant coronal craniosynostosis and are characterized by incomplete penetrance and marked phenotypic variability. However, clinical and molecular data from Asian pediatric populations remain limited. METHODS: Trio-based whole-exome sequencing was performed on ten pediatric patients with cranial deformities and their parents. The identified TCF12 variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and validated by Sanger sequencing. Detailed clinical and radiological data were collected. In addition, a comprehensive literature review was conducted to summarize previously reported TCF12 variants and associated phenotypes. RESULTS: Ten distinct heterozygous TCF12 variants were identified in ten unrelated pediatric patients, all of which were classified as pathogenic or likely pathogenic according to ACMG criteria. Six variants were inherited, and four occurred de novo. Seven patients had imaging-confirmed craniosynostosis, predominantly involving the coronal sutures (five bilateral and one unilateral), while one patient presented with multisuture craniosynostosis (left coronal and sagittal sutures). Three patients showed cranial deformities without radiographic evidence of suture fusion. Phenotypic heterogeneity and incomplete penetrance were observed, including a mildly affected parent. Most pathogenic variants were truncating variants distributed mainly across exons 14-19 and predicted to induce loss of function, either through nonsense-mediated mRNA decay or the production of truncated proteins lacking the entire C-terminal bHLH domain. Structural modeling analysis further indicated that the bHLH-domain-located missense variant p.Arg603Trp alters the local DNA-binding conformation of TCF12 and impairs its binding affinity to the E-box DNA motif. CONCLUSIONS: This study provides additional clinical and molecular data on TCF12-related craniosynostosis in a pediatric cohort from an Asian population. Our findings support haploinsufficiency as the central pathogenic mechanism, primarily driven by truncating variants affecting the C-terminal bHLH domain. The marked clinical heterogeneity, the presence of mild or evolving phenotypes, and incomplete penetrance observed in our cohort underscore the importance of early diagnosis and longitudinal clinical surveillance in affected families.

Humans↗
PubMed1978

Premature craniosynostosis: A common complication of juvenile thyrotoxicosis.

Cranial vault suture opacification (apparent closure) and bone age were evaluated roentgenographically in ten children with thyrotoxicosis. The bone age was advanced greater than 2 SD in only one. In comparison to 96 control children of similar age, craniosynostosis was present in each of the patients with thyrotoxicosis. Children with advanced bone age, nine due to virilizing adrenal hyperplasia and three with precocious puberty, had normal radiographic patterns of cranial suture closure. Thyrotoxic premature craniosynostosis did not interfere with continued head circumference growth nor did it result in clinical or radiographic evidence of increased intracranial pressure. We conclude that premature craniosynostosis appears to be a common feature of juvenile thyrotoxicosis. Investigation of the possible long-term adverse effects of this entity on central nervous system function is advocated.

Adolescent↗
PubMed1975

An etiologic and nosologic overview of craniosynostosis syndromes.

In the past, a great deal of confusion in the nosology of craniosynostosis syndromes has been apparent. Such syndromes should never be classified on the basis of which sutures are synostosed nor on the presence or absence of mental retardation. In this paper, they are classified on the basis of overall clinical similarity and genetic considerations. The findings in each syndrome, the genetic aspects and the problems in differential diagnosis are discussed. Disorders presented include the Kleeblattschädel anomaly, Crouzon syndrome, Apert syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Carpenter syndrome, Christian syndrome, Summitt syndrome, Baller-Gerold syndrome, Lowry syndrome, Gorlin-Chaudhry-Moss syndrome and three sporadic craniosynostosis syndromes. A discussion of spurious craniosynostosis syndrome entities is also presented.

Abnormalities, Multiple↗
PubMed2026

Evaluating the pathogenic significance of unique chromosomal variants in craniosynostosis using patient-derived induced pluripotent stem cells and mouse modelling.

PURPOSE: Unravelling causal links between unique structural/copy-number variants (SV/CNV) and associated phenotypes is essential for correct genetic counselling. We investigated two families in which patients with craniosynostosis had SV/CNV potentially dysregulating a fibroblast growth factor (FGF)-encoding gene; a 730 kb dup(4)(q21.21) including FGF5; and a complex 568 kb interspersed 13q12.11 duplication, located 841 kb from FGF9. METHODS: We combined bioinformatic predictions of altered topologically-associating domain (TAD) structure, with experimental analysis (RNA- and ATAC- [assay for transposase-accessible chromatin] sequencing) of patient induced pluripotent stem cell lines (iPSCs) differentiated to neural crest (NCC) and osteoprogenitor (OPC) identities. For the dup(4)(q21.21) we generated a mouse bearing an equivalent rearrangement using CRISPR-Cas9 targeting. RESULTS: TAD analysis suggested potential dysregulation of the FGF5/FGF9 gene by bringing it into a novel genomic milieu. The RNA- and ATAC-seq assays demonstrated FGF5/FGF9 upregulation (2.7-18x) and local opening of chromatin, in 3/4 cell lines. For the dup(4)(q21.21), a causal role was supported by the mouse model, whereas interpretation of the 13q12.11 SV is confounded by a co-existing FOXP2 pathogenic variant. CONCLUSION: Patient iPSC-differentiated NCC and OPC lines, combined with TAD-based modelling to generate testable functional hypotheses, provide valuable functional evidence when evaluating causation of unique SV/CNV in craniosynostosis.

copy-number variant↗
PubMed1978

Craniosynostosis associated with limb reduction malformations and cleft lip/palate: a distinct syndrome.

Craniosynostosis associated with short stature, radial and fibular aplasia, and cleft lip and/or palate represents a distinct syndrome. One original case and one previously undiagnosed case from the literature were found to have many distinct features in common, permitting them to be separated from craniosynostosis with radial or fibular aplasia, Robert's syndrome, pseudothalidomide or SC syndrome, and the hypomelia-hypotrichosis-facial hemangioma syndrome. Each had multiple craniofacial abnormalities: dysplastic ears, hypertelorism, strabismus, and malocclusion. Ulnae and humeri were hypoplastic; tibiae were bowed and hypoplastic. Testes were small. Associated mild to moderate mental retardation may be related to early institutionalization.

Abnormalities, Multiple↗
PubMed1979

Terminal 7p deletion and 1;7 translocation associated with craniosynostosis.

A female infant with presumptive deletion of the 7p2 region and an unusual translocation between a part of the short arm of chromosome 1 and a deleted chromosome 7 is described. The patient showed congenital craniosynostosis of the coronal and metopic sutures; marked turricephaly; hypotelorism; deeply cleft palate; shallow orbits with prominent bulging eyes; a depressed nasal bridge; anteverted nostrils; short hands with broad thin fingers and elongated thumbs; a mild talipes calcaneovalgus deformity of the feet; a systolic murmur due to a small VSD; and psychomotor retardation. The child died of bronchopneumonia at 10 weeks of age. The parents are chromosomally normal.

Abnormalities, Multiple↗
PubMed1977

Cephalometric observations in premature craniosynostosis.

Forty patients with premature craniosynostosis of variable extent and severity were subjected to cephalometry. The majority of the children and adolescents involved had undergone bilateral cranial fenestration at age 6 months to 11 years. Lateral cephalometric radiographs were used for analysis. The measurements obtained were compared with normal values of comparable age groups. In two thirds of the patients examined facial skull growth was found to be impaired, the clinical appearance ranging from pronounced faciostenosis to abortive forms. In some cases the clinical appearance was normal. One of the conclusions derived from the cephalometric data is that inhibited growth primarily affects the anterior portions of the skull base, which are found to be shorter than normal. The defect appears to involve the spheno-ethmoidal, intersphenoidal and sphenofrontal synochondroses.

Cephalometry↗
PubMed1977

Craniosynostosis: a new operative technique.

In the treatment of craniosynostosis several methods have been proposed to prevent craniectomies from early reclosure. New bone is formed at the edge of the craniectomy, but particularly at the outer surface of the dura. The author has developed a method to separate the edges from each other and to stop osteogenesis inside the craniectomy. The outer layer of the dura is dissected free from the inner layer folded over the edge of the groove and sutured to the outer periosteum. The operative technique and the results in 40 patients with a follow up of 17 years are described.

Child↗
PubMed1979

Craniosynostosis: correlation of bone scans, radiographs, and surgical findings.

Skull scintigraphy was performed in 68 children with suspected craniosynostosis after injection of technetium-99m methylene diphosphonate. The scans demonstrated four patterns of sutural activity: normal, absent, increased, and wide. When correlated with surgical findings, "absent" indicated fused sutures, "increased" indicated fusing hyperactive sutures or sutures reacting to fusion elsewhere, and "wide" indicated splite sutures. Upon correlation with the radiographs, it was found that when the radiograph was normal, the scan contributed little; when the radiograph was abnormal or equivocal, the scan was often of great assistance in confirming fused sutures and detecting other abnormal sutures.

Child, Preschool↗
PubMedDate not supplied

Surgical management of unilateral and bilateral coronal craniosynostosis: 21 years of experience.

From 1955 to 1975, 116 patients with unilateral and bilateral coronal synostosis, including 39 with craniofacial dysmorphism, were treated surgically. Five techniques were used: multiple linear craniectomies, linear craniectomies with supraorbital grafting, morcellation craniotomies, lateral canthal advancement of the supraorbital margin, and radical cranio-orbitofacial reconstruction. Analysis of clinical and radiological indices of the synostotic process, coupled with evaluation of the surgical results, indicates that the anterior skull base is the site of origin of the bony dysplasia. Therefore, early creation of artificial sutures in the skull base is recommended to provide adequate expansion of the frontal bones and consequently of the entire facial skeleton.

Adolescent↗
PubMed1979

Craniofacial growth following experimental craniosynostosis and craniectomy in rabbits.

Premature fusion of the coronal suture was produced in 9-day-old rabbits by immobilization of the suture area bilaterally with methyl-cyanoacrylate adhesive. The effects of suture fusion and its surgical release on suture growth and on skull morphology were evaluated by radiographic cephalometry. Immobilization resulted in significant changes in the angular dimensions in the vault toward an anteroposterior shortening. No permanent deformity was observed in the angular relationship between the cranial base and the facial skeleton. Craniectomy at 30 days, when a skull deformity had been established, resulted in rapid separation of the bones at the suture site which returned the deformed skull to a normal configuration by 90 days of age. Surgical removal of a normal suture in a control group also resulted in accelerated separation of the bones at the excised suture site, but it was less than after removal of an immobilized suture. The experimental data indicate that premature fusion of rapidly growing sutures results in consistent skull deformity. Early release of the fusion, when this is the primary abnormality, will result in spontaneous correction of the deformity.

Age Factors↗